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.

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/

The post US FDA Approves Belzutifan for Tumors Associated With Certain Types of Von Hippel-Lindau Disease 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.

Robert J. Motzer, MD¹, Eric A. Jonasch, MD²,Bradley A. McGregor, MD³, Robert A. Figlin, MD, FACP⁴

1 Memorial Sloan Kettering Cancer Center (MSKCC), Weill Cornell Medical College in New York, New York;

2 Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center;

3 Lank Center for Genitourinary Oncology at Dana Farber Cancer Institute, Harvard Medical School, Boston MA

4 Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles, CACorrespondence to:

ABSTRACT

In this roundtable discussion, nation’s leading cancer experts from across the country share their perspectives on current changes, challenges and opportunities for delivering cancer care during the COVID-19 era. The roundtable panel examines long-term implications of the pandemic on the management and treatment of cancer especially focusing on significant issues in patient safety, toxicities associated with the use of immunotherapy, COVID-19 vaccination, and clinical trial designs. In this discussion, experts also brainstorm a range of recommendations focusing especially on how the cancer community can capitalize on lessons learned from the pandemic to develop creative approaches that can be taken forward.

Roundtable video

Webinar Transcript

INTRODUCTION

The COVID-19 pandemic has caused unprecedented disruption across the spectrum of cancer care services, including cancer diagnosis, screening, clinical trials, and therapeutic management^{1- 7}. Since the COVID-19 outbreak, substantial decrease in launching new cancer trials or discontinuation of existing trials disrupted the pace of clinical research and new drug discovery with long-term negative consequences for cancer care^2-5. At the outset of the ongoing COVID-19 crisis, the cancer community is adapting to the substantial challenges that the pandemic continues to pose^7,8. The lessons learned by the cancer community in the wake of the COVID-19 pandemic offers an opportunity to reflect on the significant issues for delivering optimal cancer care and cancer treatment^9-11. Interestingly, this outbreak has stimulated innovative approaches in cancer care in an unprecedented way¹². Here, our distinguished panelists shared a year’s worth of lessons that could be used to redesign the delivery of a high standard cancer care and the conduct of cancer clinical trials. The objective of this roundtable program is to gain insights into newly developed measures and recommendations for the cancer community to overcome the long-term impact of the outbreak.

Roundtable questions were distributed to panelists a week before the roundtable session, and the discussion was video recorded and transcribed. The following is a transcript of the roundtable edited for clarity.

Dr. Figlin:         

This is the Kidney Cancer Journey roundtable focusing on challenges and opportunities in the cancer clinical trials in the COVID-19 era. The purpose of today’s roundtable is to gain your insights into how we are all thinking about delivering GU cancer care during the post COVID-19 pandemic world. I am Robert A. Figlin, Editorin- Chief of the Kidney Cancer Journal and the Spielberg family chair at Cedars Sinai Center in Los Angeles. I am really very happy to be joined by three distinguished kidney cancer and GU investigators from across the country. Joining me today are my colleagues Dr. Robert Motzer, the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center (MSKCC) and Professor of Medicine at Weill Cornell Medical College in New York, Head of the Genitourinary Oncology Service. Dr. Eric Jonasch, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, Director, VHL Clinical Center, MD Anderson Cancer Center and Co-Chair, Renal Cancer Program, MD Anderson Cancer Center and Dr. Bradley McGregor, Clinical director for the Lank Center for Genitourinary Oncology at Dana Farber Cancer Institute, Professor of Medicine, Harvard Medical School. Gentlemen, thank you for taking time out of your busy schedules to join us today.

Bob, let me start out with you. Can you share your view on the role of delivering immunotherapy to kidney cancer patient population in the COVID-19 era?

