Chung-Han Lee, MD, Memorial Sloan Kettering Cancer Center, highlights the phase 2 clinical trial results of nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma, presented at the 2021 ASCO Annual Meeting. 

Transcript

Hi. I am Chung-Han Lee at Memorial Sloan Kettering Cancer Center in New York, New York. Today, I will be talking about abstract 4509, which was the results of our non-randomized phase 2 clinical trial of cabozantinib plus nivolumab for patients with non-clear cell kidney cancer.

This was a clinical trial in which we looked at patients who had up to one prior line of systemic therapy with either advanced or metastatic non-clear cell kidney cancer and treated them at the FDA-approved dose of cabozantinib plus nivolumab, which is 40 mg of cabozantinib daily and either 240 mg IV of nivolumab every two weeks or 480 mg by IV every four weeks.

As you all know, this combination is FDA-approved based off of the results of the 9ER study, which studied solely clear cell kidney cancer. Non-clear cell kidney cancer still remains a very heterogeneous group of diseases and is essentially an orphan disease of sorts that we have bucketed together for all of the various histologies that are not considered to be clear cell.

Our study focused on trying to better understand how this VEGF-IO combination would respond to this diverse set of diseases. What we ended up doing for this study is we separated the diseases into two main cohorts, the first of which looked at people with either papillary, unclassified, or translocation RCC and also patients who had, as a separate cohort in Cohort 2, chromophobe RCC.

What we were interested in seeing is when we did this type of separation, what was the efficacy like, with a primary endpoint of looking at the objective response rate. What we noticed in our study was that there were actually distinct differences in the outcomes for our patients.

Within the first cohort, we enrolled about 40 patients and demonstrated an objective response rate of 47.5 percent. Whereas for the chromophobe cohort. We actually did not see any objective responses. We ended up closing that arm relatively early because of the lack of responses.

Within the patients with the papillary and unclassified and translocation cohort, we saw fairly impressive disease control rates of up to 97.5 percent, with a clinical benefit rate of 75 percent and a median progression-free survival of 12.5 months and a median duration of response of 13.8 months.

These results are very impressive, especially for still a relatively heterogeneous group of diseases that historically has been fairly resistant to systemic therapy. I think that the other key thing that we ended up seeing is within this disease group, the adverse events were fairly similar between what we saw within non-clear cell and clear cell kidney cancer.

Because this remains such a heterogeneous group of diseases, we did some correlative studies where we did targeted exome sequencing. We tried to correlate and see whether or not any of the mutations that we can find within this disease group were associated within the responses.

What we noted from our targeted exome sequencing is, as you would expect, there were no VHL mutations, as that is typically associated with clear cell type kidney cancer. The most common mutations that we saw were mutations in NF2, FH, SETD2, which are characteristic of this type of cohort.

Looking at those mutations specifically, we actually saw five out of six patients with NF2 mutations have an objective response, four out of five patients with FH mutations have an objective response, and only one out of six patients with SETD2 mutations achieving an objective response.

Certainly, a lot of this data needs to be interpreted with a lot of caution, given the fact that the numbers remain fairly small, but it does give some hint that maybe there is a correlation between the underlying mutational status and the efficacy of the treatments that really warrants further exploration.

In summary, I think that what we really have demonstrated is that the combination of cabozantinib plus nivolumab has showed promising efficacy for patients with metastatic non-clear cell renal cell carcinoma with papillary, unclassified, and translocation-associated histologies.

We really do need further genomic studies because our studies have demonstrated that there is quite a bit of heterogeneity within non-clear cell. I think that as we explore this more, we may end up finding things that may help guide us and predict response.