Abstract A20: MK-3475 monotherapy for previously treated non-small cell lung cancer (NSCLC): Preliminary safety and clinical activity.
Authors: Garon Edward B. , Balmanoukian Ani , Hamid Omid , Hui Rina , Gandhi Leena , Leighl Natasha , Gubens Matthew , Goldman Jonathan W. , Lubiniecki Gregory M. , Emancipator Kenneth , Dolled-Filhart Marisa , Lunceford Jared , Gergich Kevin , Rizvi Naiyer A. 
Published: August 2014

Abstract
Background: Currently approved cytotoxic chemotherapies for patients with previously treated NSCLC produce few objective responses, which are generally of short duration and have a limited impact on progression-free survival and overall survival. Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor that when activated upon interaction with its ligands, PD-L1 and PD-L2, can lead to suppression of antitumor immunity. Preclinical and clinical data indicate that this pathway is important in NSCLC. MK-3475 is a highly selective, humanized monoclonal IgG4 anti-PD-1 antibody against PD-1 that exerts dual ligand blockade of the PD-1 pathway. This phase 1 study was conducted to assess the safety and antitumor activity of MK-3475 in patients with previously treated NSCLC.
Methods: MK-3475 was administered at 10 mg/kg every 3 weeks to patients with NSCLC previously treated with 2 systemic regimens. At least 1 measurable tumor lesion, ECOG performance status of 0 or 1, and adequate organ function were required for enrollment. A new tumor biopsy performed no earlier than 60 days before the first dose of MK-3475 was required for study entry. Imaging assessments were performed every 9 weeks until confirmed disease progression by investigator review per the immune-related response criteria (irRC). Independent central review of images was assessed per RECIST v1.1. PD-L1 expression on pretreatment tumor samples was determined by immunohistochemistry. A cut point associated with the Youden Index of the receiver-operating characteristic curve for PD-L1 staining was identified.
Results: Between April 2012 and September 2012, 38 patients were enrolled. Median age was 63 years (range 34-85 years), with 42% men and 42% with an ECOG performance status of 0. Previously treated, stable brain metastases were allowed and were present in 11%. Eight patients had an EGFR mutation, 6 had a KRAS mutation, and 2 had an ALK gene rearrangement in their tumor. Drug-related adverse events were experienced by 53% of patients, most commonly rash (21%), pruritus (18%), and fatigue (16%). The incidence of diarrhea was 13% (only grade 1 or 2 reported). One drug-related grade 3/4 adverse event (grade 3 pulmonary edema: 3%) was seen. No drug-related deaths were reported. By investigator-assessed irRC, the objective response rate (ORR; confirmed and unconfirmed) was 24%, including squamous and non-squamous subtypes. Similar results were obtained using RECIST v1.1, yielding an ORR (confirmed and unconfirmed) of 21%. Most responses by irRC were observed by the time of first planned assessment at Week 9. The median duration of response by irRC has not been reached over a median duration of follow-up of 62 weeks. As of October 2013, 7 of the 9 responding patients by irRC continue on therapy. Pretreatment tumor PD-L1 expression was a significant predictor of response. Among patients with PD-L1 expression greater than a potential cut point, response rates of 67% (irRC)/57% (RECIST) were observed, compared with response rates of 4% (irRC)/9% (RECIST) among patients with PD-L1 expression below the potential cut point.
Conclusion: MK-3475 is generally well tolerated and provides durable objective responses in patients with previously treated advanced NSCLC.
Citation Format: Edward B. Garon, Ani Balmanoukian, Omid Hamid, Rina Hui, Leena Gandhi, Natasha Leighl, Matthew Gubens, Jonathan W. Goldman, Gregory M. Lubiniecki, Kenneth Emancipator, Marisa Dolled-Filhart, Jared Lunceford, Kevin Gergich, Naiyer A. Rizvi. MK-3475 monotherapy for previously treated non-small cell lung cancer (NSCLC): Preliminary safety and clinical activity. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A20.