Experts Debate PD-1 Rechallenge After ICI Progression in RCC

Renal cell carcinoma (RCC) treatment after progression on prior immune checkpoint inhibitor (ICI) therapy remains a clinical challenge, particularly when considering whether to rechallenge with PD-1/PD-L1 blockade. In a virtual Case-Based Roundtable event, Sumanta Pal, MD, FASCO, medical oncologist and co-director of the Kidney Cancer Program at City of Hope, led a discussion with oncologists in the Southwest, Rocky, and Pacific Regions on the role of ICI rechallenge after progression.

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This part 2 of a 2-part series. Read part 1.

EVENT RECAP

Prior to discussion, the group reviewed the data from 2 trials in advanced RCC following progression on prior immune checkpoint inhibitor (IO) therapy. They first reviewed data from the phase 3 TiNivo-2 study (NCT04987203), which evaluated tivozanib (Fotivda) plus nivolumab (Opdivo) vs tivozanib alone.¹ The group also reviewed data from the phase 3 CONTACT-03 study (NCT04338269), which studied atezolizumab (Tecentriq) in combination with cabozantinib (Cabometyx) vs cabozantinib alone.²

DISCUSSION QUESTION

• Do you agree that the results of the TiNivo-2 and CONTACT-03 studies clearly demonstrate that anti-PD(L)1-antibody rechallenge is not efficacious?

Sumanta Pal, MD, FASCO: What are your thoughts? Do you feel quite confident that perhaps we shouldn't rechallenge with PD-1 or PD-L1?

Rishi Sawhney, MD: I think we have pretty definitive data in terms of looking at…the response rates. And I think what we run into this second-line situation is, patients are already coming in with progression; they are already beat up and are trying to use a doublet again that may lead to some toxicity without any efficacy. I think I pretty much agree that there isn't a role for repeating IO rechallenge.

I think what I found interesting was the tivozanib data post IO-IO—a pretty robust 32% response rate. [Dr Pal], I think you mentioned that in a robust [case] you would still go for cabozantinib, maybe in a frail [case] go for tivozanib. How do you do that in the practice setting? Obviously not doing cross-trial comparison, but what we see is with cabozantinib, we have response rates that [range from] 32% and even some studies all the way up to 40%. And with cabozantinib, in spite of dose modification, we are still able to get a good robust response. I'm just trying to figure out in my mind, in that IO-IO patient, should I change my practice pattern to go away from cabozantinib and look at tivozanib? That's kind of the question I have in my mind, looking at these data.

Pal: It's a great question. I feel like you sort of know it when you see it, right? You have that patient in front of you who's maybe struggling to get to the clinic and needs a robust response after progressing on nivolumab-ipilimumab [Yervoy], but you think is no way going to tolerate a full dose of cabozantinib; those are the ones where I'm sort of thinking about tivozanib. It's hard to paint a precise picture of it. On the other hand, if you have a 45-year-old patient who's progressed on nivolumab-ipilimumab fairly quickly and wants to be super aggressive about his disease, those are the patients where I'm thinking, let's give it a shot with cabozantinib. So, it really just relies on that good old clinical intuition, I would say, to make that decision. It's a great question.

Robert Havard, MD: I have a patient with metastatic disease who came off nivolumab after starting on cabozantinib-nivolumab, and she stopped that because of a rectovaginal fistula that she developed, and then we continued maintenance nivolumab. She was on that for 3 years without progression and just had a brain metastasis. I'm in this position where I'm deciding what to do. It seems like if they're off IO, would you rechallenge, or are these data not supportive of that either?

Pal: How long has she been off IO now?

Havard: Her last nivolumab dose was a year ago, and now she has a brain metastasis. So, I was almost thinking about doing dual checkpoint vs—I don't know, I think you could really do a grab bag of options here… but she hasn't had any therapy in a year.

Pal: Does she have any other systemic progression elsewhere?

Havard: There's no other systemic progression. It was just a [central nervous system] progression.

Pal: The data for checkpoint inhibition in RCC are so different from the data in melanoma, where it really looks like checkpoint inhibitors evoke responses across the blood-brain barrier. And in RCC, the data that we have come from a French study, and it looks to be a bit weaker from that perspective.³ So I personally would suggest just treating the brain—give her stereotactic, and then just watch her to see if she progresses elsewhere.

Havard: She just finished radiation. I was just trying to decide whether to put her back on treatment or not.

Pal: Because it's a bit of an oddity. I've seen a handful of these patients very recently, and I think it's, from the patient's perspective, a little harrowing to think, “Oh gosh, I just had this systemic disease evolve, and my doctor wants to watch me.” But it might actually be best for her to save her from any therapy unless she has true, more overt systemic progression.

Havard: Right. Well, thank you for the quick tumor board. I thought it was actually applicable.

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DISCLOSURES: Pal previously disclosed institutional research funding from Eisai, Genentech, Roche, Exelixis, Merck, Osel, Adicet Bio, ArsenalBio, Xencor, Miyarisan Pharmaceutical, Pfizer, CRISPR Therapeutics, and Allogene Therapeutics.

REFERENCES

1. Chehrazi-Raffle A, Motzer RJ, Beckermann K, et al. Efficacy of second line (2L) treatment with tivozanib (Tivo) as monotherapy or with nivolumab (Nivo) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with an immune checkpoint inhibitor (ICI) combination of ipilimumab (Ipi)/Nivo or vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)/ICI in the phase 3 TiNivo-2 study. J Clin Oncol. 2025;43(16_suppl):4540-4540. doi:10.1200/jco.2025.43.16_suppl.4540

2. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4

3. Flippot R, Dalban C, Laguerre B, et al. Safety and Efficacy of Nivolumab in Brain Metastases From Renal Cell Carcinoma: Results of the GETUG-AFU 26 NIVOREN Multicenter Phase II Study. J Clin Oncol. 2019;37(23):2008-2016. doi:10.1200/JCO.18.02218