Abstract 1196P
Background
Lorlatinib, a potent, brain-penetrant, 3rd-generation (gen) ALK/ROS1 tyrosine kinase inhibitor (TKI) active against most known resistance mutations, showed robust clinical activity in ALK+ or ROS1+ NSCLC in a Ph 1/2 study that enrolled mostly heavily pretreated pts with CNS metastases. We evaluated potential resistance mechanisms, pre-existing or acquired, and efficacy in these settings.
Methods
Pts with ALK+ NSCLC previously treated with ≥1 2nd-gen ALK TKI (N=139) were treated with lorlatinib 100 mg QD in the ongoing Ph 1/2 study (NCT01970865). Plasma samples were collected at baseline (BL) and at end of treatment (EoT) for circulating tumor (ct)DNA. Objective response rate (ORR), duration of response (DOR), and median progression-free survival (mPFS) by independent central review were evaluated according to mutation status.
Results
TP53 mutations were found in 44 of 103 (42.7%) samples with detectable ctDNA at BL. ORR was 38.6% (95% CI: 24.4–54.5) and 45.8% (95% CI: 32.7–59.2) in pts with or without TP53 mutations, respectively; median DOR was 15.1 and 12.5 mo; and mPFS was 4.1 and 6.9 mo (hazard ratio [HR] = 0.83; 95% CI: 0.52–1.31). Restricting analysis to pts’ samples harboring ALK fusion (n=58) led to similar results. Pre-existing aberrations in potential bypass mechanisms (eg, BRAF, KRAS known mutations, or EGFR, CDK4/6 or MET amplification) resulted in weaker efficacy, with mPFS of 3.2 and 6.9 mo (HR = 0.49; 95% CI: 0.29–0.84) in pts with (n=21; 20.4%) or without (n=82; 79.6%) aberrations, respectively. Confirmation of these results in tumor tissue is ongoing. In pts with matched paired samples (N=53), 7.5% had ALK compound mutations, while 20.8% had potential bypass mechanism aberrations at progression. The remaining pts did not show specific patterns of resistance.
Conclusions
Limitations apply to ctDNA analyses, but in this heavily pretreated group of pts with ALK+ NSCLC, presence of TP53 mutations at BL was potentially associated with decreased lorlatinib efficacy, while presence of bypass mechanism aberrations with reduced activity. Upon progression, ALK compound mutations and bypass mechanism aberrations emerged in ∼28% of pts.
Clinical trial identification
NCT01970865.
Editorial acknowledgement
Medical writing support was provided by Meredith Rogers, MS, CMPP, of CMC AFFINITY, McCann Health Medical Communications, and was funded by Pfizer.
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc.
Disclosure
B.J. Solomon: Financial Interests, Personal, Other, Consulting or Advisory Role, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting or Advisory Role, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Other, Consulting or Advisory Role, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Consulting or Advisory Role, Honoraria: Pfizer; Financial Interests, Personal, Other, Consulting or Advisory Role, Honoraria: Roche/Genentech; Financial Interests, Personal, Other, Consulting or Advisory Role: Amgen; Financial Interests, Personal, Other, Consulting or Advisory Role: Lilly; Financial Interests, Personal, Royalties: Veristrat (Biodesix); Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Personal, Other, Research Funding: Sanofi-Regeneron. J. Martini: Financial Interests, Personal, Other, Full-time employee and owns stock: Pfizer. A. Bearz: Financial Interests, Personal, Other, Honoraria for lecture and speaker bureau: Takeda; Financial Interests, Personal, Other, Honoraria for Lecture, Speaker Bureau, Advisory Board: Pfizer; Financial Interests, Personal, Other, Honoraria for Lecture, Speaker Bureau, Advisory Board: Roche; Financial Interests, Personal, Other, Honoraria for Lecture and Speaker Bureau: MSD; Financial Interests, Personal, Other, Honoraria for Lecture, Speaker Bureau, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Honoraria for Lecture and Speaker Bureau: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly. R. Soo: Financial