Sequencing Therapies for Advanced RCC


Experts discuss how they sequence I/O–TKI treatments for advanced renal cell carcinoma.

Robert Alter, MD: The bigger question that we always think about is sequencing therapy. We always think about what we have next for our patients. When we had I/O [immuno-oncology] therapy, the sequencing was easy. We gave them a TKI [tyrosine kinase inhibitor]. In the old days, when we had only TKIs, our limited choices were that when you failed a TKI, you went on an mTOR [inhibitor]. If you failed on an mTOR, you went on a TKI. Then you bring in a new mechanism of I/O therapy.

The purists would always say that I/O–I/O was good. Now when we’ve treated with up-front I/O–TKI therapy, the question I always get asked is, “What do you treat when they progress?” It’s so hard to know. There aren’t any first-line data that have good evidence at this point. Level 1 evidence has yet to be proven. But if you progress after receiving first-line lenvatinib-pembrolizumab, you’re probably going to receive Cabometyx [cabozantinib] at this point. I wouldn’t use single-agent mTOR therapy. It’s interesting, because I’ve always used lenvatinib-everolimus as a second- or third-line measure on patients who failed a TKI. I don’t think we have that opportunity. If you fail lenvatinib-pembrolizumab, we can’t use lenvatinib-everolimus as your next therapy. It’s going to be a sequence of therapies.

Eventually, we’re going to have to incorporate tivozanib into this conversation. Tivozanib is a regimen we’re going to have to start playing with. Belzutifan is another regimen coming. It’s FDA approved in patients who have VHL mutations, but soon we’re going to have enough data. Michael Atkins presented data at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] 2 years ago, and that’s going to result in more approval. That’s the question. If you use a great regimen up front with an I/O–TKI, what do you use in the second line? Now that we have KEYNOTE-564 data presented that look at adjuvant immunotherapy, what happens to our patients if they progress at that point? What do you think? How would you take care of those patients?

Elan Diamond, MD: The answer is unknown at this point because this is uncharted territory. These are data that came out very recently. We haven’t had the chance to have clinical experience or conduct clinical trials in this disease space. When I imagine what I’d do in that setting, it would depend on when the patient progressed following treatment with pembrolizumab.

For example, I have a patient I’m treating with adjuvant pembrolizumab. He had T3 N1 clear cell renal cell carcinoma, got a couple of cycles of pembrolizumab, and then developed omental metastatic disease. This is a patient who clearly is refractory to the I/O mechanism. This is someone whom I focus on TKI-based therapy, with either cabozantinib or lenvatinib-everolimus. But then you may have a patient who has recurred 2 or 3 years later, and the question is whether you can rechallenge them with an I/O–I/O or an I/O–TKI combination. That’s unknown at this point, but it’s very tempting based on a priori reasoning. That’s probably what I’d do in that situation.

Robert Alter, MD: Yes. Good case.

Transcript edited for clarity.

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