1. Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles CA

2) Kidney Cancer Journal, Cary NC
CORRESPONDENCE: Robert A Figlin, MD, FACP

ABSTRACT

The last two decades of the kidney cancer therapeutic landscape encapsulate the most dramatic advances ever achieved in the management of localized and advanced renal cell carcinoma (aRCC). During these years, Kidney Cancer Journal also published some important pieces of research and provided coverage in the kidney cancer space. Herein, we would like to reflect on the journal’s contents that informed key advances in the treatment strategies, milestones, and management of cancer during the last two decades of the KCJ’s journey.

INTRODUCTION

There has been tremendous progress in the treatment landscape of aRCC with the expansion of the therapeutic armamentarium of targeted therapies. The vast knowledge that we have gained in the last few years, at a certain point, led to a qualitative and quantitative leap in the treatment era. Over the last two decades, KCJ disseminated and educated clinicians about groundbreaking research and translational scientific discoveries that served as a touchstone for potential treatment strategies. Our editorial contents have kept clinicians on the leading edge of the evolution in cancer therapy as well as closely reflected on advances in cancer care. The original concept of quarterly publication representing in-depth articles, future perspectives, scientific forums, timely reviews, latest breakthroughs, and conference coverages offered tantalizing previews of practice-changing research updates. In this review, we explore novel first-line treatment strategies and provide an overview of the efficacy and safety of emerging investigational

agents in the front-line aRCC setting.

VEGF-targeted therapies

The first-line treatment landscape has transitioned from recombinant cytokines to tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and most recently, immune checkpoint inhibitors (ICI) in recent years. With the improved understanding of the implications of von Hippel– Lindau gene mutations in angiogenic pathways, many VEGF-based tyrosine kinase inhibitors (TKIs) evolved as the de facto choice of first-line systemic therapy¹.

TABLE 1 | Summary of phase III front-line combination trials in Renal Cell Carcinoma.

For the favorable-risk disease category. Over the last few years, KCJ provided in-depth coverage on VEGF-TKI-based targeted therapies. In particular, our roundtable discussion provided expert perspectives on cabozantinib in 2015 and 20172,3. Similarly, our roundtable discussions provided coverage for tivozanib monotherapy based trials in 2021 and 2022^4,5 and its combinations^6,7. Based on the phase III trial outcomes, sunitinib, pazopanib, and bevacizumab/IFN-α angiogenic agents8-11 were approved by FDA/ EMA as a front-line treatment. Sunitinib and pazopanib represent an effective first-line VEGFR TKIs and NCCN Kidney Cancer Panel has listed sunitinib and pazopanib as preferred category I. For more than a decade, sunitinib, an orally administered multi-target TKI remained the standard-of-care targeted therapy and as main comparator in clinical trials as well. The survival benefit of sunitinib was evident in the pivotal randomized phase III trial in which sunitinib treatment resulted in improved PFS as compared with IFN-α in the first-line setting (11.0 vs. 5.0 months)8. Although a higher OS in patients treated with sunitinib was observed as compared with those treated with IFN-α (26.4 versus 21.8 months, respectively), it lacked statistical significance^8,9 . In 2006 by the FDA and EMA sunitinib was approved multi-nationally for the first- and second-line treatment of metastatic renal cell carcinoma (mRCC).

TABLE 1 | Summary of phase III front-line combination trials in Renal Cell Carcinoma.

.Based on a randomized, double-blind, phase III VEG105192 study, the FDA approved the use of pazopanib for the treatment of aRCC in 2019 and the EMA approved it for the first-line treatment of aRCC in patients who received prior cytokine therapy for advanced disease in 201010. In a phase 3 AVOREN trial of bevacizumab, a monoclonal antibody directed against the VEGF receptor (VEGFR) plus interferon-2α (IFN) showed significant improvements in PFS (10.2 vs. 5.4 months, p = 0.0001) in contrast to treatment with interferon-α monotherapy in mRCC¹⁰. Overall, this AVOREN trial confirms that bevacizumab plus IFN remains the first-line standard of care for patients with mRCC¹¹. Multiple phase III randomized studies for eg. TARGET, COMPARZ demonstrated the survival benefits of sorafenib, pazopanib respectively^10,12. Altogether these clinical trials validated the use of VEGF targeting agents the first-line standard of care for patients with mRCC.

Cabozantinib is an oral TKI that targets multiple tyrosine kinases, including hepatocyte growth factor (cMet), VEGFRs, and AXL. The randomized, phase 2 CABOSUN trial compared cabozantinib with sunitinib in treatment-naïve patients with intermediate-/poor-risk disease by IMDC. Cabozantinib therapy improved PFS (8.2 vs. 5.6 months) and ORR (46% vs. 18%) and reduced rate of progression or death as compared to sunitinib in treatment-naïve patient13,14. Following the encouraging results from the CABOSUN trial, NCCN treatment guideline included cabozantinib as a first-line treatment option for IMDC poor- and intermediate-risk patients (category 2A). Currently, cabozantinib represents a suitable targeted first-line agent, especially among patients who are not eligible to receive immunotherapy. The safety profile of cabozantinib data from the phase III METEOR study was also consistent as seen in CABOSUN, where cabozantinib therapy was associated with significantly improved PFS, OS, and ORR versus everolimus in VEGFR-TKI pretreated patients with aRCC^13,14.

Tivozanib, a highly selective and potent VEGF TKI, has demonstrated single-agent efficacy with minimal off-target toxicities and a favorable adverse event (AE) profile. A randomized controlled TIVO-1 trial has shown that tivozanib, a potent VEGFR-1, VEGFR-2, and VEGFR-3 inhibitor prolongs PFS (12.7 months) as compared with sorafenib (9.1 months) in the prespecified subpopulation of treatment-naive patients^15,16. Although, ORR was higher with tivozanib compared with sorafenib per independent review, the sorafenib arm had higher OS. Tivozanib treatment was associated with fewer AE-related dose reductions and dose interruptions compared with sorafanib. Due to the limited benefits from the data, tivozanib monotherapy has not been approved outside of the EU for the treatment of adult patients with relapsed or refractory advanced RCC who have received two or more prior systemic therapies. Later, revised data from the second prespecified analysis of the TIVO-3 trial indicated better survival benefits with a hazard ratio for OS of 0.99 for tivozanib compared with sorafenib^15-18. These durable improvements further validated the potential for tivozanib. In KCJ, we closely covered insightful developments of specific targeting agents especially cabozantinib, and tivozanib^2-5.

mTOR inhibitors

mTOR inhibitors also evolved in parallel to the development of VEGF inhibitors in the mRCC landscape. Currently, both everolimus and temsirolimus are effective mTOR agents for the treatment of aRCC. Temsirolimus, a potent mTOR inhibitor, was approved for first-line treatment of advanced RCC following the favorable outcome obtained from the multicenter, phase 3 ARCC trial (NCT00065468). Temsirolimus monotherapy as compared to temsirolimus plus IFN-α combination significantly prolonged OS compared with IFN-α¹⁹. However, superior A more pronounced survival advantage was observed only in patients with non-clear cell histology¹⁹. Given such modest results and also due to its weekly intravenous injection limitation, temsirolimus is not a widely used therapy in the front-line for patients and its utility has been relegated to second or later lines of therapy for patients with poor risk prognostic features.

Immune Checkpoint Inhibitors

In the last decade, a new avenue of immune checkpoint inhibitors has revolutionized the treatment of patients with advanced renal cell carcinoma, with the potential for dramatic changes in the therapeutic landscape. Owing to their superior and improved overall survival across multiple clinical trials, immune checkpoint-inhibitors (CPIs) such as PD-1 (anti-programmed death receptor 1), PD-L1 (anti-programmed death receptor ligand 1), and CTLA-4 (anti-cytotoxic T lymphocytes antigen 4) have been integrated into the first-line therapeutic landscape for moderate to high-risk mRCC. Since the approval of the CTLA-4 antibody ipilimumab in patients with melanoma in 2011, the footprints of ICIs expanded across the RCC landscape following studies of several PD-1/PD-L1 inhibitors and our coverages in KCJ highlighted the following progress made as well.

Nivolumab, an ICI that targets the programmed cell-death protein 1 (PD1), has become the standard treatment for patients with mRCC following progression to single-agent tyrosine kinase inhibitors (TKI)20. CheckMate-214 (NCT02231749) evaluated the CTLA-4 blocker (ipilimumab) and PD-1 inhibitor (nivolumab) combination in the IMDC intermediate or high-risk population21. The outcomes validated the proof of concept that this combination can deliver better outcomes as compared to the anti-VEGF TKI sunitinib in the first line metastatic RCC setting. Importantly, improved response rates (42%, 9% CR vs 27%, 1% CR), PFS (11.6 mo vs 8.4 mo), and OS (NR vs 26.6 mo) were observed in combination arm as compared to sunitinib. In particular, the addition of ipilimumab to nivolumab resulted in significantly better overall survival and improved ORR as compared to sunitinib. This nivolumab/ip¬ilimumab combination is considered for intermediate-risk disease for patients who cannot receive a TKI, particularly those who are younger (< 65 years) or with tumors having high PD-L1 TPS. PD-L1 expression did not predict treatment response and survival benefit was independent of PD-L1 expression21. IMmotion010 examined the utility of anti-PD-L1 atezolizumab monotherapy as adjuvant therapy in RCC patients at increased risk of recurrence after resection. Atezolizumab adjuvant therapy did not improve clinical outcomes as compare to placebo after resection in the ITT population22. Median INV-DFS was 57.2 mo for atezo and 49.5 mo (47.4, NE) for placebo. Safety analysis offered manageable profile for atezolizumab; grade 3/4 adverse events occurred in 27% (106/390) and 21% (81/383) of pts receiving atezo or placebo, respectively; Grade 5 AEs occurred in <1% (1/390) and <1% (3/383)^22,23.

The 30-month follow-up of phase III KEYNOTE-564 trial showed a continued disease-free survival benefit with adjuvant pembrolizumab vs placebo in patients with clear cell renal cell carcinoma who are at increased risk of disease recurrence. Updated results support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy²⁴. At 30 months, the cumulative incidence of local recurrence was 3.8% in the pembrolizumab group vs 7.6% in the placebo group, and distant metastasis–free survival rates were 77.3% vs 68.8²⁴. Recently, results from the CheckMate 914 trial examining the role of adjuvant nivolumab and ipilimumab were presented at ESMO2022²⁵. This study did not meet the primary endpoint of DFS over a median follow-up of 37.0 months. In patients treated with nephrectomy for localized renal cell carcinoma (RCC) at a high risk of relapse, median DFS was not reached among patients who received nivolumab and ipilimumab and was 50.7 months among those who received placebo²⁵.

ICIs in combination with VEGF-TKI

Emerging data validate the synergistic effect of ICI agents in combination with anti-VEGF targeted agents that gaining momentum as the first-line treatment landscape of aRCC. The ongoing phase 3 COSMIC-313 trial evaluates the combination of cabozantinib, nivolumab and ipilimumab versus the combination of nivolumab and ipilimumab in patients with previously untreated advanced intermediate- or poor-risk RCC. In the COSMIC-313 study²⁶, cabozantinib was predicted to synergize with nivolumab plus ipilimumab CPI combination, as a triplet regimen for the first-line standard-of-care treatment in patients with advanced RCC of intermediate or poor risk. At a median follow-up of 20.2 months, patients who received the triplet had a 27% lower risk for progression or death compared with those receiving the checkpoint inhibitor doublet. Median progression-free survival, the primary endpoint, was not reached in the triplet group, versus 11.3 months with the doublet. Overall response rates were 43% and 36%, respectively, with complete responses achieved in 3% of patients in each group²⁶. The disease control rates were 86% and 72%; the incidence of progressive disease as the best response was just 8% in the triplet therapy arm and 20% in the control arm. Rates of grade 3 or 4 treatment-related adverse events were higher with the TKI added, at 73% versus 41% without it. Rates of discontinuation of all treatment components were 12% with the triplet and 5% without it²⁶.

The CLEAR trial is the latest of the IO-TKI studies examining the first-line treatment of patients with advanced clear cell RCC. The outcome data continues to show a clinically meaningful benefit from lenvatinib and pembrolizumab and reinforces this as a first-line treatment option for people with non–clear cell renal cell carcinoma (RCC) ²⁷. After 8.2 months of follow-up, 47.6% responded to treatment with three complete responses (3.7%) and 36 partial responses (43.9%). The disease was controlled in 79.3% of patients27. In phase III, randomized keynote-426 trial (NCT03075423), treatment with pembrolizumab plus axitinib resulted in significantly longer OS and PFS, as well as a higher ORR, than treatment with sunitinib among patients with previously untreated advanced renal-cell carcinoma. After a median follow-up of 12.8 months, the combination resulted in better OS (median not reached) as compared to therapy with sunitinib (35.7 months) and superior PFS (median 15.4 vs 11.1 months)¹⁶. This study validated the benefit of pembro + axi combination therapy28. The benefit of pembro/axi was observed across all IMDC risk groups, regardless of PD-L1 expression.

In another randomized phase III JAVELIN Renal 101 (NCT02684006) trial, investigators evaluated the efficacy of axitinib and avelumab combination in treatment-naive RCC patients²⁹. Avelumab plus axitinib therapy resulted in prolonged PFS and a significantly higher objective response rate than those who received sunitinib monotherapy. The mPFS in the combination arm was 13.8 months versus 8.4 months in sunitinib arm, and the ORR and CR rate were 55% and 4% in the combination arm versus 26% and 2% in the sunitinib arm respectively²⁹. In CheckMate 9ER study, nivolumab plus cabozantinib combination had significant benefits over sunitinib in terms of PFS and OS in patients with treatment naïve aRCC. The mPFS was 16.6 months with nivolumab plus cabozantinib and 8.3 months with sunitinib30. The probability of OS at 12 months was 85.7% with the combination arm and 75.6% with sunitinib. An OR occurred in 55.7% of patients in the combination arm versus 27.1% in sunitinib arm (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups30. In a non-randomized Phase Ib/II study, tivozanib plus nivolumab combination was assessed in patients previously treated with one oral TKI (NCT03136627). The combination of tivozanib with nivolumab prolonged disease control (median PFS of 18.9 months) and also showed a tolerable AE profile in both treatment-naïve and previously treated metastatic RCC³¹. The ORR was 56%, with one patient achieving a complete response.

