A phase Ib/II study of pepinemab in combination with avelumab in advanced non–small cell lung cancer

Michael R. Shafique, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae E. Pastore, Crystal L. Mallow, Ernest Smith, Vikas Mishra, Andreas Schröder, Kevin M. Chin, Joseph T. Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Y. Gabrail, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Rachel E. Sanborn, Jonathan W. GoldmanMaurice Zauderer

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Original languageEnglish (US)
Pages (from-to)3630-3640
Number of pages11
JournalClinical Cancer Research
Volume27
Issue number13
DOIs
StatePublished - Jul 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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