1199P - Dose modification for the management of CNS adverse events in the phase III CROWN study of lorlatinib in non-small cell lung cancer (NSCLC)

Background

In the ongoing phase III CROWN study (NCT03052608), lorlatinib, a 3rd-generation inhibitor of anaplastic lymphoma kinase (ALK), improved progression-free survival (PFS) and intracranial response rates vs crizotinib in patients with previously untreated ALK-positive NSCLC. Here we present data on lorlatinib dose modification for the management of CNS adverse events (AEs).

Methods

296 patients were randomized 1:1 to oral lorlatinib (100 mg QD) or crizotinib (250 mg BID). Guidelines for AEs management included medication, dose interruption, dose reduction to 75 or 50 mg QD, or a combination of the above. PFS landmark analysis was used to assess the effect of lorlatinib dose modifications (as relative dose intensity [RDI]) on efficacy.

Results

In total, 86 CNS AEs (all-causality) were reported in 52/149 (35%) patients who received lorlatinib: most were cognitive (38/86, 44%) or mood effects (34/86, 40%). Maximum CNS AE severity was Grade 1 in 32/52 (62%) and Grade 2 in 15/52 (29%) patients. In 53/86 (62%) CNS AEs, lorlatinib dose was not modified and no medication was initiated; of 53 CNS AEs, 28 resolved spontaneously (53%), 1 improved (2%), and 24 did not resolve (45%). The majority (23/24) of the not resolved events were Grade 1. 20/86 (23%) CNS AEs were managed with lorlatinib dose modifications, with or without concomitant medication. A total of 15/20 (75%) of CNS AEs resolved, 2/20 (10%) improved, and 3/20 (15%) did not resolve (Table). Landmark analysis showed no difference in PFS between patients categorized by mean RDI within the first 16 weeks of treatment. The percentage of patients event-free at 12 months was 90% (95% CI, 82 to 94) in the subgroup whose RDI was ≥ mean and 93% (95% CI, 59 to 99) in those whose RDI was < mean. Table: 1199P

CM, concomitant medication; DI, dose interruption; DR, dose reduction.

Conclusions

CNS AEs spontaneously resolved in 53% of cases, and lorlatinib dose modification was effective in managing CNS AEs without compromising efficacy.

Clinical trial identification

NCT03052608.

