Regimen ‘highly active’ among certain patients with non-clear cell renal cell carcinoma
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The combination of cabozantinib and nivolumab showed promising efficacy for certain patients with metastatic non-clear cell renal cell carcinoma, according to phase 2 study results presented at International Kidney Cancer Symposium.
Researchers observed the most activity among patients with papillary, unclassified or translocation-associated histologies. The regimen appeared less active among patients with chromophobe renal cell carcinoma.
The combination also exhibited an acceptable safety profile.
“Cabozantinib and nivolumab is highly active in patients with select non-clear cell histologies, and accurate characterization of the tumor histology remains a key clinical determinant in outcomes to systemic therapy,” researcher Chung-Han Lee, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, told Healio.
Clear cell renal cell carcinoma accounts for 60% to 80% of kidney cancer cases. Other subtypes collectively are grouped as non-clear cell renal cell carcinoma; however, this classification comprises multiple heterogeneous malignancies, according to study background.
“Non-clear cell renal cell carcinoma remains a highly unmet need for patients, as large industry-sponsored clinical trials for renal cell carcinoma often restrict patients to the most common clear cell histology,” Lee said. “Although regulatory approval of drugs often does not specify histologic subtypes, there remains limited data for non-clear cell histologies.”
Previously reported results of a phase 3 trial showed the anti-PD-1 antibody nivolumab (Opdivo, Bristol Myers Squibb) plus the multitargeted tyrosine kinase inhibitor cabozantinib (Cabometyx, Exelixis) improved response rate, PFS and OS vs. sunitinib (Sutent, Pfizer) as first-line treatment for metastatic clear cell renal cell carcinoma.
Lee and colleagues conducted a single-institution phase 2 trial to assess the nivolumab-cabozantinib combination for patients with advanced or metastatic non-clear cell renal cell carcinoma who had not received prior PD-1/PD-L1-targeted treatment.
Study participants had received no more than one prior systemic therapy — excluding prior immune checkpoint inhibitors — and had measurable disease by RECIST criteria.
Researchers divided patients into two cohorts.
Cohort 1 included 40 patients (median age, 57 years; range, 33-78; 70% men) with papillary (80%), unclassified (15%) or translocation-associated (5%) renal cell carcinoma.
About one-third (35%) had received prior systemic therapy and 67% had undergone nephrectomy. Most patients had favorable-risk (20%) or intermediate-risk (67%) classification per International Metastatic RCC Database Consortium criteria.
Cohort 2 included seven patients (median age, 54 years; range, 46-68; 57% women) with chromophobe disease. Two patients had received prior systemic therapy, and all had undergone nephrectomy. Most patients had favorable-risk (43%) or intermediate-risk (43%) classification per International Metastatic RCC Database Consortium criteria.
Patients received 40 mg daily cabozantinib plus nivolumab dosed either at 240 mg every 2 weeks or 480 mg every 4 weeks.
Objective response rate served as the primary endpoint. PFS, OS and safety served as secondary endpoints.
Median follow-up was 13.1 months (range, 2.2-28.6).
Cohort 1 met its primary endpoint. Researchers reported an ORR of 47.5% (95% CI, 31.5-63.9), median PFS of 12.5 months (95% CI, 6.3-15.9), 12-month PFS of 52.8%, median OS of 28 months (95% CI, 16.3-not estimable) and 18-month OS of 68.7%.
Researchers reported responses among 15 (47%) patients with papillary histology, three (50%) with unclassified renal cell carcinoma, and one (50%) with translocation-associated histology.
Best responses included partial response (48%), stable disease (50%) and progressive disease (3%). Median duration of response was 13.6 months (95% CI, 9.7-19.8).
“We were excited and surprised to see high objective response rates associated with specific histologies,” Lee said. “A response rate of 47.5% is among the highest seen for non-clear cell renal cell carcinoma.”
No patients in cohort 2 responded to treatment. Researchers closed this cohort early due to lack of efficacy.
Grade 3/grade 4 treatment-emergent adverse events appeared consistent with those reported in the phase 3 trial of patients with clear cell renal cell carcinoma.
A combined analysis of treatment-related adverse events in both cohorts showed the most common all-grade adverse events were fatigue (57%), palmar-plantar erythrodysesthesia syndrome (57%), diarrhea (53%), hypertension (38%), dry mouth (36%) and nausea (30%). The most common grade 3/grade 4 treatment-related adverse events were hypertension (13%), diarrhea (6%), palmar-plantar erythrodysesthesia syndrome (4%) and nausea (2%).
Thirteen percent of patients discontinued cabozantinib due to toxicity, and 17% discontinued nivolumab for the same reason.
“Our plan is to further expand the patients on this clinical trial and do biomarker analysis to identify genomic biomarkers [that] may better predict the response to cabozantinib-nivolumab,” Lee told Healio.
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Lee CH, et al. Abstract E43. Presented at: International Kidney Cancer Symposium; Nov. 5-6, 2021; Austin, Texas.
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