Robert A. Figlin, MD, 

Editor-in- Chief of the Kidney Cancer Journal.

These recommended abstracts from ESMO 2022 Annual meeting have been selected by Robert A. Figlin, MD, Editor-in- Chief of the Kidney Cancer Journal. The chosen abstracts provided here highlight some of the most important trends in ongoing trials and reflect the foremost research and strategies from latest clinical trials that impact the current standard of care in renal cancer.

Abstract Titles

ABSTRACT LBA8:

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ABSTRACT 14480:

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ABSTRACT 14470:

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ABSTRACT 1464P:

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ABSTRACT 1466P

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ABSTRACT 1450MO

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ABSTRACT 1677P

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ABSTRACT 1451MO

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ABSTRACT 1461P

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ABSTRACT 1453P

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The post ESMO’22 Recommended Abstracts in RENAL CANCERS first appeared on GUcancers.

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.

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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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REFERENCES

1. Campbell SC, Clark PE, Chang SS, Karam JA, Souter L, Uzzo RG. Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-Up: AUA Guideline: Part I. J Urol. 2021;206(2):199-208.

2. Apolo AB, Msaouel P, Niglio S, et al. Evolving Role of Adjuvant Systemic Therapy for Kidney and Urothelial Cancers. Am Soc Clin Oncol Educ Book. 2022;42:1-16.

3. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2018;379(5):417-427.

4. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021;385(8):683-694.

5. Gleeson JP, Motzer RJ, Lee CH. The current role for adjuvant and neoadjuvant therapy in renal cell cancer. Curr Opin Urol. 2019;29(6):636-642.

6. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab for postnephrectomy renal cell carcinoma (RCC): Expanded efficacy analyses from KEYNOTE-564. 2022;40(16_suppl):4512-4512.

7. Ryan CW, Tangen C, Heath EI, et al. EVEREST: Everolimus for renal cancer ensuing surgical therapy—A phase III study (SWOG S0931, NCT01120249). 2022;40(17_suppl):LBA4500-LBA4500.

8. McKay RR, Bosse D, Choueiri TK. Evolving Systemic Treatment Landscape for Patients With Advanced Renal Cell Carcinoma. J Clin Oncol. 2018:JCO2018790253.

9. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021;384(9):829-841.

10. Suárez C, Choueiri TK, Burotto M, et al. Association between depth of response (DepOR) and clinical outcomes: Exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER. 2022;40(16_suppl):4501-4501.

11. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290.

12. Cella D, Hamilton M, Blum SI, et al. The relationship between health-related quality of life (HRQoL) and clinical outcomes in patients with advanced renal cell carcinoma (aRCC) in CheckMate (CM) 214. 2022;40(16_suppl):4502-4502.

13. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127.

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.

Ochsner Precision Cancer Therapies Program and Ochsner Cancer Institute, Benson Cancer Center. New Orleans LA

Correspondence to: Marc R. Matrana. Ochsner Precision Cancer Therapies Program and Ochsner Cancer Institute 1514 Jefferson Highway, New Orleans LA – 70121. E-mail: MaMatrana@ochsner

ABSTRACT

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The post ASCO21 Meeting Summary – Kidney Cancer first appeared on GUcancers.

These recommended abstracts have been selected by Robert A. Figlin, MD, Editor-in- Chief of the Kidney Cancer Journal. The chosen abstracts provided here highlight some of the most important trends in ongoing trials and reflect the foremost research and strategies from latest clinical trials that impact the current standard of care in renal cancer.

ABSTRACT 4500:

