A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors.

3001^ Background: Immune-suppressing molecules such as PD-L1 can be co-opted by cancer cells to suppress the natural immune response to cancer. Upregulation of PD-L1 and inhibition of antitumor T-cell activation is observed in several tumor types. MEDI4736 is a human IgG1 antibody which binds specifically to PD-L1, preventing binding to PD-1 and CD80. Methods: An ongoing phase 1 multicenter, open-label study (NCT01693562) is evaluating safety, pharmacokinetics (PK), and antitumor activity of MEDI4736 given IV every 2 (q2w) or 3 wks (q3w) in a 3+3 dose escalation with a 28-day (q2w) or 42-day (q3w) dose-limiting toxicity (DLT) window, followed by expansion in 8 solid tumors. Response was assessed by immune-related response criteria in escalation. Results: As of Jan 17, 2014, 26 patients (pts) (13 NSCLC, 8 melanoma, 5 other) in dose escalation (median age 59 yrs; 35-77), all PS 0-1, with a median of 4 prior treatments, received a median of 5 (1-25) q2w and 4. 5 (1-7) q3w doses of MEDI4736 across 6 cohorts (0. 1 – 10 mg/kg q2w; 15 mg/kg q3w). MEDI4736 showed dose-dependent PK. Evidence of ADA impacted PK exposure in only 1 patient. No DLTs or maximum tolerated dose were identified for q2w or q3w dosing. Treatment-related AEs occurred in 34% of pts, all Grade 1-2; none led to discontinuation of study drug. The most frequent treatment-related AEs were diarrhea, fatigue, rash, and vomiting (12% each). No pneumonitis, colitis, or hyperglycemia occurred. Of 26 pts, 4 PRs (3 NSCLC, 1 melanoma) and 5 additional pts with tumor shrinkage not meeting PR were observed. Disease control rate (PR + SD ≥ 12 wks) was 46%. Tumor shrinkage, as early as 6 wks, was seen at all dose levels, and benefit was durable; 11 pts remain on study as of the data cutoff (2+ to 14. 9+ mos). Expansion cohorts opened Sep 2013 using a 10 mg/kg q2w dose; 151 pts have been dosed, with the opportunity to enroll > 600 pts. Preliminary clinical activity has been observed with acceptable safety across a range of tumors including SCCHN, pancreatic, gastric, NSCLC, and melanoma. Conclusions: MEDI4736 has demonstrated an acceptable safety profile and durable clinical activity in this dose-escalation study. Expansion in multiple cancers and development of MEDI4736 as monotherapy and in combination is ongoing. Clinical trial information: NCT01693562.