Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM).

Abstract

9010Background: mM is an immunotherapy responsive disease where PD-L1 overexpression is prevalent. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Initial antitumor activity observed during dose escalation supported further expansion in mM with MPDL3280A as monotherapy and in combination with targeted therapy. Methods: Pts with mM of any histologic subtype received MPDL3280A administered IV q3w for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. In addition, a separate Ph 1b was initiated to evaluate the safety and efficacy of MPDL3280A with vemurafenib (vem) in pts with BRAF-V600 mutated mM. Results: As of Jan 10, 2013, 45 mM pts were treated at ≤1 (n=4), 10 (n=10), 25 (n=20) and 20 mg/kg (n=11) and evaluable for safety. Median pt age was 63 y (range 21-83 y), 100% were PS 0-1, 91% had prior surgery and 64% received prior systemic therapy. Pts received MPDL3280A treatment for a median duration of 127 days (range 1-282). The incidence of all G3/4 AEs, regardless of attribution, was 33%, including hyperglycemia (7%), elevated ALT (7%) and elevated AST (4%). No G3-5 pneumonitis was reported. No treatment-related deaths occurred on study. 35 mM pts who initiated treatment at doses of 1-20 mg/kg and enrolled prior to Jul 1, 2012, were evaluable for efficacy. An ORR of 26% (9/35) was observed, with all RECIST responses ongoing or improving. Further, some responding pts experienced tumor shrinkage within days of initial treatment. The 24-week PFS was 35%. Several additional pts had delayed antitumor activity after apparent radiographic progression and were counted as PD for the above analyses. Analysis of mandatory archival tumors showed a correlation between PD-L1 status and efficacy. Further, of three initial pts treated with MPDL3280A and vem, 2 experienced tumor shrinkage, including 1 CR. Conclusions: MPDL3280A was well tolerated as monotherapy, and durable ORs were observed. Therefore, further assessment of MPDL3280A as monotherapy and combination therapy is warranted. Clinical trial information: NCT01375842.