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Rashid Sayyid: Hello, everyone, this is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recently published KEYNOTE-B61 trial, which is a single-arm, multicenter, phase II trial that looked at the combination of pembrolizumab plus lenvatinib as first-line therapy for patients with advanced non-clear cell RCC. This trial was recently published in the Lancet Oncology with Dr. Laurence Albiges as the first author.

We know that non-clear cell RCC accounts for about 25% of all renal cell carcinoma cases and includes the following subtypes, papillary, which is about 10-15% of the total RCC, chromophobe about 5-10%, and there's also the subtype of translocation-related non-clear cell RCC. The phase III RCTs have advanced renal cell carcinoma, predominantly, or exclusively, included patients with clear cell RCC, and have led to the following approved combinations. We know that we have dual immune checkpoint inhibitors with nivolumab and ipilimumab based on the results of the CheckMate 214 trial. We also have combinations of the immune checkpoint inhibitors plus the vascular endothelial growth factor tyrosine kinase inhibitors, or the VEGF-TKIs, which include the combination of pembrolizumab plus axitinib based on the results KEYNOTE-426, avelumab plus axitinib, the JAVELIN 101, we also have Nivo and Cabo based on the CheckMate 9ER, and more recently we have the pembrolizumab plus lenvatinib combination based on the results of the CLEAR trial.

What are the current guidelines saying about non-clear cell RCC? Quite clearly, there's a paucity of data, and if we look at the EAU guidelines and we look at the recommendation section, currently, the EAU recommends offering sunitinib to patients with non-clear cell RCC subtypes other than papillary RCC, and we know that, clearly, we've had a lot more advancements in this space since sunitinib emerged as first-line therapy, and quite clearly, the non-clear cell RCC disease space is lagging compared to the clear cell RCC space. So further studies in this space are clearly of utmost importance.

What do we have in this disease space? The majority of the trials for non-clear cell RCC have focused on papillary RCC. We have, most recently in 2021, the results that PAPMET trial published, and this included 152 patients with papillary RCC who were randomized received sunitinib, cabozantinib, crizotinib, or savolitinib. And if we look at the comparison of cabozantinib versus sunitinib, we see that Cabo improved progression-free survival from 5.6 to 9 months, with a hazard ratio of 0.6, and also improved the objective response rate from 4% to 23%. However, we saw there was no significant benefit for crizotinib or savolitinib compared sunitinib. So clearly cabozantinib may have improved efficacy in this disease space for papillary RCC patients.

Next, we also had a phase II single-arm trial of Cabo plus nivolumab in 47 patients with advanced non-term cell RCC. This included patients with papillary, unclassified, or translocation-associated RCC, an objective response rate of 48%, with a median progression-free survival just over a year and a median overall survival OF 2.5 Years. Conversely, we saw the chromophobe RCC patient objective response rate as 0%. So although we lump papillary and chromophobe together within the heading of non-clear cell RCC, this is mainly because of limitations with regards to the numbers out there and ability to recruit patients. But quite clearly, these are two different disease subtypes, and so we need to consider the efficacy of these agents in each subtype independently.

Why should we evaluate the combination of pembrolizumab plus lenvatinib and non-clear cell RCC? What is the rationale behind trying this combination? We know in the phase II KEYNOTE-427 cohort B trial, which evaluated single-agent pembrolizumab, which is an anti-programmed death-1 agent, in patients with advanced non-clear cell RCC, the majority of which were papillary 72%, 13% chromophobe, and the remaining unclassified, we saw that pembrolizumab monotherapy was associated with an objective response at 27%, with the median duration of response of just over 2.5 years. The median progression-free survival was 4 months. The median overall survival was 29 months, and also had an acceptable safety profile. So, quite clearly, pembrolizumab monotherapy works well in the non-clear cell RCC, mainly papillary subtype.

But can we make these results even better? Evidence that that may be the case comes from the phase III CLEAR trial which evaluated the combination of Pembro plus lenvatinib in patients with clear cell RCC and was shown to improve progression-free survival and overall survival compared to sunitinib. So can we transfer these results to the non-clear cell RCC subtype? And so, this was the study objective of the KEYNOTE-B61 trial, was to evaluate the activity and safety of first-line pembro plus lenvatinib in patients with advanced non-clear cell RCC.

