A Phase 1b/2 Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer.

Purpose The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized monoclonal antibody 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 1b/2, single arm study was designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 patients with advanced NSCLC, including immunotherapy-naive (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety / tolerability, establish a RP2D, obtain a preliminary evaluation of anti-tumor activity and investigate candidate biomarker activity. Results The combination was well tolerated with no major safety signals identified. Pepinemab, 10mg/kg with avelumab, 10mg/kg, Q2W, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit {greater than or equal to} 1 year, and the DCR was 81%. Notably, ORR 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 {greater than or equal to} 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.