Safety and Efficacy of Durvalumab (MEDI4736) Plus Tremelimumab in Advanced Non-Small-cell Lung Cancer (NSCLC)

Background: Durvalumab (D) is a selective and high-affinity modified human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4. D and T block distinct interactions contributing to immunosuppression, and the combination may provide greater antitumor activity than either agent alone. Methods: A Phase 1, open-label dose escalation and expansion study (NCT02000947) is assessing the safety/tolerability and preliminary antitumor activity (with investigator-reported RECIST v1.1) of D + T combinations in US patients (pts) with advanced NSCLC. Archival tumor or fresh biopsy was collected at baseline and analyzed using the Ventana SP263 assay to determine PD-L1 status (PD-L1+ defined as tumor membrane staining ≥25%). Results: As of 1 Jun 2015, 102 pts have been treated during the dose-escalation phase, which has been completed. D 20 mg/kg (D20) q4w + T 1 mg/kg (T1) q4w was identified as the MTD and recommended Phase 3 dose. 80% of pts had ≥1 drug-related AE; the most frequent were diarrhea (32%), fatigue (24%), and pruritus (21%). 42% of pts had ≥1 G3/4 drug-related AE; most frequent were diarrhea (11%), colitis (9%), and increased lipase (8%). 28% of pts had drug-related AEs leading to discontinuation. AEs were generally manageable with standard therapy; there were 3 treatment-related deaths (myasthenia gravis, pericardial effusion, neuromuscular disorder). For 63 pts with ≥ 24-wk scan, confirmed ORR was 17% (ongoing in 9/11 pts). Among 26 pts receiving D10-20 q2w/q4w + T1 q4w, confirmed ORR was 23% (5/6 ongoing), 22% (2/9) in PD-L1+ pts and 29% (4/14) in PD-L1― pts. Conclusions: The D20 + T1 combination has a manageable safety profile with evidence of clinical activity, even in PD-L1-negative disease. Similar safety results were reported with this combination in an ongoing study of Japanese patients with advanced solid tumors (NCT02141347)1. 1. Takahashi Y et al, Eur J Cancer 2015;51(suppl 3):abstr 512