ASCO Link – https://meetinglibrary.asco.org/record/195569/abstract

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426

Brian I. Rini, Elizabeth R. Plimack, Viktor Stus, Tom Waddell, Rustem Gafanov, Frédéric Pouliot, Dmitry Nosov, Bohuslav Melichar, Denis Soulieres, Delphine Borchiellini, Ihor O. Vynnychenko, Raymond S. McDermott, Sergio Jobim Azevedo, Satoshi Tamada, Anna Kryzhanivska, Chenxiang Li, Joseph E. Burgents, L. Rhoda Molife, Jens Bedke, Thomas Powles; Vanderbilt-Ingram Cancer Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro, Ukraine; The Christie NHS Foundation Trust, Manchester, United Kingdom; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; CHU of Québec and Laval University, Québec City, ON, Canada; Central Clinical Hospital With Outpatient Clinic, Moscow, Russian Federation; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada; Centre Antoine Lacassagne, Université Côte d’Azur, Nice, France; Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine; Adelaide and Meath Hospital and University College Dublin, Dublin, Ireland; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Osaka City University Hospital, Osaka, Japan; Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine; Merck & Co., Inc., Kenilworth, NJ; MSD UK, London, United Kingdom; Eberhard Karls Universität Tübingen, Tübingen, Germany; Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom

Background: In the first interim analysis of the randomized, multicenter, open-label, phase 3 KEYNOTE-426 study (NCT02853331), treatment with pembro + axi significantly improved OS, PFS, and ORR vs sunitinib monotherapy in treatment-naive advanced ccRCC. Extended follow-up (median, 30.6 mo) continued to demonstrate the superior efficacy of pembro + axi vs sunitinib monotherapy in this patient population. Here, we present the results of the prespecified final analysis with 42.8-mo median follow-up.

Methods: Treatment-naive patients (pts) with advanced ccRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, intolerable toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs Rest of World). Dual primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR, and safety. The protocol-specified final analysis was based on a target of 404 OS events. No formal hypothesis testing was performed because all efficacy endpoints were met previously at the first interim analysis; nominal P values are reported.

Results: Overall, 861 pts were randomly assigned to receive pembro + axi (n=432) or sunitinib (n=429). Median duration of follow-up, defined as time from randomization to the database cutoff date, was 42.8 mo (range, 35.6-50.6). At data cutoff, 418 pts had died: 193 (44.7%) of 432 pts in the pembro + axi arm vs 225 (52.4%) of 429 pts in the sunitinib arm. Compared with sunitinib, pembro + axi improved OS (median: 45.7 vs 40.1 mo; HR, 0.73 [95% CI, 0.60-0.88]; P<0.001) and PFS (median: 15.7 vs 11.1 mo; HR, 0.68 [95% CI, 0.58-0.80]; P<0.0001). The 42-mo OS rate was 57.5% with pembro + axi vs 48.5% with sunitinib; the 42-mo PFS rate was 25.1% with pembro + axi vs 10.6% with sunitinib. For pembro + axi vs sunitinib, ORR was 60.4% vs 39.6% (P<0.0001); CR rate was 10.0% vs 3.5%; median DOR was 23.6 mo (range 1.4+ to 43.4+) vs 15.3 mo (range, 2.3-42.8+). Subsequent anticancer therapy was administered to 47.2% of pts in pembro + axi arm vs 65.5% of pts in sunitinib arm. Although a similar proportion of pts in each arm received VEGF/VEGFR inhibitors, only 10.2% of pts in the pembro + axi arm received subsequent treatment with a PD-1/L1 inhibitor compared to 48.7% of pts in the sunitinib arm. No new safety signals were observed. Conclusions: With a median follow-up of 42.8 mo, this is the longest follow-up of an anti-PD–1/L1 immunotherapy combined with a VEGF/VEGFR inhibitor for first-line RCC. These results show that pembro + axi continues to demonstrate superior efficacy over sunitinib with respect to OS, PFS, and ORR, with no new safety signals.

Clinical trial information: NCT02853331

Research Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA  

ABSTRACT 4501 :

ASCO Link – https://meetinglibrary.asco.org/record/195568/abstract

CANTATA: Primary analysis of a global, randomized, placebo (Pbo)-controlled, double-blind trial of telaglenastat (CB-839) + cabozantinib versus Pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mRCC) patients (pts) who progressed on immune checkpoint inhibitor (ICI) or anti-angiogenic therapies.