This was a single-arm, phase II trial across 48 centers in 14 countries across Australia, Europe, Asia, North America as well. This included patients with histologically confirmed stage IV non-clear cell RCC with measurable disease per RECIST criteria. Patients were systemic therapy treatment naive, had a good performance status as evidenced by Karnofsky Performance status of at least 70%, no collecting duct histology, and no central nervous system metastases. Patients in this single arm trial received pembrolizumab 400 milligrams of IV every 6 weeks as opposed to sometimes we see it every 3 weeks, here it's given every 6 weeks, plus lenvatinib given 20 milligrams orally once daily. Treatment was planned for about 2 years or until disease progression, unacceptable toxicity, or if the patient or physician decided to withdraw consent. Patients with complete response could discontinue pembrolizumab if they received at least four cycles. Conversely, patients with stable disease or better could receive an additional 1 year of Pembro as indicated.

So again, based on a shared decision, either patients stop early if they're satisfied with the response, had a complete response. Conversely, if patients have a stable disease or better, they could continue or prolong the therapy for an additional 1 year in addition to the 2 years that were planned. Dose interruptions or discontinuations were allowed for pembrolizumab, but no dose reductions were allowed. Conversely, for lenvatinib, dose reductions were allowed to manage adverse events. All patients had PD-L1 levels measured and reported using the combined positive score, the CPS, and the way this is calculated is by the number of PD-L1 positive staining cells, meaning tumor cells, lymphocytes, or macrophages, divided by the total number of viable cells, and that's how you get the combined positive score.

Patients underwent cross-sectional imaging with CT or MRI every 6 weeks during the first year and then every 12 weeks thereafter. Tumor response was assessed by a blind independent central review using the adjusted RECIST version 1.1 criteria. Adverse events were monitored for up to 90 days post-treatment discontinuation.

The primary study outcome was objective response defined as either complete or partial response, and then this was analyzed using subgroup analysis by the IMDC risk. The PD-L1 CPS score less than 1 versus greater equal 1, histologic subtype, and whether sarcomatoid features were present, yes versus no. Secondary endpoints included clinical benefit defined as complete response, partial or stable disease for at least 6 months, and also disease control, which was the same as clinical benefit, but this was stable disease of any duration. It could be less than six months as well. They also duration of response, progression-free survival, overall survival, and safety outcomes, as well.

The calculated sample size for this study was 152 patients and outcomes were assessed only in patients that received at least one dose of study treatment. So this was defined as the as-treated population by the authors. Survival analysis with no parametric Kaplan-Meier curves was used to evaluate time to event outcomes as well. At this point, I'll turn it over to Zach to go over the results and discussion for this paper.

Zachary Klaassen: Thanks so much, Rashid, for that great introduction. This is the trial profile for KEYNOTE-B61. 215 patients were screened, ultimately 158 were assigned to treatment, and 92 remained on treatment at the time of the data cutoff. With regards to baseline demographic and clinical characteristics, we can see that the median age for this trial was 60 years of age. Roughly three-quarters of patients were male and one-quarter were female. Majority of patients were White, at 81%, although there was 8% Asian and 2% Black or African-American. Majority of patients were recruited outside of Europe and North America, at 49%. You can see the IMDC risk category breakdown, 44% favorable risk, 47% intermediate, and 8% poor risk. Majority of these patients, more than three-quarters, had excellent performance status with a Karnofsky score of 90 to 100. Presence of sarcomatoid features was evident in 12% of these tumors and PD-L1 status CPS greater than or equal to 1 in 59% of patients.

With regards to histology breakdown, which is always of interest when these patients are grouped together as non-clear cell RCC, papillary 59%, chromophobe 18%, unclassified 13%, translocation 4%, and other histology 6%. Just over half of patients had a prior nephrectomy, at 59%, and 82% of patients had two or more organs involved at the time of screening, and this was most commonly in the lymph nodes, at 65%, the lung, at 34%, the bone, at 31% and the liver, at 20%.

