A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients with Small Cell Lung Cancer
- PMID: 39287821
- PMCID: PMC11565168
- DOI: 10.1158/1078-0432.CCR-24-1547
A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients with Small Cell Lung Cancer
Abstract
Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy.
Patients and methods: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated.
Results: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1 mg/kg, n = 40)]; the median age was 63 years (range, 41-79 years). Also, 32%, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. The most common treatment-emergent adverse events were fatigue (50%), nausea (42%), and thrombocytopenia (41%). The most common hepatic treatment-emergent adverse events were increased aspartate aminotransferase (22%), increased γ-glutamyltransferase (21%), and hyperbilirubinemia (17%); two patients experienced veno-occlusive liver disease. The objective response rate was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n = 40), the objective response rate was 25%; the median response duration was 4.2 months (95% confidence interval, 2.6-6.7); and the median progression-free survival was 3.5 months (95% confidence interval, 1.5-4.2).
Conclusions: ABBV-011 1.0 mg/kg every 3 weeks monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.
©2024 The Authors; Published by the American Association for Cancer Research.
Conflict of interest statement
D. Morgensztern reports other support from AbbVie, G1 Therapeutics, Mirati, Arcus, Merck, Celgene, AstraZeneca, Incyte, Bristol Myers Squibb, Eli Lilly and Company, Array, Pfizer, Surface, Boehringer Ingelheim, and Genprex outside the submitted work. N. Ready reports personal fees from AbbVie outside the submitted work. M.L. Johnson reports grants, nonfinancial support, and other support from AbbVie during the conduct of the study; grants and other support from AbbVie, Amgen, Arcus Biosciences, ArriVent Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Fate Therapeutics, Genentech/Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Immunocore, Janssen, Merck, Mirati Therapeutics, Novartis, Pfizer, Revolution Medicines, Sanofi, and Takeda Pharmaceuticals; grants from Adaptimmune, Array BioPharma, Artios Pharma, Bayer, BeiGene, BerGenBio, BioAtla, Black Diamond, Calithera Biosciences, Carisma Therapeutics, City of Hope National Medical Center, Conjupro Biotherapeutics, Corvus Pharmaceuticals, Curis, CytomX, Dracen Pharmaceutical, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Genocea Biosciences, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immuneering Corporation, Immunitas Therapeutics, IMPACT Therapeutics, Incyte, Kartos Therapeutics, LockBody Therapeutics, Loxo Oncology, Memorial Sloan Kettering, Merus, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, NextPoint Therapeutics, Numab Therapeutics, Nuvalent, OncoC4, Palleon Pharmaceuticals, PMV Pharma, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Ribon Therapeutics, Rubius Therapeutics, Seven and Eight Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Summit Therapeutics, Syndax Pharmaceuticals, SystImmune, Taiho Oncology, TCR2 Therapeutics, Tempest Therapeutics, Theras, Tizona Therapeutics, Tmunity Therapeutics, Turning Point Therapeutics, Vividion, Vyriad, and Y-mAbs Therapeutics; and other support from Alentis Therapeutics, Biohaven Pharmaceuticals, D3 Bio Limited, Gilead Sciences, Hookipa Biotech, Jazz Pharmaceuticals, ModeX Therapeutics, Molecular Axiom, Normunity, Novocure, Pyramid Biosciences, Seagen, Synthekine, and Zai Lab outside the submitted work. A. Dowlati reports other support from AstraZeneca, Amgen, and AbbVie during the conduct of the study. N. Choudhury reports other support from AbbVie during the conduct of the study, as well as other support from Harpoon Therapeutics, AbbVie, Amgen, Monte Rosa Therapeutics, Roche/Genentech, Sanofi, G1 