A Phase I Open-Label Study to Evaluate the Safety and Tolerability of Medi4736, an Anti-Programmed Cell Death-Ligand 1(Pd-L1) Antibody, in Combination with Tremelimumab in Patients with Advanced Non-Small Cell Lung Cancer (Nsclc)

Abstract

ABSTRACT Aim: Programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are inhibitory regulators of T cell activation. MEDI4736 (M) is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. Tremelimumab (T) is a human IgG2 monoclonal antibody directed against CTLA-4. M + T in NSCLC may have greater antitumor activity compared with each agent alone. Methods: A Phase 1 study (NCT02000947) is evaluating the safety/tolerability, pharmacokinetics, immunogenicity and antitumor activity of M + T in patients (pts) with NSCLC. The study has dose-escalation phase and dose-expansion phase (immunotherapy-naive and -pretreated cohorts). The study will assess pharmacokinetic, pharmacodynamic parameters, including serum/tissue PDL1, immune cell phenotypes and cytokine profiling. Pharmacogenomic analysis of blood/tumor samples may be performed to examine gene expression patterns at baseline versus changes in response to treatment. Results: As of April 23, 2014, 12 pts were treated: 3 pts each in Cohort 1a (3 mg/kg M + 1 mg/kg T), Cohort 2a (10 mg/kg M + 1 mg/kg T); Cohort 3a (15 mg/kg M + 1 mg/kg T), Cohort 3b (10 mg/kg M + 3 mg/kg T). Pts had 2–5 lines of prior therapy (Median = 3). ECOG PS ranged from 0–1. The most frequent drug-related AEs (reported in ≥ 2 pts) included increased amylase, abdominal pain, arthralgia, colitis, diarrhea, epigastric discomfort, fatigue and nausea. ≥Grade (Gr) 3 drug-related AEs: 2 pts with Gr 3 (Cohort 2a: increased AST/ALT, 3b: diarrhea/colitis), 1 pt with Gr 4 (Cohort 3a: increased amylase), and 1 pt with Gr 5 (Cohort 2a: myasthenia gravis resulting in respiratory failure). Drug-related AEs leading to treatment discontinuation: 2 pts (Cohort 2a: increased ALT, myasthenia gravis, 3b: colitis). On first assessment at 8 weeks for 12 subjects: 2 unconfirmed PRs, 3 additional pts with tumor shrinkage not meeting PR, and 5 pts (Cohort 1a: 3; Cohort 3b: 2) with PD. 10 pts remain on study. Conclusions: The current safety profile and early anti-tumor activity of M + T supports continued clinical assessment. Disclosure: S.J. Antonia: Honoraria from BMS and MedImmune/Astra Zeneca for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Goldberg: I have received research funding from MedImmune and AstraZeneca. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Balmanoukian: Research/clinical trials funded by MedImmune. I have also agreed to be a speaker for Boehringer Ingelheim Pharmaceuticals. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; R. Narwal: Employee of Medimmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of Medimmune and owns stock/stock options in AstraZeneca; G. D'angelo: Employed by MedImmune. I currently hold stock ownership of AstraZeneca; A. Blake-Haskins: Employee of Medimmune and owns stock/stock options in AstraZeneca; J.J. Karakunnel: Employee of Medimmune and owns stock/stock options in AstraZeneca; N. Rizvi: I receive consulting income from Medimmune, Roche, Merck and BMS. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.