Patients with the favorable-risk disease tend to have highly angiogenic tumours, and results from IMmotion151 support the notion of superior clinical benefits from VEGFR TKIs in this setting. The phase 3 IMmotion 151 study compared atezolizumab/bevacizumab with sunitinib32. The combination was favored over sunitinib for PFS in PD-L1+ patients. The PFS benefit was maintained in the ITT population and across subgroups of clinical interest in the PD-L1+ population, including patients with liver metastases, sarcomatoid subtype, or favorable-risk disease. Safety analysis indicated that atezolizumab/bevacizumab combination was well tolerated as patients receiving the combination had fewer treatment-related AEs relative to those receiving sunitinib (40% vs 54% for grade ¾)³². Although the combination of ICI and antiangiogenics has shown encouraging preliminary antitumor activity for advanced or mRCC, a high incidence of toxicity along with a less favorable tolerability profile may compromise the benefits in patients. For instance, in the phase I study CheckMate 016 (NCT01472081), the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab for the treatment of mRCC. The addition of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities, limiting its scope in future trials³³. Given the possibility that long-term cumulative adverse effects from the antiangiogenic and ICI combination may accumulate over time to outweigh the benefits, such combinatorial therapies warrant close monitoring to avoid unprecedented risks. In phase 3 PIVOT-09 trial, investigators sought to evaluate the combination efficacy of bempegaldesleukin plus nivolumab compared to sunitinib or cabozantinib as the first-line therapy for advanced renal cell carcinoma (RCC) ³⁴. This combination did not improve outcomes vs the investigator’s choice of TKI in first line treatment of advanced/metastatic clear-cell RCC. Among patients with intermediate or poor risk disease, the ORR was 23.0% for combination arm vs 30.6% for the TKI arm. The complete response rates and clinical benefit rates were higher in the TKI arm. However, among responders, the duration appeared somewhat longer in the combination arm34.

Other novel approaches

Belzutifan, a highly selective hypoxia-inducible factor inhibitor (HIF-2α), offers a novel approach, taking a different path than commonly used to treat RCC. Most recently, the open-label study 004 (NCT03401788) has validated the efficacy and safety of belzutifan in patients with VHL-associated RCC³⁵. Treatment with belzutifan resulted in an ORR of 49%. Based on these data, FDA approved belzutifan for adult patients with von Hippel-Lindau (VHL) disease who require therapy for RCC and other tumors36. The LITESPARK-003 trial (NCT03634540) evaluated the synergistic effect of adding belzutifan to cabozantanib therapy in patients with aRCC who previously received immunotherapy at 24.6 months of follow-up³⁷. Results showed that the overall ORR in the intention-to-treat population (N = 52) was 31%. The ORR was 27% and 32% among patients with favorable-risk disease (n = 11), and intermediate/poor-risk disease (n = 41) respectively37. Trial recruitment is underway for the phase 3 LITESPARK-011 trial (NCT04586231) assessing belzutifan plus lenvatinib vs cabozantinib in patients who previously had anti–PD-1/PD-L1 therapy.

Surgical management

Even in the era of targeted therapy, we have been continuously providing coverages on the latest updates in the surgical management of kidney cancer, including a recent article in KCJ that reported the Latinx disparity in surgical approach for kidney cancer. Despite revolutionary advances in targeted systemic therapies, durable responses remain rare. Currently, CN is the only opportunity for the cure at an early stage. Therefore, until systemic agents provide significant curative impact, surgical resection will remain the benchmark for a long-term cure. On the other hand, despite the curative impact of surgical resection, it is estimated that nearly 30% of the patients will experience a relapse of renal cancer. Whereas, the role of CN and metastasectomy of local recurrence in advanced RCC remains unclear in the era of targeted therapies. In a Phase III PROSPER (ECOG-ACRIN EA8143) study³⁸, investigators compared perioperative nivolumab versus observation in patients undergoing nephrectomy alone. RFS was similar between the arms. The median RFS was not reached. OS was not mature at the time of analysis but was not statistically different between study arms. Similar withdrawal rates occurred in both arms, approximately 12% (48/404 patients in nivo arm vs. 50/415 in the surgery alone arm). 20% of patients treated with nivo experienced at least one Grade 3-4 AE that could be attributable to nivo, compared with 6% in the control arm38.

CONCLUDING REMARKS

The frontline treatment paradigm in renal cell carcinoma continues to evolve, with the advent of novel ICI or ICI/TKI combinatorial regimens as reflected in the coverages published in the KCJ over the few years. In the future, a deeper understanding of immune checkpoint biology might reveal new therapeutic targets beyond PD-1, PD-L1, and CTLA-4, as well as new combination approaches. However, controversies remain regarding the precise treatment selection, sequencing, and individualized therapeutic strategy, thanks to unmet clinical need of identifying reliable predictive markers of response to immune agents and absence of head-to-head comparison among the randomized trials. Currently available approaches viz. PD-L1 expression, gene expression signatures, CD8+ T cell density cannot still predict treatment response to ICIs and/or TKIs. Importantly, validated biomarkers are essential to match patients to single-agent treatment with TKIs or immunotherapy, or combinations of immunotherapies with TKIs or novel agents. As novel treatments come to the clinic, there is a need to develop strategies for sequencing new and established therapies. Once optimized, such strategies will deliver robust survival outcomes while preserving the quality of life and as well the ability to tailor therapy to the individual patient.

The post A 20-year retrospective: How Kidney Cancer Journal Reflected on Advances in The Therapeutic Strategies first appeared on GUcancers.

ESMO’22 Special

Robert A. Figlin, MD, FACS

Cedars Cinai Cancer Center, Los Angeles, CA

Correspondence: RAF

There was never a dull moment at this year’s ESMO’2022 as the congress ends with a sign of progress in a few clinical studies but also delivers the negative outcomes in some follow-up studies. About 30,000 participants from more than 150 countries attended the congress to witness nearly 1900 abstracts from various oncology disciplines. Among five important phase III studies presented in the renal cancer space, the highly anticipated results from the “adjuvant trio” – IMmotion010, CheckMate 914, and PROSPER – fell short of the expectation. Results from the CheckMate 914 trial that assessed nivolumab and ipilimumab vs placebo as adjuvant therapy did not meet the primary endpoint of DFS. After 37.0 months of median follow-up, the DFS in the combination arm showed only sub-10% numerical improvements with insignificant p values in patients with localized RCC at high risk of relapse after nephrectomy. While the safety profile was consistent with its known profile in advanced RCC, the rate of discontinuation due to treatment-related AEs was higher with adjuvant NIVO and IPI as compared to placebo in this trial. These findings showed that NIVO + IPI combination is no better than placebo in terms of DFS improvement. Further analyses are underway to assess the role of adjuvant nivolumab monotherapy (part B cohort study). Even though this combination fails to demonstrate clinical and statistical significance in the adjuvant RCC setting, this combination or nivolumab alone have demonstrated clinical benefits in the advanced disease settings.

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Similarly, results obtained from PROSPER showed that neoadjuvant nivolumab prior to nephrectomy followed by adjuvant nivolumab did not improve recurrence free survival in RCC patients at high risk for recurrence. OS data remains immature but is not statistically different between arms. Subset analyses including risk stratification by pathologic stage are ongoing. In the phase 3 IMmotion 010 study, authors explored the utility of anti-PD-L1 atezolizumab as adjuvant therapy in RCC patients at increased risk of recurrence after resection. Atezolizumab adjuvant therapy did not improve clinical outcomes vs placebo after resection in the ITT population but had a manageable safety profile. Although there may be some caveats in study design and methodology which led to unsuccessful outcomes in these three trials, researchers are cautiously optimistic that future trials and analyses will provide better outcome as we learn and move forward.

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The dilemma that is faced by clinicians and patients is that despite these results we have the Keynote 564 trial that demonstrated clinical benefit in both high-risk resected patients and those with oligometastatic disease treated with Pembro. We need to understand the differences in study populations studied that can help explain why similar drugs succeeded in some patient populations but not in others. We await the presentations of these abstracts in peerreviewed publications for additional scrutiny.

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COSMIC-313 trial (NCT03937219) is the first phase III trial that compares a triplet regimen to IO doublet therapy as a control in aRCC. In this study, investigators sought to assess the impact of combining a third agent (TKI) to the dual checkpoint inhibitor backbone in the poorand intermediate-risk RCC patient population. Addition of cabozantinib to nivolumab and ipilimumab combination prolongs progression-free survival in patients with intermediateto poor-risk RCC. However, there are some drawbacks as well; the response rate was only marginally improved in the triplet arm as compared to the doublet arm. In both arms, median duration of response was not reached. The safety profile was consistent with known safety profiles for each monotherapy as well as the combination regimens used in this study. Grade 3 or 4 toxicity was higher in the triplet arm possibly due to the overlapping toxicity (73% vs 41%). Another potential limitation comes from the rate of TRAEs leading to discontinuation with almost half of the patients receiving triplet therapy needing some discontinuation of one of the three components. Follow-up data for the overall survival involving the entire study population (855 patients) is ongoing. We have to wait to see if further updates can make the triplet regimen as “practice changing” therapy in the clinical setting. Additionally, although cross-trial comparisons are fraught with complications, one would like to know how this triplet would deliver as compared to the already published Cabo/Nivo data.

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The CLEAR study is the latest of the IO-TKI studies evaluating first-line treatment of patients with advanced clear cell RCC. The outcome data from CLEAR study presented at ESMO22 confirmed the clinically meaningful benefit from lenvatinib and pembrolizumab as a firstline treatment option. The median PFS is 23.3 months in the combination arm versus 9.2 months in the control arm. When compared with alternative doublet treatment approaches such as CheckMate 214, KEYNOTE-426, and CheckMate-9ER, outcome data from the CLEAR trial demonstrated better safety/efficacy profile as compare to other trials in terms of median PFS (23.3 months), ORR (71%), and complete response rate (17%) in the experimental arm. For further details of the abstracts mentioned here, please refer Recommended Abstracts – ESMO2022 section in this issue.

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Results from the phase 3 PIVOT-09 trial have shown that the combination of bempegaldesleukin with nivolumab failed to demonstrate a benefit compared to TKI monotherapy, in terms of overall survival, progressionfree survival, or objective response rate. Especially, in the intermediate and poor-risk subgroup, ORR was less common (23%) in the bempegaldesleukin plus nivolumab arm than in the TKI arm (30.6%). Given that the ORR of combination arm is lower to single agent nivolumab therapy, addition of bempegaldesleukin is rather providing reversing effect of nivolumab. The interim analysis from the phase 2 of LITESPARK-003 trial (NCT03634540) shown the meaningful survival advantage of HIF inhibitor belzutifan plus cabozanitinib as first-line therapy for patients with intermediate and poor-risk disease in advanced renal cell carcinoma (RCC). Overall objective response rate (ORR) was 57% and the combination had manageable safety.

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It is remarkable to be celebrating the 20th anniversary and the incredible journey of our journal for the last two decades. We have reached this important milestone only through unwavering commitment for the cancer community we serve. Over the years, the KCJ has continuously placed itself at the forefront of providing roundtable discussions, webinars, expert perspectives and conference coverages that set the stage for the KCJ to evolve as a voice of the kidney cancer community. Today, our KCJ is more relevant and important than ever as we serve for the last two decades. As a part of our 20th Anniversary series, we provide a retrospective review of advances in the clinical research and therapeutic strategies. I am so proud to have been part of the evolution of KCJ, and I want to thank and recognize the visionary editorial staff and volunteers. We look forward to our continued reporting of scientific discoveries for the many decades to come!

The post 2022 ESMO: Promise and Pitfalls of Adjuvant Immunotherapy first appeared on GUcancers.

1. Duke University Medical Center

2) Duke Cancer Institute Center for Prostate and Urologic Cancers

CORRESPONDENCE: Michael R. Harrison, MD

ABSTRACT

The optimal duration of treatment for patients with metastatic renal cell carcinoma (mRCC) on dual immune checkpoint inhibitor (ICI) therapy remains unknown. However, there is evolving evidence that a portion of patients who achieve a complete or partial response will have a durable response, even after therapy discontinuation, leading to a prolonged treatment free survival (TFS). TFS with dual ICI is a phenomenon not seen with targeted agents and has the potential to improve patient reported outcomes and quality of life, without altering overall survival (OS). Despite this understanding, treatment of mRCC remains lifelong, as there has yet to be a prospective, randomized control trial to evaluate this key question. In this review, we analyze available studies in patients with mRCC on dual ICI therapy and propose considerations for early treatment discontinuation. Additionally, we discuss vital questions and next steps to help physicians and patients navigate these challenging treatment decisions.

INTRODUCTION

Each year there are approximately 79,000 new cases of kidney cancer in the United States ¹ . This number has steadily risen since early 1990s, at least in part due to more sensitive imaging techniques. Over the last 10 years the number of new kidney and renal pelvis cases has increased by 0.6%, though death rates over this period have fallen by 1.6% ². Nevertheless, despite our diagnostic and therapeutic advances, kidney cancer ultimately results in about 13,920 deaths per year in the United States¹ . Over the last 20 years, treatment of metastatic renal cell carcinoma has drastically changed resulting in prolonged survival. Systemic therapeutic options now include immune checkpoint inhibitors (ICI) and targeted therapies (TT) in combination or sequence based on Phase III clinical trials demonstrating an overall survival advantage. Most of these studies were designed for treatment to continue indefinitely, until disease progression or unacceptable toxicities. Historically, this approach made sense since most patients progressed or developed unacceptable toxicities by year two. However, in the setting of immune checkpoint inhibitors, a substantial percentage of patients tolerate therapy without disease progression for several years. By protocol, these patients should continue therapy indefinitely, but is that necessary? To date, few if any studies have been designed to address this question.

Prognosis and Phases of Overall Survival.

As we continue to investigate novel biomarkers to help predict how patients may respond to therapy, many other factors, both patientand disease-specific, should be examined to help determine optimal treatment duration. Overall survival is considered the gold standard when evaluating new therapeutics in RCC. However, in patient-centric oncologic care, other endpoints are also important to consider. Overall survival can be broken down into three distinct phases: time on therapy, treatment-free survival (TFS) and time on subsequent therapy or death (Figure 1). In the targeted therapy era, monotherapies were typically sequenced, with little TFS, since outcomes were linked to dose intensity; however, in the ICI era, there may be an opportunity for meaningful TFS without compromising OS³. Critically evaluating these intervals are of the utmost importance when determining the optimal treatment strategy. Median overall survival for intermediate/poor risk mRCC has dramatically improved with the use of combination therapy, with OS approaching 47 months with dual ICI and 37.7 months with nivolumab plus cabozantinib^4,5. Despite these significant advancements, a large majority of this time is spent in the clinic, between lab draws, scans, provider visits and infusion appointments. This does not account for any unplanned hospital admissions to address severe adverse events. Time spent interacting with the healthcare system, in addition to the potential for a wide spectrum of side effects, limits the quality of life(QOL). Identifying a finite treatment duration, without reducing OS, would provide patients with the needed balance between maintaining an adequate QOL outside of the hospital while continuing to battle their disease.