Dr. Motzer:

         The COVID-19 pandemic really impacted our practice in many different ways. For one, this pandemic made it difficult for patients to access cancer care and to evaluate patients in our cancer center in Manhattan. This pandemic also made it difficult for healthcare providers to deliver timely cancer therapy to RCC patients. In terms of access to care, patients were screened coming into our clinic and patients were also concerned about coming into Manhattan with the COVID-19 and many times patients would postpone the standard follow-up tests or put them on hold. In return for that, we boosted our remote medical care using videos and so forth. Remote healthcare has been a real challenge. Because it is really new to us and for the most part we have all been practicing hands-on in-person visits. It really forced us to become familiar with these technical aspects. It is also been a challenge in terms of managing people with metastatic kidney cancer who are on therapies. Because for the most part in the past, you gain so much from seeing somebody in the clinic and talking to them and getting their blood work done rather than speaking with them virtually and not having the comfort level of actually seeing them in person. It also influenced the very close doctor-patient relationship which is very important for a medical oncologist. This pandemic basically put a barrier on that relationship. It also made it difficult for clinical trials. I think that the number of patients going into clinical trials decreased during the pandemic. Patients did not want to come into centers to get into clinical trials as there was more of a concern about experimental medicines and their side effects and also about the impact of the COVID-19 infection. It also made it much more difficult to assess patients from a safety standpoint, because a lot of our safety assessments were compromised by the lack of ability for patients to come and get evaluated. I think it also impacted our treatment to a certain extent for many patients. With the uncertainty around the pandemic and the uncertainty around immunosuppression with the use of steroids, our decision was influenced in terms of when to start patients on systemic therapy or delay it. So it was really an extreme challenge to manage our population of patients with metastatic kidney cancer during the pandemic.

Dr. Figlin:

         Bob, that is a great summary. The bigger question is to Eric at MD Anderson Cancer Center in Houston, should we as an organization establish some more coherent guidelines on how to think about our post-pandemic kidney cancer treatments? What are your thoughts about that?⁴.

Dr. Jonasch:

         Yes, so a couple of things here Bob. First of all, the current guidelines that have been developed by ASCO and ESMO with regards to the general management of immunotherapies are excellent. We can certainly use them as guideposts on how to treat people with immunotherapy, and how to manage immunotherapy related side effects. Layering in then the specter of COVID-19, number one, what happens to an individual who is on immunotherapy who then gets the COVID-19 infection? How does that affect how we treat that individual? Unfortunately, a number of my patients have been infected with COVID-19 while they have been on active checkpoint antibody therapy. It is difficult to see on an individual or an anecdotal level whether or not they have suffered more. Some data suggests that COVID-19 outcomes in cancer patients are worse than people who are without cancer with COVID-19. So I think it is probably impacted them to some degree. As we then assess these individuals from a response perspective, the next question really would be – does the new lymphadenopathy we see on scans correlate with the recent COVID-19 infection or COVID-19? The answer is possibly yes. While you are looking at an individual who has COVID-19, who has pulmonary metastasis, who has inflammatory changes, you would do a RECIST assessment on that person. If patients are on a clinical trial, it certainly creates additional challenges, but not insurmountable ones. I think the last question really is, with the vaccines that are coming out, should we now not vaccinate individuals because of its potential risk? The data has been a little mixed. But there has been a recent paper that came out in the Lancet Oncology by Waissengrin et al, suggesting that the toxicities associated with IO therapy as a function of treatment after vaccination are not dramatically different. And so when my patients asked me, should they get vaccinated? I say, from a toxicity perspective, it is probably better to have a COVID-19 vaccine. From an efficacy perspective, I think it is still an unanswered question. If they get a COVID-19 vaccination, will this worsen the outcome of IO therapy? We still do not have answers.

Dr. Figlin::

         That is a brilliant summary. So Brad in Boston, let’s just turn our attention to designing clinical trials. how do we need to be thinking about clinical trial design and placing people who are recently COVID-19 vaccinated in the clinical trials post-pandemic?

Dr. McGregor:

        I think that is a great question. I get the radiology reports for patients who are on the trials and they are concerned about increased lymphadenopathy correlated with the recent COVID-19 vaccine. So our radiologists are already putting this in the reports on a routine basis. But how do we interpret such data and put blinded, independent review in perspective? I think it is a difficult question to answer at this point of time. We have these different caveats especially once patients receive the recent COVID-19 vaccine. And we started looking at criteria and interpreted that it may be related to the COVID-19 vaccine. Because from a clinical standpoint, our radiologists are doing this in trials all the time. So it remains to be seen how we incorporate such aspects into trial design.