Nizar M. Tannir, Neeraj Agarwal, Camillo Porta, Nicola Jane Lawrence, Robert J. Motzer, Richard J. Lee, Rohit K. Jain, Nancy B. Davis, Leonard Joseph Appleman, Oscar B. Goodman, Walter Michael Stadler, Sunil G. Gandhi, Daniel M. Geynisman, Roberto Iacovelli, Begona Mellado, Robert A. Figlin, Thomas Powles, Lalith V Akella, Keith W. Orford, Bernard Escudier; The University of Texas MD Anderson Cancer Center, Houston, TX; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; University of Bari ‘A. Moro’ and Policlinico Consorziale di Bari, Bari, Italy; Auckland City Hospital, Auckland, New Zealand; Memorial Sloan Kettering Cancer Center, New York, NY; Massachusetts General Hospital, Boston, MA; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Pittsburgh Medical Center, Pittsburgh, PA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; The University of Chicago, Chicago, IL; Florida Cancer Specialists, Lecanto, FL; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Hospital Clínic, Provincial de Barcelona, Barcelona, Spain; Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; St Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom; Calithera Biosciences, Inc., South San Francisco, CA; Gustave Roussy, Villejuif, France

Background:Dysregulated metabolism is a hallmark of RCC, driven by overexpression of glutaminase (GLS), a key enzyme of glutamine metabolism. Telaglenastat (Tela) is an investigational, first-in-class, selective, oral GLS inhibitor that blocks glutamine utilization and critical downstream pathways. Preclinically, Tela synergized w/ cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, against RCC tumors. In a Ph 1 study cohort, Tela+Cabo showed encouraging safety/efficacy as 2L+ therapy for mRCC. This trial compared Tela+Cabo vs Pbo+Cabo in previously treated pts w/ clear-cell mRCC (NCT03428217).

Methods: Eligible pts had 1-2 prior lines of systemic therapy for mRCC, including ≥1 anti-angiogenic therapy or nivolumab + ipilimumab (nivo/ipi), KPS ≥70%, measurable disease (RECIST 1.1), no prior Cabo or other MET inhibitor. Pts were randomized 1:1 to receive Cabo (60 mg PO QD) with either Tela (800 mg PO BID) or Pbo, until disease progression/unacceptable toxicity, and were stratified by prior PD-(L)1 inhibitor therapy (Y/N) and IMDC prognostic risk group. Primary endpoint was progression-free survival (PFS; RECIST 1.1) by blinded independent radiology review. The study was designed to detect a PFS hazard ratio (HR) of 0.69 w/ alpha 0.05 and 85% power. Data cutoff date: August 31, 2020.

Results: 444 pts were randomized (221 Tela+Cabo; 223 Pbo+Cabo). Baseline characteristics were balanced between arms. Median follow-up was 11.7 mo; 276 pts received prior ICI, including 128 w/ prior nivo/ipi. Median PFS (mPFS) was 9.2 mo for Tela+Cabo vs 9.3 mo for Pbo+Cabo (HR = 0.94; 95% CI: 0.74, 1.21; stratified log-rank P= 0.65) with overall response rates (ORR; confirmed) of 31% with Tela+Cabo vs 28% Pbo+Cabo, respectively. Overall survival was not mature at data cutoff. In a prespecified subgroup analysis in pts w/ prior ICI, mPFS was numerically longer w/ Tela+Cabo than Pbo+Cabo (11.1 vs 9.2 mo, respectively; unstratified HR = 0.77; 95% CI: 0.56, 1.06). In the Pbo+Cabo arm, mPFS was 9.2 mo for pts w/ prior ICI exposure and 9.5 mo for pts without, and ORR was 32% and 20%, respectively; if ICI included nivo/ipi, ORR was 37%. Rates of adverse events (AEs) were similar between arms.Grade 3-4 AEs occurred in 71% of Tela+Cabo pts and 79% of Pbo+Cabo pts and included hypertension (17% vs 18%) and diarrhea (15% vs 13%). Cabo was discontinued due to AEs in 10% of Tela+Cabo pts and 15% of Pbo+Cabo pts.

Conclusions: The addition of Tela did not improve the efficacy of Cabo in mRCC in this study. Tela+Cabo was well tolerated with AEs consistent with known risks of both agents. The study provides valuable insight on efficacy outcomes of a contemporary population of pts w/ mRCC who receive Cabo in the 2/3L setting.

Clinical trial information: NCT03428217

Research Funding: Calithera Biosciences, Inc

LATE BREAKTHROUGH ABSTRACT LBA 5 :

ASCO Link – https://meetinglibrary.asco.org/record/196683/abstract

Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study.