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Immunotherapy for mRCCThe systemic treatment landscape for metastatic renal cell carcinoma has been dramatically changed by the advent of immunotherapy, initially with nivolumab (N), a PD-1 inhibitor and later with combination therapy including PD- (L)1 inhibitors with TKI as well as dual immune checkpoint inhibitor therapy. Based on the groundwork laid by CheckMate 025, 016 and 214, ipilimumab (I) and nivolumab (N) are currently the only combination immunotherapies approved in the metastatic, treatment-naïve intermediate and poor-risk (I/P) setting. However, the optimal duration of maintenance therapy with N has yet to be elucidated. This vital piece of information is critical, yet there is no robust data to predict who will respond to treatment and when to consider treatment discontinuation.

CheckMate 025 was the first phase III study to evaluate single-agent nivolumab versus everolimus in patients with previously treated metastatic RCC. Nivolumab demonstrated an improvment in OS and toxicity profile when compared to everolimus⁶. Given the benefits seen with ICI monotherapy, CheckMate 016, a phase I study, evaluated the efficacy and safety of dual ICI with ipilimumab and nivolumab (I+N) in the first-line setting. Patients were randomized into three treatment arms to evaluate varying dosing schema, ultimately concluding that N at 3 mg/kg plus I at 1 mg/kg provided similar ORR and 2-year-OS to other dosing regimens, while minimizing toxicity7. Based on these results, a larger, randomized phase III multicenter placebo control study, CheckMate 214, began enrolling patients with previously untreated, I/P, and metastatic RCC8. Patients were randomized to either N at 3 mg/kg plus I at 1 mg/kg every 3 weeks for 4 doses followed by N at 3mg/kg every 2 weeks (I+N) or sunitinib (S), continued until disease progression or unacceptable toxicity. Notably, a protocol amendment was made 3 years into data collection, which allowed for nivolumab discontinuation at 2 years in the absence of progression or toxicity. Initial 18 month follow-up demonstrated improved median progression-free survival (PFS), overall response rate (ORR), treatment-free survival (TFS), median overall survival (OS) and patient-reported outcomes (PRO) in those treated with I + N vs S⁸.

Treatment with dual immune checkpoint inhibitor (ICI) therapy has improved overall survival for patients with metastatic RCC, with about 10% of patients achieving a durable complete response (CR), and another 28% achieving a partial response (PR) with varying degrees of tumor shrinkage⁸. There are many theories as to why patients have such a heterogeneous response to ICIs, with two possibilities involving the “cancer-immune set point” and tumor microenvironment (TME). The “cancer-immune set point” is defined as the equilibrium between anti-tumor immunity promoters and suppressors. A certain threshold must be surpassed for a patient to optimally respond to immunotherapy. This “set-point” is felt to vary widely between patients, and likely contributes to the heterogeneous treatment responses⁹. This equilibrium can wax and wane overtime, reflecting the tumor’s development of novel resistance patterns. In such cases, the continued priming of the immune system with ongoing therapy may be vital to maintain a durable response. Varying dosing schema is currently under investigation^10,11. The presence of immune cell infiltration in the tumor and the surrounding microenvironment are also thought to be necessary, though not sufficient, to achieve a response to ICI. Checkpoint inhibitor therapy is known to decrease T cell exhaustion and promote the conversion to effector and memory T cells, which is likely necessary to achieve a durable treatment response despite treatment discontinuation9. This unique durable response has not been seen with other cancerdirected therapies and has allowed physicians to consider treatment discontinuation; allowing patients to benefit from a prolonged treatmentfree survival.

Definition of Treatment-free Survival and Key Questions Treatment-free survival (TFS) is an important metric to understand how patients live with their cancer. TFS is defined as the time from treatment discontinuation until the start of subsequent therapy or death. While overall survival is the gold standard to determine optimal therapy, treatment-free survival should not be overlooked, as it almost certainly leads to improved financial, physical, and psychological burdens that come along with chronic monthly infusional therapy. The key question is, what treatment-free interval is meaningful to patients? If overall survival is similar, would a prolonged treatment-free survival be appealing, or would it simply promote increased anxiety and fear of recurrence? These important questions will need to be explored further in subsequent studies to help physicians and patients make important treatment decisions.

TFS in CheckMate 214

The treatment-free survival has been evaluated as a secondary endpoint in numerous studies. One such study included work by Regan et. al, who sought to evaluate the TFS following the discontinuation of therapy in patients with I/P risk disease treated on CheckMate 214. Treatment-free survival and overall survival were evaluated at 42 months. At time of evaluation 20% of patients treated with a dual immune checkpoint inhibitor (ICI) compared to 9% treated with sunitinib were treatment-free. Over the 42-month, the mean TFS and OS for patients with I/P risk mRCC was significantly longer when treated with I+N vs S, 6.9 (22.9% of OS) and 30.1 months versus 3.1 months (11.9% of OS) and 25.9 months respectively (Figure 2). In the favorable risk population, TFS was even longer, 11.0 months vs 3.7 months¹². When TFS was further broken down, it was significantly longer for patients who had an objective response to therapy and even longer in those who achieved a CR, a median (range) of 23.5 months and 34.6 months (0.5-49.7 months) respectively ^{13, 14}. Ongoing studies across risk groups are aimed at predicting who is mostly like to objectively respond to treatment.

The median treatment duration reported in the 42-month analysis in the I/P risk population was 14.1 months on I+N versus 10.8 months on S. Responders remained on therapy longer, with a median duration of treatment of 20.6 months (17.7-23.2) and 21.2 months (18.9-24.4) for the I+N and S cohorts respectively 8, 12, 15. Despite differing time on protocol therapy, the median time between treatment discontinuation until death was similar, at 16 months on I+N vs 15.1 months on S; but the differences were seen in the percentages of patients reaching a TFS, with 43% vs 20% of patients recording a TFS for I+N vs S respectively (Figure 2). When critically evaluating the TFS in patients treated on CheckMate 214, one must take into consideration that the initial protocol did not allow discontinuation of therapy until disease progression or TRAE until an amendment almost 3 years into the trial. Presumably, there are a portion of patients with CR/PR who could have stopped therapy at 2 years, or earlier, if protocol allowed, which would have further prolonged the treatment-free survival ¹².

Since the initial publication of CheckMate 214, updated analyses have been performed. At 4 years since randomization (median follow up 55 months), 53 (10%) of 547 patients in I+N arm and 15 (3%) of 535 patients in S arm were continued on therapy. The median OS in I/P risk groups was an impressive 48.1 months with I+N vs 26.6 months for sunitinib (HR 0.65; 95% CI, 0.54- 0.78). Dual ICI demonstrated a fouryear OS probability of 50%, vs 35.8% with sunitinib (53.4% vs 43.3% in the ITT population)⁴. Five-year data was recently published (median follow-up 67.7 months), which again confirmed superior OS for I/P risk patients with I+N vs S, median OS 47.0 vs 26.6 months (HR 0.68 and 95% CI 0.58 to 0.81), respectively. Five-year OS probabilities were 43% on I+N versus 31% on S^16,17. Responders to I+N appeared to have decreased disease burden and higher PD-L1 expression as compared to non-responders, with 75% of responders achieving an objective response by 4 months ¹⁵.

TFS with Complete Response (CR)

.At 4 years, 10.7% (59) of patients achieved a complete response on I+N, with over 75% of these responses occurring by 11.3 months (3.8-15.4). Most converted from a PR (75.9%) or SD (19%), as opposed to achieving a CR at the time of initial scan15. Of the fifty-nine patients who achieved a CR on I+N, 19 (32.2%) remained on therapy for 4 years. 94.7% (18/19) of patients who were continued on I+N had an ongoing response at the time of analysis. 45.8% (27) patients treated with I+N discontinued therapy and did not require additional treatment. 92.5% (25/27) of patients on I+N who discontinued therapy after a CR, had an ongoing response off treatment. This is in stark contrast to only 2.6% (14) patients who achieved a CR on S. Of the 14 patients with a CR, 3 remained on therapy, 3 had treatment discontinued and an additional 8 were started on subsequent therapy with 3 (100%), 2 (66%) and 7(87.5%) patients demonstrating an ongoing response^4,14.

The percentage of patients with the ongoing response on I+N was almost identical for patients who continued on therapy compared to those who discontinued, 94.7% and 92.5%, respectively. Notably, only 21.4% (3/14) patients on S who had a CR discontinued therapy with 66% (2/3) of patients demonstrating an ongoing response. 22% (13) of patients treated with I+N went on to subsequent therapy after ICI discontinuation, though only 23% (3/13) of these patients had findings of progressive disease. Strikingly, in the favorable risk group treated with I+N, thirteen patients discontinued treatment with 5/13 receiving subsequent therapy despite only 7.6% (1/13) of patients demonstrating evidence of disease progression. Conversely, even after achieving a CR, 57% (8/13) of patients treated with S were started on subsequent therapy with 87.5% (7/8) with an ongoing response (Table 1)⁴. Based on these data, it may be reasonable to conclude that patients who achieve a CR on I+N can safely discontinue therapy with a high likelihood of having a durable response. Discontinuation may be further supported in patients with favorable risk disease who achieve a CR, though notably, combined immunotherapy is not approved in this setting. Further analysis of this group should include time to first response, time to complete response and time on therapy before discontinuation. Evaluation of minimal residual disease (MRD), circulating tumor DNA (ctDNA) and other pathologic factors should be investigated further, to help clinicians make educated treatment decisions.

TFS with Partial Response (PR)

One-hundred and fifty-six (28.5%) patients achieved a partial response on I+N. 17.9% (28) remained on treatment for 4 years, with 78.5% (22) of these patients demonstrating an ongoing response. In contrast, only 5.5% (9) of patients on S remained on treatment at 4 years, with 88% (8/9) maintaining an ongoing response. 42.9% (67) of patients treated with I+N discontinued therapy without the need for subsequent treatment. 31.3% (21/67) of patients with a PR off I+N eventually progressed, whereas 51.2% (20/39) of patients who discontinued therapy with S eventually progressed (Table 2)⁴. So, in summary, the CheckMate 214 data suggests there is about a 31% chance of disease progression for patients who discontinue I+N after a PR vs a 51% chance of disease progression in patients treated with S. This is in comparison to a 21% chance of disease progression in those who remain on therapy after PR compared to 11% of disease progression on S. These odds may give physicians pause when considering therapy discontinuation in patients with a PR. In the future, the Depth of Response (DepOR) should be further evaluated to see if patients who achieve a greater DepOR have improved durable responses after treatment discontinuation. Depth of Response in Contemporary Studies In the analysis above, patients who achieved a PR were not further separated by their Depth of Response (DepOR). Suarez et al looked at the association between DepOR and clinical outcomes in patients with advanced RCC, treated on CheckMate 9ER. This phase III trial compared cabozantinib plus nivolumab versus sunitinib in patients with advanced, previously untreated RCC. The depth of response was defined as the best percent tumor reduction from baseline. This study concluded that deeper responses led to improved 12-month PFS and 18-month OS rates. Interestingly, patients with a CR and PR1 (≥80% reduction in tumor burden) achieved similar OS18. The median time to respond was similar across groups, suggesting that time to respond may not be as vital. Further analysis should be pursued, to see if patients with varying DepOR can discontinue therapy early.

TFS for Dual ICI Therapy in Context

Based on what we learned from CheckMate 214, when treated with dual checkpoint inhibitors, the TFS appears to be far longer than with targeted therapy alone. Tzeng et al sought to expand this data, performing a systematic review and meta-analysis to evaluate the treatment-free survival in objective responders with mRCC who discontinued ICIs13. Sixteen cohorts were analyzed, comprising 1833 patients treated with either ICI monotherapy, dual ICI or an ICI plus targeted therapy. A total of 572 (31.2%) patients had either a partial or complete response and 327 (57%) of those patients discontinued therapy. Interestingly, 85 (26%) patients demonstrated an ongoing response off therapy with TFS of 35%(95% CI 20-50%) and 20% (95% CI 8 to 35%) at 6 and 12 months respectively. However, these 16 studies were extremely heterogeneous. Differences in TFS between patients achieving a CR vs PR were not analyzed. When this data was broken down by treatment, the TFS was significantly higher when treated with dual immunotherapy as compared to an immunotherapy plus VEGF combination. Six- and 12-month TFS rates were 57% (95% CI, 41-73%) and 50% (95% CI, 32- 68) when treated with dual ICI as compared to only 20% (95% CI, 2-45%) and 5% (95% CI 0-17%) when treated with and an ICI plus VEGR TKI combination¹³. This significant difference should be considered when choosing initial therapy for patients whose goal is to achieve a period of TFS.

Correlation of Immune-Related Adverse Events and TFS

The durability of response and treatment-free survival is especially important for patients who have had severe immune-related adverse events (irAE), as these are often a driving factor for treatment discontinuation. While some patients have mild irAE and can be restarted on therapy, others develop life-threatening issues mandating that treatment be halted. Treatmentrelated adverse events leading to discontinuation were more common with dual checkpoint inhibitor therapy vs sunitinib, occurring in 22% vs 13% respectively. Patients treated with ICI spent more time off treatment, with two-thirds of this time without a grade ≥2 treatmentrelated adverse events (TRAE). Conversely, patients treated with sunitinib had a shorter treatmentfree survival with about two-thirds of this time with a grade ≥ 2 TRAE¹².

Understanding the depth and durability of response, as well as the safety of restarting therapy following an irAE, is of utmost importance. A multicenter retrospective review by Alaiwi et. al. evaluated patients with mRCC who required at least a 1-week break on immunotherapy. Sixteen percent (80 patients) of patients required treatment interruptions with 45% able to restart therapy, while 55% percent discontinued treatment permanently. The median treatment break was 0.9 months (0.2-31.6 months). Following retreatment, half experienced a second irAE. Interestingly, only onethird of these patients experienced the same adverse reaction while two-thirds experienced a new side effect with the the median time to recurrent irAE of 2.8 months, which was similar to the time of first irAE, 2.7 months¹⁹. Future studies should investigate if patients who have an irAE have an increased chance of achieving a durable response. This should be further broken down by degree and type of irAE.

Dosing Strategies to Promote TFS with IO Therapy

While prolonged TFS has the potential to improve QOL, alternative dosing strategies may also improve toxicity profiles and patient-reported outcomes, without reducing OS. Intermittent dosing strategies have been under investigation to help answer these questions. Ornstein et al conducted a small phase II trial to evaluate the role of intermittent nivolumab dosing for patients with IMDC I/P risk mRCC, previously treated with antiangiogenic therapy with the hope of gaining additional insights into optimal treatment schedule and duration. Patients were treated with nivolumab monotherapy for twelve weeks at which point disease response was assessed. Patients with less than 10% tumor burden reduction were continued on nivolumab monotherapy and reassessed at 3-month intervals. However, if patients had ≥10% tumor burden reduction they were placed in a treatment-free observation phase, again with imaging every 3 months. This classification and intervention were continued until the RECISTdefined progression of disease (PD). Patients who did not achieve at least 10% tumor burden reduction at 6 months were removed from the study and treated with nivolumab standard of care ¹⁰.