Dr. Figlin::

Yeah, but just to push you a little bit right now, I agree with that completely. Maybe Bob can weigh in as well. I see most of the trials that Bob, Eric and you have reported, are international trials. So patients are from all over the world where the population is highly heterogenous and patients may not have had the vaccine or have the same imaging evaluation as the Farber has, so how are we going to do these pivot international trials, post COVID-19.

Dr. McGregor::

         Yes, overall, it is challenging when dealing with international pivot trials. If you especially look at the COVID-19 vaccine-induced lymphadenopathy aspect, often these are not large enough to meet RECIST criteria as a new node. I think that is the fortunate thing. So if you are strictly going by RECIST criteria, you may not actually have 3 or 4 centimeter enlarged nodes from a COVID-19 vaccination in the international clinical trials.

Dr. Figlin::

         So I want to stay on this topic just for a little bit. Bob, you have led some of the major international trials in kidney cancer, your thoughts about how the datasets will evolve over the next, six to 24 months, and then how we are going to be interpreting that data and how to navigate that. Any thoughts about that?

Dr. Motzer:

         We do not really know what the impact of the pandemic will be on the clinical trial data. I think that has been somewhat industry sponsor-specific and the various sponsors have had their own plan in place to monitor follow- up and safety procedures during the COVID-19 pandemic. So, in terms of the studies that I am involved in, I am not aware that there has been a dramatic impact on safety for these trials. There was a study that I was involved with, where there was an issue in terms of getting imaging follow up on patients because of COVID. I think that is something we have to deal within the trial. But for the big phase-3 trials, we have not seen the data come back yet so we are not aware of the impact that you are speaking of. I have been also intrigued by the adenopathy associated with vaccination. So, what we have been doing is we have been timing the scans around vaccine, because I do not think it is a good idea to have a scan on a patient two days after they have a vaccine. But if you do scans two days before vaccination, it is It will be less of an issue and we have noticed that the adenopathy is really quick to resolve. Certainly, in blinded review, core imaging review, people would not know whether there was a vaccine that was responsible for the lymphadenopathy. So I think it is a difficult situation to resolve in trials.

Dr. Figlin::

         It is a wonderful conversation, because I think just from the four of us, it may be that the timing of scan imaging and vaccination is important and should become part of data collection during trials, so that we are at least removing the variables from our evaluation of cancer therapy. So Eric, let me turn to you. We have had patients on immunomodulatory steroids and antibodies when they are getting immunotherapy. So how are you navigating through the conversation with your fellows and your patients about the appropriate role for managing the immune-related adverse events associated with immunotherapy?

Dr. Jonasch::

         Yes, I guess the big question is – are we changing how we are doing this for individuals in the COVID era? The answer is no. We are clearly using immunomodulatory agents like steroids, IL-6 antibodies, and TNF antibodies, which can have an impact on immunosuppression. But I think it becomes a competing risk argument, which is more important? – managing the severe side effects from immunotherapy, or dealing with the potential increased risk of infectivity while they are on those treatments. I think you have to manage the toxicities from immunotherapy. You can also manage the risk of exposure by making sure that individuals follow safe practices. Recently CDC has announced that people do not need to wear a mask anymore if they are vaccinated. So, there are relaxations of guidelines at a national level. But I think that for our patients, especially for our vulnerable patients, we should probably continue to urge caution and take a conservative approach to the risk of COVID-19 exposure.

Dr. Figlin::

        Brad, I want to change the conversation a little bit for all of us to talk about the impact of telemedicine. Bob made an absolutely critical point that the relationship between the medical oncologist and their patient inside that patient care room is a very intimate setting and that is not exactly captured by the Zoom call we are doing today. So, Brad, my question is how have you incorporated telemedicine, and do you think that there will be increased telemedicine going forward as the pandemic winds down or is that just going to dissipate?

