Promising Results of Cabozantinib/Nivolumab in Non-Clear Cell RCC Could Guide Future Research

Chung-Han Lee, MD, PhD

The combination of cabozantinib (Cabometyx) plus nivolumab (Opdivo) showed promising efficacy in patients with metastatic non-clear cell renal cell carcinoma (RCC) who had papillary, unclassified, or translocation-associated histologies, according to Chung-Han Lee, MD, PhD, a medical oncologist specializing in genitourinary malignancies at Memorial Sloan Kettering Cancer Center.

Cabozantinib plus nivolumab was approved by the FDA based on the results of the CheckMate 9ER study (NCT03141177) which examined the combination in patients with clear cell kidney cancer. The positive results led researchers to further explore how the combination would affect more rare variants of kidney cancer. Thus, the phase 2 trial of nivolumab and cabozantinib in patients with non-clear cell renal cell carcinoma (CA209-9KU; NCT03635892) was created.

The CA209-9KU study will enroll 47 patients with advanced non-clear cell RCC. The patients must have received either no prior systemic therapy or a single line of treatment other than immune checkpoint inhibitors. Patients also had to have measurable disease by RECIST.

The trial used 2 cohorts. Cohort 1 consisted of patients with papillary, unclassified, or translocation-associated RCC while cohort 2 included patients with chromophobe RCC.

The primary end point of the study was objective response rate (ORR) and secondary end points included profession free survival, overall survival, and safety.

At a data cut-off of January 20, 2021, 40 patients were treated in cohort 1 and 7 in Cohort 2. The median follow-up time was 13.1 months.

In cohort 1 the ORR was 48% (95% CI 31.5–63.9%), the median PFS was 12.5 months (95% CI 6.3–16.4) and the median OS was 28 months (95% CI 16.3–NE). No responses were seen among the patients in cohort 2 with chromophobe histology.

In regard to safety, grade 3/4 treatment-emergent adverse events remained the same as those observed in the CheckMate 9ER trial, as AEs were observed in 32% of patients. Grade 3/4 elevations in aspartate aminotransferase and alanine aminotransferase seen in 9% and 15% of patients, respectively. Additionally, cabozantinib and nivolumab were discontinued due to toxicity in 13% and 17% of patients.

Additionally, the investigators performed targeted exome sequencing in 32 patients within cohort 1 and 5 patients in cohort 2. Five of 6 patients with NFS 2 mutations and 4 of 5 with FH mutations had objective responses. Only 1 of 6 with SETD2 mutations showed objective response.

In an interview with Targeted OncologyTM following the 2021 International Kidney Cancer Symposium: North America, Lee further discussed the results of the phase 2 trial of the combination of cabozantinib and nivolumab in patients with metastatic non-clear cell RCC and how it impacts the future of this space.

Can you provide a brief overview of the presentation you gave at IKCS?

The poster I presented to IKCS this year was the phase 2 results of the combination of cabozantinib plus nivolumab for patients with non-clear cell kidney cancer. This was a phase 2 trial that looked at non-clear cell kidney cancer, which is a rare variant of kidney cancer. Clear cells are the most common, making up about 70 or 80% of the kidney cancers. Cabozantinib plus nivolumab is now FDA approved, based on the studies of CheckMate 9ER, which examined cabozantinib plus nivolumab versus sunitinib [Sutent] for clear cell kidney cancer.

We decided to do a study for non-clear cell kidney cancer to see what the efficacy was like. We divided the patients into 2 cohorts, 1 of which included papillary unclassified translocation associated and fH deficient RCC and the second cohort was limited to chromophobe kidney cancer. What we ended up seeing was for patients in the first cohort, so unclassified papillary translocation and fH deficient, we saw an objective response rate of approximately 47.5%. Whereas in comparison, for people who had chromophobe kidney cancer, we didn't see any objective responders.

This indicated that there really is some degree of histologic stratification for these regimens and made us decide that there would be interest in further expanding this clinical trial, from the original design of 40 patients within the first cohort to now an expanded cohort of 80 patients.

What unmet needs does this study address in this population?

Right now, most of the clinical trials that are done are focused on clear cell kidney cancer because it is the most common histology. Because of this, we really don't quite understand what the results within the rare histologies are because they are often excluded from clinical trials even though they do represent us a still not insignificant portion of the patients. By better identifying the response rates and with the systemic therapies we have right now, it allows a benchmark for us to develop other trials in the future for this population.

What unmet needs are still a major priority within the non-clear cell population?

Within the non-clear cell population, because it is a very heterogeneous population of patients, I think that we have to do better in terms of molecular stratification. Also determining whether or not there are particular mutations or genomic features that would predict responses to very specific treatments and actually designing clinical trials that are specific to the small even the smaller subsets of patients.

What are some of the benefits and challenges of immunotherapy? What still needs to be done?

In that space right now, we are treating essentially empirically. We're assuming patients, regardless of any sort of clinical features unless they have obvious contraindications to treatment, to give them treatment and just see down the line whether or not they work. I think one of the things that we need to determine are either biomarkers for either response or biomarkers for toxicity and being able to integrate that into clinical practice to make a decision about what's the most appropriate treatment.

What were some of the adverse events seen with the combination of Cabozantinib plus nivolumab?

The adverse events that we saw were quite similar to what we saw for the clear cell population. We saw an incidence of LFT abnormalities, increases in blood pressure. Overall, we didn't see any new toxicity signals related to it and our drug discontinuation rates and our rates of immune-related adverse events were very similar to what we saw with clear cells.

What do you think the space of non-clear cell kidney cancer looks like for the future?

I think that the non-clear cell space as a whole really remains an area of desperate need of new therapies and new treatments. I think that what we need to do is better understand the biology of the different histologies associated with non-clear cell kidney cancer so that we can develop novel clinical trials using novel agents that we don't necessarily use in the clear cell setting.

_References:

_{1. Lee CH, Voss MH, Carlo MI et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2. Presented at the International Kidney Cancer Symposium: North America. November 5-6, 2021; Austin, TX.}

_{2. A Study of nivolumab in combination with cabozantinib in patients with non-clear cell renal cell carcinoma. ClinicalTrials.gov. Accessed March 9, 2022.https://bit.ly/3KhBoxf}