This is the table looking at best overall response per adjusted RECIST version 1.1. We can see among all 158 patients, confirmed objective response was 49%. Across the histologies we see papillary 54%, chromophobe 28%, unclassified 52%, translocation histology 67%, and other histology 56%. With regards to confirmed disease control, this was actually quite good, at 82% disease control among all patients, particularly notable for unclassified, at 90%, and papillary, at 85%. For confirmed clinical benefit, all patients, this was 72%. Always of interest in these trials is confirmed complete response. There was a 6% complete response rate among all patients, notable for 9% of papillary histology and 11%, or 1 patient, in the other histology. What's also important to point out on this table is that progressive disease was only seen in 11% of patients, which is quite impressive across these non-clear cell histologies.

This figure looks at the best percentage change from baseline and target lesion size. This is the figure on the left, papillary in light blue, chromophobe in dark blue, unclassified in green, and translocation or other histology subtypes in gray. This figure shows that 91 of 158 patients had a 30% or greater reduction in target lesion size in this trial.

This is the Kaplan-Meier estimate for a duration of response in patients with a confirmed response, and you can see that among these responders, the median duration of response has not been reached at the time of this analysis.

This figure looks at the time to response in patients with a confirmed objective response. We see that 75% of patients with a complete or partial response had response of at least 12 months, and among the 9 patients with complete response, 6 had ongoing response at the time of the data cutoff.

This is a subgroup analysis objective response rate, and just by way of comparison, the overall response rate, again, was 49%. We see amongst these subgroups that there was a very good response among most of these subgroups, particularly I'll point out patients with sarcomatoid features had an objective response rate of 47%, with the remainder of these factors quite similar to the overall objective response rate of 49%.

This Kaplan-Meier curve looks at progression-free survival per adjusted RECIST criteria, and we can see that the median progression-free survival was 18 months, with a 95% confidence interval of 14 months to not reached, and the 12-month progression-free survival rate was 63%. This is the Kaplan-Meier estimate of overall survival, which has not been reached in terms of the median, with a 12-month overall survival rate in this trial of 82%.

This is the summary of the treatment emergent adverse events. You can see the full list on this slide here. I've highlighted some of interest. Any treatment emergent adverse event, grade 1 to 2 was 43%, grade 3 was 46%, and grade 4 was 5%. Some of interest hypertension grade 1 to 2, was 34%, grade 3 23%, diarrhea grade 1 to 2 41%, hypothyroidism, 36% grade 1 to 2, and dysphonia, 28% grade 1 to 2 treatment emergent adverse event.

By way of discussion, the phase II KEYNOTE-B61 trial is the largest clinical trial to date assessing a checkpoint inhibitor combination in the first line for advanced non-clear renal cell carcinoma. As this trial showed, this showed promising anti-tumor activity, with a 49% objective response rate. Median duration of response not reached. Approximately 75% of responders having at least a response for 12 months, a 12 month PFS rate of 63% and a 12-month overall survival rate of 82%.

The KEYNOTE-B61 trial compared very favorably with other first-line targeted agents. In the phase II ESPN, everolimus was not superior to sunitinib for progression-free survival, and in the phase II ASPEN trial, PFS improved with first-line sunitinib versus everolimus, but there was a low response rate of 18 versus 9%.

Additionally, KEYNOTE-B61 compares favorably with first-line immune checkpoint inhibitor agents. If we recall the KEYNOTE-427 trial, this was pembrolizumab monotherapy, this had a 26.7% objective response rate, which is quite a bit lower than the 49% in this trial, a 12-month PFS rate of 24.9%, again, this was 63% in the B61 trial, and a 12-month OS rate of 73%, which is lower than the 82% in this trial.

In conclusion, pembrolizumab plus lenvatinib showed durable anti-tumor activity in patients with previously untreated non-clear cell renal cell carcinoma, including in patients with papillary and chromophobe histology, and a safety profile consistent with that of other patient populations. These results support the use of pembrolizumab plus lenvatinib as a first-line treatment option for patients with advanced non-clear cell renal cell carcinoma regardless of histology. We thank you very much for your attention and hope you enjoyed this UroToday Journal Club discussion of the recently published KEYNOTE-B61 trial in Lancet Oncology.