Dr. McGregor::

         Good question. I think telemedicine is here to stay. There are certain aspects that patients just really enjoy. We have been able to function with telemedicine to an extent and telemedicine will likely incorporate into medicine going forward. It is important to realize that telemedicine is a nice adjunct to in-person care. I do not think it is a replacement for in-person care if you intersperse it between in-person visits. Occasionally, I use telemedicine for the patients who got scared to come into the clinic but when significant cancer care is required or to make important decisions, I would also ask them to visit the hospital in-person to make sure how the patients are actually doing and get a better sense. So it comes out to a fine line where we need to use telemedicine in conjunction with in-person visits. I think that goes the same for clinical trials as well. As we look at the future of clinical trial designs, we can look to incorporate telemedicine as an adjunct wherever possible but not to the extent that it can completely replace in-person visits

Dr. Figlin::

        What would be your recommendation for our community doctors who always prefer to have doctor- patient interaction but now have a hard job to deliver long-term VEGF TKI therapy without ever seeing the patient.

Dr. McGregor:

         From my standpoint, I see out-front. When I start VEGF TKI and check labs for a patient probably every couple of weeks for the first month or so I feel comfortable doing maybe a telemedicine visit at two weeks. But after a month, I like seeing the patient in-person to assess and bring a blood pressure log. It does not put more onus on the patient, because anyway, the patient has to be in the clinic for other data collection that we would otherwise do in-person. I would be happy to see virtually at two weeks, but then I want to have more of a sense of what’s actually going on with direct in-person interaction with patients. So it is actually beneficial for patients to come in. In the end, it just comes down to individual discussion with some patients.Dr. Figlin::

         And Bob, what’s been your experience in Manhattan with your large patient population?

Dr. Motzer::

        I think telemedicine is really a great tool that we need to incorporate into patient care. What I found is telemedicine is particularly useful for our patients who are getting routine follow up with scans and bloodwork and maybe are cancer free or do not require systemic therapy. For these patients, talking via zoom seems reasonable. But, for people who have significant medical problems, or who are on systemic therapy, physicians really need to be seeing those patients. In addition to just providing medications, another important component that really requires seeing the patients, is that physicians provide a tremendous amount of emotional support. It is much more effective to provide that emotional support and contact in person than doing only on a telephone or on a video screen. In the end, it is individual’s preference in terms of the physician and the needs of the patient. Certainly, some would say safety visits for patients on chronic TKIs could be done by zoom. On the other hand, if people have symptoms or pain, or are having a very difficult time with regard to family situations, those patients are better off visiting their doctors in person. Dr. Figlin: Eric, so many of our patients who come to see us also see other health care providers, social workers, our dieticians and get supportive care, etc. what’s been your experience with telemedicine at your center in Houston?

Dr. Jonasch::

         Yes, it is clear that there are some advantages and disadvantages to telemedicine that Bob and Brad have outlined here. The access to other specialties in a timely manner as you pointed out is a downside in telemedicine. Another downside is the lack of access to labs that are done locally so patients may not have the reports in hand when speaking with the physicians. Also, the comprehensive care to some degree gets diminished. However, I would actually venture to say that from a social context perspective, patients still cannot bring their loved ones into the hospital with them. Being able to have a conversation with the patient, their spouse, and their children on Zoom without the need for wearing masks in their home environment is great. There are some advantages as patients find that it is more of a conversation with a friend on Zoom than it is a conversation with a doctor. We could improvise telemedicine approaches, for example, incorporate wearables to get vitals on the patient. Apple Watch 4.0 will be able to provide that information to us prior to us actually seeing the patient or while we are seeing the patient. Incorporating these elements into telemedicine and intercalating them with the in-person visits is the future. And I sincerely hope that medical authorities around the country will see that as being an advantage.

Dr. Figlin::

         Brad, I would like to get a sense from the three of you whether you have seen patients presenting with a bit more advanced disease, because of maybe not seeing the physician early enough due to COVID-19. And we all get many of our referrals from our surgical colleagues or urologists. What are your thoughts about that? I mean, we do not necessarily need to speak about prostate cancer, where that is happening as well, or bladder cancer, but is there a clinical substantive delay in care that we are starting to experience and worry about in the kinds of patients that you are seeing?

