A Phase 1b/2 Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer
Mené sur 62 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase IB/II évalue la dose maximale tolérée du pépinémab (un anticorps ciblant la sémaphorine 4D) en combinaison avec l'avélumab et l'efficacité, du point de vue du taux de réponse, de cette combinaison
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-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 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.