How comparable are outcomes for approved PD-1/PD-L1 checkpoint inhibitors (CPI)? A model-informed drug development approach to answer the question.

Abstract

e21152 Background: Treatment strategies in metastatic non-small cell lung cancer (mNSCLC) have been implemented by anti-PD-(L)1 based therapies. This work aimed to develop a model-based meta-analysis (MBMA) to compare ORR, median PFS (mPFS), median OS (mOS), and treatment-related adverse events Grade 3-5 (TRAEs Gr3+) among anti-PD-(L)1 therapies in mNSCLC. Methods: A curated database of phase 1, 2, and 3 study results in mNSCLC patients treated with at least one FDA-approved PD-(L)1 CPI was used for these analyses. The ORR, mPFS, mOS, and TRAEs Gr3+ analysis datasets included results from 40, 39, 35 and 45 studies, and represented 13324, 13220, 13029, and 21077 patients, respectively. Treatments included: platinum doublet (Pt), pembrolizumab (+/- Pt), nivolumab (+/- Pt and +/- ipilimumab), atezolizumab (+/- Pt), and cemiplimab. Models were developed to quantify drivers of variability on outcomes across trials (i.e., treatment, covariates, random effects). The following covariates were evaluated: PD-L1 expression, line of therapy, ECOG PS, histology, geography/race, sex, age, and smoking status. Results: Treatment naïve patients showed better efficacy than treatment experienced patients, while higher PD-L1 expression was associated with improvement for CPI-containing therapies. Asian-majority trials and patients with PS 0 achieved higher mOS. After adjusting for covariates, similar efficacy was observed across PD-(L)1 within both mono- and combination therapy groups (Table 1). No clinically meaningful covariates were identified for TRAEs Gr3+. Rates were comparable between chemotherapy +/- PD-(L)1, but lower for PD-(L)1 monotherapy. Conclusions: MBMA enables an appropriate comparison of CPI-containing therapy using published study results. To our knowledge, this is the first such analysis in mNSCLC comparing efficacy and safety across PD-(L)1 based therapies. Results suggest PD-(L)1 CPI have similar treatment outcomes in mNSCLC, and PD-L1 expression may be more impactful on clinical benefit of monotherapy compared to CPI combination with chemotherapy. [Table: see text]