Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC.

Abstract

3014 Background: The inhibitory PD-L1 and CTLA-4 pathways control T-cell activation. MEDI4736 (M) is a human IgG1 mAb that blocks PD-L1 binding to programmed cell death-1 and CD80 with high affinity and selectivity. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4. M and T have demonstrated acceptable safety profiles and clinical activity as single agents. M and T block distinct interactions contributing to immunosuppression and the combination may provide greater antitumor activity versus either agent alone. Methods: A Phase 1, open-label dose escalation and expansion study (NCT02000947) is assessing the safety/tolerability and antitumor activity of M + T combinations in pts with advanced NSCLC. Results: As of 4 Dec 2014, 61 pts have been treated during the dose escalation phase (table). An MTD has not yet been defined; the Cohort 5a dose exceeded the MTD (n=2 with dose-limiting toxicities; Grade [G] 3 increased AST/ALT, G4 increased lipase). 64% of pts had ≥1 drug-related AE; the most frequent were fatigue (26%), diarrhea (21%), and increased amylase (13%). 31% of pts had ≥1 G3/4 related AE; the most frequent (>5%) were diarrhea (8%) and colitis (7%). Increasing doses of T with a constant dose of M were associated with greater severity and frequency of AEs. 18% of pts had drug-related AEs leading to discontinuation; the most frequent was colitis (7%). All AEs were manageable with standard therapy, including steroids, except G4 myasthenia gravis and G5 polymyositis in 1 pt in Cohort 2a. Of 31 pts with ≥18-week scan, 8 (26%) had partial response (PR) and 11 pts (35%) had stable disease. PRs occurred in 3 of 10 pts with PD-L1-negative tumors. Conclusions: The combination has a manageable safety profile with evidence of clinical activity, including in PD-L1-negative disease. These data support continued study of the combination; recruitment is ongoing. Clinical trial information: NCT02000947. M Q4W M Q2W Cohort 1a 2a 3a 3b 4 4a 5 5a 8 9 Dose M (mg/kg) + T (mg/kg) 3 + 1 10 + 1 15 + 1 10 + 3 20 + 1 15 + 3 15 + 10 20 + 3 10 + 1 10 + 3 n 3 3 11 3 6 11 9 6 3 6 Pts with ≥1 drug- related AE, n All grades 1 3 5 3 2 7 8 5 0 5 Grade 3/4 0 2 2 1 1 2 4 5 0 2 All grades leading to discontinuation 0 1 1 1 0 2 2 3 0 1