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Cabozantinib plus nivolumab, a combination approved in 2021 for metastatic clear-cell renal carcinoma, showed promising efficacy in some patients with non-clear cell disease, said authors of a phase II trial.

"Although therapeutic approaches have evolved greatly over the past decade for metastatic clear cell disease, treatment standards for nccRCC [non-clear cell renal cell carcinoma] remain poorly defined," said Chung-Han Lee, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues. "Non–clear-cell kidney cancer represents a diverse mix of histologies and has been more resistant to treatment."

The study, published in the , included two cohorts of patients treated with the combination and followed for a median of 13 months. The first cohort (n=40) comprised patients with papillary, unclassified, or translocation-associated non-clear cell disease. The second (n=7) included patients with chromophobe disease.

The patients with chromophobe disease did not respond to the treatment. But in the other cohort, the objective response rate was 47.5%, median progression-free survival was 12.5 months, and the clinical benefit rate was 71%, Lee and colleagues said.

"Cabozantinib plus nivolumab showed promising levels of activity in non–clear-cell histologies. Larger studies are necessary to see whether histologic subtypes or genomic factors may lead to differential responses to systemic therapy," the researchers concluded.

Lee elaborated on the results in the following interview.

What is the current standard of care for patients with non-clear cell renal cell carcinoma, and how well does it work?

Lee: The current standard of care for non-clear cell is, per NCCN [National Comprehensive Cancer Network guidelines], still a clinical trial. Historically speaking, in the absence of a clinical trial, there are two options that have shown efficacy, and that has been sunitinib, or Sutent, and then more recently, based off the trial, for people with papillary kidney cancer, they showed improvement in using cabozantinib over sunitinib in that setting.

Right now, we would typically use treatments that are directed toward clear cell for the non-clear cell space. However, we do know from an efficacy standpoint, the efficacy for non-clear cell overall has been worse, and this is why we have been interested in studying whether or not any of the combination therapies that are available can be superior or can get better efficacy results. Because certainly the efficacy for clear-cell combinations have done much better than monotherapy, and we're hoping to see whether or not that also translates for the non-clear cell space.

In your study, why do you think the combination did not demonstrate efficacy in patients with chromophobe carcinoma?

Lee: The combination we used was a combination of a VEGF [vascular endothelial growth factor]-targeted therapy plus an immunotherapy. One thing that we found quite interesting for chromophobe is it does seem to be an immune-excluded histology, so that may actually contribute to the fact that immunotherapy did not seem to work as well.

I think there is something unique about chromophobe. In other studies that have used mTOR inhibitor-based combinations, so that includes bevacizumab plus everolimus, and lapatinib plus everolimus, the chromophobes did seem to respond fairly well, so I think there is something very unique about that biology that may be very important.

You also looked at whether genetic alterations affected response to treatment in your study. What did you find?

Lee: We did targeted exome sequencing in the majority of patients that were on the clinical trial, and we did that for multiple reasons. The first was we wanted to verify that we didn't accidentally include any clear-cell patients, and we certainly didn't see that to be the case. Granted the numbers are small, so the subsets within non-clear cell, we're talking about very small numbers, but we did see some signals there.

We saw that people with mutations in FH and also NF2 seemed to respond fairly well to the combination. Historically speaking, people with those types of mutations are more resistant to treatment, but given the small numbers that we have, I think that we are excited to see a high response. Nearly all the patients with FH mutations or NF2 mutations had an objective response. That was unexpected, and it needs to be validated in larger studies.

And then we saw that for people with SETD2 mutations, only one of the patients had an objective response. Again, that's something that needs to be validated. I think we're very interested in seeing whether or not with larger numbers this initial observation will hold up.

Are there any additional trials planned or ongoing of combination therapies in this patient group?

Lee: Yes, so in this space I think there is a lot of interest in further developing things. Things on the near horizon that we're excited about are looking at other TKI [tyrosine kinase inhibitor]-IO [immuno-oncology] combinations. So right now there's an ongoing study with lapatinib plus pembrolizumab, so another TKI and another immunotherapy, to see what the response rates might be like in the first-line setting.

The other clinical trial that we're excited about is a combination of cabozantinib plus ipilimumab plus nivolumab, so thinking about whether or not triplet therapy for those more rare histologies might be beneficial.

And further beyond that, I think chromophobe remains an untapped space, so at some point we'll probably be thinking about more directed therapy specifically for that population.

How did the safety profile of the combination in your study compare with other patients with renal cell carcinoma?

Lee: I think we have a lot of experience with cabozantinib plus nivolumab based off the phase III trial in clear cell kidney cancer, and we didn't identify any new safety signals. I think that it's generally well tolerated for this type of combination, and the histologies did not have a huge impact in terms of the potential side effects related to it.

Is there anything else you want to make sure oncologists understand?

Lee: I think that non-clear cell is a very exciting space right now. We're starting to see more and more clinical trials in this setting. One of the things that's also very hopeful for non-clear cell, especially because it is this grab bag of histologies, so to say, is to remind all the oncologists that histology matters, especially when we're talking about slightly lower response rates.

The other thing to mention, because a lot of oncologists think about the other potential treatment options, for example other TKI combinations like axitinib plus pembrolizumab, is there's actually no prospective data for that regimen. And then dual immunotherapies such as ipilimumab plus nivolumab does show activity in this space, although the response rates are significantly lower than what we've seen in the clear-cell setting.

So I think it's important to think about what prospective data is available, and to really take that into account when selecting treatment regimens for patients with non-clear cell.

Read the study here.