Dr. McGregor::

         That is a great question. I think from a GU cancer standpoint, it is more challenging because if you look at something like kidney cancer, bladder cancer, there’s no screening in place. So patients often present with symptoms of disease, or we find kidney cancer because they have appendicitis incidentally. I have not seen patients in my clinic who have had hematuria that they have ignored for three months because of the pandemic. Generally, they still see their primary care doctor and get forwarded to the urologist with that workup. So far, I have not seen such a delay in screening but I think time will tell us how this changes with GU cancer people getting less PSA screening or less follow up due to COVID-19 related issues.

Dr. Figlin::

         Bob, I know at Cedars during the height of the pandemic, we were having hundreds and hundreds of patients in the hospital with COVID-19, we had a postponement of elective and non-elective surgeries. What’s been the experience at MSK?

Dr. Motzer::

         that is exactly the same situation we had at MSKCC where during the worst part of the pandemic, a lot of the operating rooms were actually turned into ICU rooms with respirators for COVID patients and a lot of the surgeries that were considered non-emergent were not undertaken or postponed. It was a very difficult situation for patients who had a kidney tumor waiting for their nephrectomy. That is another aspect in terms of how the pandemic has affected us. I agree with Brad’s point. Now, I have not actually noticed in person that patients with kidney cancer presenting to me with a delayed diagnosis because of COVID-19. It certainly seems like a reasonable trend, but I have not observed that with people with GU cancer yet.

Dr. Figlin::

        Over the last 15 years, the advancements that we have made in kidney cancer have been a direct result of aggressively placing patients on trials, asking important pivotal questions, and moving therapeutics to the system in a way that is unprecedented in our disease that we all manage. How do you think as a leader in this area that the future clinical trial, whether it is IITs or industry- sponsored research or novel immunotherapy should be designed?

Dr. Jonasch::

         Yes, we clearly need to improve. Especially, we need to take lessons from the COVID-19 pandemic in terms of how we can make clinical trials more efficient and how we design our next generation of clinical trials. I am the head of the kidney cancer research consortium of DOD grant-funded mechanism that allows us to try to use informatics solutions to create efficiencies in clinical trial design and execution. I think broadly speaking as a field, we need to embrace such efficient strategies. It is challenging for patients to undergo treatment on a clinical trial with logistical issues. It is a sacrifice that patients are making on behalf of future cancer patients and we have to make that sacrifice as minimal as possible. We may want to add other strategies such as virtual visits, remote monitoring in design so that clinical trials can get less expensive, safer, quicker, and more efficient. So overall, it is going to be a win-win situation.

Dr. Figlin::

         So Brad, let me ask you, What are your thoughts if you were to design a 1000 patient international clinical trial tomorrow in kidney cancer, will you be stratifying patients based on COVID-19 infection to ensure the arms are balanced and we are really evaluating the effects of treatment, not the comorbidities that the patients are undergoing?

Dr. McGregor::

        It would be very challenging to do that going forward. The challenge is that how to find out if patients had COVID-19 or not in a certain area? And, it is difficult to assess if the side effect comes from the vaccine or from the cancer therapy? These important questions remain to be answered. So, for the clinical trial design, I would include the evaluation of the vaccine efficacy in patients who are on systemic therapy for cancer immunotherapy or chemotherapy. Also, I would be looking to see the antibody titers and how well the vaccines affect side effects overall. Until we really know how to assess COVID-19 and how it affects patients, it becomes very difficult to design a trial stratified by COVID-19 infection criteria.

Dr. Figlin::

         I think we all do not want to see the COVID epidemic postpone or delay what we accomplished these years in the kidney cancer space? How are you thinking about that when you are meeting with either your junior investigators or your faculty that are under your guidance? How would you want us to be thinking about that going forward?

Dr. Motzer::

         From one point, it is important to minimize the impact of COVID-19. So I recommend that patients who are not only in the US but also outside the United States get the vaccination. As Eric mentioned, the other point is to ensure patients who are treated in the clinical trials get adequate protection including wearing a mask to protect themselves as best as possible. We certainly do not want to see the COVID pandemic truncate our progress in kidney cancer. And so I think along those lines, it is important to discuss the impact of COVID in forums like this so that people are aware of COVID-19 and its potential impact on clinical trials so that we can conduct clinical trials in the setting of the pandemic. Conducting safety evaluations with telemedicine minimizes patients coming into centers and getting exposed. That is been very effective in United States, it would be a wonderful thing if it could be implemented outside of the the United States. We really have not seen a detrimental effect of either the vaccination or the impact of COVID-19 on immunotherapy response. It certainly has been a distraction but I do not think it is a reason to stop clinical trials. Such efforts should help us focus to continue our efforts in clinical trials in RCC.