Interests, Personal, Other, Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Roche/Genentech, Taiho Pharmaceutical, Yuhan, Takeda, Amgen, Lilly, Merck; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan, Amgen, Bayer, Merck; Financial Interests, Personal, Other, Research Funding: AstraZeneca, Boehringer Ingelheim. B. Besse: Financial Interests, Personal, Other, Sponsored research: Gustave Roussy Cancer Center, 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE Immunotherapeutics. T.M. Bauer: Financial Interests, Institutional, Funding, Received funds for research support paid to his institution: AbbVie, Aileron, Amgen, Armo, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Calithera, Clovis Oncology, Daiichi Sankyo, Deciphera, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Immunocore, ImmunoGen; Financial Interests, Institutional, Other, Consulting fees paid to his institution: Ignyta, Moderna, Pfizer; Financial Interests, Personal, Other, Received consulting fees: AstraZeneca, Bayer, Blueprint Medicines, Exelixis, Foundation Medicine, Guardant, Loxo, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Bayer, Bristol Myers Squibb, Lilly. D. Shepard: Financial Interests, Personal, Other, Full-time Employee and own stocks: Pfizer. F. Toffalorio: Financial Interests, Personal, Full or part-time Employment: Pfizer. A. Abbattista: Financial Interests, Personal, Full or part-time Employment: Pfizer. E. Felip: Financial Interests, Personal, Other, Advisory Boards and Speaker’s Bureau: Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffman-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Sharp & Dohme, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, Takeda, Medscape, P; Financial Interests, Personal, Other, Research Funding: Fundación Merck Salud; Financial Interests, Personal, Other, Grant: Oncology Innovation; Financial Interests, Personal, Other, Independent member of the board: Grifols. A.T. Shaw: Financial Interests, Personal, Other, Compensated Consultant or Received Honoraria: Achilles, Archer, ARIAD/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Guardant, Ignyta, KSQ Therapeutics, Loxo Oncology, Natera, Novartis, Pfizer, Roche-Genentech, Servier, Syros, Taiho Pharmaceutical, TP; Financial Interests, Institutional, Other, Research funding: ARIAD, Ignyta, Novartis, Pfizer, Roche-Genentech, TP Therapeutics; Financial Interests, Personal, Other, Travel support: Genentech, Pfizer; Financial Interests, Personal, Full or part-time Employment: Novartis. S. Viteri: Financial Interests, Personal, Other, Consulting or Advisory Role: AbbVie, BMS, Roche, Janssen, Puma Biotechnology; Financial Interests, Personal, Speaker’s Bureau: BMS, MSD, Roche, AstraZeneca; Financial Interests, Personal, Other, Travel expenses: Roche, OSE Pharma, BMS, MSD, Merck Serono. D.R. Camidge: Financial Interests, Personal, Other, Honoraria: AbbVie, Achilles Therapeutics, Apollomics, Archer, Arrys/Kyn, AstraZeneca, BeyondSpring Pharmaceuticals, Bio-Thera Solutions, Blueprint Medicines, Bristol Myers Squibb, CBT Pharmaceuticals, Daiichi Sankyo, Elevation, EMD Serono, G1 Therapeutics, Hansoh, H; Financial Interests, Personal, Other, Research funding: Takeda. S.I. Ou: Financial Interests, Personal, Other, stock and other ownership interests: Elevation Oncology; Financial Interests, Personal, Other, stock and other ownership interests: Turning Point Therapeutics; Financial Interests, Personal, Other, Honoraria: ARIAD/Takeda, AstraZeneca, Foundation Medicine, Genentech/Roche, Merck, Pfizer, Roche Pharma AG; Financial Interests, Personal, Other, Consulting or advisory: AstraZeneca, Pfizer, Roche/Genentech, Takeda, TP Therapeutics; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Genentech, Takeda; Financial Interests, Institutional, Other, Research Funding: ARIAD/Takeda (Inst), AstraZeneca (Inst), Genentech (Inst), Janssen/JNJ (Inst), Merus (Inst), Mirati (Inst), Pfizer (Inst), Revolution Medicines (Inst), Roche Pharma AG (Inst). All other authors have declared no conflicts of interest.