Discussion
NSCLC, death, melanoma, diarrhea, rash, fatigue/asthenia, RCC, hypertension
NON-SMALL CELL LUNG CANCER, DISEASE PROGRESSION, MELANOMA, ADVERSE EVENTS, DISEASE, CPH, NSCLC, HYPOTHYROIDISM, HYPERTENSION, RCC
The CheckMate 9ER trial investigated the efficacy and safety of nivolumab in combination with cabozantinib compared with sunitinib in patients with previously untreated advanced RCC [Nivolumab plus cabozantinib significantly improved the primary efficacy endpoint of PFS compared with sunitinib [In patients receiving the combination, 68.1% had at least one cabozantinib dose hold and 56.3% had a reduction in their cabozantinib dose, but the rate of discontinuations due to adverse events was low (7.5% of patients discontinued cabozantinib only due to AEs), indicating effective AE management with dose modification to maintain tolerability [Exploratory KM plots showed no clear difference between quartiles of cabozantinib exposure and the fraction of patients receiving the combination in CheckMate 9ER with progressive disease or death, but higher cabozantinib exposure was associated with increased risk of PPE (Grade ≥ 1) and diarrhea (Grade ≥ 3). Simulation using the final CPH model parameters estimates for a 20-mg, 40-mg, or 60-mg dose of cabozantinib also showed no statistically significant relationship with disease progression or death, while a dose of 20 mg vs. 40 mg was predicted to reduce the risk of PPE and diarrhea. Taken together, these data support the dosing strategy of cabozantinib when used in combination with nivolumab—initiate the cabozantinib dose at 40 mg/day to ensure efficacious cabozantinib exposure across the spectrum of cabozantinib clearance in a patient population: patients with high cabozantinib clearance are predicted to maintain tolerability at the efficacious exposure level without the need for dose modification; patients with low cabozantinib clearance are predicted to require dose modification to manage tolerability, and dose reduction to 20 mg/day will maintain cabozantinib exposure at an efficacious level. These findings are consistent with previous exposure–response analyses of single-agent cabozantinib [ALT/AST increases, and diarrhea, hypothyroidism, and rash are part of known safety profiles of both cabozantinib and nivolumab and were more frequently reported with the combination than with sunitinib in CheckMate 9ER study [An increased risk of hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg) and fatigue/asthenia at higher cabozantinib concentrations were reported with single-agent cabozantinib 60 mg QD in the METEOR study [Covariate analysis for CPH modeling of PFS indicated a higher predicted rate of disease progression or death with lower baseline albumin level or higher baseline nivolumab clearance but not with other baseline covariates for patients with advanced RCC. These findings are consistent with results from previous analysis of nivolumab. In a prospective cohort study of patients receiving nivolumab monotherapy for non-small cell lung cancer (NSCLC), melanoma, or RCC, exposure–response analyses demonstrated a significant clearance–response relationship in NSCLC, a non-significant trend in RCC, and no relationship in melanoma [In summary, the exposure–response analysis reported here further supports the dosing strategy implemented in CheckMate 9ER: administering cabozantinib at 40 mg orally QD in combination with a standard dose of nivolumab to ensure all patients receive an efficacious dose of cabozantinib regardless of cabozantinib clearance variability (i.e., both high and low clearance) and using dose modification to manage AEs. Reducing cabozantinib exposure was not predicted to significantly impact the PFS benefit in patients with advanced RCC treated with nivolumab plus cabozantinib in the CheckMate 9ER trial, but was predicted to reduce the risk of PPE and diarrhea, two of the more common AEs associated with cabozantinib. Thus, the dose of cabozantinib can be reduced from 40 mg QD to 20 mg QD in patients requiring a dose reduction (i.e., patients with low cabozantinib clearance) to improve tolerability without adversely affecting efficacy. Further, administering cabozantinib at 60 mg QD instead of 40 mg QD in combination with nivolumab was not predicted to improve PFS.