RESUMEN
BACKGROUND: The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and healthcare efficiencies. PATIENTS AND METHODS: CheckMate 67T (NCT04810078) was a phase 3, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20,000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). Primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis (time-averaged serum concentration over the first 28 days [Cavgd28], and minimum steady-state serum concentration [Cminss]; noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios [GMR] ≥0.8). Objective response rate (ORR) was a key secondary endpoint powered for noninferiority (noninferiority threshold: lower boundary of 95% CI of relative risk of ORR [subcutaneous versus intravenous nivolumab] ≥0.60). RESULTS: Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of Cavgd28 and Cminss was 2.098 (90% CI, 2.001-2.200) and 1.774 (90% CI, 1.633-1.927), respectively. After 8 months minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI, 19.0-30.0) versus 18.2% with intravenous nivolumab (95% CI, 13.6-23.6; relative risk: 1.33 [95% CI, 0.94-1.87]). Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar. CONCLUSION: Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed.
RESUMEN
BACKGROUND: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. PATIENTS AND METHODS: A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of â¼80 kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. RESULTS: The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. CONCLUSION: Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.