Dr. Figlin::

         Eric, in the Department of Defense and in the funding of clinical trials, are there special questions that we should be asking in the context of the post-pandemic?

Dr. Jonasch::

        I think the two key questions we want to answer first are does treatment with immunotherapy worsen side effects from immunotherapy? The second question is, does having COVID or a vaccination alter the ability to respond to treatment? We have an opportunity probably with some of the trials that were winding down as the pandemic occurred. We have to do some retrospective analyses to see whether or not we can tease some of these important questions out. Moving forward, it is going to be a question of what is going to be the issue with COVID. Are we actually going to have this controlled at a national level? Will we have it controlled at an international level?

Dr. Figlin::

         Brad, as the clinical director of the Lank Center, a very important center nationally for GU studies at the Farber how are you taking the macro view as an institution to contribute to this effort?

Dr. McGregor::

        I think when COVID first happened in March of 2020, everything came to a screeching halt for about a month. But then, we quickly sort of started coming back and started taking samples as we started adapting to the system and tried to incorporate those things. And overall, I would say like our clinical operations standpoint, therapies now are very close to where they were pre COVID with telemedicine as an adjunct. Even throughout the pandemic, we have seen clinical trials have been successful in accruing rapidly, Therefore, well designed smart trials can continue to thrive in this setting.

Dr. Figlin::

         Well, gentlemen, it is been a pleasure hearing your thoughts. It is always nice to see friends and colleagues. And I think our community will welcome as Bob mentioned, conversations like this and can start to inform both how we think about it as well as how we should think about it going forward, especially in the context of not losing the momentum, to address this difficult disease during COVID-19 era, and still wanting to accomplish all the things that we can still accomplish in this setting.

CONCLUDING REMARKS

As we move into the next stage of the pandemic, the biggest challenge is to rapidly adapt to much needed reforms and effectively translate emerging evidence into best practices in delivering a high standard cancer care and treatment. In this discussion, experts reinforced that although the current emphasis is on the management of oncology services, the cancer community should work towards bringing a fresh momentum to quality of care and clinical research in the era of COVID-19 and beyond.

Contributions

The roundtable panelists (authors) were invited to participate in this discussion by the journal. All authors listed in the manuscript contributed significantly to KCJ roundtable. All authors have read and approved the final version. The final content and article is the sole work of the authors.

Acknowledgments

This roundtable program is supported in part by Bristol-Myers Squibb.BMS Study Connect

Declaration of interests

RJM reports grants and other from Bristol Myers Squibb during the conduct of the study; grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Eisai, grants and personal fees from Exelixis, personal fees from Merck, grants and personal fees from Genentech/Roche, personal fees from Lilly, personal fees from Incyte, and personal fees from EMD Serono Research and Development Institute outside the submitted work. EAJ: consulting/advisory relationship/ Honoraria received – Exelixis, Merck, Pfizer, Eisai, Novartis, Roche. Research funding – Exelixis, Merck, Pfizer. BAM: consultancy for Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono. Received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. RAF: no relevant financial relationships with commercial interest to disclose pertaining to this article.

ONLINE CONTENT

Full online contents with additional information available atKCJ Roundtable doi.org/10.52733/KCJ19n2-r1

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• 12. Waterhouse DM, Harvey RD, Hurley P, et al. Early impact of COVID-19 on the conduct of oncology clinical trials and long-term opportunities for transformation: findings from an American Society of Clinical Oncology Survey. JCO Oncol Pract. 2020; 16: 417- 421. doi:10.1200/OP.20.00275

The post Roundtable Discussion – Cancer and COVID-19 first appeared on GUcancers.