Editorial acknowledgement

Medical writing support was provided by Paul O’Neill 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, Advisory Role, Also received Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Also received Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Also received Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Role, Also received Honoraria: Pfizer; Financial Interests, Personal, Advisory Role, Also received Honoraria: Roche/Genentech; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Personal, Other, Research Funding: Sanofi/Regeneron; Financial Interests, Personal, Royalties: Veristrat (Biodesix). T.S.K. Mok: Financial Interests, Institutional, Other, Grant/research funding: AstraZeneca, Bristol Myers Squibb, Clovis Oncology, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery; Financial Interests, Personal, Other, Speaker's fees: ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before January 2019), Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, InMed Medical Communication, MSD, Novartis, Pfizer, prIME Oncology, Roche/Genentech, Taiho; Financial Interests, Personal, Other, Honoraria for consultation services: AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol Myers Squibb, Celgene, CStone Pharmaceuticals, Daiichi Sankyo, Eli Lilly, Fishawack; Financial Interests, Personal, Stocks/Shares: Hutchison Chi-Med, Sanomics, Ltd.; Financial Interests, Personal, Advisory Board: AbbVie, Inc., ACEA Pharma, Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Daiichi Sankyo, Eli Lilly, Fishawack Facilitate, Ltd., G1 Therapeutics, Inc., GeneD; Financial Interests, Personal, Other, Board of Directors/leadership (remunerated): AstraZeneca, Hutchison Chi-Med; Financial Interests, Personal, Other, Board of Directors/leadership (non-remunerated): American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Soci. H. Hayashi: Financial Interests, Personal, Research Grant, Contracted/Support Research Grant: AstraZeneca K.K.; Financial Interests, Personal, Research Grant, Contracted/Support Research Grant: Boehringer Ingelheim Japan Inc.; Financial Interests, Personal, Research Grant, Contracted/Support Research Grant: Chugai Pharmaceutical Co. Ltd.; Financial Interests, Personal, Research Grant, Contracted/Support Research Grant: Ono Pharmaceutical Co. Ltd. A. Bearz: Financial Interests, Personal, Other, Honoraria for lecture and speaker bureau: Takeda; Financial Interests, Personal, Other, Honoraria for lecture, speaker bureau and grant, Advisory Board: Pfizer; Financial Interests, Personal, Other, Honoraria for lecture, speaker bureau and grant, Advisory Board: Roche; Financial Interests, Personal, Other, Honoraria for lecture and speaker bureau: MSD; Financial Interests, Personal, Other, Honoraria for lecture, speaker bureau and grant, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Honoraria for lecture and speaker bureau: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly. K.D. Penkov: Financial Interests, Personal, Other, Investigational Grant: AbbVie; Financial Interests, Personal, Other, Investigational Grant: AstraZeneca; Financial Interests, Personal, Other, Investigational Grant: GlaxoSmithKline; Financial Interests, Personal, Other, Investigational Grant: Takeda; Financial Interests, Personal, Other, Investigational Grant: MSD; Financial Interests, Personal, Other, Investigational Grant: Novartis; Financial Interests, Personal, Other, Investigational Grant: Pfizer; Financial Interests, Personal, Other, Investigational Grant: Roche; Financial Interests, Personal, Other, Investigational Grant: Sanofi. Y. Wu: Financial Interests, Personal, Other, Research Funding, Speakers Bureau, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Research Funding, Speakers Bureau: Boehringer Ingelheim; Financial Interests, Personal, Other, Research Funding, Speakers Bureau: BMS; Financial Interests, Personal, Other, Research Funding, Speakers Bureau: Eli Lilly; Financial Interests, Personal, Other, Research Funding, Speakers Bureau, Advisory Board: Hengrui; Financial Interests, Personal, Other, Research Funding, Speakers Bureau, Advisory Board: MSD; Financial Interests, Personal, Other, Research Funding, Speakers Bureau: Pfizer; Financial Interests, Personal, Other, Research Funding, Speakers Bureau: Roche; Financial Interests, Personal, Other, Research Funding, Speakers Bureau: Sanofi; Financial Interests, Personal, Other, Advisory Board: Takeda. O. Arrieta: Financial Interests, Personal, Other, Honoraria as an advisor, participated in speakers’ bureau, and given expert opinions to: Pfizer; Financial Interests, Personal, Other, Honoraria as an advisor, participated in speakers’ bureau, and given expert opinions to: AstraZeneca; Financial Interests, Personal, Other, Honoraria as an advisor, participated in speakers’ bureau, and given expert opinions to: Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria as an advisor, participated in speakers’ bureau, and given expert opinions to: Roche; Financial Interests, Personal, Other, Honoraria as an advisor, participated in speakers’ bureau, and given expert opinions to: Lilly; Financial