1318MO - First-in-human study of ABBV-637, an EGFR-targeting BCL-XL–inhibiting antibody-drug conjugate combined with osimertinib (OSI) in relapsed/refractory, EGFR-mutated non-small cell lung cancer (NSCLC)

Background

ABBV-637 is an antibody-drug conjugate consisting of an epidermal growth factor receptor (EGFR)–targeting antibody and BCL-X_Linhibitor. Preclinical data demonstrate potent antitumor activity of ABBV-637 plus OSI in mutant EGFR NSCLC through reactivation of the apoptotic pathway.

Methods

This phase 1 dose escalation and expansion study (NCT04721015) explored the safety and preliminary efficacy of ABBV-637 as second- (2L) and third-line (3L) combination therapy with OSI. Enrolled adults had relapsed/refractory (RR) NSCLC with EGFR mutation, ECOG 0–1, and prior response and subsequent disease progression on OSI. Enrolled patients being treated at 2L and 3L had no inclusion/exclusion criteria for specific targetable mutations. ABBV-637 (12 or 20 mg/kg) was dosed IV Q4W; OSI (80 mg) was given daily in 28-day cycles. Endpoints included the rates of treatment-emergent adverse events (TEAEs), objective response (ORR), disease control (DCR), and best overall response. Disease- and drug-related biomarkers were evaluated.

Results

Forty-two patients were treated; median age was 65 (range: 44–79), and 64% had ≥2 prior lines of therapy. Median duration of ABBV-637 treatment was 113 days (range: 28–288). Most common TEAEs were increases in aspartate (38%) and alanine aminotransferase (33%), nausea (33%), and fatigue (21%). The ORR was 14% in 3L cohorts and 10% in 2L (Table). DCR was 73% and 65% in 3L and 2L, respectively. In 2L, confirmed responders did not have targetable bypass alterations. Table: 1318MO

*Based on RECIST 1.1; ^†dose escalation (3L; n=5); ^‡dose expansion (3L; n=17); ^§dose expansion (2L). 2L, 2nd-line therapy (post osimertinib alone); 3L, 3rd-line therapy (post osimertinib and platinum chemotherapy).

Conclusions

ABBV-637 plus OSI showed clinical activity and a manageable safety profile in patients with RR NSCLC. Biomarker data suggest that response to ABBV-637 plus OSI may be enriched by excluding patients with targetable bypass mechanisms; ongoing research is needed to confirm association of mutation and patient selection.

Clinical trial identification

NCT04721015.

Editorial acknowledgement

AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Medical writing support was provided by Vasileios Stamou, PhD, of Fishawack Facilitate Ltd, part of Fishawack Health, funded by AbbVie.

Legal entity responsible for the study

AbbVie Inc.

Funding

AbbVie.

Disclosure

J.K. Rotow: Financial Interests, Personal and Institutional, Advisory Board: AbbVie, AstraZeneca, BioAtla, Loxo, Lilly; Financial Interests, Personal and Institutional, Principal Investigator: AbbVie, AstraZeneca, BioAtla, Loxo, Lilly; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: G1 Therapeutics, Genentech, Guardant, Janssen, Sanofi, Summit, Takeda, Gritstone Oncology; Financial Interests, Institutional, Principal Investigator: Bicycle Therapeutics, Daiichi Sankyo, Blueprint, Enliven, EpimAb, ORIC, Redcloud. S.N. Waqar: Financial Interests, Institutional, Research Funding: SWOG-Clinical Trials Partnership; Financial Interests, Personal, Other, Honorarium: Hoosier Cancer Research Network; Financial Interests, Personal, Advisory Board: AstraZeneca ; Financial Interests, Institutional, Principal Investigator: AbbVie, Ariad Pharmaceuticals, Genentech, Immunomedics, Millennium Pharmaceuticals, Roche, Astellas Pharma, Daiichi Sankyo, Cullinan Pearl, Verastem Oncology, GSK/GSK, Janssen, Elevation Oncology, Genentech, Loxo Oncology, Takeda. K.P. Papadopoulos: Financial Interests, Personal, Advisory Board: Turning Point Therapeutics, Bicycle, Basilia; Financial Interests, Institutional, Full or part-time Employment: START; Financial Interests, Personal, Ownership Interest: START; Financial Interests, Institutional, Local PI, For conduct of clinical trial: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Daiichi Sankyo, EMD Serono, F-Star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, Merck, Mersana, Mirati Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revolution Medicines, Syros Pharmaceuticals, Tempest Therapeutics, Treadwell Therapeutics. J. Hung: Financial Interests, Personal, Other, Speaker Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Eli Lilly and Company, Novartis, Ono Pharma, Chugai, Merck, Janssen Pharma, Takeda. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: Next Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. H. Gan: Financial Interests, Personal, Advisory Board: Merck Serono, Telix Pharma, Curis. T. Yoshida: Financial Interests, Personal, Advisory Board: Pfizer, MSD, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Pfizer, Takeda, Lilly, Ono Pharmaceutical, Novartis, Daiichi Sankyo, MSD, BMS; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, Amgen, Daiichi Sankyo, BMS, MSD, Ono Pharmaceutical, BluePrint, Chugai Pharmaceutical, AbbVie. C.S. Kuo: Financial Interests, Personal, Other, Speaker Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Eli Lilly, Novartis, Ono Pharma, Chugai, Merck, Janssen Pharma, Takeda, Guardant Health; Financial Interests, Personal, Other, Consulting: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Chugai, Takeda, Novartis, Guardant Health. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi Sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. G. Morrison-Thiele: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie; Financial Interests, Personal and Institutional, Stocks/Shares: AbbVie. R. Robinson: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie; Financial Interests, Personal and Institutional, Stocks/Shares: AbbVie. N. Rudraganguly: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie, AbbVie. R. Saab: Financial Interests, Personal and Institutional, Full or part-time Employment: AbbVie; Financial Interests, Personal and Institutional, Stocks/Shares: AbbVie. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Janssen; Financial Interests, Personal, Advisory Board: Kanaph Therapeutic Inc, BridgeBio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Other, Advisory role: Medpacto, Blueprint medicines, RandBio, Hanmi; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, BridgeBio therapeutics, Kanaph Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine., Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, BridgeBio Therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center; Other, Founder: Daan Biotherapeutics. All other authors have declared no conflicts of interest.