Novel Drug Combinations Gain Traction Across Therapeutic Landscape

More than a year since the COVID-19 crisis upended the face of health care in the United States, its impact on cancer clinical trials has continuously been seismic. Right now, it seems likely to be a while before we enroll newly designed studies and start gathering trial data at the rate they once were. While there is only a limited capacity for bringing in new trials or launching new therapies into clinical practice, the oncology community certainly moved quickly with a concerted effort to get the halted cancer trials back up and running. This year’s ASCO Genitourinary Cancers Symposium sessions offered tantalizing preview of clinical breakthroughs and practice-changing research updates in GU cancers landscape despite the pandemic’s impact on clinical trials space worldwide.

As highlighted in the recent Kidney Cancer Journal online edition, GU ASCO21 abstracts provided snapshots of the most important trends, foremost research and key strategies from latest clinical trials that impact the current standard of care in renal cancer. Certainly, looming on the horizon are the new IO/IO and IO/TKI combinations, which generated a lot of buzz at this year’s ASCO in the renal cancer therapeutics space. Least to say, while targeted agents and immune monotherapies are still moving the needle to some extent, combination regimens comprised of IO/IO, IO/TKI, or other molecularly targeted agents are gaining momentum in evolving RCC landscape.

Let’s have a quick snapshot of the latest data from the GU21 sessions. In the pivotal phase 3 CLEAR study (KEYNOTE-581), lenvatinib plus pembrolizumab demonstrated statistically significant and clinically meaningful improvements in progression-free survival, overall survival and objective response rate versus sunitinib, supporting the regimen as a potential first-line treatment for advanced RCC. Also, improvement in ORR and PFS, but not OS was observed for lenvatinib at 2 different starting doses in combination with everolimus vs sunitinib. Other related abstract presented quality of life outcome data from a phase II trial of lenvatinib plus everolimus in patients with RCC. Investigation by Choueiri and colleagues was the first to report efficacy of combining the novel HIF-2alpha inhibitor plus cabozantinib (a VEGF TKI) in 118 patients with advanced clear-cell RCC. Belzutifan in combination with cabozantinib demonstrated promising antitumor activity and better tolerability in previously treated patients with metastatic ccRCC. CheckMate 9ER (NCT03141177), a phase III open-label trial has shown that nivolumab + cabozantinib demonstrated statistically significant HRQoL benefits and superior efficacy versus sunitinib. Also, nivolumab + cabozantinib demonstrated improved efficacy and prolonged survival vs sunitinib in previously untreated aRCC patients regardless of sarcomatoid status. In a phase II SWOG 1500 study by Pal and colleagues that put cabozantinib, crizotinib, or dacomitinib to the test, the small molecule inhibitor cabozantinib was found most effective in treating 180 patients with metastatic papillary RCC following progression. The exploratory analysis by Plimack and colleagues provide an update of phase III KEYNOTE-426 study which demonstrates that a significant proportion of patients in the pembrolizumab and axitinib arm were able to complete 2 years of pembrolizumab with ongoing clinical benefit. In previous reports of KEYNOTE-426, investigators showed that pembrolizumab plus axitinib prolonged OS and PFS vs sunitinib in patients with treatment-naive advanced RCC.

Emerging data from these trials will position such IO/IO or IO/TKI combination regimens as the new standards of care for patients with renal cell carcinoma. There were several useful additions to the repertoire of currently approved therapies, which should prompt further conversations. As oncologists gear up to gauge the potency of newly available combination regimens in a real-world perspective, significant challenges remain in regard to management of overlapping toxicities, while maintaining quality of life in patients. Ultimately, the rationale for optimal treatment selection for a given combination regimen depends on multi-factorial elements including safety/efficacy, tolerability, cancer progression, comorbidities, drugs cost etc.

I would like to bring your attention to a stimulating roundtable discussion which I chaired, participated by expert panelists Drs. Brian I Rini and Thomas E. Hutson. Full transcript of the roundtable can be accessed here: https://www.kidney-cancer-journal.com/Roundtable.php. This discussion shed light into the robust safety/tolerability portfolio of VEGF-TKIs especially tivozanib which could potentially carve out a space within the area of unmet need : third- or fourth-line therapy for heavily pretreated RCC population. The discussion also integrated new concepts emerging from the phase-3 TIVO-3 trial and analyze the potential impact of novel data. On the heels of the recent US FDA approval of tivozanib (Fotivda) in the relapsed/ refractory RCC setting based on data from phase 3 TIVO-3 trial, tivozanib is now being investigated in combination with the PD-1 inhibitor nivolumab (Opdivo) in the phase 3 TiNivo-2 trial in patients with relapsed/refractory RCC.

