A Phase 1 first-in-human study of MEDI0680, an anti-PD-1 monoclonal antibody (mAb) in adult patients (pts) with advanced tumors

Abstract

Background: Programmed cell death‐1 (PD‐1) inhibits T‐cell activation. Blocking the PD‐1/programmed cell death ligand 1/2 (PD‐L1/2) axis has an acceptable safety profile, induces antitumor responses, and provides clinical benefit across tumors. MEDI0680 is a humanized IgG4κ mAb specific for human PD‐1 that blocks interaction with PD‐L1/2. Methods: This is an ongoing Phase 1, multicenter, open‐label, first‐in‐human, dose‐escalation and expansion study of single‐agent MEDI0680 in immunotherapy‐naïve pts with advanced solid tumors. Primary objectives are safety/ tolerability and maximum tolerated dose (MTD). Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity (modified RECIST v1.1). Results: As of 2 Nov 2015, 58 pts have enrolled across 9 cohorts (0.1‐20 mg/kg given Q3W, Q2W, QWx2 then Q2W, or QWx4 then Q2W). MTD was not reached. Treatment‐related AEs occurred in 46 pts; most common (>10%) were fatigue (21%), nausea (14%) and arthralgia (14%). Related Grade 3/4 AEs occurred in 10 pts; most common (>1 pt) were anemia, arthralgia and increased AST (3% each). 2 pts discontinued due to related AEs: pyrexia in 1 pt; and increased AST, myasthenia gravis and myositis in 1 pt. There were no Grade 5 related AEs. MEDI0680 had a linear PK profile with dose‐proportional increases in peak serum concentration. Median PD‐1 receptor occupancy on CD3+ T cells was ≥70% after 1 cycle of 10 or 20 mg/kg Q2W. Increased percentages of Ki67 + , ICOS+ and HLA‐DR+ T cells; increased levels of plasma IFNγ; and enhanced intra‐tumor gene expression for these factors were seen after treatment, demonstrating biological activity of MEDI0680. Of 51 evaluable pts, 9 (18%) had an objective response (8 had renal cancer or melanoma), including 1 (2%) complete response (renal cancer). 14 (28%) pts had stable disease as their best response. The recommended dose is 20 mg/kg Q2W, based on PK, PD, safety and efficacy. Conclusions: MEDI0680 has an acceptable safety profile, with preliminary signs of efficacy. A Phase 1 combination study with durvalumab to test the concept of complete PD‐1/PD‐L1 axis blockade is ongoing in advanced solid tumors.