Selection Of The Recommended Phase 2 Dose (Rp2d) For M7824 (Msb0011359c), A Bifunctional Fusion Protein Targeting Tgf-Beta And Pd-L1.

2566 Background: The transforming growth factor β (TGF-β) pathway plays an important role in tumor immune escape and may enhance the response to PD-L1 monoclonal antibodies (mAb). M7824 is an innovative first-in-class bifunctional fusion protein composed of a human IgG1 mAb against PD-L1 fused with 2 extracellular domains of TGF-β receptor II (a TGF-β “trap”) and has shown promising antitumor activity and manageable safety in phase 1 trials, including as 2L treatment for NSCLC. Methods: A population PK model for M7824 was developed based on serum concentration data from 350 pts from 2 clinical trials of M7824 in multiple solid tumor types. Simulations were performed using the model to explore exposure variability for various dosing regimens. Exposure-response analysis was performed for 500 and 1200 mg biweekly (q2w) 2L NSCLC cohorts (combined) using logistic regression for the investigator-assessed overall response rate (ORR) and Kaplan-Meier analyses for progression-free survival (PFS). Results: Simulations of AUC and Cmin showed that variability in exposure was slightly higher for weight-based dosing compared with flat dosing, supporting the use of a flat-dose approach for M7824. Preliminary univariate analyses relating M7824 exposure (AUC and Cmin after a single dose) to ORR in 500 and 1200 mg 2L NSCLC cohorts did not show a conclusive relationship. However, there was a trend for pts in the lowest exposure quartile (Q1, comprised of pts in 500 mg cohort only) to have a lower ORR (10% for AUC Q1; 5% for Cmin Q1) than those in the higher exposure quartiles (25-30% and 20-40% ORR for AUC and Cmin Q2-Q4, respectively). Results of Kaplan-Meier analysis of PFS by exposure quartiles were in line with the exposure-ORR analyses, supporting 1200 mg q2w as the RP2D. At the Cmin associated with the RP2D, nearly complete target occupancy for PD-L1 (PBMC) and TGF-β trapping (plasma) was achieved. Moreover, these Cmin values were associated with 95% tumor-growth inhibition in mouse models. Conclusions: Based on the integrated analysis and modeling data available to date, a flat dose of 1200 mg q2w is the RP2D for M7824.