Assessment, Analysis, and Discussion
toxicity, toxicities, VTE, RCC, venous thromboembolism
DISEASE, HYPERCOAGULABLE STATE, RCC
This phase I study demonstrates that the combination of avelumab and cabozantinib is safe with manageable toxicities in patients with mccRCC. No DLT was observed in any of the patients enrolled in this phase I study. However, 6 patients (The venous thromboembolism (VTE) rate in our study was notably high. Due to the single-arm design of the study, it is impossible to accurately determine the relative contribution from the disease, cabozantinib, and/or avelumab. Metastatic RCC is known to cause a hypercoagulable state predisposing to VTE.The combination demonstrated preliminary anti-tumor activity in our study. After a median period of 19 months of treatment, the reported ORR was 50% (Overall, the combination of avelumab and cabozantinib showed an acceptable safety profile, an acceptable rate of grade 3/4 TRAEs, and a preliminary anti-tumor activity against mccRCC. However, this combination is unlikely to be developed further in the mccRCC setting because of multiple other combinatorial regimens of cabozantinib plus immune checkpoint inhibitors either garnering regulatory approval (CheckMate 9ER trial), or reaching advanced phases of development in the registration trials (NCT03937219, NCT04338269).In this phase I study involving patients with previously untreated advanced mccRCC, avelumab, and cabozantinib was found to be safe and demonstrated tolerable AEs with preliminary evidence of anti-tumor activity. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for cabozantinib is 40 mg/day due to a high incidence of intolerable grade 2 toxicity for cabozantinib 60 mg/day.