Abstract CT086: Interim results from CLASSICAL-Lung, a Phase Ib/II study of VX15/2503 (pepinemab) in combination with avelumab in advanced NSCLC
Authors: Shafique Michael , Fisher Terrence L. , Evans Elizabeth E. , Leonard John E. , Pastore Desa Rae , Mallow Crystal , Smith Ernest , Zauderer Maurice , Schröeder Andreas , Chin Kevin , Beck Thaddeus , Baumgart Megan , Sanborn Rachel E. , Goldman Jonathan W. 
Published: August 2019

Abstract
Background: Blockade of the PD/PD-L1 pathway is an effective immunotherapy for NSCLC, however rational combination therapies are needed to overcome resistance mechanisms. VX15/2503 (pepinemab) is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. Avelumab is a fully human IgG1 antibody specific for PD-L1 and has been approved for both Merkel cell and urothelial carcinomas. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Here, we present interim results of the dose escalation portion of the CLASSICAL-Lung study.
Methods: This Phase Ib/II, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced (IIIB/IV) NSCLC. The trial is split into dose escalation (n=12) and dose expansion (n=50) phases. The dose escalation portion includes patients who are immunotherapy naïve and have either progressed or declined standard first or second-line systemic anticancer therapy. The expansion phase includes a similar patient cohort as well as a second cohort of patients whose tumors progressed during or following immunotherapy. Patients in the dose escalation cohorts received ascending doses of pepinemab (5, 10, 20 mg/kg, Q2W) in combination with avelumab (10mg/kg, Q2W). The primary objective of dose escalation is safety, tolerability, and identification of the RP2D for dose expansion. Secondary objectives include evaluation of efficacy, immunogenicity, and PK/PD, and an exploratory objective is to identify candidate biomarkers of activity.
Results / Conclusions: Dose escalation was successfully completed. The combination was found to be well tolerated at all dose levels tested and the RP2D was selected as 10mg/kg pepinemab Q2W (with 10mg/kg avelumab Q2W) for the dose expansion phase. No concerning safety signals have been identified to date. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AE occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, resolved and did not recur in that same subject or additional subjects in any cohort. The disease control rate to date in all dose escalation patients treated for at least two months is 90%. More detailed data from the dose escalation cohorts will be presented, as well as an enrollment update for the dose expansion phase.
Clinical trial information: NCT03268057
Citation Format: Michael Shafique, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Maurice Zauderer, Andreas Schröeder, Kevin Chin, Thaddeus Beck, Megan Baumgart, Rachel E. Sanborn, Jonathan W. Goldman. Interim results from CLASSICAL-Lung, a Phase Ib/II study of VX15/2503 (pepinemab) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT086.