1302 - Safety of lorlatinib in subgroups of patients from a phase 1/2 trial

Background

Lorlatinib, a potent, brain-penetrant 3^rd-generation (gen) ALK/ROS1 tyrosine kinase inhibitor (TKI), is approved for the treatment of patients (pts) with ALK+ metastatic NSCLC whose disease has progressed on 2^nd-gen ALK TKIs. The safety profile of lorlatinib has been previously reported; treatment-related adverse events (AEs) were primarily mild–moderate in severity and manageable through dose modification or standard medical therapy. Here, we report safety data in key subgroups of pts based on age, gender and race.

Methods

This analysis was based on 295 pts with ALK+ or ROS1+ advanced NSCLC, ± CNS metastases, enrolled in the ongoing ph 1/2 trial (NCT01970865) who received lorlatinib 100 mg once daily. All causality AEs were graded per CTCAE v4.03. Data cutoff was 02 Feb 2018.

Results

Of the 295 pts, 241 were aged <65 years (y) and 54 were ≥65 y. AEs were reported at frequencies of 99.6% and 100% in the <65 y and ≥65 y subgroups respectively; however, there were generally more AEs in the ≥65 y subgroup, e.g. anemia (<65 y: 13.7% vs ≥ 65 y: 25.9%), edema (51.5% vs 68.5%), cognitive effects (26.1% vs 40.7%), dyspnea (25.7% vs 37.0%) and fatigue (26.6% vs 35.2%). AEs were generally balanced between males (n = 125) and females (n = 170). Among Asian (n = 108) and non-Asian (n = 161) pts, AEs were reported at a similar incidence (99.1% vs 100%). Grade 3/4 and grade 5 AEs were reported, respectively, in 57.4% and 12.0% of Asian pts and 58.4% and 14.9% of non-Asian pts. There were generally more AEs in non-Asian pts (Table). With multiple dosing, there were no substantial differences in lorlatinib plasma exposure in Asian vs non-Asian pts and neither steady-state AUC nor C_max met the threshold for dose-adjustment.Table:

1542P

AEs reported in descending order of frequency in Asian pts.

Unspecified race (n = 26)

Clustered term comprising AEs that represent similar clinical symptoms/syndromes.

Conclusions

There were no clinically relevant differences in the AEs based on age or gender. The frequencies of most AEs known to be associated with lorlatinib were generally lower in Asian than in non-Asian pts; however, hypertriglyceridemia was more frequently reported in Asian vs non-Asian pts.

Clinical trial identification

NCT01970865.

Editorial acknowledgement

Jade Drummond of inScience Communications, Springer Healthcare (Chester, UK); funded by Pfizer Inc.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc.

Disclosure

E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Research grant / Funding (institution): Fundación Merck Salud; Research grant / Funding (institution): EMD Serono. B.J. Solomon: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Eisai; Licensing / Royalties: Veristrat (Biodesix); Licensing / Royalties: UpToDate; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Institution: Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution), Institution: Pfizer; Advisory / Consultancy, Institution: Genentech. B. Besse: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Onxeo; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Inivata; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Biogen; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): MSD Oncology; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tiziana Therapeutics. T.M. Bauer: Full / Part-time employment: Tennessee Oncology; Full / Part-time employment: Sarah Cannon Research Institute; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Loxo Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Institution: Ignyta; Advisory / Consultancy, Institution: Moderna Therapeutics; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto, Inc.; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Leap Therapeutics; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Merrimack Pharmaceuticals; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Kolltan Pharmaceuticals; Research grant / Funding (institution): Principa Biopharma; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Aileron Therapeutics; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Top Alliance BioScience; Research grant / Funding (institution): Janssen Pharmaceuticals; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Onyx Pharmaceuticals; Research grant / Funding (institution): Phosplati Therapeutics; Research grant / Funding (institution): Foundation Medicine. R.A. Soo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Yuhan; Honoraria (self), Advisory / Consultancy: Celgene. D.R. Camidge: Honoraria (self): Roche; Honoraria (self): G1 Therapeutics; Honoraria (self): Mersana; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): AstraZeneca; Honoraria (self): Genoptix; Honoraria (self): Ignyta; Honoraria (self): Daiichi Sankyo; Honoraria (self): Hansoh; Honoraria (self): Lycera; Honoraria (self): Biothera; Honoraria (self): Revolution Medicines. R. Chiari: Speaker Bureau / Expert testimony: Takeda. A. Bearz: Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. C. Lin: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): Roche; Honoraria (self), Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Blueprint Medicines; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: BeiGene. S.M. Gadgeel: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: ARIAD Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AbbVie; Research grant / Funding (institution), Travel / Accommodation / Expenses: Takeda; Research grant / Funding (self), Research grant / Funding (institution): Merck; Research grant / Funding (institution): Blueprint Medicines. E. Tan: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim. T. Seto: Honoraria (self), Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant / Funding (institution): Kissei Pharmaceutical; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Pfizer Japan; Honoraria (self), Research grant / Funding (institution): YakultHonsha; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Mochida Pharmaceutical; Honoraria (self): Nippon Kayaku; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Roche Singapore; Honoraria (self): Sanofi; Honoraria (self): Showa Yakuhin Kako; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Takeda Pharmaceutical; Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Novartis Pharma; Research grant / Funding (institution): Verastem. G.R. Oxnard: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Inivata; Advisory / Consultancy: Janssen; Advisory / Consultancy: Loxo; Honoraria (self): Foundation Medicine. G. Peltz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. A. Abbattista: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. H. Thurm: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. F. Toffalorio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. S.I. Ou: Advisory / Consultancy, Shareholder / Stockholder / Stock options: TP Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Honoraria (self), Research grant / Funding (institution): Ariad Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self): Merck; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Revolution Medicines. A.T. Shaw: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): ARIAD Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: KSQ Therapeutics; Advisory / Consultancy: Natera; Advisory / Consultancy: Loxo Pharmaceuticals; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bayer; Advisory / Consultancy: Chugai Pharma; Research grant / Funding (institution): TP Therapeutics.