Toni K. Choueiri, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Tom Ferguson, Yen-Hwa Chang, Jaroslav Hajek, Stefan N. Symeonides, Jae-Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Mauricio Mahave, Naomi B. Haas, Piotr Sawrycki, Eric (Pingye) Zhang, Jaqueline Willemann Rogerio, Kentaro Imai, David I. Quinn, Thomas Powles; Dana-Farber Cancer Institute, Boston, MA; Szpital Kliniczny Przemienienia Pańskiego UM, Poznan, Poland; Division of Hematology-Oncology, Samsung Medical Center, Department of Medicine, Seoul, South Korea; University of Glasgow, Glasgow, United Kingdom; Royal Perth Hospital, Perth, Australia; Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan; Fakultni Nemocnice Ostrava, Ostrava, Czech Republic; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Imperial College Healthcare NHS Trust, London, United Kingdom; University Hospital Jean Minjoz, Besançon, France; Centre Hospitalier Universitaire de Bordeaux-Hôpital Saint-André, Bordeaux, France; Lopez Perez Foundation, Santiago, Chile; Abramson Cancer Center, University of Pennsylvania (ECOG-ACRIN), Philadelphia, PA; Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu, Torun, Poland; Merck & Co., Inc., Kenilworth, NJ; USC Norris Cancer Hospital, Los Angeles, CA; Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust,, London, United Kingdom

Background:Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC.

Methods: KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts.

Results: Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred.

Conclusions: Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting.

Clinical trial information: NCT03142334

Research Funding: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

ABSTRACT 4502 :

ASCO Link -https://meetinglibrary.asco.org/record/196538/abstract

Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC).

Robert J. Motzer, Camillo Porta, Boris Alekseev, Sun Young Rha, Toni K. Choueiri, Maria Jose Mendez-Vidal, Sung-Hoo Hong, Anil Kapoor, Jeffrey C. Goh, Masatoshi Eto, Jinyi Wang, Janice Pan, Alemseged Ayele Asfaw, Cixin Steven He, Kalgi Mody, David Cella; Memorial Sloan Kettering Cancer Center, New York, NY; San Matteo University Hospital Foundation, Pavia, Italy; P.A. Herzen Moscow Oncological Research Institute, Moscow, Russian Federation; Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea; Dana-Farber Cancer Institute, Boston, MA; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain; Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea; McMaster University Hamilton, Hamilton, ON, Canada; ICON Research, South Brisbane & University of Queensland, St Lucia, QLD, Australia; Kyushu University, Fukuoka, Japan; RTI Health Solutions, Research Triangle Park, NC; Eisai Inc., Woodcliff Lake, NJ; Merck & Co., Inc., Kenilworth, NJ; Northwestern University, Chicago, IL

Background:LEN + PEMBRO improved PFS, OS and ORR vs SUN in the first-line treatment of pts with aRCC; LEN + EVE improved PFS and ORR vs SUN (Motzer R et al. NEJM. 2021). We report results of a secondary objective of the CLEAR trial comparing the impact of LEN + PEMBRO or EVE vs SUN, on HRQoL.

Methods: Pts (N=1069) were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 wks on/2 wks off). HRQoL was assessed per FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L, at baseline, on day 1 of subsequent 3 wk cycles starting with cycle 2, and at the off-treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized pts with any HRQoL data who received ≥1 dose of study treatment. No adjustments for multiple testing or estimation were used; P-values and CIs are nominal and descriptive.

Results: For comparisons of LEN + PEMBRO vs SUN, overall changes from baseline at mean follow-up (wk 46) favored LEN + PEMBRO with significant differences between treatments for physical functioning (least squares mean difference [LS MD] [95% CI]: 3.0 [0.5, 5.5]) and fatigue (−2.8 [−5.5, −0.1]), dyspnea (−2.8 [−5.3, −0.3]), and constipation (−2.2 [−4.2, −0.2]). LS MD of the FKSI-DRS total score was 0.2 (−0.4, 0.7). For comparisons of LEN + EVE vs SUN, overall changes from baseline at wk 46 favored SUN with significant differences in overall HRQoL (−2.8 [−5.1, −0.5] assessed by the EORTC QLQ-C30 GHS/QoL scale) and pain (2.8 [0.1, 5.5]), appetite loss (4.2 [1.3, 7.1]), and diarrhea (5.3 [2.6, 7.9]). LS MD of the FKSI-DRS total score was −0.4 (−1.0, 0.2). 14 of 18 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in LS MD comparisons. The LEN + PEMBRO arm is favored over SUN for the median time to first deterioration (TTD) for physical functioning, dyspnea, appetite loss and EQ-5D VAS (Table). 15 of 19 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in TTD comparisons.