Fourteen patients were included in the study. ORR was 29%, with 4 patients (29%) achieving a PR, 6 with SD (49%) and 4 with PD (29%) at a median follow-up of 6 months. Median PFS was 7.97 months. Five out of fourteen (38%) of patients were eligible to stop therapy and all agreed. Four out of the five patients achieved this response after only 12 weeks of treatment. At median follow up of 48 weeks only 1 patient needed to restart therapy. The four remaining patients have had a clinical response for a median of 34 weeks (range 16- 54) off therapy and a median tumor burden decrease of 46.5% (38- 80%)10. This study demonstrates that patients may be interested in less frequent therapy, with the notion that treatment breaks result in decreased cumulative toxicity, with the possibility for decreased adverse events along with possibly reduced financial toxicity.

CONCLUSION AND SUMMARY

Systemic treatment of metastatic renal cell carcinoma has dramatically improved in the last 5 years with the use of immune checkpoint inhibitors and targeted therapy. These treatment breakthroughs have led to improved overall survival, though currently, treatment for mRCC remains indefinite. When it comes to first-line treatment, physicians have a variety of therapeutics to choose from including dual ICI and ICI/ TT combinations. There are many patient and disease-specific factors that can help guide these important treatment decisions. For example, a critically ill patient with the need for a rapid treatment response would likely choose the ICI+TT combination over dual ICI. Similarly, a patient with a strong history of autoimmune disorders may choose to forego ICI therapy altogether and begin TT monotherapy. However, for the right patient, dual ICI therapy offers the potential for a more durable response with improved TFS and QOL^{8, 12, 13}. Overall survival is the hallmark of effective treatment. However, many other factors should be considered when determining the ideal treatment strategy, including treatment tolerability, risk of TRAE, the durability of response, and the ability to discontinue therapy in favor of close monitoring. CheckMate 214 and subsequent subanalyses provided great insight into answering these questions. Patients treated with dual ICI were noted to have more durable and deeper responses, as compared to ICI/TT combination or TT monotherapy12, 13. Overall, TFS was more than two times longer with dual ICI vs S, 6.9 months compared to 3.1 months which represents meaningful time away from the hospital and clinic12. Patients treated with dual ICI also had a significantly higher chance of achieving a CR, 10.7% as opposed to only 2.6% of patients treated with S. In this subset of patients, the mean TFS after dual ICI was 34.6 months (0.5-49.7) with objective responders treated for an average of 20.6 months (17.7-23.2) before treatment discontinuation^14,15 Secondary analyses noted that patients with lower disease burden and higher PD-L1 status were more likely to achieve this coveted CR, though more robust data is needed to help predict who will best respond to therapy¹⁵.

Ultimately, there are many questions still left unanswered. The optimal treatment duration for patients treated with dual ICI is still unknown. After considering that the data presented above, it may be reasonable to consider treatment discontinuation for patients who achieved a CR, in favor of active surveillance. Ongoing response rates after CR was similar regardless of whether therapy was continued or stopped, 94.7% versus 92.5% respectively. However, based on the data currently available, the risk of discontinuing therapy after a PR in the I/P risk population may be too great. Future studies should further evaluate TFS based on the depth of response (DepOR), as patients with a deeper DepOR may also have a prolonged TFS, similar to those with a CR. Additionally, biomarkers, such as the use of next-generation sequencing results, ctDNA and MRD, may prove beneficial to help predict who may best respond to ICI therapy. For example, patients with more favorable mutations, such as PBRM1, may be able to discontinue therapy earlier than patients with BAP1 alterations, which have been traditionally associated with a worse prognosis²⁰. Finally, while CheckMate 214 reported improved patient-reported outcomes on dual ICI vs S, there is limited QOL data during the treatment-free period. These and other questions must be answered to provide patients with improved treatment strategies and QOL, Table 3.

REFERENCE

The post Optimal Duration of Therapy in Metastatic RCC: Exploring Treatment-Free Survival with Checkpoint Inhibitors first appeared on GUcancers.

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Updated

Yasser Ged,¹ and Nirmish Singla^2,*

1) Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

2) Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

ABSTRACT

The 2022 American Society of Clinical Oncology (ASCO) annual meeting was held June 3-7, 2022, in Chicago, Illinois. This hybrid meeting gathered international cancer experts across multidisciplinary specialties and was held both virtually and in-person. Here, we highlight key kidney cancer research updates presented at the meeting. Slides from the meeting’s presentations are available on the ASCO meeting library website.

INTRODUCTION

Adjuvant Therapy Updates Locally advanced kidney cancer has traditionally been managed surgically alone1. However, approximately 30% of patients develop recurrent metastatic disease after surgical resection despite curative intent, and the optimal approaches to integrate surgery with systemic therapies in a neoadjuvant or adjuvant approach to reduce the risk of recurrence has been an area of active research.2 The U.S. Food and Drug Administration (FDA) has approved two adjuvant therapies in renal cell carcinoma (RCC) thus far, including sunitinib in 2017 and most recently pembrolizumab in 2021.3,4 The use of adjuvant sunitinib has been limited despite FDA approval because of its increased toxicity and lack of overall survival benefit.5 Pembrolizumab is the first approved adjuvant immunotherapy for clear cell RCC patients with intermediate-high or high risk of recurrence after nephrectomy based on the phase 3 doubleblind, multicenter, randomized KEYNOTE-564 study (NCT03142334).4

Updated analysis from KEYNOTE-564 was presented at the meeting evaluating the time to first subsequent drug treatment or any-cause death (TFST) and time from randomization to progression on next line of therapy or any-cause death (PFS2) after treatment with pembrolizumab or placebo in the study.6 Overall 67 patients (13.5%) in the pembrolizumab group and 99 patients (19.9%) in the placebo group received ≥1 line of subsequent anticancer drug therapy. A total of 108 PFS2 events were observed, 40 (8.1%; 12 death events and 28 progression events) in the pembrolizumab group and 68 (13.7%; 14 death events and 54 progression events) in the placebo group. PFS2 was also delayed with pembrolizumab compared with placebo (HR, 0.57; 95% CI, 0.39-0.85; medians not reached). The authors concluded that treatment with adjuvant pembrolizumab reduced risk for TFST and PFS2 compared with placebo. LITESPARK-022 (NCT05239728) is the next iteration of the KEYNOTE-564 study which is a phase 3 study designed to compare the efficacy and safety of belzutifan plus pembrolizumab with that of placebo plus pembrolizumab as adjuvant treatment for clear cell RCC after nephrectomy, and this study is currently actively enrolling.

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Multiple adjuvant and neoadjuvant vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) studies in RCC were reported previously.5 To better understand the role of mammalian target of rapamycin (mTOR) inhibitors in the adjuvant setting, the Southwest Oncology Group (SWOG) launched the phase 3 study of everolimus in treating patients with kidney cancer who have undergone surgery (EVEREST) study (NCT01120249), which was reported at ASCO 2022.7 Individuals with clear or non-clear cell RCC immediately post-nephrectomy whose tumors show intermediate high-risk to high risk features were included in the study. Between 4/2011 and 9/2016, 1545 patients were randomized to e ither 1 2 m onths o f a djuvant e verolimus (n = 7 75) o r placebo (n = 7 70) including 83% w ith clear cell RCC and 17% with non-clear cell RCC. With a median follow-up of 76 months, the recurrence free survival was improved with everolimus compared to placebo (HR 0.85, 95% CI, 0.72 – 1.00; P (one sided) = 0.0246), narrowly missing the pre-specified, one-sided significance level of 0.022 which accounted for interim analyses, and the effect of everolimus was especially pronounced in patients with very high risk disease. Adverse events were consistent with safety profiles of everolimus, although there was a high discontinuation rate of everolimus in this population (47%).

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First Line Metastatic Kidney Cancer Treatment Updates The first line treatment landscape of metastatic RCC has rapidly evolved in recent years.8 New updates on some of the registration first line metastatic RCC studies were presented during the meeting. The CheckMate 9ER trial is a phase 3 trial which compared nivolumab plus cabozantinib versus sunitinib in patients with untreated advanced clear cell RCC and demonstrated superior overall survival (OS), progression free survival (PFS) and objective responses of the nivolumab plus cabozantinib combination9. Updated analysis from the depth of response was presented at ASCO 2022.10 Patients’ responses were classified as complete response (CR) or partial response (PR) subdivided by a tumor reduction of ≥80%–<100% (PR1), ≥60%–<80% (PR2), or ≥30%–<60% (PR3). Overall, greater proportions of patients receiving nivolumab plus cabozantinib had deeper responses versus sunitinib (CR, PR1, PR2), and deeper responses with nivolumab plus cabozantinib were associated with improved 12-months PFS rate versus sunitinib for CR (94.9% vs 82.4%), PR1 (81.3% vs 37.5%), and PR2 (72.1% vs 53.2%).

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Updates on health-related quality of life (HRQoL) from the CheckMate-214 phase 3 clinical trial, which compared nivolumab plus ipilimumab versus sunitinib in patients with untreated advanced clear cell RCC, were also presented during the meeting.11,12 As previously reported, nivolumab plus ipilimumab was associated with improved HRQoL compared to sunitinib. At ASCO 2022, the investigators reported on a post-hoc analysis on the prognostic ability of HRQoL to inform the risk of disease progression or death. The results of the analysis showed that higher (better) baseline scores were associated with significantly reduced risk of death (HR [95% CI] for FKSI- 19 Total Score and DRS score was 0.83 [0.80-0.87] and 0.80 [0.76-0.84], respectively). Furthermore, patients with improved/stable HRQoL had a 52% reduction in risk of death compared to patients who had worsened (HR 0.48 [95% CI: 0.39-0.59]).

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Post-hoc exploratory analyses of PFS2 were conducted in the KEYNOTE 426 (phase 3 study comparing pembrolizuamb plus axitinib versus sunitinib in patients with untreated advanced clear cell RCC)13,14 and the CLEAR (phase 3 study comparing pembrolizumab plus lenvatinib versus sunitinib in patients with untreated advanced clear cell RCC)15,16 studies. Both analyses demonstrated prolongation of PFS2 in patients who received pembrolizumab plus axitinib in KEYNOTE 426 study and pembrolizumab plus lenvatinib in the CLEAR study. Novel Kidney Cancer Therapies Highlights Several exciting data were presented on novel therapies in RCC. Batiraxcept is a GAS6-AXL inhibitor, a pathway which is overexpressed in clear cell RCC.17 Interim results of a phase 1b study of batiraxcept plus cabozantinib 60 mg daily were presented at the meeting.18 A total of 26 patients were enrolled in the phase 1b study so far, and the recommended phase 2 dose of batiraxcept was identified as 15 mg/kg every 2 weeks. Encouraging early anti-tumor efficacy results of the combination were observed with an objective response rate of 67% and 6 months PFS of 79%. Hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in RCC.19 Belzutifan is a HIF-2α inhibitor which was recently approved by the FDA for patients with VHL syndrome and currently under investigation in sporadic RCC.20,21 LITESPARK-001 is a phase 1 study which was designed to evaluate belzutifan in heavily pretreated RCC and showed durable antitumor activity and an acceptable safety profile.21 An update of the clear cell RCC cohort in the study with more than 3 years of total followup was presented at the meeting.22 With extended followup of 41 months, the objective response rate was 25% with 80% disease control rate and median PFS of 14.5 months (95% CI, 7.3-22.1). Belzutifan monotherapy continued to show a high rate of disease control and durable responses in this heavily pre-treated population.

The CALYPSO study results were presented at the meeting as well.23 This is a randomized phase II study of durvalumab alone or with savolitinib or tremelimumab in previously treated advanced clear cell RCC. Savolitinib is a potent MET inhibitor with established dosing and activity in papillary RCC; however, its role in clear cell RCC is unclear.24 Between 2017 and 2021, 139 patients were randomized across the treatment arms. Savolitinib alone and in combination with duravlumab was associated with modest confirmed response rates (5% and 13%, respectively) compared to confirmed response rates of 10% for durvalumab and 28% for durvalumab plus tremelimumab. All regimens studied in the trial appeared to be safe and tolerable.

SUMMARY

In summary, ASCO 2022 was enriched with novel results and concepts continually expanding the field of kidney cancer research. Indeed, the data presented are both hypothesis-generating and practice-informing. Herein, we highlighted a snapshot of some of the oral presentations from the meeting in the kidney cancer space; however, there are considerably more exciting abstract and poster presentations that are available for review on the meeting’s website. In addition to the scientific content, ASCO 2022 also provided ample opportunities for networking and collaborations among the academic kidney cancer community, with the first in-person option since the beginning of the COVID-19 pandemic.

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14. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Analysis of progression after first subsequent therapy in KEYNOTE-426. 2022;40(16_suppl):4513-4513.

15. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300.

16. Voss MH, Powles T, McGregor BA, et al. Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study. 2022;40(16_suppl):4514-4514.

17. Rankin EB, Fuh KC, Castellini L, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014;111(37):13373-13378.

18. Shah NJ, Beckermann K, Vogelzang NJ, et al. A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell (ccRCC) carcinoma who have received front-line treatment (NCT04300140). 2022;40(16_suppl):4511-4511.

19. Choueiri TK, Kaelin WG, Jr. Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med. 2020;26(10):1519-1530.20. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for Renal Cell Carcinoma in von Hippel- Lindau Disease. N Engl J Med. 2021;385(22):2036-2046.

21. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2alpha in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805.

22. Jonasch E, Bauer TM, Papadopoulos KP, et al. Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: Update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up. 2022;40(16_suppl):4509-4509.

23. Powles T, Mendez-Vidal MJ, Rodriguez-Vida A, et al. CALYPSO: A three-arm randomized phase II study of durvalumab alone or with savolitinib or tremelimumab in previously treated advanced clear cell renal cancer. 2022;40(17_suppl):LBA4503-LBA4503.

24. Choueiri TK, Heng DYC, Lee JL, et al. Efficacy of Savolitinib vs Sunitinib in Patients With METDriven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6(8):1247-1255.

Correspondence to:

Nirmish Singla, MD, MSCS. Departments of Urology and Oncology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine. Baltimore MD 21287.

EMAIL: nsingla2@jhmi.edu

The post Kidney Cancer Research Highlights from ASCO 2022 Annual Meeting first appeared on GUcancers.

