Unraveling the Efficacy of PD-1/PDL-1 Re-challenge in Kidney Cancer: CONTACT-03 Study - Toni K. Choueiri

June 2, 2023

Alicia Morgans interviews Toni Choueiri about the CONTACT-03 study, which explored the efficacy of re-challenging patients with renal cell carcinoma (RCC) using a PD-1 or PDL-1 inhibitor, post-tumor progression on prior PD-1 or PDL-1 inhibitor treatments. The study specifically used atezolizumab (a PDL-1 inhibitor) and cabozantinib (a tyrosine kinase inhibitor or TKI). The findings, unfortunately, showed no benefit in progression-free survival, overall survival, response rate, or complete response. The combination therapy also presented higher toxicity. Subgroup analysis also found no significant differences. This implies the possibility of sparing patients from unnecessary toxicity by avoiding the additional use of PD-1/PD-L1 inhibitors in these scenarios. Despite the disappointing results, Dr. Choueiri hopes this study will spark similar investigations in other types of cancer. A further study (Nivo II) examining similar issues in renal cell carcinoma is ongoing and currently recruiting participants.


Toni K. Choueiri, MD, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Toni Choueiri, where we're talking about CONTACT-03, which was simultaneously published in the Lancet and presented at ASCO this year. Thank you so much for being here with me today.

Toni Choueiri: Thank you Dr. Morgans for having me.

Alicia Morgans: Wonderful. So this is a really interesting study. Can you set up for us what the premise was and what you investigated?

Toni Choueiri: Yeah, no. I think one of the question that get answered that surprisingly we haven't found a lot of data, if any, and even other tumors beside kidney cancer. So kidney is the first to launch that study in a phase three fashion, is the use of PD-1, PDL-1 inhibitor. We're going to call them IO, but just their PD-1, PDL-1 inhibitor. Post progression, tumor progression, on prior PD-1, PDL-1 inhibitor. And we see this practice, I can tell you in kidney cancer I see patient who had nivolumab ipilimumab, they didn't experience benefit and they moved to pembrolizumab, lenvatinib, pembrolizumab, axitinib. The other day I saw patient and that also didn't benefit from nivolumab ipilimumab. And then they were put on Cabozantinib nivolumab because that combo is approved first line. So we asked whether re-challenging after progression on prior PD-, PDL-1 makes any sense.

For that the PDL-1 inhibitor was atezolizumab. The TKI was Cabozantinib. And we know Cabozantinib is a standard post first line, as well as first line treatment. But in this situation, patient whose tumor progressed on prior PD-1 or PDL-1 based therapy were randomized to Cabozantinib 60 milligram first Cabozantinib plus atezolizumab. The safety for Cabozantinib atezolizumab was established already. Was established from prior trial, not in untreated patient and no prior TKI. Overall there was a lot of patient who had TKI followed by nivolumab. Some of them had nivolumab ipilimumab first line. But the bottom line in this 500 plus patient that involved clear cell. As well some of the unclear cell, we did not see any benefit. Any benefit. There was no... The primary endpoint was progression-free survival. There was no benefit in progression-free survival, none in overall survival, none in response rate, none in complete response, none in PD as best response.

Even more the toxicity was higher, at least numerically, in the combination arm. We looked at several subgroup analysis. Sarcomatoid patient who received a TKI versus not. Gender, age, there was no difference. No difference whatsoever. And the toxicity were higher. So we call into practice in renal cell for sure, but I would venture to say in other malignancies where PD-1 and PDL-1 inhibitor, this practice of sequencing I call it... There aren't many studies like that, so I call on other expert in tumor type to do these phase three studies where post-progression on PD-1, PDL-1 inhibitor, you randomize the patient to drug A versus A plus pick a new PD-1, PD-L1 inhibitor. Now, you may argue atezolizumab is not as effective and active as other immune checkpoint inhibitor. I would argue that as a single agent, an untreated clear cell RCC from IMmotion 150 atlizumab response rate is 25%.

