TY - JOUR
T1 - A phase Ib/II study of pepinemab in combination with avelumab in advanced non–small cell lung cancer
AU - Shafique, Michael R.
AU - Fisher, Terrence L.
AU - Evans, Elizabeth E.
AU - Leonard, John E.
AU - Pastore, Desa Rae E.
AU - Mallow, Crystal L.
AU - Smith, Ernest
AU - Mishra, Vikas
AU - Schröder, Andreas
AU - Chin, Kevin M.
AU - Beck, Joseph T.
AU - Baumgart, Megan A.
AU - Govindan, Ramaswamy
AU - Gabrail, Nashat Y.
AU - Spira, Alexander I.
AU - Seetharamu, Nagashree
AU - Lou, Yanyan
AU - Mansfield, Aaron S.
AU - Sanborn, Rachel E.
AU - Goldman, Jonathan W.
AU - Zauderer, Maurice
N1 - Funding Information:
M.R. Shafique reports personal fees from Jazz Pharmaceuticals outside the submitted work. T.L. Fisher reports other from Vaccinex, Inc. outside the submitted work. T.L. Fisher also has a patent for anti-CD100 antibodies and methods for using the same issued, a patent for anti-SEMA4D antibodies and epitopes issued, and a patent for semaphorin-4D antagonists for use in cancer therapy pending. E.E. Evans reports other from Vaccinex outside the submitted work. E.E. Evans also has a patent for use of anti-semaphorin-4D antibodies in combination with an immune modulating therapy to inhibit tumor growth and metastases issued to Vaccinex and a patent for Use of antibodies or antigen-binding fragments thereof that specifically bind semaphorin-4D to increase tumor infiltrating leukocyte frequency issued to Vaccinex. D.E. Pastore reports personal fees from Vaccinex during the conduct of the study, as well as personal fees from Tarus Therapeutics outside the submitted work. C.L. Mallow reports personal fees from Vaccinex, Inc. outside the submitted work. E. Smith reports other from Vaccinex. Inc outside the submitted work. E. Smith also has a patent for anti-SEMA4D antibodies and epitopes issued to Vaccinex, a patent for use of antibodies or antigen-binding fragments thereof that specifically bind semaphorin-4D to increase tumor infiltrating leukocyte frequency issued to Vaccinex, a patent for use of semaphorin-4D inhibitory molecules with an immune modulating therapy to inhibit tumor growth and metastases issued to Vaccinex, and a patent for humanized anti-CD100 antibodies issued to Vaccinex. V. Mishra reports other from Vaccinex, Inc. outside the submitted work. V. Mishra also has a patent for anti-SEMA4D antibodies and epitopes issued to Vaccinex, Inc., a patent for use of antibodies or antigen-binding fragments thereof that specifically bind semaphorin-4D to increase tumor-infiltrating leukocyte frequency issued to Vaccinex, Inc., a patent for use of semaphorin-4D inhibitory molecules with an immune modulating therapy to inhibit tumor growth and metastases issued to Vaccinex, Inc., and a patent for humanized anti-CD100 antibodies issued to Vaccinex, Inc. A. Schroder reports personal fees and other from Merck KGaA during the conduct of the study, as well as personal fees and other from Merck KGaA outside the submitted work. K.M. Chin reports other from EMD Serono Research & Development Institute, Inc.; an affiliate of Merck KGaA during the conduct of the study. J.T. Beck reports grants, nonfinancial support, and other from Vaccinex during the conduct of the study, as well as grants from Lilly, Pfizer, Genentech, Novartis, Seattle Genetics, AstraZeneca, Abbvie, SCRI, DSI, and Merck Serono outside the submitted work. M.A. Baumgart reports grants and nonfinancial support from Vaccinex Inc. during the conduct of the study. M.A. Baumgart also reports grants and nonfinancial support from Pfizer, grants from Merck, grants and nonfinancial support from Halozyme Therapeutics, and personal fees from Bristol Myers Squibb outside the submitted work. R. Govindan reports research support for the institution from Vaccinex during the conduct of the study, as well as personal fees from Roche, GlaxoSmithKline, Merck, Pfizer, Celgene, AstraZeneca, GenePlus, and Achilles outside the submitted work. A.I. Spira reports grants from Vaccinex during the conduct of the study, as well as personal fees from Amgen, Mirati, Merck, BMS, Novartis, and Sanofi outside the submitted work. N. Seetharamu reports personal fees from Amgen, Takeda, AstraZeneca, Genentech, Pfizer, and Boehringer Ingelheim outside the submitted work. Y. Lou reports grants from Vaccinex during the conduct of the study. Y. Lou also reports personal fees from AstraZeneca and Janssen, grants from Macro-Genics, Tolero Pharmaceuticals, Blueprint Medicines, Merck, AstraZeneca, Harpoon Therapeutics, and Tesaro; and grants from Bayer HealthCare and Janssen outside the submitted work. A.S. Mansfield reports grants from Novartis and Verily, as well as other from AbbVie, AstraZeneca, BMS, Genentech, Chugai Pharmaceutical Co, Ltd. (Roche), Janssen, Roche, and Mesothelioma Applied Research Foundation outside the submitted work. R.E. Sanborn reports other from AstraZeneca, Amgen, Genentech/Roche, EMD Serono, Blueprint Medicines, Daiichi Sankyo/Lilly, Janssen Oncology, and Macrogenics outside the submitted work. J.W. Goldman reports grants and personal fees from Pfizer during the conduct of the study. J.W. Goldman also reports grants and personal fees from Merck, Genentech, and BMS, as well as grants, personal fees, and nonfinancial support from AstraZeneca outside the submitted work. M. Zauderer reports other from Vaccinex, Inc. outside the submitted work. M. Zauderer also is a patent inventor on several patents related to this work issued to Vaccinex, a patent for anti-SEMA4D antibodies and epitopes issued to Vaccinex, a patent for use of antibodies or antigen-binding fragments thereof that specifically bind semaphorin-4D to increase tumor infiltrating leukocyte frequency issued to Vaccinex, a patent for use of semaphorin-4D inhibitory molecules with an immune modulating therapy to inhibit tumor growth and metastases issued to Vaccinex, and a patent for humanized anti-CD100 antibodies issued to Vaccinex. No disclosures were reported by the other authors.
Funding Information:
The authors would like to thank the patients, their families and caregivers, and the research staff at all the sites for their efforts. We would also like to thank Dr. Jerome-Jean Gilles for pathology support with biopsy multiplex analysis. This study was sponsored by Vaccinex, Rochester, NY, and was also financially supported by Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck KGaA and Pfizer.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85109179271&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109179271&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4792
DO - 10.1158/1078-0432.CCR-20-4792
M3 - Article
C2 - 33820783
AN - SCOPUS:85109179271
SN - 1078-0432
VL - 27
SP - 3630
EP - 3640
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -