Abstract 1008P
Background
In the randomized, multicenter, phase III study in pts with previously untreated ALK+ advanced NSCLC (CROWN; NCT03052608), lorlatinib, a potent third-generation ALK inhibitor, improved progression-free survival (PFS) vs crizotinib (Shaw et al. NEJM 2020). Molecular profiling of circulating tumor DNA (ctDNA) was performed to identify resistance mechanisms to first-line treatment with lorlatinib or crizotinib.
Methods
Plasma samples were collected at baseline (BL) and end of treatment (EOT), from 134 and 26 pts in the lorlatinib arm, and from 129 and 80 in the crizotinib arm, respectively, and analyzed by next-generation sequencing. Resistance mechanisms explored included ALK mutations and RTK, PI3K, MAPK, and cell cycle pathways. PFS by blinded independent central review was based on a September 20, 2021, data cutoff.
Results
In BL ctDNA, EML4::ALK variants 1 or 2 (v1/v2) and 3 (v3) were detected in 27 (20%) and 18 (13%) pts in the lorlatinib arm and 28 (22%) and 23 (18%) pts in the crizotinib arm, respectively. In pts with v1/2, median PFS (mPFS) was not reached with lorlatinib and 7.2 and 7.4 mo with crizotinib in the presence or absence of TP53 mutations, respectively. In pts with v3 and TP53 co-mutation, mPFS was 14.8 mo with lorlatinib and 5.4 mo with crizotinib. In 106 pts with paired BL/EOT samples, v1/v2 and v3 were detected in 5 (19%) and 4 (15%) pts in the lorlatinib arm and 17 (21%) and 18 (23%) pts in the crizotinib arm, respectively; TP53 co-mutations were detected in most pts, except for pts treated with crizotinib harboring v1/v2. Aberrations in MAPK, PI3K, and RTK pathways but no ALK mutations were detected in 35% of pts in the lorlatinib arm at EOT; in the crizotinib arm, new ALK mutations were detected in 10% of pts, and aberrations in these pathways in 13% of pts.
Conclusions
While limitations apply to ctDNA analyses, in this treatment-naive group, pts harboring v3 and TP53 mutations at BL had a worse outcome than those with v1/v2. On treatment discontinuation, bypass mechanism aberrations were the main resistance mechanism to lorlatinib, while no ALK mutations were detected. Given the small number of pts in this analysis, the results can only be considered descriptive.
Clinical trial identification
NCT03052608.
Editorial acknowledgement
Editorial and medical writing support was provided by Ravi Subramanian of ClinicalThinking and was funded by Pfizer.
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc.
Disclosure
E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Medical Trends, Merck Sharp & Dohme, Pfizer, Puma, Sanofi, Takeda, Merck Serono, Peptomyc, Regeneron, Syneos Health, F. Hoffmann-La Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Springer, Touch Medical, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol-Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Leadership Role, President Elect (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Leadership Role, Member of Board of Directors and the Executive Committee (2017-Sept 2021): IASLC (International Association for the Study of Lung Cancer). J. Martini: Other, Personal, Full or part-time Employment: Pfizer Inc; Other, Personal, Stocks/Shares: Pfizer Inc. J. Mazieres: Financial Interests, Invited Speaker: Roche, AstraZeneca, BMS, MSD, Daiichi, Novartis, Amgen; Financial Interests, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Lilly, Merck; Financial Interests, Research Grant: Roche, AstraZeneca, Pierre Fabre, BMS; Non-Financial Interests, Principal Investigator: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Sanofi, Pfizer, Merck. D. Kim: Financial Interests, Invited Speaker: Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society, Asian Thoracic Oncology Research Group; Other, Writing Engagements: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Non-Financial Interests, Advisory Board: Amgen, AstraZeneca, BMS/Ono Pharmaceuticals, Daiichi Sankyo, GSK, Janssen, Merck, MSD, Pfizer, SK Biopharm, Takeda; Other, Member of the Board of Directors: Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology; Financial Interests, Institutional, Research Grant: Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, BMS, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GSK, Hanmi, Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan; Other, Principal Investigator, coordinating PI: Chong Keun Dang; Financial Interests, Advisory Role: Scientific advisor for Health insurance review and assessment service, Korea; Other, Travel Support: Amgen, Daiichi Sankyo, International Association for the Study of Lung Cancer, Asian Thoracic Oncology Research Group, Taiwan Lung Cancer Society. D. Shepard: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc; Financial Interests, Personal, Stocks/Shares: Pfizer Inc. A. Polli: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc; Financial Interests, Personal, Stocks/Shares: Pfizer Inc. G. Liu: Financial Interests, Personal and Institutional, Invited Speaker: Pfizer Inc, AstraZeneca, Takeda; Financial Interests, Personal and Institutional, Advisory Board: Pfizer Inc, Novartis, AstraZeneca, Takeda, EMD Serono, Jass Pharmaceuticals, Merck, BMS, Roche; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Takeda; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, Takeda. F. Toffalorio: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Thermo Fischer, Pfizer, Taiho; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Guardant Health, Preferred Network; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: Prefered Network. B. Solomon: Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Roche, Novartis, AstraZeneca, Amgen, Bristol Myers Squibb, Merck, Glaxo-Smith Kline, Takeda, BeiGene, Janssen; Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Roche, Novartis, AstraZeneca, Amgen, Bristol Myers Squibb, Merck, Glaxo-Smith Kline, Takeda, BeiGene, Janssen. All other authors have declared no conflicts of interest.