A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
oregon; portland; chiles
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.
Earle A. Chiles Research Institute
Shafique, Michael R; Fisher, Terrence L; Evans, Elizabeth E; Leonard, John E; Pastore, Desa Rae E; Mallow, Crystal L; Smith, Ernest; Mishra, Vikas; Schröder, Andreas; Chin, Kevin M; Beck, Joseph T; Baumgart, Megan A; Govindan, Ramaswamy; Gabrail, Nashat Y; Spira, Alexander I; Seetharamu, Nagashree; Lou, Yanyan; Mansfield, Aaron S; Sanborn, Rachel E; Goldman, Jonathan W; and Zauderer, Maurice, "A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer." (2021). Articles, Abstracts, and Reports. 4922.