ABSTRACT

Synthetic biology in the form of engineered antigen specific T-cells for cancer immunotherapy has demonstrated its potential to revolutionize cancer treatment. However, whereas engineered T-cell therapy is already well established in the treatment of hematologic malignancies, it remains only in the pre-clinical and early clinical development stages in solid organ cancers including RCC. In this review, we consider three T-cell target antigens that have already reached the clinic for kidney cancer, and discuss future novel directions including harnessing the immune system against patient specific neoantigens.

INTRODUCTION

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Synthetic biology in the form of engineered antigen specific T-cells for cancer immunotherapy holds promising potential to revolutionize the treatment of advanced solid malignancies. Chimeric Antigen Receptor T-cells, or CAR T-cells, are engineered to express chimeric antigen receptors to target tumor-associated antigens independently of the major histocompatibility complex (MHC).1 Hence, they mimic both antibody-based antigen recognition with T-cell receptor function to enable antitumor activity by lysis of the target cells. The genetically engineered CAR fusion protein is transduced ex vivo by means of retroviral or lentiviral vectors into autologous T-cells collected by leukapheresis. Subsequently, CAR T-cells are re-infused into patients following a lymphodepleting conditioning regimen to enable further T-cell expansion and personalized targeted therapy.2

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The primary advantage of CARs is their ability to recognize tumors based on binding with a single chain variable fragment (scFv) derived from a tumorspecific antibody, and therefore to target antigens expressed on the cell surface without MHC restriction. Autologous CAR T-cell therapy eliminates the potential risk of allogeneic reaction at the expense of a longer manufacturing time due to leukapheresis requirement for every patient, leading to treatment delays and higher manufacturing costs.3 The concept of adoptive transfer of allogeneic CAR T-cells using “off the shelf” as opposed to “made to order,” personalized T-cells aims to address these limitations. The use of allogeneic CAR T-cells from healthy donors has been explored with distinct advantages over autologous therapies, including the potential for standardization of CAR T-cell therapy, increased availability of therapy, ease of redosing or combination of CAR T-cells against multiple targets, decreased time and potentially decreased cost.3 However, one prominent drawback of allogeneic T-cells is the risk of a life-threatening graft vs host disease (GVHD) necessitating further gene editing techniques to avoid the native TCRs of the donor cells recognizing and attacking recipient host tissues as foreign. The second drawback of allogeneic T-cells includes risk of rapid elimination by the host immune system, leading to treatment failure.3

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T cell receptor-engineered T-cells (TCR-T) represent an alternative way to utilize autologous T lymphocytes to target tumor cells. Mechanistically they differ from CAR-T as they rely on antigen specificity derived from recombinant transduced antigenspecific T-cell receptors rather the antibody binding and recognition, which therefore requires MHC copresentation of the tumor antigens to initiate a further intracellular immune signaling cascade.4 This is potentially advantageous as targets are not limited to cell surface proteins but can be expanded to include intracellular antigen fragments that are presented by MHC proteins. In order to design an effective TCR-T, unique polypeptides that are presented by tumors cells must be identified and then a TCR with a higher affinity to that specific antigen can be genetically engineered.5 If an appropriate target is selected, TCR-T can be a highly effective therapy because only a small amount of tumor antigen is needed to stimulate a robust response as TCR-T rely on native T-cell signaling transduction mechanisms.6 However, similarly to CAR-T, polypeptides that are also cross-expressed in normal tissue must be screened out to limit on target, off tumor toxicity resulting from cytotoxicity of normal cells sharing expression of the target antigen. For example, TCR-T cells targeting MART-1 and MAGE-A3 led to lethal cardiotoxicity in patients with metastatic melanoma in clinical studies, as both target antigens are highly expressed in cardiac tissue.7,8 Both TCR-T and CAR-T have demonstrated striking advancements in the treatment of hematologic malignancies resulting in new standard of care paradigms and the potential for long-term durable cures of refractory liquid tumors, but currently with only limited efficacy in the treatment of solid tumors.2,4

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Background

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CAR T-cells have evolved over three generations of CAR constructs to improve the antitumor cytotoxicity and CAR-T cell persistence through the addition of costimulatory domains.1,2,9 The first-generation CAR construct includes a single-chain variable fragment (scFv) antigen-recognition domain, a transmembrane domain, and an intracellular T-cell activation domain derived from CD3 zeta chain. The 2nd generation CAR that is utilized by commercial CAR T-cell products in hematologic malignancies included the addition of a costimulatory domain (either CD28 or 4-1BB). Finally, the 3rd generation CAR incorporates two distinct costimulatory domains (e.g., both CD28 and 4-1BB).^2,9 The choice of costimulatory domain may affect T-cell proliferation and persistence^1,10

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The earliest established clinical use of CAR T-cells lies in Hematologic malignancies including leukemias and lymphomas.2 The Landmark Phase II ELIANA trial of anti-CD19 CAR T-cell therapy Tisagenlecleucel-T demonstrated 81% overall remission within 3 months11 and led to the FDA approval of tisagenlecleucel-T in August 2017 for Acute Lymphoblastic Leukemia (ALL) in pediatrics and adults up to age 25.11 The first CAR T-cell therapy for lymphoma was FDA approved after the ZUMA-1 trial of Axicabtagene ciloleucel that demonstrated efficacy of autologous anti-CD19 CAR T-cell therapy in patients with relapsed, refractory large B-cell lymphoma after failure of conventional therapy.12 In total, three CAR T-cell products have been approved to treat relapsed or refractory aggressive B-cell lymphomas: Tisagenlcleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel.13 In contrast, data on CAR T-cell therapy in solid tumors thus far suggests less robust responses and greater challenges.2,14 To date, no CAR T-cell products have been FDA approved for treatment of solid organ malignancies, but some progress has been achieved in pre-clinical and clinical studies of CAR-T and TCR-T in osteosarcoma and gynecologic malignancies.15,16 Ovarian cancer TCR-T candidate targets have focused on melanoma-associated antigen 4 (MAGE-A4) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) both commonly expressed by ovarian cancer cells. The ongoing NCT03132922 clinical trial for MAGE- 4 TCR-T in multiple cancers including ovarian, bladder, esophageal, head and neck, bladder, melanoma, and synovial sarcoma demonstrated interim partial response in 7 of 28 patients and stable disease in 11 of 28 patients at the cost of significant adverse events.17 Clinical studies have been conducted to evaluate human epidermal growth factor receptor 2 (HER2)-specific CAR T-cells in patients with HER2- positive sarcoma, demonstrating T-cell persistence for at least 6 weeks without significant toxicity.16 A positive clinical response was demonstrating by administering a single agent ultra-low dose of HER2-Car T-cells to 19 sarcoma patients with recurrent or refractory metastatic disease, with subsequent dose escalation to bypass the need for concurrent lymphodepleting chemotherapy.16 However, none of the 19 patients demonstrated a complete response although 4 of 17 measurable patients had stable disease for 12 weeks to 14 months by RECIST criteria.16

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CAR T-cells for Renal Cell Carcinoma

The utilization of CAR T-cells for solid organ malignancies, including renal cell carcinoma (RCC), is subject to numerous challenges including suppression of T-cell function, inhibition of T-cell localization, toxicity leading to adverse events, and lack of therapeutic response. As of 2020, there were 196 clinical trials of CAR T-cells targeting 57 unique solid tumor entities registered at clinicaltrials.gov, the majority of which were performed in the USA and China.9 Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor type with moderate tumor mutational burden of 1.42 mutations per megabase18 that has proven to benefit from both cytokine-based and checkpoint inhibitor immunotherapies in advanced and metastatic disease.19,20 However, despite its theoretical promise as an immune-sensitive malignancy, no large clinical trials yet exist for CAR T-cell therapy in RCC. Safety and efficacy are two major limitations that prevent CAR-T therapy from proceeding to clinical trials in RCC. To maximize both safety and efficacy of CAR T-cell immunologic response, antigen selection is vital to reduce offtarget toxicity. In the current review, we examine the furthest developed candidates for CAR-T therapy in RCC.

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CAIX

Carbonic anhydrase-IX (CAIX) is a 54/58 kDa transmembrane tumorassociated antigen and marker of hypoxia that belongs to the family of carbonic anhydrases, a family of zinc metalloenzymes that catalyzes hydration of CO2 for pH balance in living organisms.21 The CAIX gene is directly activated at a transcriptional level by hypoxia-inducible factor (HIF)-1a leading to proton transport to extracellular medium to lower pH. Therefore CAIX expression serves as a surrogate marker for hypoxia in some tumors.21,22 Specifically for RCC, CAIX is overexpressed in over 90% of ccRCC and over 80% of metastases but not on neighboring normal renal parenchyma.21,23 Patients with Von Hippel Lindau (VHL) mutation characterized by predisposition to ccRCC have also been demonstrated to have higher CAIX expression than those with wildtype VHL.24 CAIX serves as an important prognostic biomarker in patients with ccRCC, with high CAIX score on immunohistochemical staining associated with improved disease free survival and overall survival.25 Conversely, low CAIX expression and absence of VHL mutation is associated with more advanced disease and decreased survival.24 In addition to RCC, CAIX is overexpressed in several other solid tumor types including carcinomas including ovarian, breast, esophageal, bladder, colon, non-small cell lung, dysplasia of cervix and others.21 CAIX has also been proposed historically to be a prognostic marker for favorable response in IL-2 treated patients with RCC,26 though this was not demonstrated prospectively when tested in the SELECT study.

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Prior to preclinical studies, in vitro and in vivo studies focused on constructing CAR using anti- CAIX scFv.21,27 Lo et al evaluated five anti-CAIX single chain antibodies as candidates for CAR construction and constructed two generations of anti-CAIX CARs using the selected scFvG36 CAR-targeting moiety. They reported in vitro comparisons of both21 to confirm superior effector functions of second generation G36- CD28z CAR T-cells compared with first generation constructs in all in vitro assays including IFN-y, IL-2, and IL- 17 cytokine secretion, cytolytic activity, proliferation, and clonal expansion.21 The same group then reported in vivo superior antitumor activity of second generation CAR T-cells against RCC21 after adoptive transfer of CAR T-cells combined with high-dose interleukin (IL)-2 into RCC-established mice, demonstrating tumor cell apoptosis and regression of CAIX+sk-rc-52 tumors in vivo.21

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The first clinical study of T-cells genetically modified to express a CAR against CAIX was published in 2006 as a proof of principle that autologous CAR T-cell transfer can be accomplished in metastatic RCC to provide tumor-specific immunity.28 A single chain antibody-type receptor construct that recognizes CAIX was transduced into primary human T-cells. These autologous genetically retargeted T-lymphocytes were administered to three patients with CAIX-positive metastatic clear cell carcinoma who had already undergone radical nephrectomy with metastasis refractory to treatment with interferon alpha.28 The study was not designed to assess clinical efficacy but did confirm off-tumor T-cell mediated cytotoxic effects: two of three patients required cessation of therapy due to hepatotoxicity per NCI Common Toxicity Criteria grades 2-4.28 Liver biopsy confirmed cholangitis with T-cell infiltration of bile ducts and CAIX expression on bile duct epithelial cells, suggesting antigenspecific immunologic mechanism.28 A follow-up study by the same group utilized CAIX CAR-T in 12 patients with CAIX-expressing metastatic RCC and demonstrated increased plasma levels of interferon-gamma, IL-2, and tumor necrosis factor (TNF)-alpha. Similar to prior study, they confirmed grade 2-4 hepatotoxicity at the lowest CAR T doses with CAIX expression and T-cell infiltration on bile duct epithelium, but with the notable novel finding that pre-treatment with CAIX monoclonal antibody G250 helped to circumvent CAR-specific hepatotoxicity.29 This provided additional proof of principle that the on-target toxicity is antigendirected, as blockage of CAR-specific antigen expressed on normal tissue improved the toxicity profile to allow higher doses.29 There is a dose escalation and expansion clinical trial of CAIX-targeted CAR-T cells in the treatment of advanced RCC that is ongoing at The Affiliated Hospital of Xuzhou Medical Center (ClinicalTrials. gov Identifier NCT04969354).30 New progress has been made in creating CAIX-targeted CAR T-cells with different cellular composition in the ccRCC mouse model, more specifically with a CD4/CD8 ratio of 2:1 (CAR 4/8) to balance cytolytic CD8 T-cell killing capacity with cytokine-induced effect of CD4 T-cells.31 Indeed, early results demonstrated superior antitumor efficacy in the ccRCC orthotopic mouse model, increased memory phenotype, and decreased exhaustion genes compared to CAR8 T-cell groups.31
More recent attempts to target CAIX with CAR-T cells while avoiding the observed on-target off-tumor toxicities noted above have led to the development of dual-targeted CAR-T constructs that require targeting and binding of two unique antigens to mediate cellular cytotoxicity. Early pre-clinical data on such a dual construct that targets both CAIX and CD70 (see section below) has been reported.32

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CD70

CD70, a ligand for CD27, is a costimulatory receptor involved in T-cell proliferation and survival.33,34 CD70 was initially identified as a diagnostic marker for ccRCC by gene expression profiling, real time RT-PCR and IHC.35 A postulated mechanism of CD70 overexpression is due to dysregulated pVHL/HIF pathway in RCC.36 RCC and other solid tumors can constitutively overexpress CD70, making it an effective target of CAR-T cells in vitro and in vivo.37,38 Clinical studies of CD70-expressing RCC and other targeted treatment modalities have demonstrated its potential as a target: an antibody-drug conjugate targeting CD70 (SGN-CD70A) has been tested in a phase I clinical trial for patients with CD70-positive metastatic RCC demonstrating modest clinical results including 13 of 18 with stable disease but only 1 with partial response per RECIST 1.1.39 Aside from RCC, other CD70-expressing tumors include glioblastoma, and hematologic malignancies.