The post Editor’s Memo first appeared on GUcancers.

By Christopher Brown

Substances linked to bladder cancer found in the urine of e-cigarette users

Recently published scientific studies found six substances that have a strong link to bladder cancer in the urine of people who had used electronic cigarettes and sometimes other tobacco products. Researchers from the University of North Carolina Lineberger Comprehensive Cancer Center and NYU Langone Health reported in the journal European Urology Oncology.

In this recent study, researchers compiled the results of 22 different studies that analyzed the urine of people who used e-cigarettes or other tobacco products, including cigarettes, to check for evidence of cancer-linked compounds or biomarkers of those compounds. They found six biomarkers or compounds with a strong link to bladder cancer.

Smoking is the No.1 modifiable behavioral risk factor for bladder cancer. There is now evolving literature showing that people who vape may have similar carcinogens in their urine as combustible cigarette users.”

Marc Bjurlin, DO, MSc, associate professor of urology in the UNC School of Medicine

While public health agencies including the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention have warned that there are health risks of vaping, including for e-cigarette-associated lung injury, their safety profile has not been “definitively characterized,” according to Bjurlin and his colleagues.

“The first and foremost side effects that we’re seeing from electronic cigarette use are lung and pulmonary related,” Bjurlin said. “We won’t see the side effects for these other kinds of carcinogenic pathways until much later down the exposure pipeline.”

To develop a better understanding of the long-term risks of vaping, including cancer, researchers investigated possible exposure to substances that can cause bladder cancer in particular since carcinogens could be processed in the body and then passed in urine.

In their review, Bjurlin and his colleagues found 40 different parent compounds that can be processed in the body to produce 63 different toxic chemicals or carcinogenic metabolites, which are substances that remain after in the body after processing.

Six of those chemicals have a strong link to bladder cancer, according to researchers’ analysis of carcinogens databases of the International Agency for Research on Cancer and the Collaborative on Health and the Environment Toxicant and Disease Database.

They found evidence in some studies that e-cigarette users had “significantly” higher levels of several carcinogens that can be metabolized into substances linked to bladder cancer in their urine compared to people who had never used them.

“This finding shows us that people who vape will be exposed to a variety of different carcinogens,” Bjurlin said. “People who have decades of exposure to these carcinogens from vaping may be at risk for developing malignancies, especially bladder cancer.”

There were several limitations to the study, including that researchers did not know the levels of all of the cancer-causing substances in the urine of users from the studies.

In addition, some studies included people who were “dual users,” or people who both smoked and vaped e-cigarettes. There were also cases when users smoked cigarettes and switched to e-cigarettes.

“The study population was quite heterogeneous, meaning that often studies looked at dual users, meaning those who used e-cigarettes and combustible cigarettes,” Bjurlin said. “That made it difficult to assess whether the carcinogen found in the urine was actually from the e-cigarette use or from the cigarette use.”

Further research is needed, said Bjurlin, who wants to determine the threshold of exposure to carcinogens that would lead to development of bladder cancer or other cancer types. He plans to lead a study that will evaluate carcinogens in the urine of e-cigarette users, smokers and non-users.

“Although there is no definitive case yet linking bladder cancer to vaping, it may be reasonable to suspect that decades down the road after exposure to these byproducts, people who vape may be at risk of developing bladder cancer,” he said.

Source: UNC Lineberger Comprehensive Cancer Center

Journal reference:

Bjurlin, M.A., et al. (2020) Carcinogen Biomarkers in the Urine of Electronic Cigarette Users and Implications for the Development of Bladder Cancer: A Systematic Review. European Urology Oncology. doi.org/10.1016/j.euo.2020.02.004.

The post Study Discovers Link Between Electronic Cigarette Use and Bladder Cancer first appeared on GUcancers.