Safety and efficacy of durvalumab (MEDI4736) plus tremelimumab in advanced non-small-cell lung cancer (NSCLC)

Abstract

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 investigatorreported 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.