On the Radar for RCC in 2021: McGregor Discusses Combination Strategies, HIF-2α Inhibition, and Other Key Topics

In a new year in renal cell carcinoma (RCC) care, combination strategies are not only expected to expand in availability but also grow increasingly refined as experts in the field await phase 3 clinical trial data that will help answer key questions.

Various regimens including nivolumab/ipilimumab, axitinib/avelumab, axitinib/pembrolizumab, and lenvatinib/pembrolizumab have all been associated with a survival benefit vs sunitinib as first-line treatment of RCC. In the advanced clear cell RCC setting specifically, data from the pivotal, phase 3 COSMIC-313 study (ClinicalTrials.gov Identifier: NCT03937219) will help to provide insight into how best to select one regimen from among many, according to Bradley McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts. 

The ongoing COSMIC-313 trial is testing the safety and efficacy of combination cabozantinib, nivolumab, and ipilimumab followed by cabozantinib and nivolumab doublet therapy in patients with systemic, therapy-naive RCC that is either not amenable to curative surgery or radiation therapy, or meets American Joint Committee on Cancer (AJCC) staging criteria for metastatic disease (stage IV). The COSMIC-313 investigators are comparing the tyrosine kinase inhibitor (TKI)-immunotherapy (IO) combination with a control regimen comprising nivolumab and ipilimumab, followed by nivolumab monotherapy.

“I think it will be interesting to see if we could potentially get the durability of responses from nivo/ipi and decrease the chance for progressive disease at best response, which exceeds 20% with nivo/ipi but was less than 10% with nivolumab and cabozantinib,” Dr McGregor said in an interview with Cancer Therapy Advisor.

Later down the line, findings from the adaptive phase 3 PDIGREE trial (ClinicalTrials.gov Identifier: NCT03793166), which is currently recruiting 1046 patients with metastatic RCC, will be applied in efforts to answer the following question: can agents in combination modalities be administered on an as-needed basis later in the course of therapy rather than concurrently at the time of treatment initiation?

“The PDIGREE trial is looking to start with nivo/ipi and then based on response, add cabozantinib. Those who have progressive disease as best response to nivo/ipi will go on to cabozantinib, and those who have a complete response can actually stop therapy after a defined time period, but those who have a partial response or stable disease will then be randomized to nivolumab maintenance vs cabozantinib. Within this framework, we will see how we can optimize therapy,” explained Dr McGregor.

Beyond these 2 clinical questions and associated studies is a phase 3 trial (ClinicalTrials.gov Identifier NCT04195750) that will position the hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan (MK-6482) against single-agent everolimus in approximately 700 patients with advanced RCC that has progressed after prior treatment with anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF)-targeted therapies.

On July 29, 2020, Merck, belzutifan’s developer, announced that the US Food and Drug Administration (FDA) granted the HIF-2α inhibitor a breakthrough therapy designation for patients with von Hippel-Lindau (VHL) disease-associated RCC with nonmetastatic tumors (<3 cm) who do not require immediate surgery and an orphan drug designation for individuals with VHL disease.¹

Belzutifan is the investigational focus of the phase 3 evaluation, as well as an active phase 2 study (ClinicalTrials.gov Identifier: NCT03401788) in patients with VHL disease-associated RCC and an ongoing phase 1/2 dose-escalation and dose-expansion trial (ClinicalTrials.gov Identifier: NCT02974738) in individuals with advanced solid tumors, including RCC. From these trials, potential combination strategies involving HIF-2α inhibition can be identified.

