HOUSTON – Nivolumab combined with cabozantinib was demonstrated to significantly improve outcomes for patients with renal cell carcinoma in a trial released last year. Now, a new study suggests that dose modifications won’t affect efficacy in first-line treatment.
Based on results of the phase 3 CM 9ER trial, the combination had positive effect on progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs sunitinib in first-line advanced RCC.
In a study at the 2021 American Society of Clinical Oncology (ASCO) annual meeting, The University of Texas MD Anderson Cancer Center-led authors pointed out that nivolumab and cabozantinib together was generally well tolerated with low rates of treatment-related discontinuations. That indicated successful adverse event (AE) management with dose modification to maintain tolerability, advised the study team, which included National Institutes of Health researchers.1
In the study, investigators sought to determine the effect of cabozantinib exposure on efficacy and safety outcomes in the CM 9ER exposure-response (ER) analysis. To do that, they provided therapy to 320 previously untreated advanced RCC patients. Participants received 40 mg of cabozantinib once a day in combination with 240 mg of nivolumab every two weeks. Dose reductions of cabozantinib to 20 mg a day or 20 mg every two days were allowed to manage adverse effects.
Adverse effects of concern included palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]).
In the ER analysis of progression-free survival, the authors determined that predicted cabozantinib exposure at 40-mg and 20-mg daily doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of adverse effects, meanwhile, lower predicted cabozantinib exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation.
While higher predicted cabozantinib apparent clearance was associated with a lower rate of necessary dose modification, that association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr), according to the report.
Based on ER modeling, researchers advised that a starting dose of cabozantinib daily at 40 mg in combination with nivolumab with appropriate dose modifications to manage side effects “will not adversely affect the efficacy of the combination in 1L aRCC.”
- Shah AY, Motzer RJ, Apolo AB, Powles T, et. Al. (June 4-8, 2021). Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). ASCO 2021 annual meeting. Virtual. https://meetinglibrary.asco.org/record/197689/abstract