Optimal Sequencing Key to Capitalizing on RCC Advances

Thai H. Ho, MD, PhD

The frontline treatment paradigm of renal cell carcinoma (RCC) has been shaken up over the past year with the success of immunotherapy combinations and the FDA approval of cabozantinib (Cabometyx).

Results from the CheckMate-214 trial indicated that frontline treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 32% compared with sunitinib (Sutent) for patients with metastatic RCC.¹ Among patients with intermediate- and poor-risk disease the risk reduction was 37%.

The phase II CABOSUN trial showed that cabozantinib reduced the risk of progression or death by 52% compared with sunitinib in patients with previously untreated advanced RCC, leading to the FDA approval.²

OncLive: Please give an overview of your presentation.

Can you speak to the findings of the ChekMate-214 trial, and other frontline treatments in development?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Malignancies, Thai H. Ho, MD, PhD, a consultant in the division of Hematology/Oncology at Mayo Clinic, discussed treatment advances in first-line RCC and how biomarker development and optimal sequencing are critical next steps to building on recent breakthroughs.Ho: I talked about first-line therapies, including various therapies that are already approved, as well as some of the agents currently under process. Some of the agents that I highlighted were sunitinib and pazopanib (Votrient), which were studied in the noninferiority trial COMPARZ. I also talked about the recent FDA approval of cabozantinib, which was based on an ALLIANCE phase II study, in which patients who met the poor- and intermediate-risk metastatic RCC consortium prognostic criteria were stratified to receive either cabozantinib or sunitinib. Patients who received cabozantinib had an improved PFS. CheckMate-214 combined a CTLA-4 antibody with an anti—PD-1 agent. These patients were stratified by IMDC risk criteria. Patients with intermediate- and poor-risk disease had an improved overall survival benefit when compared to the sunitinib comparator.

Please expand on the value of combinations in this setting.

How are molecular subtypes effecting sequencing?

Looking to the future, where do you believe research needs to be focused?

One of the challenges in first-line therapy is that we have all of these various tyrosine kinase inhibitors (TKIs), VEGF blockade, as well as high-dose interleukin-2 (IL2) and rapalogs. The challenge has been identifying agents that improve upon complete response (CR). Traditionally, the use of IL2 has been limited to specialized centers, even though it was approved in 1992. This is due to special handling requirements and the toxicities associated with it. With the new frontline therapies, [investigators] are trying to boost the CR rate by using immune checkpoints. The…major [study was] the IMmotion150 study, which was atezolizumab plus bevacizumab, that looked at the rationale for combining VEGF blockade with immune checkpoints. The rationale for doing combination therapy is that you can target 2 different mechanisms of action at the same time. You can target VEGF, which is one of the drivers of angiogenesis in RCC. And to get a durable response, you can use immune checkpoint therapy, which restores tumor immune surveillance. If tolerable, combinations afford the ability to shrink the tumor early on, and provide the potential for durable response. In terms of molecular subtypes from The Cancer Genome Atlas analysis, we learned that there are certain mutations that are recurrent in RCC. These include Von Hippel—Lindau (VHL), which is the most common mutation, followed by polybromo 1 (PBRM1), BAP1—these are common alterations in the epigenetic pathway. Dr Toni Choueiri of Dana-Farber Cancer Institute published that certain types of epigenetic mutations are associated with a favorable response to immunotherapy. Those are the molecular genotypes that we are currently studying now. There are also some molecular phenotypes, where you can define patients as poor- and intermediate-risk, based on routine lab work. These patients who have poor- or intermediate-risk are the ones who were enriched in the CABOSUN study, leading to their approval of cabozantinib, as well as the patients studied in CheckMate214 that had an improved response with the combination of nivolumab and ipilimumab. Even though we know about all of these various mutations in kidney cancer, we do not integrate them into our clinical routine. That is one area of need, whereas some of the other solid tumors, such as colon, breast, and lung cancer, have therapies that target certain molecular alterations. In kidney cancer, we unfortunately do not have any of that right now.

What is your take-home message for community oncologists?

The other challenge is finding the optimal sequencing of therapies, because now with potential combination VEGF blockade with immune checkpoint versus 2 different immune checkpoint inhibitors, it’s going to complicate the waters in terms of first-line sequencing versus second-line sequencing. I think that one of the things to keep in mind is that with these immune checkpoint therapies, they have a slightly different adverse event profile. When you suspect any pneumonitis or autoimmune colitis, I would start steroids earlier rather than later, because I think some of these side effects can cause issues if not recognized early. There is some emerging data from various groups in France and at Dana-Farber that suggest that, even if you use steroids, you are still able to preserve the durable response to immunotherapy. With the TKIs, it is also important to remember that you can dose-adjust and not feel like you should be locked into a particular dose level, but feel free to adjust the dosing schedule to potentially increase the tolerability of these TKIs. It is a very exciting time in RCC, I think the field is going to expand and become more complicated.

References

1. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.
2. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.