That's not an inert agent. So that's what we did. And I think the study should have implication. That's different than challenging after PD-1 inhibition with let's say Nivo ipi because that could be ipi only. But I think one more piece of the puzzle we're going to learn, if you can challenge with a PD-1 inhibitor. We have a study also in renal cell. Renal cell paving the way and geo malignancies paving the way for other tumors. We have a study by the name Nivo II where patient also who experienced progression on prior PD-1, PDL-1 inhibitor will be randomized to tivozanib. It's an accepted standard of care versus tivozanib plus nivolumab. So if you say, "Oh, that's the PD-L1 inhibitor atezolizumab, now you have nivolumab." So this study is currently as the time of the conduct of this interview ongoing and accruing.

Alicia Morgans: Wonderful. And to your point, it's really important that we investigate these things because if in our day-to-day practice we are switching from a combination that has a PD-1 or PD-L1 inhibitor to a different combination, even if that combination is known to be a good one, pembrolizumab and axitinib for example. Or ipi and nivo for example, we know that these combinations can have activity. But to your point, it could be the other agent. And it probably is the other agent that's really driving the responses that we might be seeing. And we could spare our patients the toxicity of that second agent or of that PD-1, PD-L1 agent I should say, if they don't need to be on it.

Toni Choueiri: Absolutely. The toxicity also to the society itself and the healthcare system, the financial toxicity. These are not cheap agents. And we'll be happy to be proven wrong with other solid tumors. I think we should investigate that.

Alicia Morgans: Yeah. Well, so your take home message from this really important trial is just switch to Cabozantinib. Is that what I understand?

Toni Choueiri: Cabozantinib, I think, or a TKI. I think the response rate seen with Cabozantinib is the higher we've seen. Usually what we've seen before from trials is 20 to 30%. Here it was 40%. So it's really interesting and that make me think is that a carrying effect from the prior PD-1 inhibitor, what's happening? But it was really very disappointing to us not see any subgroup benefiting. It was just like, where did that go? What did we do?

But let's see what the Nivo II will show. We will also look at some correlative. Although when you have a negative study, you know how that goes. We will look at correlative, the sponsors, Roche here have done very elegant work in the past with IMmotion 150 151 and others. So we are going to team up our team and other members of the steering committee to look at specific biomarkers. We're going to look at FC with Dr. Braun and others. Maybe we can tease out something because these are baseline patients that are exposed and experienced progression their tumors on prior PD-1 inhibitor. But I wouldn't be surprised if I don't find anything.

Alicia Morgans: Interesting. So other than the correlatives, is there anywhere else to go from here other than really repeating this, maybe another tumor type?

Toni Choueiri: I would love to repeat it in other GU tumors like bladder cancer. So imagine a patient that got GemCis, GemCarbo let's say the standard of care doesn't change, then they get maintenance avelumab. And later on the tumor experience progression, maybe this one study design will be give them an antibody drug conjugate alone versus an antibody drug conjugate plus a new PD-1, PD-L1 inhibitor. Maybe pembro, maybe... Who knows? But I think it's important. And maybe it shows something else, but if the wealth of information coming doesn't show that activity, then the answer will be that you will use a PD-1, PD-L1 inhibitor first and foremost when it's applicable. And it may have implications in the adjuvant setting, knowing that we have to be careful how we define progression patient. The last therapy has to be PD-1, PDL-1 inhibitor. You could not have had, let's say, great response, came years off, then... That's not, that is real recent progression.

Alicia Morgans: And I think that makes sense. Your example in urothelial carcinoma is very prescient. Given that EV pembro is a combination that we're now planning to use and are using. And is this something that we should give? Or if they've had progression on a PD-1 or PDL-1 one in the past, even in the adjuvant setting, should we maybe just give the EV?

Toni Choueiri: Correct.

Alicia Morgans: I don't know. I think that's a really, really interesting question that we ask ourselves all the time. And you and your team actually put together a study to answer the question. So I congratulate you, and I thank you and the patients for doing the work to help us understand how to put the best foot forward.

Toni Choueiri: They always go back to the patient, the families. They're the one that really goes through this. So without them, there will be no clinical trial. There'll be no research.

Alicia Morgans: Well, thank goodness for them. And thank you and your team for doing this too. And thank you for your time today.

Toni Choueiri: Thank you. Thank you Dr. Morgans, and PCF, and UroToday.