The field also eagerly awaits the full dataset from the phase 3 KEYNOTE-581/CLEAR trial (Study 307; ClinicalTrials.gov Identifier: NCT02811861), which is broadly expected to support the approval of another TKI-IO combination as first-line treatment for RCC: pembrolizumab plus lenvatinib. The frontline doublet therapy was found to elicit a statistically significant improvement in progression-free survival, overall survival, and objective response rate vs sunitinib monotherapy in patients with advanced RCC, Merck and Eisai announced on November 10, 2020.²

Though pembrolizumab and lenvatinib’s indication would further advance the treatment paradigm for RCC in the metastatic setting, the January 22, 2021, approval of nivolumab in combination with cabozantinib for the first-line treatment of patients with advanced RCC³ has already moved the needle some, closing the gap between the last FDA-approved therapy, single-agent avelumab. On May 14, 2019, the monoclonal antibody was greenlit for frontline use in patients with advanced disease based on efficacy data from the phase 3 JAVELIN Renal 101 study (ClinicalTrials.gov Identifier: NCT02684006).⁴

In an interview with Cancer Therapy Advisor, McGregor discussed the pending KEYNOTE-581/CLEAR data and additional clinical topics of interest in the RCC space that will guide research efforts in 2021, such as how to respond to unmet needs in patients whose disease does not contain clear cell components.

At the end of 2019, we were awaiting data from the CheckMate-9ER and KEYNOTE-581/CLEAR trial (Study 307) trials, both of which met their primary end points in 2020. How can these findings be expected to shape RCC care in 2021? 

Dr McGregor: The management of renal cell carcinoma has changed significantly over the past couple of years. Combination therapy is the new standard of care, and we have 3 combinations now for which we’ve seen data that show an improvement in overall survival. Nivolumab and ipilimumab showed improvement in overall survival in those with IMDC intermediate- to poor-risk disease, while the TKI-IO combinations of pembrolizumab with axitinib and most recently, cabozantinib and nivolumab, both showed an improvement in overall survival not just in intermediate- to poor-risk disease but across risk groups while the combination of axitinib and avelumab was approved given improvement in PFS across risk groups. This has established combination therapy as a standard of care for those with advanced RCC independent of risk group.

Several trials are in different stages in the RCC setting, such as the ongoing COSMIC-313 trial and the currently accruing PDIGREE study. What trial data have the potential to be the most compelling in the RCC space over this next year? 

Dr McGregor: We have 3 different regimens that improve overall survival, and we’re going to see data for lenvatinib and everolimus, which also met its primary end point for overall response rate and progression-free survival across risk groups. The question is, “How do we decide between these different regimens?”

They have different toxicity profiles. With nivo/ipi, 30% of patients need high-dose steroids for the adverse events, with a response rate of 40%. When we look at the IO-TKI combinations, there is potential for less need for high-dose steroids with higher response rates.

It’s all certainly exciting. We have COSMIC-313, which is looking at giving the dual checkpoint blockade with nivo/ipi with or without cabozantinib, given some very intriguing phase 1 data from Andrea Apolo, MD, showing this as a well-tolerated regimen. I think it will be interesting to see if we could potentially get the durability of responses from nivo/ipi and decrease the chance for progressive disease at best response, which exceeds 20% with nivo/ipi but was less than 10% with nivolumab and cabozantinib.

On the flip side, we have the question, “Do we need to do all 3 or can we add as needed?” We have the PDIGREE trial, which is looking to start with nivo/ipi and then based on response, add cabozantinib. Those who have progressive disease as best response to nivo-ipi will go on to cabozantinib, and those who have a complete response can actually stop therapy, but those who have a partial response or stable disease will then be randomized to nivolumab maintenance vs cabozantinib. Within this framework, we will see how we can optimize therapy.

I think these are important questions as we move forward, in addition to seeing data for the other IO-TKI combination of lenvatinib and pembrolizumab in the next year.

What were the key insights that specifically came to light over the past year about RCC management? 

Dr McGregor: We have a lot of new regimens that certainly have activity in the frontline setting, and we haven’t even talked about the combination of axitinib and avelumab, which has been shown to improve progression-free survival across risk groups. No improvement in overall survival has been reported yet, but potentially with longer follow-up that may change, so we look forward to continuing follow-up.

