COSMIC-313 and Role of Triplet Regimens in Frontline Setting in Advanced RCC


A panel of experts on renal cell carcinoma discuss triplet therapy and review COSMIC-313, a study of cabozantinib, nivolumab, and ipilimumab in the first line.


Elizabeth Wulff-Burchfield, MD: I’d like to talk a little about COSMIC-313 and then round out our discussion. This has been an interesting and evolving story. If I had participated in a pool about this, I would have lost in terms of what I thought we might be seeing. Such great lessons have been learned here. COSMIC-313 was presented last fall [at the European Society for Medical Oncology Congress]. It included intermediate- and poor-risk patients who had at least a clear cell component to advanced renal cell carcinoma on their first line of systemic therapy. These patients were randomized to receive nivolumab-ipilimumab plus placebo vs nivolumab-ipilimumab plus cabozantinib. This is the most modern comparison that we’re seeing. To see that the comparator was nivolumab-ipilimumab is meaningful. The use of placebo may have impacted some of the treatment decisions that were made. That’s one of my own theories, and it’s important.

The primary end point was looking at progression-free survival [PFS]. Even though that wasn’t the primary end point of CheckMate 214, I understand why the investigators did that given that they had cabozantinib. We have a table looking at progression-free survival. It hasn’t been reached yet, so the jury is still out. We have some other end points. I’m not sure if we have slides for that, but we’re still waiting on additional updates to understand the degree of benefit patients derived from this investigational regimen compared with nivolumab-ipilimumab. We’re seeing a hazard ratio of 0.73, but potentially we’ll see it evolve over time.

Unfortunately, we don’t have some of the data about overall response rates, even though that’s some of what we’ve been thinking about. In looking at these data, some things I find interesting are the difference in the liver signal with the investigational regimen compared with the standard-of-care regimen of nivolumab-ipilimumab. As with CheckMate 9ER, the rate of any-grade and high-grade AST and ALT elevation was quite a bit higher. It’s not included on this slide.

The rate of steroid use was substantially higher in the investigational regimen. There have been a lot of questions about the extent to which the placebo control may have contributed to investigators wanting to pull the rip cord on steroids sooner if they thought that their patient might be getting a placebo and therefore something like diarrhea, or elevated AST-ALT may have been immune related rather than more chemically related from the VEGF TKI [tyrosine kinase inhibitor]. There are a lot of theories floating around about that, but we’re going to see a lot more. Many of us are eager to see the longer-term follow-up, to get not only that primary end point mature but also a sense about durability of benefit and what patients may have experienced. What other benefits could be derived from that triplet therapy?

I’d love to hear from you all about the availability of triplet regimens and how it does? How might you project it so that it could impact treatment choice in the first and subsequent settings? I’ve heard some great debate on this from 2 of our panelists. Dr McKay and Dr McGregor, I’d love to hear your thoughts regarding triplet therapy and how it impacts decision-making. Do you have any thoughts about how you expect it to?

Rana McKay, MD: The data are premature. They’re not ready for prime time. We need to see more data presented about the trial—follow-up data and overall survival data. Other triplet regimens are being investigated, so that’s going to be informative. Is it going to be something for everybody? Probably not. Is it going to be something that could be used for a subset of patients? I don’t know. We’ll see.

Keep in mind that the COSMIC-313 population was dramatically different from all the other phase 3 trials that were reported out. All of us want to compare the response rates, the CR [complete response] rates, and all the efficacy data, but this patient population was different: 0% of patients had favorable-risk disease on this trial, compared with almost one-third with the KEYNOTE-581 study, and 69% had prior nephrectomy. We’re seeing the lowest rates of prior nephrectomy and sarcomatoid disease. The patient population was different, so I don’t know if we’re going to see those same numbers that we saw for the other studies because of that. That being said, toxicity is something we need to understand better and whether there’s a potentiating effect of the added ipilimumab with cabozantinib. Is this unique for cabozantinib, or is this unique to the triplets? I don’t think we know those data yet.

Bradley McGregor, MD: I agree 100%. The triplet data are certainly intriguing but ultimately very confusing. The toxicity concerns are very real. One thought I had going into this is that if I have a patient with poor-risk disease, I can throw the kitchen sink [at them]. That’s who’s going to get the most benefit. They presented some subgroup analysis, and the poor-risk patients didn’t have any benefit with the cabozantinib even though it looks like the dose amount, exposure, and treatment are the same. If you look at the PFS curve, maybe intermediate-risk [patients] get the real benefit. There seems to be some separation of the curves. They seem to be maintained with short follow-up, so longer-term follow-up is going to be important.

Who is the right patient? Right now, I don’t think we can say the poor-risk patient is where we have to go all in. The concerns are real. Triplets may have a role, especially in variant-histology renal cell carcinoma. We have an ongoing IST [investigator-sponsored trial] with the combination of cabozantinib-nivolumab-ipilimumab…in non–clear cell [carcinoma with] all the variant histologies. Given what we saw, the cohort is starting dosing at 20 mg in cabozantinib to see if giving a lower dose of cabozantinib up front can mitigate some of the toxicity concerns and still have some efficacy. That’s enrolling at Dana-Farber [Cancer Institute] and UCSD [University of California San Diego]. It’s certainly an option.

For triplets, adding to therapy is what we’re looking at. The ongoing trial is lenvatinib-pembrolizumab vs lenvatinib, pembrolizumab, and the HIF2 inhibitor belzutifan or lenvatinib-pembrolizumab and a low-dose CTLA4 inhibitor for the entire 2 years. That trial is rapidly accruing. It’s going to be accrued over the next several months, and that’s going to be the next line of triplet therapy that will hopefully help us better determine how to treat our patients.

Elizabeth Wulff-Burchfield, MD: I’m glad to know that those trials are enrolling as quickly as we were hoping they would. Oncologists are always data hungry, so we’re always ready for the next thing that we can present to our patients. I’m also a palliative care doctor, so I love that we’re learning from the data that we have and asking, with all these regimens, “At what cost?” With treatment intensification, that needs to be the next question. Efficacy, but at what cost? It’s great to see that being incorporated into trial design in new ways. This is such an exciting time to practice in the field.

Transcript edited for clarity.

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