Conclusions: Compared with SUN, pts in LEN + PEMBRO group had similar or better symptoms and HRQoL.

Clinical trial information: NCT02811861

Research Funding: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

ABSTRACT 4509 :

ASCO Link – https://meetinglibrary.asco.org/record/195580/abstract

Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.

Chung-Han Lee, Martin H Voss, Maria Isabel Carlo, Ying-Bei Chen, Eduard Reznik, Andrea Knezevic, Robert A Lefkowitz, Natalie Shapnik, Diana Tassone, Chloe Dadoun, Neil J. Shah, Colette Ngozi Owens, Deaglan Joseph McHugh, David Henry Aggen, Andrew Leonard Laccetti, Ritesh Kotecha, Darren R. Feldman, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; Columbia University Medical Center, New York, NY; MD Anderson Cancer Center, Houston, TX

Background:Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC.

Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented.

Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively.

Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited.

Clinical trial information: NCT03635892

Research Funding: Exelixis, BMS

ABSTRACT 4555 :

ASCO Link – https://meetinglibrary.asco.org/record/197609/abstract

Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC).

Ramaprasad Srinivasan, Frede Donskov, Othon Iliopoulos, Wendy Kimryn Rathmell, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Sarah Joanne Welsh, Ananya Roy, Yanfang Liu, Rodolfo F. Perini, W. Marston Linehan, Eric Jonasch; Center for Cancer Research, National Cancer Institute, Bethesda, MD; Aarhus University Hospital, Aarhus, Denmark; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Pennsylvania, Philadelphia, PA; University of Utah, Salt Lake City, UT; Hôpital Européen Georges Pompidou, Paris, France; University of Michigan, Ann Arbor, MI; University of Pittsburgh, Pittsburgh, PA; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Merck & Co., Inc., Kenilworth, NJ; The University of Texas MD Anderson Cancer Center, Houston, TX

Background:Inactivation of VHL leads to aberrant stabilization and accumulation of HIF-2α, which drives tumor growth. Patients (pts) with VHL disease are at risk for ccRCC, pancreatic neuroendocrine tumors (pNETs), and hemangioblastomas. Repeated surgeries are often needed to control ccRCC and other VHL disease manifestations. Prior results of this ongoing open-label phase 2 study (NCT03401788) showed activity with belzutifan in VHL disease. Updated results are presented.

Methods: Adults with germline VHL alterations, measurable and localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS 0 or 1 received belzutifan 120 mg once daily until progression, intolerable toxicity, or decision to withdraw. The primary end point is ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points include DOR, time to response (TTR), PFS, and safety

Results: As of June 1, 2020, 61 pts enrolled. Most pts (82%) had ECOG PS 0, and the median number of prior tumor reduction procedures (eg, partial nephrectomy, craniotomy, radiation therapy) per pt was 5 (range, 0-15). Lesions outside the kidney (non-RCC tumors) evaluable by IRC included pNETs (33%) and CNS hemangioblastomas (82%). Median follow-up was 69 wk (range, 18-105), median duration of treatment was 68 wk (range, 8-105), and 56 pts (92%) remain on therapy. There were 22 confirmed responses (ORR, 36% [95% CI, 24-49]) and 7 (11%) unconfirmed responses (documented at 1 time point, to be confirmed at subsequent time point); all were PRs. In pts with confirmed PR, median DOR was not reached (range, 12+ to 62+ wk), median TTR was 31 wk (range, 12-61), and 56 pts (92%) had some reduction in the sum of all target lesion diameters. PFS rate at 52 wk was 98% (95% CI, 89-100). For non-RCC tumors, ORR was 80% (16/20; 1 CR) in pNETs and 32% (16/50; 1 CR) in CNS hemangioblastomas. Of 16 pts with evaluable retinal hemangioblastomas at baseline, 11 (69%) showed improvement per IRC. In those 16 pts, 29 eyes were monitored for retinal hemangioblastomas: 16 eyes (55%) showed improvement, 12 (41%) were stable, and no evaluation was available for 1 eye (3%). All 61 pts (100%) had at least one AE. The most common all-cause AE was anemia (90%), which is considered an on-target toxicity. Treatment-related AEs (TRAE) were reported by 60 pts (98%), and 8 pts (13%) had a grade 3 TRAE. No pts had grade 4/5 TRAEs. One pt discontinued treatment because of a TRAE (grade 1 dizziness).

