(M-008) Exposure-Response Analysis of Efficacy and Safety for Nivolumab + Relatlimab Fixed-dose Combination (FDC) to Support Dose Justification in Patients with Unresectable or Metastatic Melanoma
Research Investigator Bristol Myers Squibb , United States
Disclosure(s):
Sai Praneeth Bathena, n/a: No financial relationships to disclose
PARIDHI GUPTA, PhD: No financial relationships to disclose
Objectives: Nivolumab in combination with relatlimab FDC (Opdualag) demonstrated clinical benefit and is indicated for the treatment of patients with advanced melanoma [1]. The population pharmacokinetics of nivolumab and relatlimab has been characterized previously [2]. The objective of this work was to characterize the relationship between nivolumab and relatlimab exposure and efficacy and safety to support dosing of nivolumab + relatlimab combination in advanced melanoma subjects, and to evaluate the impact of covariates and clinical factors on the exposure-response (E-R) relationship of efficacy and safety.
Methods: E–R analysis of efficacy and safety was conducted with data from patients with unresectable or metastatic melanoma enrolled in two clinical studies CA224020 (phase 1/2) and CA224047 (phase 2/3), who received nivolumab alone or a combination of nivolumab + relatlimab. E-R analysis was characterized by relating the nivolumab and relatlimab time-averaged concentration over 28 days (Cavgd28) to four endpoints: Objective Response (OR), Progression Free Survival (PFS), Overall Survival (OS) and Grade 2+ Immune-mediated adverse events (IMAEs). The relationship between the probability of achieving an OR and exposure was described using a logistic regression model. The E–R analysis of PFS, OS, and Grade 2+ IMAEs characterized the hazard ratios (HRs) of PFS, OS, and Grade 2+ IMAEs with respect to Cavgd28 exposures using a Cox proportional hazard model. The E-R relationship for all the endpoints was assessed by a full model, which incorporated the covariates. Bayesian Information Criterion (BIC) was used for model comparison and selection. Model evaluation was assessed using visual predictive check.
Results: OR, PFS, and OS were significantly associated with exposure to relatlimab, resulting in a higher OR and longer PFS and OS in subjects treated with nivolumab + relatlimab compared to nivolumab monotherapy. Predicted probability of OR was higher with nivolumab 480 mg + relatlimab 480 mg Q4W compared with nivolumab 480 mg + relatlimab 160 mg Q4W. PFS, OS, and Grade 2+ IMAEs were similar between nivolumab 480 mg + relatlimab 160 mg Q4W and nivolumab 480 mg + relatlimab 480 mg Q4W as the predicted HRs were close to 1, suggesting a flat E-R relationship for both efficacy and safety.
Conclusions: Although higher exposures of relatlimab may be associated with increased OR, E-R relationship of PFS, OS, and Grade 2+ IMAEs were relatively flat supporting the recommended dose of nivolumab 480 mg + relatlimab 160 mg Q4W in adult subjects with unresectable or metastatic melanoma. These E-R analyses were used to inform the benefit–risk assessment and support the registration of Opdualag.
Citations: [1] Tawbi et al. N Engl J Med 2022 Jan 6;386(1):24-34. [2] Zhao et al. Clin Cancer Res. 2024 Jul 15;30(14):3050-3058.