Therapeutics, and Merck outside the submitted work. D.P. Carbone reports other support from GSK, inThought, Pfizer, Iovance Biotherapeutics, Mirati, Arcus Biosciences, Roche, Bristol Myers Squibb (Israel), AstraZeneca, AbbVie, Novartis, Regeneron, Merck Sharp & Dohme, Pfizer (Egypt), Genentech, Novocure, OncoHost, Merck US, Amgen, Daiichi Sankyo, Bristol Myers Squibb (Brazil), Eli Lilly and Company, Janssen, J&J, Merck, Lumanity, DAVA, and Pfizer during the conduct of the study. S.M. Arnold reports other support from AbbVie during the conduct of the study. S. Puri reports personal fees from Pfizer, Bristol Myers Squibb, Novocure, Takeda, and OncoHost and nonfinancial support from Henlius outside the submitted work. Z. Piotrowska reports grants, personal fees, and nonfinancial support from AstraZeneca and Janssen; personal fees from Black Diamond Therapeutics, Taiho, Sanofi, C4 Therapeutics, Merck, Bayer, Boehringer Ingelheim, and Eli Lilly and Company; personal fees and other support from Genentech; grants and personal fees from Daiichi Sankyo, Blueprint Medicines, Takeda, and Cullinan; and grants from Novartis, Spectrum, and TESARO/GSK outside the submitted work. A. Hegde reports other support from Revolution Medicines outside the submitted work. A.C. Chiang reports personal fees and other support from AstraZeneca Amgen, and Genentech (any division); other support from AbbVie; personal fees from Janssen, Zai Lab, and Daiichi; and other support from Bristol Myers Squibb during the conduct of the study. W. Iams reports personal fees from Novocure, Genzyme Corporation, EMD Serono, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, AbbVie, Amgen, Genentech, and Janssen outside the submitted work. A. Tolcher reports personal fees and other support from AbbVie, Inc., Aclaris Therapeutics, Affinia Therapeutics, Inc., Agenus, Inc., Asana BioSciences, Ascentage, Astex Pharmaceuticals, AxImmune, Bayer, BluPrint Oncology, Coretag Therapeutics, Cytel, Daiichi Sankyo, Inc., Exelixis, Inc., FibroGen, Gilde Healthcare Partners, HBM Partners, IDEA Pharma, Ikena Oncology, Immuneering, ImmunoMet Therapeutics, Inc., IMPACT Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Medicxi, Merck KGaA, MEKanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Nerviano Medical Sciences S.r.I., Novo Nordisk Inc., Novo Venture, Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., Pierre Fabre, Praxis Precision Medicines, Pyramid Biosciences, Qualigen Therapeutics, Mythic Therapeutics, Roche, Ryvu Therapeutics, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology Co., Senti Biosciences, Sun Pharma Advanced Research Company, Theratechnologies, Transcenta Therapeutics Inc., Transgene, Trillium Therapeutics Inc., Tubulis, Venus Oncology, Verastem Oncology, Vida Ventures Advisors, LLC, Adagene, Inc., BioInvent, Boehringer Ingelheim International GmbH, Bright Peak Therapeutics, Cullinan Oncology, Elucida Oncology, EMD Serono/Merck KGaA, Hexagon Bio, Inc., Immunome, Jazz, Leerink, Mirati, NBE Therapeutics, Nested Therapeutics, Inc., Pheon Therapeutics, Pyxis Oncology, Roche, Sun Pharma Advanced Research Company, Spirea Limited Inc., Tagworks Pharmaceuticals, Vincerx, VRise Therapeutics, Inc., Zentalis Pharmaceuticals, and ZielBio, Inc. during the conduct of the study; personal fees and other support from AbbVie, Inc., Aclaris Therapeutics, Affinia Therapeutics, Inc., Agenus, Inc., Asana BioSciences, Ascentage, Astex Pharmaceuticals, AxImmune, Bayer, BluPrint Oncology, Coretag Therapeutics, Daiichi Sankyo, Inc., Exelixis, Inc., FibroGen, Gilde Healthcare Partners, HBM Partners, IDEA Pharma, Ikena Oncology, Immuneering, ImmunoMet Therapeutics, Inc., IMPACT Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Medicxi, Merck KGaA, MEKanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Nerviano Medical Sciences S.r.I., Novo Nordisk Inc., Novo