Conclusions: Belzutifan demonstrates clinical benefit and has a favorable safety profile in patients with VHL disease–associated ccRCC, pNETs, and hemangioblastomas.

Clinical trial information: NCT03401788

Research Funding: Research Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA  

ABSTRACT 4562:

ASCO Link – https://meetinglibrary.asco.org/record/197543/abstract

Post hoc analysis of the CLEAR study in advanced renal cell carcinoma (RCC): Effect of subsequent therapy on survival outcomes in the lenvatinib (LEN) + everolimus (EVE) versus sunitinib (SUN) treatment arms.

Thomas E. Hutson, Toni K. Choueiri, Robert J. Motzer, Sun Young Rha, Anna Alyasova, Jaime R. Merchan, Howard Gurney, Avivit Peer, Toshio Takagi, Camillo Porta, Thomas Powles, Viktor Grünwald, Ugo De Giorgi, Ulka N. Vaishampayan, Manuela Schmidinger, Hilary Glen, Karla Rodriguez-Lopez, Dongyuan Xing, Lea Dutta, Masatoshi Eto; Texas Oncology, Dallas, TX; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea; Prevoljskiy Region Medical Centre, Novgorod, Russian Federation; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; Macquarie University Hospital, Sydney, NSW, Australia; Rambam Health Care Campus, Haifa, Israel; Tokyo Women’s Medical University, Tokyo, Japan; San Matteo University Hospital Foundation, Pavia, Italy; The Royal Free NHS Trust, London, United Kingdom; University Hospital Essen, Essen, Germany; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; University of Michigan, Ann Arbor, MI; Medical University of Vienna, Vienna, Austria; Beatson West of Scotland Cancer Center, Glasgow, United Kingdom; Merck & Co., Inc., Kenilworth, NJ; Eisai Inc., Woodcliff Lake, NJ; Kyushu University, Fukuoka, Japan

Background:The multicenter, open-label, randomized, phase 3 CLEAR study showed that LEN + EVE had a significant PFS benefit (HR 0.65, 95% CI 0.53-0.80, P<0.001) and improved objective response rate (relative risk 1.48, 95% CI 1.26-1.74) vs SUN in the first-line treatment of patients (pts) with advanced RCC. The difference in overall survival (OS) for LEN + EVE vs SUN was not statistically significant (HR 1.15, 95% CI 0.88-1.50) (Motzer R et al. NEJM. 2021). Post hoc subgroup analyses were performed to assess the impact of subsequent therapy on OS.

Methods:Pts in the CLEAR study were randomly assigned (1:1:1) to 1 of 3 treatment arms, including LEN 18 mg + EVE 5 mg once daily (QD) and SUN 50 mg QD (4 weeks on then 2 weeks off). These post hoc analyses examined OS by subsequent systemic anticancer medication in the LEN + EVE and SUN arms. Hazard ratios (HR; LEN + EVE vs SUN) were based on stratified (geographic region and MSKCC prognostic risk groups) Cox proportional hazards model.

