1.The objective response rate was 30.8% with the majority attributing to partial response.

2. Most common adverse events (grade 3 or higher) included anemia, fatigue, and hypertension, with the majority of patients needing a dose reduction or dose interruption.

Evidence Rating Level: 2 (Good)

Study Rundown: The use of anti-PD-1 or anti-PD-L1 agents has become a standard of care for first-line combination therapy in patients with advanced renal cell carcinoma. However, studies are needed to evaluate treatment after disease progression on immunotherapy. This study investigates the antitumour activity and safety of belzutifan (HIF-2α inhibitor) plus cabozantinib (a multikinase tyrosine-kinase inhibitor) in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy. The primary endpoint was ORR (objective response rate, including both CR (complete response) or PR (partial response)), and secondary endpoints included DoR (duration of response), time to response, PFS (progression-free survival), OS (overall survival), and safety. Generally, 92.3% of patients had an objective response (ORR was 30.8% with a CR of 2% and a PR of 29%) or a best response of stable disease. The median time to response was 3.2 months and the median DoR was 18.6 months. The median PFS was 13.8 months and the median OS was 24.1 months. With regards to safety, all patients experienced at least one adverse event, with 73% experiencing grade 3-5 all-cause adverse events. The most common grade 3 or higher treatment-related adverse events were anemia (15%), fatigue (12%), and hypertension (27%). Adverse events led to belzutifan dose reductions in 27% of patients and dose interruptions in 58% of patients, while adverse events led to cabozantinib dose reductions in 73% of patients and dose interruptions in 75% of patients. The strengths of this study included a long follow-up period and the limitations of this study included the small sample size and its single-arm design. Overall this study showed there is some efficacy with using belzutifan plus cabozantinib in patients who already received immunotherapy for advanced renal cell carcinoma.

Click to read the study in The Lancet

Click to read an accompanying editorial in The Lancet Oncology

Relevant Reading: Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis

In-Depth [prospective cohort]: This was a multi-center, open-label, single-arm, phase 2 study that investigated the efficacy of belzutifan (120mg) plus cabozantinib (60mg) in 52 adults with locally advanced or metastatic renal cell carcinoma that previously received immunotherapy and up to two previous systemic regimens. Dosing of belzutifan plus cabozantinib could be reduced to manage adverse events. Median follow-up was 24.6 months. Median age was 63 years with 73% of the sample being male and 92% being white. Only 10 patients were continuing treatment at data cutoff with progressing disease and adverse events being the primary reasons for discontinuation. The ORR was 30.8% (95%CI, 18.7 to 45.1) with a CR of 2% and a PR of 29%. Generally, 92.3% (95%CI, 81.5 to 97.9) of patients had an objective response or a best response of stable disease. The median time to response was 3.2 months and the median DoR was 18.6 months (95%CI, 8.3 to 22.8). The median PFS was 13.8 months (95%CI, 9.2 to 19.4), with the 12-month estimate PFS 56.2% (95%CI, 40.5 to 69.2). The median OS was 24.1 months (95%CI, 20.0 to 37.4), with the 12-month estimate OS 76.5% (95%CI, 62.3 to 85.9). With regards to safety, all patients experienced at least one adverse event, with 73% experiencing grade 3-5 all-cause adverse events (63% being treatment-related). The most common grade 3 or higher treatment-related adverse events were anemia (15%), fatigue (12%), and hypertension (27%). Adverse events led to belzutifan dose reductions in 27% of patients and dose interruptions in 58% of patients, while adverse events led to cabozantinib dose reductions in 73% of patients and dose interruptions in 75% of patients. Overall this study showed there is some efficacy with using belzutifan plus cabozantinib in patients who already received immunotherapy for advanced renal cell carcinoma.

Image: PD

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