Andy Blake-Haskins

988PDCLINICAL ACTIVITY AND SAFETY OF MEDI4736, AN ANTI-PD-L1 ANTIBODY, IN PATIENTS WITH HEAD AND NECK CANCER

ABSTRACT Aim: Squamous cell carcinoma of the head and neck (SCCHN) is associated with tobacco use, human papillomavirus (HPV) infection, and PD-L1 expression. An ongoing Phase I, multicenter, open-label study (NCT01693562) is evaluating the safety and efficacy of MEDI4736, a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. Methods: MEDI4736 is administered IV every 2 weeks (q2w) at a dose of 10 mg/kg in a recurrent/metastatic SCCHN expansion cohort. Retreatment is permitted upon progression after 12 months of therapy. Smoking history, HPV status and prior treatments are collected at baseline. PD-L1 expression within the tumor is assessed by immunohistochemistry. Response is assessed by RECIST v1.1. Results: As of 14 Apr, 2014, 50 pts with SCCHN; mean age 58 y (range 24–96); 86% male, 63% current/prior smokers, with median 3 prior treatments (1–11), received median 3 doses (1–12) of MEDI4736 10 mg/kg q2w. Treatment-related adverse events (TRAE) were observed in 39% of pts; most frequently nausea (6%), diarrhea, dizziness, and rash (4% each). Dyspnea, syncope, raised gamma-glutamyltransferase (GGT) and sepsis (each 5%) were the most common grade ≥3 AEs; only raised GGT (n = 1) was considered treatment-related. No TRAEs led to study discontinuation and no pts had pneumonitis or colitis. Median time of follow up was 8 wks at data cutoff. In all, 29 SCCHN pts were evaluable for efficacy (first assessment at 6 weeks), with 7 having radiographic shrinkage in target tumor lesions ranging from 7% to 76%. Five of the 7 pts have been followed for at least 12 wks (6–24 wks) and none have evidence of objective progression. Four pts have a partial response (confirmed + unconfirmed). Further assessment of clinical activity and its potential relationship to clinical attributes (HPV status, smoking history, prior therapies), and biomarkers, including PD-L1 expression, are ongoing. Conclusions: Preliminary clinical activity in pts with SCCHN has been observed with manageable safety profile consistent with previous reports for MEDI4736. These data support continued clinical development of MEDI4736 in SCCHN. Disclosure: M. Fury: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; S.I. Ou: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; A. Balmanoukian: Our clinic, including myself, is involved with research/clinical trials funded by MedImmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I have agreed to be a speaker for BI.; A. Hansen: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; E. Massarelli: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; A. Blake-Haskins: Employee of MedImmune and owns stock/stock options in AstraZeneca X. Li: Employee of MedImmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; J. Vasselli: Employee of MedImmune and owns stock/stock options in AstraZeneca; N.H. Segal: Ad Board participation with MedImmune, Alkermes Scientific, Imugene Research funding from BMS and Pfizer. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

1131TiPPHASE 1 STUDY EVALUATING SAFETY AND TOLERABILITY OF MEDI4736, AN ANTI-PROGRAMMED CELL DEATH LIGAND-1 (PD-L1) ANTIBODY, IN COMBINATION WITH DABRAFENIB AND TRAMETINIB OR TRAMETINIB ALONE IN PATIENTS WITH UNRESECTABLE OR METASTATIC MELANOMA

