New First-Line Combination Therapies in Advanced RCC - Episode 17

mRCC Treatment: Novel-Based Approaches on the Horizon

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An overview of novel-based treatment strategies and biomarkers that are currently under investigation to help address current unknowns when treating patients with metastatic renal cell carcinoma.

Sumanta Kumar Pal, MD: We’re going to shift gears and talk about trials on the horizon. We talked a lot about the data that’s hot off the press from the ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], particularly the CLEAR study looking at quality of life and CheckMate 9ER. I’m going to turn to Tian because she’s 1 of the folks at the forefront of a lot of these emerging studies. Can you tell us about what’s next in kidney cancer?

Tian Zhang, MD: Sure. Thank you for that. We’re now firmly in the immunotherapy era of trials. These contemporary trials are based on what we’ve learned from CheckMate 214 and all these immunotherapy regimens. We have COSMIC-313, which just finished accruals of the triplet cabozantinib-nivolumab-ipilimumab compared with nivolumab and ipilimumab alone. We have our PDIGREE trial in the Alliance Cooperative Group, which is an adaptive phase 3 trial. It’s ipilimumab with nivolumab up front, followed by randomization to nivolumab or nivolumab with cabozantinib at the 3-month response. We also have special populations. We talked a little about cytoreductive nephrectomies. The PROBE trial is investigating up-front immunotherapy combinations with or without cytoreductive nephrectomy. There are really pertinent clinical questions in all these trials, and we’re basing all these regimens on the immunotherapy combination standards of care right now.

Sumanta Kumar Pal, MD: Thanks a lot, Tian. That’s a great overview of what’s to come. It’s so critical that we all think about these clinical trials for our patients. It’s clear we still have a ways to go to optimize their care. One other topic that we have to cover is biomarker development in kidney cancer. Dave, I don’t think I’ve been to a meeting over the past 3 or 4 years where I haven’t seen a graphic from your IMmotion150 paper. That’s still frequently cited as perhaps the potential of biomarkers in the kidney cancer space. How close are we to identifying a predictive biomarker in this disease that helps us home in on the best frontline treatment?

David F. McDermott, MD: It’s safe to say we continue to learn from the analysis of tissue, and not just tumor but increasingly blood. We’re learning a lot about the biology of kidney cancer. IMmotion150, the phase 2 trial of atezolizumab-bevacizumab, was not designed to come up with a biomarker. It was more designed to look at kidney cancer biology and connect biology with outcome in hopes of moving toward that. The phase 3 trial with atezolizumab-bevacizumab did do that. In that recent cancer cell paper from November 2020—Bob Motzer is the first author—we have 7 categories of kidney cancer that may be relevant in predicting which patients have more angiogenic-driven tumors that could get VEGF alone, which group seems to respond to I/O [immuno-oncology]–based regimens, and then several other groups that may need completely different therapies that we need to develop, like cell cycle inhibitors or novel therapies we haven’t even developed. That is 1 way we need to go. We need to get more rational about our application of PD-1, particularly as the toxicity goes up. In the ideal world, we would make it easier for people to choose ipilimumab-nivolumab by narrowing the population of patients who are going to benefit. That may be 1 way of securing that space for a toxic regimen, particularly if you’re going to build on it with something that’s even more toxic.

If you’re doing single-agent TKIs [tyrosine kinase inhibitors], we do have markers that predict that benefit. The problem is the clinical development is outstripping the biomarker development. You’re essentially fusing the 2 biologies together with the predominant first-line strategy. So if everyone’s going to get PD-1 and VEGF in the front line, you can’t select the winners there. You might be able to select patients who will never get a benefit, but that’s going to be a small group. More important than just doing predictive work, we should be studying these tumors to understand resistance so we can come up with novel therapies. This is going to be critically important when we think about what works after PD-1. We continue to do tissue-based trials and continue to learn. It’s the only way we’re going to find more cures in kidney cancer. Coming up with a marker like we have in melanoma or lung cancer doesn’t seem to be on the immediate horizon for kidney cancer.