However, even with these regimens, there are patients whose disease does not respond, and so there is a need for novel targets. We’ve seen data for the HIF-2α inhibitor in both patients with VHL syndrome as well as those with refractory disease, showing that this agent has activity with a very manageable toxicity profile. There is some anemia and some decreased oxygen levels that come with it, but it’s certainly active, and so this is a new drug that will certainly move forward.

We have a phase 3 trial that’s ongoing right now looking at the HIF-2α inhibitor belzutifan vs everolimus. In addition, there have been some exciting data with glutaminase inhibition. We saw phase 1 data for patients who received cabozantinib with a glutaminase inhibitor telaglenastat, ensuring that none of the patients had progressive disease. Unfortunately, a recent press release showed that the combination did not meet its end point for improvement in PFS,⁵ so there is a need for new therapies.

Looking ahead, what are the areas of unmet need that would benefit from future drug development and research? 

Dr McGregor:  Beyond novel therapies, we need to continue to explore combinations and patients’ varying histologies in RCC. We’ve made remarkable progress in the management of clear cell RCC, but the majority of these trials include patients with varying histology, so we are looking to improve outcomes in those patients who we know generally can respond to our therapies but do worse than their counterparts with clear cell RCC.

We saw some interesting data for VEGF in combination with immune checkpoint inhibition. We published data from a phase 2 trial on atezolizumab and bevacizumab, so there was certainly some activity of VEGF plus IO in these patients, and a phase 1 trial showed activity of cabozantinib in combination with atezolizumab. Building on this, we have a phase 2 trial testing the combination of cabozantinib and nivolumab plus ipilimumab in patients with variant-histology RCC, which should be a nice companion to the COSMIC-313 trial to assess if these combinations have activity in patients with varying-histology RCC.

We also look forward to trials such as PAPMET [ClinicalTrials.gov Identifier: NCT02761057], which will look at MET inhibitors vs sunitinib in patients with advanced papillary renal cell carcinoma.

We’ve made a lot of progress in frontline therapy and the questions always are, “If you progress on IO therapy, what can we do next? What is the next best option? Should we continue IO beyond progression? Should we switch to TKI therapy?” We have interesting phase 2 data that the combination of lenvatinib and pembrolizumab post-IO or post-VEGF-IO shows remarkable response rates close to 60%. There is a randomized trial that is going to look at patients who experienced progression on IO or IO-VEGF and who will receive either cabozantinib or the combination of cabozantinib plus atezolizumab. This will help to answer the question, “Should we continue IO beyond progression?’”

This Q&A has been edited for style and clarity.

Dr McGregor discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Dendreon, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, EMD Serono, BMS and Calithera. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. 

References

1. FDA grants breakthrough therapy designation to Merck’s novel HIF-2α inhibitor MK-6482 for treatment of certain patients with Von Hippel-Lindau Disease-associated renal cell carcinoma [press release]. Kenilworth, NJ: Merck; July 29, 2020. Accessed January 30, 2021.
2. Keytruda® (pembrolizumab) plus Lenvima® (lenvatinib) demonstrated statistically significant improvement in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) versus sunitinib as first-line treatment for patients… [press release]. Kenilworth, NJ and Woodcliff Lake, NJ: Merck and Eisai; November 10, 2020. Accessed January 30, 2021.
3. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma [press release]. Silver Spring, MD: FDA; January 22, 2021. Accessed February 1, 2021.
4. FDA approves avelumab plus axitinib for renal cell carcinoma [press release]. Silver Spring, MD: FDA; May 14, 2019. Accessed February 1, 2021.
5. Calithera Biosciences reports CANTATA study of telaglenastat in renal cell carcinoma did not achieve primary endpoint [press release]. San Francisco, CA: Calithera Biosciences, Inc.; January 4, 2021. Accessed February 1, 2021.

 

This article originally appeared on Cancer Therapy Advisor