ABSTRACT Background: Targeted treatments have significantly improved outcomes in patients (pts) with metastatic melanoma (MM). The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, provides high response rates in BRAF mutation-positive melanoma (BRAF V600E/K melanoma). Trametinib has also shown clinical activity in BRAF wild-type (WT) melanoma. The addition of an immunomodulator may further improve clinical outcomes in metastatic melanoma pts. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies, showed durable clinical activity in a Phase 1 study of pts with solid tumors including melanoma. MEDI4736 is being evaluated in combination with dabrafenib/trametinib or trametinib alone in BRAF mutation-positive or BRAF mutation-negative melanoma. Trial design: This global multicenter, open-label Phase 1b study (NCT02027961) is enrolling adults with unresectable or MM and ECOG performance status 0–1 into 3 cohorts. In cohort A, BRAF-V600E/K melanoma pts receive dabrafenib orally (PO) twice daily, trametinib PO once daily (QD) and MEDI4736 intravenously (IV) every 2 wks (q2w), given concomitantly followed by continued dabrafenib/trametinib until progressive disease (PD). In cohorts B and C, BRAF mutation-negative (BRAF-WT) pts receive trametinib PO QD and MEDI4736 IV q2w according to 2 different treatment schedules,until PD. Primary objectives are determination of maximum tolerated dose (dose-limiting toxicity) and safety profile (adverse events, laboratory evaluations, physical exams, echocardiograms/electrocardiograms) of MEDI4736 in combination with dabrafenib/trametinib or trametinib alone. Secondary objectives include antitumor activity (objective response based on RECIST, duration of response, PFS, and overall survival), pharmacokinetic profile, and immunogenicity of the combination. Exploratory objectives include biomarkers, patient-reported outcomes, and tumor growth parameters. Recruitment is ongoing (target: 69 pts). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 (TPS9108). Disclosure: M.S. Gordon and D. Lawrence: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; J. Lutzky: Medimmune/Astra-Zeneca: clinical trial support. Genentech, BMS, Prometheus: both clinical trial support and speaker bureau. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Financial support from MedImmune to cover the costs of conducting sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; P.A. Ascierto: Consultancy/research funding/honoraria: BMS, Roche-Genentech, Merck Sharp & Dohme, GSK, Ventana, and Novartis. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; B. Hug: Employee of GlaxoSmithKline. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins, A. Di Pietro, X. Li and P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; A. Ribas: Consultant/funding/stock options Amgen Daiichi-Sankyo GSK Genentech-Roche Merck Novartis Pierre-Favre Kite Pharma Flexus. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

1325PCLINICAL ACTIVITY AND SAFETY OF MEDI4736, AN ANTI-PROGRAMMED CELL DEATH-LIGAND 1 (PD-L1) ANTIBODY, IN PATIENTS WITH NON-SMALL CELL LUNG CANCER

ABSTRACT Aim: This ongoing Phase I, multicenter, open-label study (NCT01693562) evaluates the safety and efficacy of MEDI4736 in patients (pts) with multiple solid tumor types including non-small cell lung cancer (NSCLC). MEDI4736 is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. PD-L1 is expressed in many NSCLC tumors and may be associated with poor prognosis. Methods: MEDI4736 was administered IV every 2 weeks (q2w) or every 3 weeks (q3w) using a standard 3 + 3 dose escalation (6 dose levels: 0.1–10 mg/kg q2w; 15 mg/kg q3w). In dose expansion, NSCLC pts were assigned to cohorts by histology and line of therapy and administered MEDI4736 10 mg/kg q2w. Retreatment was permitted for progression after 12 months of therapy. Response is assessed by immune-related response criteria in escalation and RECIST v1.1 in expansion. Results: As of 14 April 2014, 114 NSCLC pts have been treated with MEDI4736 in dose escalation and expansion cohorts. Of the 101 pts treated at the 10 mg/kg q2w dose (median 3 doses received; range 1–14), mean age 63 y (37–83), all were PS 0–1, with a median of 2.5 prior treatments (range1–8). In this group, treatment-related adverse events (AEs) were reported in 20% of pts; most frequently dyspnea (16%), fatigue (15%) and nausea (15%). Grade ≥ 3 treatment-related AEs were reported in 4 pts. AEs led to study discontinuation in 6 pts, none of which were treatment-related. Pneumonitis (grade 2) occurred in 1 pt. With a median follow up of 10 wks, 46 pts were followed ≥ 12 wks. Objective response + stable disease was observed in 18 pts to date. While some responses or stabilization were reported at first assessment (6 wks), others appeared following initial progression. Benefit was durable; 72/114 pts remain on study (including 4 pts >52 wks) at data cutoff. Assessment of clinical activity by PD-L1 expression, underlying mutation, smoking history, and line of therapy continues. Conclusions: Durable clinical activity has been observed with manageable AEs, no grade ≥3 pneumonitis, and no colitis of any grade. Further development of MEDI4736 alone and in combination is ongoing in NSCLC. Disclosure: S. Antonia: Received honoraria from BMS and MedImmune/AstraZeneca for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers research funding received for conduct of a MedImmune-sponsored study as conflict of interest; Ou: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor; J.R. Brahmer: My institution receives funding for the conduct of a MedImmune-sponsored study. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of Medimmune and own stock/stock options in AstraZeneca; P.B. Robbins: Employee of Medimmune and own stock/stock options in AstraZeneca; X. Li: Employee of Medimmune and own stock/stock options in AstraZeneca; J. Vasselli: Employee of Medimmune and own 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.