Highlights on Renal Cell Carcinoma From the 2021 Genitourinary Cancers Symposium

What were some of the most clinically impactful abstracts in renal cell carcinoma (RCC) presented at the 2021 ASCO Genitourinary Cancers Symposium?

At this meeting, 2 abstracts for addressing the first-line treatment of kidney cancer were very important. The first of those [abstracts] presented data from the CLEAR study (ClinicalTrials.gov Identifier: NCT02811861), which compared lenvatinib plus pembrolizumab or everolimus to sunitinib for the treatment of advanced RCC.¹ The study showed a significant progression-free survival (PFS) and overall survival (OS) advantage with lenvatinib and pembrolizumab. So, these findings establish a potential frontline standard.

An equally important data set was from the CheckMate 9ER study (ClinicalTrials.gov Identifier: NCT03141177), which looked at the combination of nivolumab and cabozantinib as frontline therapy for advanced RCC.² Although we have already seen primary data from that important study, this was a supplement with quality-of-life data. The CheckMate 9ER study findings add to the richness of the data set and support the use of cabozantinib [compared to sunitinib] as frontline treatment based on quality-of-life improvements (assessed using well accepted metrics such as the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and the 3-level version of the EQ-5D (EQ-5D-3L)), [along with] improvements in PFS, OS, and overall response rates (ORRs).

As you mentioned, results from the CLEAR study showed that lenvatinib plus pembrolizumab vs sunitinib improved OS, PFS, and ORRs when administered in the advanced RCC first-line setting, supporting the use of this doublet therapy as a potential frontline treatment. What implications does this promising activity hold for immuno-oncology-tyrosine kinase inhibitor (IO-TKI) combination sequencing in advanced RCC should lenvatinib/pembrolizumab receive approval by the US Food and Drug Administration (FDA)?

I am quite confident that we are going to see FDA approval granted for this regimen. I think the lingering question is around utilization, in the sense that it will be quite challenging because data wiI am quite confident that we are going to see FDA approval granted for this regimen. I think the lingering question is around utilization, in the sense that it will be quite challenging because data with pembrolizumab indicate that it certainly is associated with some toxicity, which needs to be balanced with the activity of the regimen. As I mentioned before, the quality of life that we see with cabozantinib and nivolumab is quite impressive, and that certainly may potentially push us in that direction. In addition, taking that frontline regimen and [comparing] studies is just fraught with difficulties because of the nature of cross-trial comparisons. All 3 studies had very different baseline characteristics, which makes comparison difficult.

Updated data from a phase 1/2 study demonstrated activity associated with belzutifan (MK-6482) in patients with advanced clear cell RCC (ccRCC),³ while data from a phase 2 trial established the antitumor efficacy of belzutifan in combination with cabozantinib in patients with previously treated metastatic ccRCC.⁴ Notably, the former study was the first to report the efficacy of combined HIF-2α/VEGF-TKI inhibition. Based on the data presented on HIF-2α blockade, both as a single agent and in combination with cabozantinib, how is belzutifan expected to advance the RCC paradigm and in what settings could it be of the greatest benefit?

I am quite excited to see some of the studies in the second- and third-line settings that are looking at this regimen compared to everolimus or what I think is a more relevant competitor, cabozantinib. It is going to be interesting to see frontline data, which looks at a triplet of lenvatinib, pembrolizumab and belzutifan in combination (ClinicalTrials.gov Identifier: NCT04736706).
 
It does remain to be seen how it will compare with existing earlier-line strategies. For instance, there is an ongoing trial that is comparing belzutifan to everolimus (ClinicalTrials.gov Identifier: NCT04195750). I’m not sure how much we’ll gain from that evaluation, although, overall, it appears to be a low bar to exceed. Perhaps we’ll gain more out of a comparison of belzutifan with cabozantinib. Ultimately, it is going to be important to see whether or not cabozantinib can truly advance into the frontline setting and compliment inhibition with belzutifan.

Data from the phase 2 SWOG 1500 study demonstrated a statistically significant Data from the phase 2 SWOG 1500 study demonstrated a statistically significant prolongation of PFS with cabozantinib vs sunitinib in patients with metastatic papillary RCC, justifying cabozantinib as the new reference standard for systemic therapy in this patient population.⁵ What questions remain regarding the optimal use of cabozantinib in this setting, and what might be the next steps for drug development in metastatic papillary RCC, given the unmet need in this space?

My personal perspective is that there was no existing standard of care for patients with papillary kidney cancer prior to the SWOG 1500 study (ClinicalTrials.gov Identifier: NCT02761057). We would use sunitinib for most patients, but the level of evidence for that was relatively weak. With the SWOG 1500 study, we now [have] randomized data that support cabozantinib as a frontline treatment.
 
I think that one of the things that is quite exciting is that we are awaiting results from biomarkers accompanying the trials. So hopefully those data will be available later in the year, and they will shed some important light on the relevance of the MET status of patients with advanced papillary kidney cancer.

In a phase 2 study, you and your team found that overall efficacy outcomes were better when lenvatinib was administered at a higher starting dose (18 vs 14 mg) in combination with everolimus in patients who had previously received an antiangiogenic agent, irrespective of prior immune checkpoint inhibition.⁶ Can administering lenvatinib at 18 mg now be considered a one-size-fits-most approach in the treatment of advanced RCC?

Yes, it definitely seems like the right approach for patients. It looks as though lenvatinib at 18 mg carries a higher degree of clinical activity based on data that we assessed in terms of PFS and RR. The trial was built around the premise of noninferiority, but noninferiority is [certainly] not what we ultimately observed with lenvatinib.