Cabozantinib/Nivolumab Combination Demonstrates Efficacy in nccRCC

In the open-label phase 2 trial (NCT03635892), cabozantinib (Cabometyx) plus nivolumab (Opdivo) showed promising efficacy in metastatic non–clear cell renal cell carcinoma (nccRCC) among patients with papillary, unclassified, or translocation-associated histologies, according to findings presented in a poster at the 2021 International Kidney Cancer Symposium.¹

Although kidney cancer encompasses many different subtypes of cancer based on pathobiology that vary in sensitivity to treatments, clear cell renal cell carcinoma (ccRCC) makes up 60% to 80% of kidney cancer cases and is found to be dependent on VEGF signaling.² The rest are considered to be nccRCC, which comprises a heterogeneous mix of malignancies.

Previously, the combination of cabozantinib and nivolumab showed improved efficacy over sunitinib (Sutent) in patients with advanced ccRCC in the phase 3 CheckMate 9ER trial (NCT03141177).³

The phase 2 study enrolled patients with advanced or metastatic nccRCC who did not receive prior PD-1/PD-L1– targeted treatment. The study was split into 2 cohorts. Cohort 1 included patients with papillary, unclassified, or translocation-associated RCC. Cohort 2 included patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST v1.1, and the secondary end points were progression-free survival (PFS), overall survival (OS), and safety.

A total of 47 patients between the 2 cohorts were treated with 40 mg of oral cabozantinib daily plus 240 mg of nivolumab intravenously every 2 weeks or 480 mg intravenously every 4 weeks.

Patients must have had advanced or metastatic nccRCC, 0 or 1 prior lines of systemic therapy, and measurable disease according to RECIST v1.1 to be included in the trial. Cohort 1 initially consisted of 20 patients and functioned within its single-stage design, met its primary end point, and was later expanded to 40 patients to find a more precise estimate for ORR. Cohort 2 consisted of 7 patients and had a Simon 2-stage design that closed early.

The median age of patients was 57 years (range, 33-78) and 54 years (range, 46-68) in cohorts 1 and 2, respectively. Overall, 66% of patients were male and 72% had a Karnofsky performance score of 90, with the remainder having a score of 80. In cohort 1, 80% had papillary histology, 15% were unclassified without papillary features, and 5% had translocation-associated disease.

The majority of patients had intermediate-risk disease by both risk stratification systems and had undergone prior nephrectomy. Patients had a median of 2 sites of disease (range, 1-7).

Between the 2 cohorts, 31 (66%) patients received no prior treatment, 16 (34%) received 1 prior line of systemic treatment, 12 (26%) received prior VEGF-targeted therapy, 8 (17%) received prior mTOR-targeted therapy, and 2 (4%) patients received chemotherapy.

Patients were followed for a median of 13.1 months (range, 2.2-28.6).

The ORR was 48% (95% CI, 31.5%-63.9%) for patients in cohort 1, and no responses were reported in cohort 2. Within cohort 1, 15 of 32 patients with papillary histology showed an objective response (47%; 95% CI, 29%-65%). A response was seen in 3 of 6 patients with unclassified RCC, and 1 of 2 patients with translocation-associated RCC also responded to the combination regimen. All responses were partial responses (PRs). Half of all patients in cohort 1 and 71% in cohort 2 achieved stable disease (SD).

The disease control rate was 98% (95% CI, 86.8%-99.9%) in cohort 1 and 71% (95% CI, 29.0%- 96.3%) in cohort 2. Clinical benefit (PR or SD ≥ 24 weeks) was achieved in 58% (95% CI, 40.9%-73.0%) of patients in cohort 1 and 29% (95% CI, 3.7%-71.0%) in cohort 2.

Cohort 1 had a median PFS of 12.5 months (95% CI, 6.3-16.4) and a median OS of 28.0 months (95% CI, 16.3–not evaluable [NE]). At 12 months, the PFS rate was 52.8% and the 18-month OS rate was 68.7%.

Five of 6 patients with NF2 mutations and 4 of 5 patients with FH mutations had an objective response. Of the 6 patients with SETD2 mutations, only 1 showed a response to treatment. These genomic studies emphasize the diversity within nccRCC and will require further investigation to determine their role as predictors of response to systemic therapy, they study's authors, led by Chung-Han Lee MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, wrote in the poster.

The median treatment duration was 11.0 months (95% CI, 7.8-21.1) between the 2 cohorts.

Treatment-related adverse events (TRAEs) of any grade were reported in 87% of patients and grade 3/4 events in 32%. TRAEs led to discontinuation of either agent in 21% of patients and discontinuation of both agents in 9%.

The most common TRAEs of any grade were fatigue (57%), palmar-plantar erythrodysesthesia syndrome (57%), diarrhea (53%), hypertension (38%), and dry mouth (36%).

This safety profile was similar to that of the CheckMate 9ER trial studying the cabozantinib and nivolumab combination in patients with ccRCC, the study authors noted in the poster.

_REFERENCES

_{1. Lee CH, Voss MG, Carlo MI, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: results of a phase 2 trial. Presented at: Interna- tional Kidney Cancer Symposium 2021; November 5-6, 2021; Austin, TX, and virtual. Abstract E43.}

<sub>2. Linehan WM. Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics. Genome Res. 2012;22(11):2089-2100. doi:10.1101/ gr.131110.111
3. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982</sub>