Results:Among 1069 pts with advanced RCC randomized in the CLEAR study, 714 pts were randomly assigned to the LEN + EVE and SUN arms (N=357/each). The median duration of survival follow-up was 27 months in the LEN + EVE arm and 26 months in the SUN arm. Given the shorter median duration of study treatment with SUN (7.8 months) vs LEN + EVE (11.0 months), more pts in the SUN arm received subsequent anticancer therapy during survival follow-up (LEN + EVE, n=167; SUN, n=206). Among pts who received subsequent therapy, pts in the LEN + EVE arm had a longer median time from randomization to initiation of subsequent therapy vs those in the SUN arm (8.0 vs 6.6 months, respectively). OS for the overall population, for pts with no subsequent anticancer therapy, and for pts with no subsequent immunotherapy is shown in the table. In the US population subgroup (LEN + EVE, n=62; SUN, n=61) of the CLEAR study, in which a similar number of pts received subsequent systemic anticancer therapies in the LEN + EVE vs SUN arms (62.9% vs 65.6%, respectively), OS was comparable among the 2 arms (HR 0.95, 95% CI 0.51-1.76). Overall, the safety profile was consistent with the known safety profiles of LEN + EVE and SUN. In both arms, most treatment-emergent deaths were due to progressive disease; there were few treatment-related deaths (<1%, per arm) and no clustering of events.

Conclusions:In the CLEAR study, LEN + EVE met the primary endpoint of a significant benefit in PFS vs SUN. The results of these exploratory analyses suggest that subsequent systemic anticancer therapy affected the OS outcome results for LEN + EVE vs SUN in the CLEAR study. Clinical trial information: NCT02811861

Clinical trial information:NCT02811861

Research Funding: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA  

ABSTRACT 4578:

ASCO Link – https://meetinglibrary.asco.org/record/197514/abstract

Efficacy outcomes of nivolumab + cabozantinib versus pembrolizumab + axitinib in patients with advanced renal cell carcinoma (aRCC): Matching-adjusted indirect comparison (MAIC).

Bradley Alexander McGregor, Daniel M. Geynisman, Mauricio Burotto, Camillo Porta, Cristina Suarez Rodriguez, Maria Teresa Bourlon, Pedro C. Barata, Shuchi Gulati, Brian Stwalley, Viviana Del Tejo, Ella X. Du, Aozhou Wu, Andi Chin, Keith A. Betts, Stephen Huo, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA; Bradford Hill Clinical Research Center, Santiago, Chile; University of Bari ‘A. Moro’ and Policlinico Consorziale di Bari, Bari, Italy; Medical Oncology, Vall d´Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d´Hebron, Vall d´Hebron Barcelona Hospital Campus, Barcelona, Spain; Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, DF, Mexico; Tulane Cancer Center, New Orleans, LA; University of Cincinnati Medical Center, Cincinnati, OH; Bristol Myers Squibb, Princeton, NJ; Analysis Group, Inc, Los Angeles, CA; Analysis Group, Inc., Los Angeles, CA; Analysis Group, New York, NY; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background:Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC.

Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor.

Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940).

Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.

Research Funding: BMS

Newly Approved Drug Section

ABSTRACT 4567:

ASCO Link – https://meetinglibrary.asco.org/record/197591/abstract

Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.

Sumanta K. Pal, David F. McDermott, Bernard Escudier, Thomas E. Hutson, Camillo Porta, Elena Verzoni, Michael B. Atkins, Michael N. Needle, Brian I. Rini; Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Gustave Roussy, Villejuif, France; Texas A&M College of Medicine, Bryan, TX; University of Bari ‘A. Moro’ and Policlinico Consorziale di Bari, Bari, Italy; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Aveo Oncology, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN

Background:The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience.

Methods:Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm.

Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR.

Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR.

Research Funding: AVEO Oncology

Clinical trial information: NCT02627963.

This material on this page is ©2021 American Society of Clinical Oncology, all rights reserved. For more information, please contact licensing@asco.org. 

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Robert A Figlin, MD

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

The COVID-19 pandemic has exposed fundamental disparities in the provision of health care across our nation and exacerbated the differences in health outcomes associated with race, socioeconomic and other demographic factors. A silver lining however is that pandemic precarity has inspired tremendous scientific collaboration among clinicians, researchers, and key opinion leaders. In this line, this year’s Annual Meeting of the American Society of Clinical Oncology (ASCO21) which was kicked off virtually on June 4 through June 8, not only celebrated latest breakthroughs in cancer research, treatment and patient care, but also focused on health equity in cancer care. ASCO21’s fitting theme – Health equity “doing right by the patients for whom we care” reflected addressing complex forces and systems that have created disparities in cancer care, treatment, and research and identifying ways to ensure that all patients have access to and benefit from the latest cancer advances and high-quality cancer care.Let’s recap the key developments from some of the highest-profile clinical trials presented in the ASCO21 conference.