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Published preclinical data supports the feasibility and safety of using anti-human CD70 CAR to treat cancer patients whose tumors express CD70.40 Seven candidate anti-human CD70 CARs consisting of extracellular binding portion of CD27 fused with 41BB and/or CD3-zeta were constructed for in vitro studies and in vivo adoptive transfer into a CD27-CD3-zeta CAR murine model. In vitro results demonstrated that the CAR consisting of extracellular binding portion of CD27 fused with 41BB and CD3-zeta conferred the highest IFNy production against CD70-expressing tumors.40 In vivo data for renal cell carcinoma demonstrates that mouse xenografts treated with CD70 CAR-T cells showed significantly decreased RCC burden, longer survival times than mice treated with controls (PBS, T-cells, or mock CAR-T cells). In addition, higher cytokine levels of IL-2, TNF-alpha, and IFNy were secreted in peripheral blood of mice treated with CD70 CAR-T cells compared to controls, suggesting that CD70 CAR-T cells may be effective in treating CD70+ RCCs in vivo.38

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Clinical trials with CD70 CAR-T cells have recently entered the clinic, with the TRAVERSE trial using allogeneic, TALEN gene edited ALLO-316 anti- CD70 T-cells being given Fast Track Designation for the US FDA based on its potential to address an unmet medical need for patients with advanced RCC who have progressed on approved therapies.41–43

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HERV-E

VHL-deficient ccRCC commonly express transcripts derived from novel human endogenous retrovirus HERV-E. In current literature there are no in-vitro or in-vivo studies of CAR-T targeting HERV-E in RCC, but advancements have been achieved in the development of TCR-T targeting HERV-E.44–47 HERV-E was first identified as a target antigen of RCC-specific CD8+ T-cells due to expression in RCC cell lines and fresh RCC tissue but not in normal kidney or other tissues.47 To provide a clinical proof of principle, T-cells targeting to HERV-E family antigens mediated regression of metastatic RCC in a stem cell transplant recipient.47 Subsequently, HERV-E expression was demonstrated to restrict to ccRCC by mechanism of inactivation of the VHL tumor suppressor and stabilization of HIFs.46 HERV-E expression in ccRCC demonstrated linear correlation to HIF-2alpha levels, while transfection of normal VHL successfully silenced HERV-E expression.46 Cherkasova et al confirmed that T-cells could recognize HLA-A+0201-positive HERV-E-expressing kidney tumor cells suggesting HERV-E envelope peptides as tumor-restricted targets.45 In a separate paper, RNA-seq analysis was performed on RCC tumor samples to determine whether response to Nivolumab was associated with HERV expression, with finding of no association between T-cell reactivity to HERVs and nivolumab response,48 though other published data have supported such an association.49 Taken collectively, these studies suggest prominent potential for future TCR-T or CAR-T against HERV-E in ccRCC. Studies of other tumors have demonstrated the feasibility of CAR T-cell specific for other HERV subtypes: In vivo studies of CAR T-cell generated for breast cancer demonstrated downregulation of HERV-K expression in tumors of mice treated w/ CAR T-cell for HERV-K, upregulation of 53, downregulation of MDM2 and p-ERK.50 Additionally, HERV-K env-specific CAR T-cells demonstrated lysis of HERV-K env(+) tumor targets in melanoma.51 A clinical trial at National Institutes of Health (NCT03354390) is currently ongoing to evaluate the effectiveness and safety of HERV-E TCR transduced autologous T-cells when infused in patients with metastatic ccRCC.52

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Neoantigens and other Tumor Antigen Targets

Personalized neoantigen-based immunotherapy, based on a patient’s tumor-specific somatic mutational profile, represents the most individualized form of immunotherapy when incorporated into neoantigen long peptide vaccines, dendritic cell vaccines, and neoantigen-reactive T-cells (NRTs).53 Neoantigens are epitope peptides that originate from somatic variants in tumor cells and bind with a patient’s MHC to elicit T-cell mediated antitumor response. Neoantigen candidates may be identified for a specific patient through genomic and transcriptomic profiling of the tumor and administered via personalized neoantigen vaccination. Neoantigens are advantageous as immunologic targets due to specific expression in tumor cells and not normal cells, thereby minimizing the risk of autoimmunity.53 Neoantigenbased cancer immunotherapy has demonstrated therapeutic efficacy in multiple solid tumors including small cell lung cancer54 and glioblastoma.55 Robust data has been published in the pancreatic cancer literature utilizing TCR-T cells targeting neoantigen mutant KRAS G12D expressed in a patient’s tumors, leading to overall partial response of 72% by RECIST criteria at 6 months.56 There is currently limited data on neoantigenbased immunotherapy in renal cell carcinoma, but at least one case report has demonstrated the feasibility of neoantigen-reactive T-cells in a patient with metastatic collecting duct carcinoma refractory to tyrosine kinase inhibitor. Post-therapy biopsy demonstrated reduction in mutant allele frequency corresponding to 12/13 of the neoantigens compared to pre-therapy biopsy, indicating therapeutic efficacy against tumor cells carrying these neoantigens. The patient demonstrated stable tumor burden and significant reduction in bone pain within 3 months.53

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Renal cell carcinoma has a relatively low tumor mutational burden (TMB) but discrepantly high response to PD-1 inhibition, which counters the association between high TMB and response to immune checkpoint blockade.57 This discordance may lie in small insertions and deletions (indels), as whole-exome sequencing data demonstrates the highest proportion of indels in RCC when compared to a pan-cancer cohort including 5777 solid tumors.58 Therefore, neoantigenbased therapy may be particularly beneficial for renal cell carcinoma due to high immunogenicity of RCC despite relatively low mutation load: neoantigens derived from indel mutations were found to be 9x enriched for mutant specific binding compared to single nucleotide variant derived neoantigens, suggesting that Indels may be the key to activating increased neoantigens and increased mutantbinding specificity in RCC.58

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Other specific tumor-associated antigens highly aberrantly expressed and mutated in RCC have been identified as potential RCC-specific neoantigen targets for mRNA vaccine development including DNA topoisomerase II alpha (TOP2A), neutrophil cytosol factor 4 (NCF4), formin-like protein 1 (FMNL1) and docking protein 3 (DOK3).59 Other potential tumor antigen candidates for engineered T-cell therapy in RCC include vascular endothelial growth factor receptor 1 (VEGFR1) associated with RCC angiogenesis that has demonstrated good peptide-specific cytotoxic lymphocyte response when administered in a phase I vaccine trial.57 Hypoxia-inducible protein 2 (HIG2) is a growth factor expressed in 86% of RCC that demonstrated HIG2-specific CTL response in 8 of 9 patients after vaccination of a specific HIG2 peptide.57

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CONCLUSIONS

Engineered T-cell therapy is well established in hematologic malignancies but remains in preclinical and early clinical development for clinical applicability in solid organs including RCC. Current literature suggests that CAIX, CD70 are the primary candidate target antigens for CAR T-cell design for RCC, and HERV-E has demonstrated great promise as a target in ccRCC TCR-T therapy. Future strategies should direct towards finding an optimal target antigen for RCC and minimizing off-target toxicity prior to large-scale clinical trials. The current clinical studies of CAR T-cell therapy in other solid organs include patients with refractory or recurrent metastatic disease after failure of conventional chemotherapy. In this landscape and in part due to the risk of adverse events, we anticipate that the optimal CAR T-cell therapy candidate in the RCC space should also demonstrate failure of conventional approved therapies. CAR T-cells for RCC should be intended to target advanced and refractory disease, or those with strict contraindication to more established immunotherapy. Furthermore, future directions of CAR T-cell therapy include its potential use in combination with established immune checkpoint blockade for synergistic effect. With potential life-threatening adverse events representing a major barrier to CAR T-cell therapy in RCC, we emphasize a need to confirm safety and efficacy before progressing to large clinical trials.

DISCLOSURES

A.J.P. is a consultant for T Cure, a company that has licensed and is developing HERV-E CAR-T for renal cell carcinoma. No additional disclosures

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44. Cherkasova, E., Weisman, Q. & Childs, R. W. Endogenous retroviruses as targets for antitumor immunity in renal cell cancer and other tumors. Frontiers in Oncology 3 SEP, (2013).45. Cherkasova, E. et al. Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer. Cancer Research 76, 2177–2185 (2016).

46. Cherkasova, E. et al. Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. Oncogene 30, 4697–4706 (2011).

47. Takahashi, Y. et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T-cells. Journal of Clinical Investigation 118, 1099–1109 (2008).48. Au, L. et al. Determinants of anti- PD-1 response and resistance in clear cell renal cell carcinoma. Cancer Cell (2021) doi:10.1016/j.ccell.2021.10.001.

49. Smith, C. C. et al. Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. Journal of Clinical Investigation 128, 4804– 4820 (2018).50. Zhou, F. et al. Chimeric antigen receptor T-cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras. OncoImmunology 4, (2015).

51. Krishnamurthy, J. et al. Genetic engineering of T cells to target HERV-K, an ancient retrovirus on melanoma. Clinical Cancer Research 21, 3241–3251 (2015).

52. HERV-E TCR Transduced Autologous T Cells in People with Metastatic Clear Cell Renal Cell Carcinoma. ClinicalTrials.gov Identifier: NCT03354390 (2017).

53. Schuster, S. J. et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. The Lancet Oncology 22, 1403–1415 (2021).

54. Schubert, M. L. et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Annals of Oncology vol. 32 34–48 (2021).55. McLellan, A. D. & Ali Hosseini Rad, S. M. Chimeric antigen receptor T cell persistence and memory cell formation. Immunology and Cell Biology vol. 97 664–674 (2019).

^{Correspondence to: Allan J. Pantuck, MD, MS, FACS UCLA Institute of Urologic Oncology, Department of Urology; David Geffen School of Medicine at UCLA. Email: apantuck@mednet.ucla.edu}

The post Engineered T-Cell Therapy: The Next Direction for RCC Immuno-oncology? first appeared on GUcancers.

1. Clemson University, Hampton, GA 30228 USA.

2. School of Nursing, Clemson University, Clemson, SC 29634.

3. Mathematical and Statistical Sciences, Clemson University, Clemson, SC 29634.

4. Department of Public Health Sciences, Clemson University, Clemson, SC 29634

ABSTRACT

OBJECTIVE: The overall aim of this study was to determine if there are significant differences between type 1 and type 2 papillary renal cell carcinoma (PRCC) that can be utilized by healthcare providers. MATERIALS AND METHODS: This study performed a secondary data analysis using The Cancer Genome Atlas Kidney Renal Papillary Cell Carcinoma data to determine if there are clinically significant differences in survival, demographics (age, ethnicity, gender, and race), increased risk factors (body mass index [BMI] smoking history, neoplasm history, and malignancy history) and preferential genetic pathways between type 1 and type 2 PRCC tumors. RESULTS: Descriptive statistics were performed on a total of 156 cases to determine demographics, increased risk factors and genetic pathways. The hazard ratio, with type 1 as the reference group, was 2.459 (with 95% CI 0.9723, 6.217). Of the risk factor variables investigated, we found that smoking appeared to be associated with an increased risk of type 2 (OR 3.241 95% CI 1.066, 9.853). In the pathways analysis, we observed one significant difference between MAPK and PI3K, with the latter being significantly associated with type 2 (OR 4.968 95% CI 1.759, 14.031 Table 6). CONCLUSION: This study provides the framework for future more comprehensive research on the demographic, increased risk factor and genetic pathway differences between PRCC type 1 and type 2 tumors. Future investigations should include a more complete dataset with additional potential risk factors

INTRODUCTION

Renal cell carcinoma (RCC) is the 14th most common cancer worldwide and was the cause of 175,098 deaths in 2018¹. RCC consists of numerous subtypes including clear cell renal carcinoma, papillary renal cell carcinoma and most recently clear cell papillary renal cell carcinoma. Currently, papillary renal cell carcinoma (PRCC) is the second most common type of RCC, after clear cell renal cell carcinoma, comprising approximately 15-20% of all RCC cases^2,3. PRCC is considered a heterogeneous disease consisting of two subtypes; type 1 and type 2. These subtypes are primarily distinguished by their histology and vary in prognosis, treatment and patient outcomes. Type 1 is histologically characterized by a single layer of cells with sparse basophilic cytoplasm and small oval shaped nuclei that are present in either the renal tubules or renal papillae. This type can be associated with both hereditary and sporadic PRCC.^4,5 Conversely, type 2 tumors are histologically characterized by large pseudostratified cells with eosinophilic cytoplasm with large spherically shaped nuclei that are present in the renal papillae. These tumors can be associated with hereditary PRCC but are more often associated with the sporadic form of PRCC.⁶ Furthermore, research ⁶ has shown that patients with PRCC type 2 tumors are correlated with a higher rate of metastasis and have a lower overall survival rate compared with patients with type 1 tumors.7 The overall aim of this study was to determine if there are significant differences between type 1 and type 2 PRCC that can be utilized by healthcare p r o v i d e r s . Specifically, this study sought to determine if there are clinically s i g n i f i c a n t d i f f e r e n c e s in survival, demographics (age, ethnicity, gender, and race), increased risk factors (body mass index [BMI] smoking history, neoplasm history, and malignancy history) and preferential genetic pathways between type 1 and type 2 PRCC tumors.

Table 1 | Descriptive Statistics for Demographic Factors

T h e epidemiology and risk factors for PRCC are largely based on the broader RCC. However, there are certain conditions that may increase an individual’s risk of developing PRCC. For instance, individuals with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) have a greater chance of developing PRCC type 2. There is some evidence that suggests individuals with renal insufficiencies have a greater risk of developing PRCC.^8,9 Ethnicity is also linked to increased risk of developing RCC with African Americans having the highest incidence of RCCs. Sankin et al. (2011) found that African Americans had a four times greater incidence of PRCC as compared to non-African Americans.^10,11 Research has demonstrated that malignant tumors utilize a wide variety of genetic alterations to modify the normal cell cycle in order to be able to divide and grow without restrictions. These modifications are accomplished by altering cell signaling pathways to promote cell growth, angiogenesis and obstruct apoptosis.¹² Considering the heterogeneous nature of PRCC, there are numerous genetic alterations that occur within both type 1 and type 2 PRCC. Approximately 20% of hereditary type 1 tumors have been associated with variations in the protooncogene mesenchymal epithelial transition (MET). However, sporadic type 1 tumors have numerous genes associations as well as chromosomal abnormalities. Type 2 tumors have also been correlated with a large number of genetic and chromosomal alterations.^4,13 Similarly, research has shown that renal cancers in general utilize several signaling pathways. The alteration of MET has been shown to activate the MAPK and PI3K pathways as well as other proteins involved with tumor growth.¹⁴ Gaps in research still exist for determining if there are pathway preferences between type 1 and type 2 PRCC tumors.

Table 1 | Descriptive Statistics for Demographic Factors

Most research on PRCC has either been umbrellaed under RCC or focused on developing a basic understanding of the disease with minimal attention to the differences between type 1 and type 2 PRCC tumors. Recently, Wong et al. (2019) investigated survival rates associated with type 1 and type 2 PRCC. The researchers found that type 2 PRCC was associated with a higher all-cause mortality rate as well as with worse reoccurrence rates as compared to type 1.7 As part of our research, we analyzed the allcause mortality for discrepancies in survival rates between type 1 and 2 PRCC. Next, we selected a demographic (baseline) model to identify a set of demographic variables that are likely to be associated with the different types of PRCC. Lastly, we investigated environmental and gene pathway associations with prevalence of the two types of PRCC.

