A “Negative” RCC Trial Informs Treatment Decisions in Refractory Disease

In a one-on-one conversation between Brian Rini, MD, and Elizabeth Plimack, MD, MS, they discuss the results of the CONTACT-03 trial, presented at the 2023 ASCO® Annual Meeting, which showed what physicians “shouldn’t be doing in practice” for their patients with RCC.

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Dr. Rini: The last topic we’re going to talk about is CONTACT-03, which I think was, in many ways, the most important data in ASCO 2023 even though it was a negative trial. The background is that, as we just talked about, immune-based doublets are an initial standard of care, so this checkpoint inhibitor-refractory kidney cancer population is an increasingly common one. Now especially also with the use of adjuvant pembrolizumab, that many, many patients are going to become refractory to immune checkpoints. It’s probably the biggest population of patients we see now. We really didn’t know whether single-agent tyrosine kinase inhibitor (TKI) is the right standard or should an immune-based doublet be the standard. Stated another way is, do you have just one shot of immune therapy or can patients benefit from sequential immune therapy? There were single-arm trials of immunotherapy (IO)/TKI doublets showing benefits, but there was no randomized trials until CONTACT-03.

This was a trial that took immune-refractory kidney cancer patients; I believe about half got immune therapy frontline, half got second line. It’s a pretty typical, in my opinion, representative population of IO-refractory kidney cancer randomized to cabozantinib monotherapy or cabozantinib plus atezolizumab, which again in many different single-arm phase 2 trials and cohorts had shown activity. This was a very strikingly negative trial. Response rates were the same in the 40% range, progression-free survival (PFS) was the same in the 10-plus month range, overall survival was identical, I mean, the curves are entirely overlapping. Importantly, toxicity was increased, not surprisingly, in the combination arm, including a small number of toxic deaths. You got more toxicity, even to the point of grade 5 toxicity, with no discernible benefit.

I think it’s really important because this was happening in practice where, I would say, a lot of patients referred who were getting immune-based doublets in the second or third line when they had had it just previously. I don’t think it asks and answers all questions in this setting. Atezolizumab is a PD-L1 inhibitor, which has less activity. There was only 2 adjuvant patients. Patients rolled right into subsequent immune therapy; there was no gap, and that’s something we might see in practice. I think while it’s not the end of the story, it’s, to me, a pretty convincing evidence that we shouldn’t be doing this in practice.

Dr. Plimack: Yeah, I agree. I think this struck a blow to the idea that we can alter immune therapy and maintain the response. It’s something we all hope for, especially for patients who do really well for a long time on immunotherapy. When we lose that response, it’s a hard transition to single-agent TKI. I think this study comes close to being definitive for answering the question, can you give IO after prior IO? I just don’t think it’s definitive, mostly because I don’t think atezolizumab is the strongest immunotherapeutic that we have. We have new ones coming up the pike; I hope those continue to be explored in this setting. Maybe not a large randomized phase 3, but at least some pilot work to see if maybe with better immunotherapy we can achieve a different result. Any study in the IO-refractory population is obviously stacked against IO sensitivity because the patients who were sensitive are still on it and doing well. The patients who progressed through it are the ones who went on this study.

I think we learned a lot about cabozantinib post our new standard in the frontline. The response rate around 40% was great, really good to see. Some of this study was negative because of the strength of the control arm; it’s a very good TKI, which covers a lot of patients with clear cell renal cell carcinoma. But I don’t think this is totally the end of the story or the answer to the question, but I do think it reinforces that choosing the best upfront therapy that gives the patients the best chance of response, in my book, is the way to go when you’re making that decision at the frontline.

Dr. Rini: I agree. I don’t save therapies. I give whatever I think is best, and I’ll worry about the second therapy when the time comes. As you alluded to, there’s a TiNivo-2 study which uses nivolumab as a PD-1 inhibitor, which ostensibly certainly has more data than atezolizumab and more survival benefit in multiple settings. That’s with tivozanib versus tivozanib alone. That’ll at least answer the mechanism question of PD-1 versus PD-L1. I don’t think that’s going to necessarily be the difference, but we’ll see; that trial is accrued, and I assume results in the next 12 to 18 months.

As you point out, cabozantinib did really well in this study. I think there’s a few reasons for that. One is, as you say, you’ve selected out all the immune responsive patients and so you’ve probably enriched for an angiogenic responsive cohort. We’re seeing high response rates along with PFS. There’s probably some lingering effect of the IO in my opinion, based on half life or T-cell persistence. That’s a hypothesis of course. But we’ll see when we see the tivozanib monotherapy arm of TiNivo-2 that I just mentioned, and I’m guessing it’s going to be a pretty high response rates along with PFS, if I had to guess.

I think it just, as you said, reestablishes or reinforces that an IO-based doublet is frontline standard of care. I think, quite unexcitingly, single-agent TKI is the standard of care. We all wish there were better, we all want multiple shots of cure; it’s not from lack of desire or lack of trying, but the data is the data. I think the burden of proof, to me, especially given the toxicity, is proving that sequential immune therapy works. Not necessarily proving that it doesn’t.

Dr. Plimack: We can evolve the immune therapies beyond PD-1 PD-L1.

Dr. Rini: For sure.

Dr. Plimack: We can continue to ask this question as we improve upon the efficacy of the immunotherapies.

Dr. Rini: I have a bias that novel immune therapies are still going to need to be studied in an immune-naïve population, which I understand is difficult, but I feel like if we keep studying novel immune therapies in immune refractory, we might miss some important signals. There’s some data with a LAG-3 inhibitor in melanoma that would suggest that. It’s going to be incumbent upon us as a research community to be willing to randomize or treat those frontline patients perhaps with PD-1 plus novel immune X and not wait until the refractory setting. That’s my personal bias.

Dr. Plimack: Yeah, I think a different way of looking at that is that we need a drug that actually works after the drugs we already have. That’s where the greatest need is. If a drug is powerful enough, I agree it has a better chance of working in a naïve setting, but the best ones will work even when the chips are stacked against them. That’s what I’d love to see, aspirationally.

Dr. Rini: Fair enough. I think just to wrap this up, CONTACT-03 was a really important piece of data that was cautionary against using sequential immune therapy. As you said, it’s not the end of the story, it didn’t ask and answer all questions. There was only 2 patients who got adjuvant therapy in that study; there’ll be more in TiNivo-2, I assume. There’s other bits of data coming in. When TiNivo-2 comes in, if that’s negative, I think that probably is the end of the story, at least for PD-L1 inhibition. But I think it’s really important clinical data.

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