The results from KEYNOTE-564 trial presented during plenary session of ASCO21 have demonstrated that post-surgery treatment with pembrolizumab extends DFS for clear cell renal cell carcinoma (RCC) patients. This is the first phase III study based on adjuvant immunotherapy to demonstrate an improvement in DFS with a favorable safety profile as compared to S-TRAC and sunitinib. KEYNOTE- 564’s findings support adjuvant pembrolizumab as a potential new standard of care to reduce disease recurrence in patients with fully resected intermediate to high-risk RCC. However, further works remains to be seen especially confirmation of an overall survival benefit, usability in other RCC histologies, and the implications regarding treatment choices in advanced RCC. Additionally the trial included M1 patients post treatment of the oligometastatic disease. This is not a usual cohort of patinets included in classical adjuvant trials and may affect the DFS reported. Currently, there are four IO combinations available for the first-line treatment of metastatic RCC viz. nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, and nivolumab plus cabozantinib.

The latest outcome of CLEAR trial adding lenvatinib plus pembrolizumab combination to the growing armamentarium of first-line treatments for RCC patients. CLEAR met its primary endpoint, with lenvatinib plus pembrolizumab significantly improving progressionfree survival compared to sunitinib. This combination also achieved favorable objective response rate compared to sunitinib with an impressive complete response rate. Lenvatinib + everolimus combination resulted in similar or worse HRQoL and symptom scores compared with patients treated with sunitinib. The additional data builds on previous findings of a phase 3 KEYNOTE-581 trial has shown (Abstract 4502); PD-1 inhibitor pembrolizumab plus lenvatinib improved outcomes versus sutent on a measure of health-related quality of life in first-line renal cell carcinoma (RCC). The additional data showed an improvement of specific health-related quality of life measures including favorable disease-related symptoms scores, as well as better HRQoL and disease-related symptoms scores for physical functioning, fatigue, dyspnea and constipation versus sutent.

Results from KEYNOTE-426’s prespecified final analysis with a 42.8-month median follow-up and a 35.6-month minimum follow-up show that pembrolizumab + axitinib continues to demonstrate superior efficacy over sunitinib with respect to OS, PFS, and objective response rate. KEYNOTE-426 represents the longest follow-up of an anti- PD–1/L1 immunotherapy combined with a VEGF/VEGFR inhibitor for first line RCC and indicate pembrolizumab + axitinib as standard of care for patients with previously untreated advanced clear cell RCC.

Results from CANTATA study shows that the addition of telaglenastat did not improve the efficacy of cabozantinib in mRCC as there was no significant difference in PFS between the arms. While the addition of telaglenastat did not improve outcomes with cabozantinib in this unselected population of patients with clear cell RCC, future studies are warranted to determine the impact of glutaminase inhibition in biomarker-selected patient populations with high dependence on glutamine/ glutaminase, and in combination with other therapeutic partners. A study involving Cabozantinib plus nivolumab (CaboNivo) combination showed that CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited.

Latest results from phase 2 study of belzutifan (MK-6482) shown clinical benefit and has a favorable safety profile in patients with VHL disease–associated ccRCC, pNETs, and hemangioblastomas.. In the phase 3 CheckMate (CM) 9ER trial, Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC.In this issue, an exclusive roundtable discussion which I have moderated, participated by three distinguished kidney cancer and genitourinary investigators from across the country focusing on the current challenges in cancer trials post COVID-19 pandemic.

These renowned experts also brainstormed various important topics including cancer therapy delivery in the COVID-19 era, telemedicine, new COVID-19 guidelines, evolving clinical trial design, vaccination efforts in cancer patients, adverse events associated with vaccination, and other newly developed measures and recommendations to manage COVID-19 issues in the provision of cancer care.

Access the Full Roundtable Transcript here.

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