METHODS

Sample

This study was a secondary data analysis using data from The Cancer Genome Atlas Kidney Renal Papillary Cell Carcinoma (TCGAKIRP). A review of the literature was conducted to determine the appropriate inclusion criteria which included: 1) PRCC tumors, 2) distinguishes between type 1 and type 2, 3) demographics data, gender, race, age and ethnicity, 4) clinical data, prognosis, treatment, preexisting conditions, 5) increased risk factors, smoking history, BMI, prior neoplasms and prior malignancies, and 6) genetic analysis of the tumors. A further review of the literature revealed that TCGA-KIRP is the most current and appropriate dataset to use for this secondary data analysis. The cBioPortal for cancer genomics (cBioPortal) was used in conjunction to analyze the TCGA-KIRP data.
TCGA-Kidney Renal Papillary Cell Carcinoma (KIRP) data was collected from 41 institutions from 1996 to 2013. The database adheres to a strict inclusion policy; TCGA tumors are untreated samples that were snap frozen. Each tumor sample has to have a matched normal sample from the same patient which generally comes in the form of the patient’s blood. The tumors and subsequent molecular data are cross referenced by Biospecimen Core Resource (BCR) to ensure validity. Furthermore, the BCR analyzes each sample for pathological quality control. This maintains that TCGA has a highquality tumor samples as well as consistent molecular data.¹⁵ Additionally, each sample was reviewed by a panel of six experienced pathologist to in order to be classified into type 1, type 2 or unclassified PRCC. Moreover, any samples that were preclassified were reassessed by the same panel to ensure proper classification.15 The cBioPortal is a resource that incorporates data from TCGA as well as actively curates data sets from the literature into a researchfriendly source. The cBioPortal separates PRCC genetic variations into categories such as copy number variations and mutations. Furthermore, the cBioPortal predetermines and denotes driver genes through specific algorithms.¹⁶ The cBioPortal allows the user to analyze specific genes, as opposed to TCGA, which only allows users to view the dataset as a whole and does not denote potential driver genes.16 Even though the cBioPortal contains the same data as TCGA, the cBioPortal was used to aid in the analysis of TCGA data.

Data extraction

Both databases showed the same cases which totaled 292. The first step in evaluating the dataset was determining the demographic and clinical data. TCGA contained a manifest of demographic, clinical, and environmental data. This manifest was downloaded and converted into an Excel file. Once retrieved, the dataset was reviewed and irrelevant data was removed; such data included serum levels, blood cell counts, IDH level, tumor laterality, lymph node data, tumor dimensions, treatment data, tissue collection data, sample weights, calcium levels, and vial numbers. Data categories that were redundant were also eliminated.

Next, the cBioPortal resource was used to determine pertinent genetic information related to PRCC. The first step was to download the copy number alteration (CNA) data from this resource. A total of 10,837 genes exhibited a copy number variation. Genes that were not considered to be driver genes according to the GISTIC algorithm were eliminated from the dataset. This elimination left a total of 426 driver genes with CNA. The driver genes were then put into the BCG query to determine how many cases included one or more of the driver CNA genes. A total of 193 of the cases (66%) contained one of the driver CNA genes. In order to increase the sample population, mutated driver genes (as determined by Mutsig) were added to the query bringing the total of genes to 517 and 255 (87%) cases. Thirty-six cases did not have an association with one of the 517 driver genes and were eliminated. The driver genes were divided into categories based on their cytoband for future reference.

The remaining 255 cases were reviewed to determine whether or not they were designated type 1 or type 2 PRCC. Out of the 255 cases, 115 cases had no designation in the type category. The pathology report of each of the 115 cases was reviewed to see if a pathologist had designated the tumor as either type 1 or type 2. Seven more cases were determined to be a mix of type 1 and type 2 histology and were also removed. Additionally, eight more cases were either mislabeled as PRCC or determined to favor a different cancer type per the reviewing pathologist. These eight cases did not include a TCGA addendum that disputed the cancer typing and therefore were removed from this dataset. (See Figure 1). At the conclusion of this analysis, 88 cases were designated as type 2, 69 cases were type 1, and 83 cases were undesignated. The 83 undesignated cases were subsequently removed from the dataset in order to preserve the validity and continuity of the data.

ANALYSIS

Descriptive Statistics and Survival Analysis

Descriptive statistics were utilized to determine demographics, increased risk factors and genetic pathways. The survival analysis was conducted for the TCGA-KIRP analytic file using R version 3.6.2. , the survival(v3.2-13) and the survminer (v0.4.9) packages.21-23 A cox-proportional hazard model was fitted on the overall survival times of 156 patients (1 had a survival time of 0 indicating that they were diagnosed post-mortem or there was an error in entry) to determine if there were evidence that survival rates differ between type 1 and 2 PRCC.

Logistic RegressionFor the next three phases of our statistical analysis, SASTM software, Version 9.4 of the SAS system for Windows was utilized. The demographic model selection included age at diagnosis, race, ethnicity and sex, as candidate descriptors relating to PRCC tumor type. The demographic model selection utilized forward selection with a relaxed p value (<0.1) to determine the appropriate variables to be included in the model. The selected demographic model included Age at Diagnosis (OR 1.045 95% CI 1.014, 1.078, Table 5) as well as 3 Category Race (White, Black or African American and Other) was used as the baseline model for the increased risk factor variables. Each increased risk factor variable; BMI, smoking status, prior neoplasms and prior malignancies, were added univariately to the demographic model controlling for age at diagnosis and race to identify associations.

Figure 2 | Kaplan Meier curves for Type 1 and 2 PRCC survival

RESULTS

Descriptive StatisticsFor the 69 patients designated as type 1 tumors, 50 were male and 19 were female with a median age of 60 (range 28 to 82). In terms of race, 46 were white, 18 were black or African American, and 5 were unspecified. Ethnicity was reported as 62 non- Hispanic or Latino, 2 were Hispanic or Latino and 5 were unspecified.

For the 88 patients designated as type 2 tumors, 61 were male and 27 were female with a median age of 65 (range 28 to 88). In terms of race, 66 were white, 15 were black or African American, and 7 were unspecified. Ethnicity was reported as 75 were non-Hispanic or Latino, 5 were Hispanic or Latino and 8 were unspecified (Table 1). Due to the sparsity in the demographic factor levels, the following variable levels were collapsed; Asian and American Indian.

Table 2 | Descriptive Statistics for Increased Risk Factors

Smoking categories were defined as life-long non-smoker (1), current smoker (2), reformed smoker >15years (3), reformed smoker <15 years (4) and reformed smoker unknown length (5). Table 2 describes the smoking status of type 1 and type 2 PRCC tumors. Smoking categories 4 and 5 were collapsed together due to data sparsity in the increased risk factor variables. The existence of prior neoplasm was defined in the database as ‘yes’ or ‘no’. Two patients with type 1 PRCC had known prior neoplasm were as 9 patients with Type 2 reported prior neoplasm. Similarly, prior malignancies were also defined as ‘yes’ or ‘no’. Sixteen patients with type 1 reported prior malignancies and 14 patients with type 2 reported prior malignancies (Figure 2). The most common pathway in type 1 was the MAPK pathway and in type 2 was the PI3K pathway Table 3).

Table 4 | Demographics Model

Overall SurvivalThe hazard ratio, with type 1 as the reference group, was 2.459 (with 95% CI 0.9723, 6.217). This result did not provide sufficient evidence that the two types differ significantly in all-cause survival (α=.05). However, given the relatively small sample size and high rate of censoring, it is not surprising that our results do not provide as striking a contrast between the two as supported by Wong et al. (2019). (Censoring rates were 91.3% for Type 1 and 79.5% for type 2, respectively, which consequently prevents us from being able to report median survival without making parametric assumptions). Survival rates are illustrated via the Kaplan Meier curve included in Figure 2.

Table 4 | Increased Risk Factor Model

Logistic RegressionOdd ratios (OR) and confidence intervals (CI) are reported in Tables 5 and 6 for each variable in the increased risk factor and pathway analyses. Of the risk factor variables investigated, we found that smoking appeared to be associated with an increased risk of type 2. Specifically, being a reformed smoker of unknown length or less than 15 years, was positively associated with type 2 PRCC compared to lifelong non-smokers (OR 3.241 95% CI 1.066, 9.853 Table 5). None of the other increased risk factors had significant association with tumor type. In the pathways analysis, we observed one significant difference between MAPK and PI3K, with the latter being significantly associated with type 2 (OR 4.968 95% CI 1.759, 14.031 Table 6). All pairwise comparisons were made between pathways and the MAPK/PI3K comparison was the only one found to be significant. In all analyses, type 1 was used as the reference level for each model and the OR corresponds to odds of type 2 Vs 1.

Table 2 | Descriptive Statistics for Increased Risk Factors

DISCUSSION

It is important to note that current findings from the International Society of Urological Pathology (ISUP) suggests that the PRCC type 1 subtype is the most uniform morphologically, immunohistochemically, and in terms of molecular features. ISUP also suggests that PRCC type 2 is not a distinct neoplasm but rather a combination of multiple distinct neoplasms. As such, type 2 PRCC is a distinctly different disease as compared to type 1 and contains multiple clinically and molecularly heterogeneous subtypes.²⁴ Additionally, the use of type 1 and type 2 terminology is evolving as PRCC becomes better understood. To the best of our knowledge, our study is the first to collectively examine the demographic, increased risk and pathway associations between type 1 and type 2 PRCC tumors. Furthermore, while our findings with respect to the survival analysis were not significant, it does provide marginal evidence to confirm the findings of Wong et al. (2019) in that survival rates for type 2 are shorter than those diagnosed with type 1. 7 While our analysis was limited by small sample size, certain variables were linked to increased probability of type 2 PRCC tumors. The age at diagnosis variable was considered significant with an older adult having increased risk of type 2. Our result is consistent with Wong et al. (2019) who reported a higher age at time of nephrectomy for patients with type 2 tumors as compared with type 1 tumors.⁷

Smoking was the only increased risk factor that was significant in determining the probability of having the type 2 tumor type versus type 1. Individuals who were reformed smokers of less than 15 years (as well as reformed smokers of unknown length) had a greater risk of developing a type 2 tumors as compared to lifelong non-smokers. Furthermore, type 2 PRCC tumors tend to be sporadic as compared to type 1, meaning that increased risk factors may have a greater impact on the development of type 2 tumors.6 However, further research needs to be conducted on the effects of smoking on the growth of specific tumor subtypes.

Although smoking was the only significant increased risk factor variable, further research should be conducted on a larger sample size with less missingness to better compare increased risk factors variables between tumor types. Specific focus should be put on prior neoplasms since they have been associated with a number of renal cell cancer syndromes that are considered to increase the risk of PRCC. For example, the most common renal cell cancer syndrome, von Hippel-Lindau syndrome, is characterized by benign tumor growths and has a 40% chance of developing renal cancer, including type 2 PRCC. Additionally, hereditary leiomyomatosis and renal cell cancer (HLRCC), is characterized by harmatomas with an increased risk of developing type 2 PRCC. ^8,17 Considering the number of renal cell cancer syndromes that are both associated with an increased PRCC risk and are characterized by neoplasms; further research should be conducted to determine if prior neoplasms is a determining factor in PRCC subtype.

The findings in this study have potential implications for future treatment options. The higher rate of MAPK pathway in type 1 supports ongoing studies of the role of the MET gene in clinical trials. The MET gene codes for c-Met, a tyrosine kinase protein that is involved with the MAPK pathway. When c-Met binds to its ligand, HGF, a downstream cascade is started that leads to the activation of the MAPK pathway which promotes cell migration and tumor proliferation. ¹⁸ Seeing as 20% of type 1 tumors contain a MET mutation, it is not surprising that MAPK is the preferred pathway of type 1 tumors. Furthermore, the PI3K pathway was found to be significant in the probability of having a type 2 tumor as well as being the preferred pathway of type 2. The findings in this study support the ongoing efforts in determine drug treatment therapies that target the PI3K pathway. PI3K is comprised of lipid kinases that once activated, begin a downstream cascade that leads to cell growth and survival. PI3K pathway has a strong association with the inactivation of PTEN, which has been correlated poor patient outcomes.^19,20

CONCLUSION

Despite the imperfect database this study found that there is a trend in the data that is clinically significant Furthermore, this study provides the framework for future more comprehensive research on the demographic, increased risk factor and genetic pathway differences between PRCC type 1 and type 2 tumors. Future investigations should include a more complete dataset with additional potential risk factors. Given the differences in survival rates, such investigations will provide clinicians a better understanding of tumor types allowing for quicker more accurate diagnosis and evidence-based treatment plans.

CONFLICT OF INTEREST

All authors listed on this study have no conflicts of interest that may be relevant to the contents of this manuscript.

FUNDING

None

ACKNOWLEDGMENTS

None

REFERENCES

Correspondence to: Melissa Paquin, PhD. 235 Galway Lane, Hampton, GA 30228 Email: mpaquin@clemson.edu

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The post Comparison of Papillary Renal Cell Carcinoma Type 1 and Type 2: A Secondary Data Analysis first appeared on GUcancers.

A novel kidney cancer drug developed from UT Southwestern Medical Center received approval from the Food and Drug Administration, providing a new treatment for patients with kidney cancer.

FDA approval of belzutifan culminates a 25-year journey at UTSW from gene discovery to a first-in-class drug.

Merck’s belzutifan grew out of the discovery at UT Southwestern of a protein, hypoxia-inducible factor 2-alpha (HIF-2α), that is key to fuel the growth of kidney and other cancers. HIF-2α was discovered by Steven McKnight, Ph.D., Professor of Biochemistry.

“This is an exciting milestone for patients with inherited forms of kidney cancer who are in need of more effective therapies,” said David Russell, Ph.D., Vice Provost and Dean of Research, and Professor of Molecular Genetics, who collaborated in the early stages of the research.

The drug, once called PT2977, was developed based on a backbone discovered by UTSW researchers, with further drug development efforts conducted by a spinoff company named Peloton Therapeutics, which was launched on the UTSW campus and eventually acquired by Merck.

Drs. McKnight and Russell first identified HIF-2α in the 1990s.

HIF-2α was considered undruggable for many years until two more UTSW scientists at the time – Richard Bruick, Ph.D., Professor of Biochemistry, and Kevin Gardner, Ph.D., Professor of Biophysics, who also directs a structural biology center at the City University of New York – did the structural and biochemical work showing that the HIF-2α molecule contains a pocket that is potentially druggable. The two scientists then identified multiple compounds that fit into this pocket and inhibited the activity of HIF-2α.

“The history of belzutifan’s development demonstrates the value of cross-disciplinary collaborations at academic medical centers and how that can translate to new treatments for diseases,” said Dr. Russell. “It also underscores the value of investing in basic science discoveries at the core of advancements in medicine.”

In 2011, several researchers spun off Peloton Therapeutics, and by 2019, when Merck acquired the company, at least three HIF-2α agents were under investigation.