Venture, Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., Pierre Fabre, Praxia Precision Medicines, Pyramid Biosciences, Qualigen Therapeutics, Roche, Ryvu Therapeutics, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology Co., Senti Biosciences, Sun Pharma Advanced Research Company, Theratechnologies, Transcenta Therapeutics Inc., Transgene, Trillium Therapeutics Inc., Tubulis, Venus Oncology, Verastem Oncology, Vida Ventures Advisors, LLC, Adagene, Inc., BioInvent, Boehringer Ingelheim International GmbH, Bright Peak Therapeutics, Cullinan Oncology, Elucida Oncology, EMD Serono/Merck KGaA, Hexagon Bio, Inc., Immunome, Jazz, Leerink, Mirati, NBE Therapeutics, Nested Therapeutics, Inc., Pheon Therapeutics, Pyxis Oncology, Spirea Limited Inc., Tagworks Pharmaceuticals, Vincerx, VRise Therapeutics, Inc., Zentalis Pharmaceuticals, and ZielBio, Inc. outside the submitted work; and a patent for Zentalis issued and a patent for Acentage Pharma issued. K. Nosaki reports grants and personal fees from Takeda, AstraZeneca, MSD, and Chugai Pharma; grants from AbbVie, Daiichi Sankyo, and AnHeart Therapeutics; and personal fees from Eli Lilly and Company, Pfizer, Taiho Pharmaceutical, Janssen, Ono Pharmaceutical, Novartis, and Merck outside the submitted work. T. Kozuki reports grants and personal fees from MSD, Daiichi Sankyo, Eisai, AbbVie, Kyowa Hakko Kirin, Bayer, Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol Myers Squibb, and Ono Pharmaceutical Co.; personal fees from Sawai; and grants from Gilead Sciences, Labcorp Development Japan, IQVIA Services Japan, and Sanofi outside the submitted work. T. Li reports grants from AbbVie during the conduct of the study; grants from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Duality Biologics, Genentech/La Roche, Jounce Therapeutics, LabyRx Immuno-Oncology, Merck, OncoC4/BioNTech, Novartis, Rascal Therapeutics, Tempus, and Xilio Therapeutics; and other support from Janssen, Bristol Myers Squibb, and InxMed outside the submitted work. R. Santana-Davila reports grants from AbbVie during the conduct of the study. H. Akamatsu reports grants and personal fees from Amgen Inc., Chugai Pharmaceutical Co. Ltd., and MSD K.K.; and personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly Japan K.K., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., GSK, and Sandoz outside the submitted work. H. Murakami reports grants from AbbVie during the conduct of the study; as well as grants and personal fees from Chugai Pharma, AstraZeneca, Daiichi Sankyo, and Taiho Pharmaceutical; grants from IQVIA and Bayer; and personal fees from Takeda, Amgen, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Pfizer, Novartis, Lilly Japan, Eisai, Nippon Kayaku, Kyowa Kirin, and GAIA BioMedicine outside the submitted work. H. Yokouchi reports grants from AbbVie during the conduct of the study; grants and personal fees from AstraZeneca and Chugai Pharmaceutical; and grants from Bristol Myers Squibb, Sanofi, Takeda Pharmaceutical, MSD, and Daiichi Sankyo outside the submitted work. J. Zha reports personal fees from AbbVie, Inc. outside the submitted work. R. Li reports other support from AbbVie during the conduct of the study, as well as other support from AbbVie outside the submitted work. R.R. Robinson reports other support from AbbVie during the conduct of the study. M. Furqan reports grants and personal fees from AbbVie during the conduct of the study, as well as grants and personal fees from AstraZeneca, BeiGene, and Mirati; grants from GSK, Bristol Myers Squibb, Celgene, Checkmate, Elicio, Fate Therapeutics, Amgen, APREA, Genmab, Gilead, Genentech, Immunocore, Incyte, Jacobio, Eli Lilly and Company, Merck, and Novartis; and personal fees from Omega Therapeutics and Jazz Pharma outside the submitted work. No disclosures were reported by the other authors.
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