Interests, Personal, Other, Honoraria as an advisor, participated in speakers’ bureau, and given expert opinions to: Bristol Myers Squibb. A.M. Calella: Financial Interests, Personal, Other, Full-time employee and owns stocks: Pfizer. G. Peltz: Financial Interests, Personal, Other, Full-time employee and owns stocks: Pfizer. A. Polli: Financial Interests, Personal, Other, Full-time employee and owns stocks: Pfizer. H. Thurm: Financial Interests, Personal, Other, Full-time employee and owns stocks: Pfizer. T.M. Bauer: Financial Interests, Personal, Full or part-time Employment: Tennessee Oncology; Financial Interests, Personal, Other, Consultant/advisor: Bayer; Financial Interests, Personal, Other, Consultant/advisor: Blueprint Medicines; Financial Interests, Personal, Other, Consultant/advisor: Exelixis; Financial Interests, Personal, Other, Consultant/advisor, Research Funding: Foundation Medicine; Financial Interests, Personal, Other, Consultant/advisor: Guardant Health; Financial Interests, Personal, Other, Consultant/advisor, Research Funding: Ignyta; Financial Interests, Personal, Other, Consultant/advisor, Researching Funding: Loxo Oncology; Financial Interests, Personal, Other, Consultant/advisor, Research Funding: Moderna Therapeutics; Financial Interests, Personal, Other, Consultant/advisor, Research Funding, compensation for travel, accommodations, and expenses: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Other, Speaker's Bureau, Research Funding: Bristol Myers Squibb; Financial Interests, Personal, Other, Speaker's Bureau, Research Funding, compensation for travel, accommodations, and expenses: Lilly; Financial Interests, Personal, Other, Research Funding: AbbVie; Financial Interests, Personal, Other, Research Funding: Aileron Therapeutics; Financial Interests, Personal, Other, Research Funding: Amgen; Financial Interests, Personal, Other, Research Funding: ARMO BioSciences; Financial Interests, Personal, Other, Research Funding, compensation for travel, accommodations, and expenses: Astellas Pharma; Financial Interests, Personal, Other, Research Funding, compensation for travel, accommodations, and expenses: AstraZeneca; Financial Interests, Personal, Other, Research Funding: Boehringer Ingelheim; Financial Interests, Personal, Other, Research Funding: Calithera Biosciences; Financial Interests, Personal, Other, Research Funding, compensation for travel, accommodations, and expenses: Clovis Oncology; Financial Interests, Personal, Other, Research Funding: Daiichi Sankyo; Financial Interests, Personal, Other, Research Funding: Deciphera; Financial Interests, Personal, Other, Research Funding: Five Prime Therapeutics; Financial Interests, Personal, Other, Research Funding: Genentech/Roche; Financial Interests, Personal, Other, Research Funding: GlaxoSmithKline; Financial Interests, Personal, Other, Research Funding: Immunocore; Financial Interests, Personal, Other, Research Funding: Immunogen; Financial Interests, Personal, Other, Research Funding: Incyte; Financial Interests, Personal, Other, Research Funding: Jacobio; Financial Interests, Personal, Other, Research Funding: Janssen; Financial Interests, Personal, Other, Research Funding: Karyopharm Therapeutics; Financial Interests, Personal, Other, Research Funding: Kolltan Pharmaceuticals; Financial Interests, Personal, Other, Research Funding: Leap Therapeutics; Financial Interests, Personal, Other, Research Funding: MabVax; Financial Interests, Personal, Other, Research Funding: MedImmune; Financial Interests, Personal, Other, Research Funding: Medpacto, Inc.; Financial Interests, Personal, Other, Research Funding, compensation for travel, accommodations, and expenses: Merck; Financial Interests, Personal, Other, Research Funding: Merrimack; Financial Interests, Personal, Other, Research Funding: Millennium; Financial Interests, Personal, Other, Research Funding: Mirati Therapeutics; Financial Interests, Personal, Other, Research Funding, compensation for travel, accommodations, and expenses: Novartis; Financial Interests, Personal, Other, Research Funding: Onyx; Financial Interests, Personal, Other, Research Funding: Peleton; Financial Interests, Personal, Other, Research Funding: Phosplati Therapeutics; Financial Interests, Personal, Other, Research Funding: Principia Biopharma; Financial Interests, Personal, Other, Research Funding: Roche; Financial Interests, Personal, Other, Research Funding: Sanofi; Financial Interests, Personal, Other, Research Funding: Stemline Therapeutics; Financial Interests, Personal, Other, Research Funding: Takeda; Financial Interests, Personal, Other, Research Funding: Top Alliance Bio- Sciences; Financial Interests, Personal, Other, compensation for travel, accommodations, and expenses: Celgene; Financial Interests, Personal, Other, compensation for travel, accommodations, and expenses: EMD Serono; Financial Interests, Personal, Other, compensation for travel, accommodations, and expenses: Genentech; Financial Interests, Personal, Other, compensation for travel, accommodations, and expenses: Pharmacyclics; Financial Interests, Personal, Other, compensation for travel, accommodations, and expenses: Sysmex.