James Brugarolas, M.D., Ph.D., Director of the UTSW Kidney Cancer Program

James Brugarolas, M.D., Ph.D., Director of the Kidney Cancer Program at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, showed that the drug was effective against kidney cancer.

With funding from a prestigious National Cancer Institute SPORE award, they showed in a publication in Nature in 2016 that the drug was able to inhibit HIF-2α in human kidney tumors transplanted into mice and stop their growth.

This and other studies led to the first clinical trial of PT2385, a precursor to PT2977, which became belzutifan. The trial, which was led by the UTSW Kidney Cancer Program, showed that the drug was well-tolerated and active.

“The approval of belzutifan represents a new paradigm in the treatment of kidney cancer,” said Dr. Brugarolas, Professor of Internal Medicine. “By exclusively targeting HIF-2α, which is essential for kidney cancers but dispensable for normal processes, belzutifan specifically disables cancer cells while sparing normal cells. Belzutifan is the best-tolerated kidney cancer drug today and one suitable for patients with familial kidney cancer. It is a testament to the prowess of designer drugs and carefully chosen targets of which it is a prime example.”

TIMELINE: The Path to Developing a HIF-2α Inhibitor

1997
UT Southwestern biochemist Steven McKnight, Ph.D., and molecular geneticist David Russell, Ph.D., report the discovery of the HIF-2α gene, which they call EPAS1. The team shows that HIF-2α binds to another protein, HIF-1β. The HIF-2 partner functions like a pair of tweezers to grab DNA. HIF-2 binds DNA at specific places to initiate the production of other proteins such as VEGF, which support kidney cancer growth.

2003
The laboratories of Richard Bruick, Ph.D., and Kevin Gardner, Ph.D., uncover aspects of the atomic blueprint of HIF-2α. They show how HIF-2α docks with HIF-1β to assemble into a functional HIF-2 complex. They identify a cavity within the HIF-2α protein, hypothesizing that it may offer a foothold for a drug. Working with UT Southwestern’s High-Throughput Screening laboratory, Drs. Bruick and Gardner develop a test to identify chemicals among 200,000 drug-like molecules that bind to the HIF-2α cavity, preventing HIF-2α binding to HIF-1β. By interfering with HIF-2α binding to HIF-1β, these compounds block HIF-2 action. The most promising chemicals undergo a refinement process by medicinal chemists at UT Southwestern.

2010
Peloton Therapeutics is founded by UTSW researchers to develop the HIF-2α blocking chemicals into drugs. Peloton scientists create libraries of related compounds, ultimately identifying PT2385 and PT2977 to test in humans. A related drug, PT2399, is identified for laboratory work.

2016
Dr. James Brugarolas validates HIF-2α as a target in kidney cancer. In experiments incorporating more than 250 mice transplanted with human kidney tumors, researchers show that PT2399 blocks HIF-2α while not affecting related proteins, is active against 50% of human kidney tumors, and has more activity and is better tolerated than sunitinib (the most commonly used drug for renal cancer treatment at the time).

2018
Dr. Kevin Courtney reports the results of a phase 1 clinical trial testing PT2385 in humans. The trial represents the first-in-human study of a first-in-class inhibitor of HIF-2α. The trial, which involves 51 patients, shows that PT2385 is safe, well tolerated, and active against kidney cancer in humans. More than 50% of patients see their cancer regress or stabilize.

2019
U.S. drug manufacturer Merck acquires Peloton Therapeutics for $1.05 billion, with an additional $1.15 billion contingent on sales and regulatory milestones.

2020
Through studies of tumor biopsy samples from patients who participated in the Phase 1 clinical trial, Drs. Courtney, Brugarolas, and Ivan Pedrosa report the identification of drug resistance mutations in patients, establishing HIF-2α as the first-known core dependency of kidney cancer.

Dr. Brugarolas holds The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Dr. McKnight holds the Distinguished Chair in Basic Biomedical Research. Dr. Pedrosa holds the Jack Reynolds, M.D., Chair in Radiology. Dr. Russell holds the Eugene McDermott Distinguished Chair in Molecular Genetics. Disclosures: UT Southwestern and some of its researchers will receive financial compensation, through prior agreements with Peloton, based on belzutifan’s FDA approval.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

Source:

https://www.utsouthwestern.edu/newsroom/articles/year-2021/fda-approval-belzutifan.html

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August 20, 2021

Frontline Keytruda plus Lenvima for advanced renal cell carcinoma is an effective treatment with life-prolonging benefits, although patients should be monitored for side effects that can be easily managed.

• The FDA  approved a combination of Merck & Co. and Eisai drugs (Keytruda and Lenvima) that were shown in clinical testing to delay the progression of advanced kidney cancer and extend survival for patients when used as first-line therapy.
• Merck and Eisai view the combination as a way to give patients and doctors more weapons against cancer. Keytruda, an infusion, works by revving up the immune system. Lenvima, a capsule, works by targeting proteins on cancer cells that help tumors spread.

“It is a great time for the field of (renal cell carcinoma). What an honor and privilege to see these advances impacting the lives of patients. This combo did have though the longest (progression-free survival), and highest response rate and complete response rates as compared to other combinations, though not through a direct head-to-head comparison.” says Dr. Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston. “Keytruda plus Lenvima is another option,” Dr. Choueiri mentioned,

The latest approval was based on a three-arm study called CLEAR. which demonstrated a 61% reduced risk of disease progression or death in patients treated with the combination therapy. The regimen also contributed to a progression-free survival of 23.9 months compared with 9.3 months in patients treated with Sutent (sunitinib). The Keytruda-Lenvima group showed the biggest benefit. When compared with Sutent, the Keytruda-Lenvima combination treatment reduced the risk of death or disease progression by 61%. Patients on the two-drug therapy had a median of 23.9 months of progression-free survival, compared with 9.2 months for Sutent. Measured by overall survival, combination therapy reduced the risk of death by about a third compared to Sutent. Still, the drugs do have side effects. Adverse reactions caused 37% of patients in the Keytruda-Lenvima arm to stop taking one or both of the medications.

Merck won a priority review from the FDA for the drug combination based on benefits seen in the CLEAR study. At the time Merck inked its larger deal with Eisai in 2018, the combination had already received an FDA Breakthrough Therapy Designation for advanced kidney cancer, allowing the company to move faster through the development and review process.

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Recent findings based on the phase 1b COSMIC-021 trial in  Journal of Clinical Oncology demonstrated that treatment with the multikinase inhibitor cabozantinib (Cabometyx) plus the immune checkpoint inhibitor atezolizumab (Tecentriq) showed promising efficacy in patients with both clear cell (cc) and non–clear cell (ncc) renal cell carcinoma (RCC), according to findings from the phase 1b COSMIC-021 trial.¹ The combination reached an objective response rate (ORR) as high as 58% across two ccRCC cohorts and an ORR of 31% in patients with nccRCC.

“Cabozantinib plus atezolizumab demonstrated encouraging clinical activity in patients with advanced RCC regardless of histology. The safety profile with the combination was tolerable with dose modification and comparable to previous reports,” first author Sumanta K. Pal, clinical professor, Department of Medical Oncology & Therapeutics Research; co-director, Kidney Cancer Program, City of Hope, and coinvestigators wrote.

The multicenter, open-label phase 1b COSMIC-021 trial (NCT03170960) enrolled 102 patients with advanced RCC. Patients with ccRCC received atezolizumab plus either 40 mg (n = 34) or 60 mg (n = 36) of cabozantinib. Patients with nccRCC (n = 32) received atezolizumab plus 40 mg of cabozantinib.

In the 40-mg cabozantinib ccRCC group, the median age was 68 (range, 39-87), 79% of patients were male, and 71% were White. The ECOG performance status was 0 for 79% of patients and 1 for 21% of patients. Regarding IMDC risk, 21% were favorable, 76% were intermediate, and 3% were poor. Twenty-six percent of the cohort had a sarcomatoid component, which was significantly higher than the other 2 study arms. The PD-L1 status by CPS was ≥1 for 26% of patients, <1 for 44% of patients, and unknown for 29% of patients. Fifty-three percent of patients had ≥3 tumor sites. Metastatic sites included lung (79%), lymph node (47%), liver (15%), and bone (12%). One patient had received prior systemic anticancer therapy, 3 patients had prior radiotherapy, and 85% of patients had prior nephrectomy.

In the 60-mg cabozantinib ccRCC group, the median age was 60 (range, 42-82), 72% of patients were male, and 94% were White. The ECOG performance status was 0 for 69% of patients and 1 for 31% of patients. Regarding IMDC risk, 39% were favorable, 58% were intermediate, and 3% were poor. Six percent of the cohort had a sarcomatoid component. The PD-L1 status by CPS was ≥1 for 22% of patients, <1 for 50% of patients, and unknown for 28% of patients. Thirty-nine percent of patients had ≥3 tumor sites. Metastatic sites included lung (75%), lymph node (42%), liver (8%), and bone (11%). One patient had received prior systemic anticancer therapy, 4 patients had prior radiotherapy, and 89% of patients had prior nephrectomy.

In the nccRCC group, the median age was 62 (range, 37–78), 81% of patients were male, and 72% were White. The ECOG performance status was 0 for 75% of patients and 1 for 25% of patients. Regarding IMDC risk, 38% were favorable, 47% were intermediate, and 16% were poor. Thirteen percent of the cohort had a sarcomatoid component. Regarding histology subtype, 47% were papillary, 28% were chromophobe, and 22% were others. The PD-L1 status by CPS was ≥1 for 13% of patients, <1 for 56% of patients, and unknown for 31% of patients. Fifty-six percent of patients had ≥3 tumor sites. Metastatic sites included lung (50%), lymph node (59%), liver (16%), and bone (16%). Seven patients had received prior systemic anticancer therapy, 2 patients had prior radiotherapy, and 69% of patients had prior nephrectomy.

The median follow-up for the 40-mg ccRCC arm was 25.8 months and the ORR was 53%, including a complete response (CR) rate of 3%. The median progression-free survival (PFS) was 19.5 months. In the 60-mg ccRCC arm, the median follow-up was 15.3 months and the ORR was 58%, including an CR of 11%. The median PFS was 15.1 months. Among patients with nccRCC, the ORR was 31%, comprising all partial responses. The median PFS was 9.5 months.

Regarding safety, grade 3/4 treatment-related adverse events (TRAEs) occurred in 71% and 67% of patients in the 40-mg and 60-mg ccRCC groups, respectively. TRAE-related discontinuation of both drugs occurred in 15% and 6% of these 2 arms, respectively. In the nccRCC arm, 38% of patients had grade 3/4 TRAEs and TRAEs led to discontinuation of both drugs in 3% of patients. No treatment-related death occurred in the trial.

“These results support further evaluation of cabozantinib plus atezolizumab in patients with advanced RCC in the phase III trial setting, including those with non–clear cell histology. Patients with non–clear cell RCC have limited treatment options, and prospective data on tyrosine kinase inhibitor plus immune checkpoint inhibitor combinations are lacking for this population,” the authors wrote.

Reference

1. Pal SK, McGregor B, Suárez C, et al. Cabozantinib in combination with atezolizumab for advanced renal cell carcinoma: results from the COSMIC-021 study [published online ahead of print September 7, 2021]. J Clin Oncol. doi: 10.1200/JCO.21.00939

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August 16, 2021

FDA approves Merck’s Welireg for the treatment of adult patients with von Hippel-Lindau disease who require therapy for tumor growth.

FDA have approved the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan (Welireg, Merck) for the treatment of patients with some types of Von Hippel-Lindau (VHL) disease-associated tumors. The approval marks the first HIF-2α inhibitor therapy approved in the United States for some types of Von Hippel-Lindau disease-associated tumors.

FDA approval is based on results from the study 004 trial (NCT03401788), an open-label trial in 61 patients with VHL-associated RCC diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney.

The drug has been approved for adults with VHL disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery. It is the first HIF-2α inhibitor therapy approved in the United States, according to a press release from Merck.

VHL disease is estimated to occur in 1 of every 36,000 individuals. Patients with the disease are at risk for benign blood vessel tumors as well as some cancerous ones, such as RCC.

“VHL disease is a rare and serious condition,” said Eric Jonasch, MD, principal investigator of Study 004 and a professor at the University of Texas MD Anderson Cancer Center, in the press release. “Until today, there were no systemic therapies approved to help treat patients diagnosed with certain types of VHL-associated tumors.”

The approval was based on data from Study 004, an open-label trial of 61 patients with VHL-associated RCC and at least 1 measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors and the study excluded patients with metastatic disease. Participants received belzutifan 120 mg once daily until progression of disease or unacceptable toxicity.

According to the press release, the median duration of exposure to belzutifan was 68 weeks. In patients with VHL-associated RCC, belzutifan recipients had an overall response rate (ORR) of 49% and all responses were partial responses. The median duration of response had not yet been reached and among responders, 56% were still responding after at least 12 months. The median time to response was 8 months.

In patients with VHL-associated pancreatic neuroendocrine tumors, belzutifan showed an ORR of 83%, with a complete response rate of 17% and a partial response rate of 67%. The median duration of response had not yet been reached and among responders, 50% were still responding after at least 12 months. The median time to response was 8 months.

“Welireg is the first and only approved systemic therapy for patients with certain types of VHL-associated tumors, representing an important new treatment option for patients affected by this rare condition,” said Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, in the press release.

Serious adverse events (AEs) occurred in 15% of patients who received belzutifan and included anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion. Permanent discontinuation due to AEs occurred in 3.3% of patients and included dizziness and opioid overdose.

Furthermore, dosage interruptions due to an AE occurred in 39% of patients and included fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an AE occurred in 13% of patients and the most frequent reaction that required dose reduction was fatigue.

Finally, the most common AEs occurring in 25% or more of patients were hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).

“The approval of a non-surgical treatment option is meaningful for helping patients with certain types of VHL-associated tumors,” said Ramaprasad Srinivasan, MD, PhD, head of the molecular cancer therapeutics section of the Urologic Oncology Branch at the National Cancer Institute, in the press release. “The FDA’s approval of Welireg marks an important step forward by introducing a systemic therapy that has the potential to improve the current treatment paradigm for patients with certain types of VHL-associated tumors.”

REFERENCE

FDA Approves Merck’s Hypoxia-Inducible Factor-2 Alpha (HIF-2a) Inhibitor Welireg (belzutifan) for the Treatment of Patients With Certain Types of Von Hippel-Lindau (VHL) Disease-Associated Tumors. News release. Merck; August 13, 2021. Accessed August 16, 2021. https://www.merck.com/news/fda-approves-mercks-hypoxia-inducible-factor-2-alpha-hif-2%ce%b1-inhibitor-welireg-belzutifan-for-the-treatment-of-patients-with-certain-types-of-von-hippel-lindau-vhl-disease/

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