Abstract 979P
Background
Updated results from the ongoing phase III CROWN study (NCT03052608) confirmed the durable systemic and intracranial (IC) benefit of lorlatinib (LOR), a 3rd generation anaplastic lymphoma kinase (ALK) inhibitor, vs crizotinib (CRIZ) in patients (pts) with treatment-naive ALK-positive non-small cell lung cancer. The 3-year follow up evaluated long-term IC safety and efficacy of LOR (data cutoff 20 September 2021).
Methods
296 pts were randomized 1:1 to oral LOR (100 mg once daily) or CRIZ (250 mg twice daily). CNS adverse events (AEs) were categorized and incidence (onset of new events) of cognitive, mood, speech, and psychotic events calculated within time intervals of LOR treatment. IC time to progression (IC-TTP) was a secondary endpoint, and IC-TTP landmark analysis according to dose reduction ≤16 weeks was performed.
Results
For pts with brain mets at baseline (n=37 LOR/n=39 CRIZ), the HR for IC-TTP for LOR vs CRIZ was 0.10 (95% CI, 0.04–0.27), and for pts without brain mets (n=112/n=108) was 0.02 (95% CI, 0.002–0.14). All-causality CNS AEs occurred in 37 pts (24.8%) treated <6 months, 14 (10.9%) pts between 6 months and 1 year on treatment, 18 (15.4%) pts between 1-2 years, 10 (10.2%) between 2-3 years, and only 2 pts (2.2%) treated for ≥3 years (Table). In total, 103 CNS AEs have been reported. Of these, 61 (59.2%) events were managed without any intervention: 32 (31.1%) resolved spontaneously, 1 (1.0%) improved, 28 (27.2%) did not resolve. Twenty-six events were managed with dose reductions and/or dose interruption with or without concomitant medication. CNS AEs led to permanent discontinuation in 2 pts. Landmark analysis of IC-TTP showed comparable efficacy in pts with or without LOR dose reduction within 16 weeks. CNS AEs observed over time with LOR. Table: 979P
Time interval | |||||
≥0 to <6 months (n=149) | ≥6 months to <1 year (n=129) | ≥1 to <2 years (n=117) | ≥2 to <3 years (n=98) | ≥3 years (n=92) | |
Any CNS Adverse Events, n (%) | 37 (24.8) | 14 (10.9) | 18 (15.4) | 10 (10.2) | 2 (2.2) |
CLUSTER Term | |||||
Cognitive effects, n (%) | 21 (14.1) | 7 (5.4) | 11 (9.4) | 5 (5.1) | 1 (1.1) |
Mood effects, n (%) | 17 (11.4) | 5 (3.9) | 4 (3.4) | 4 (4.1) | 0 |
Speech effects, n (%) | 6 (4.0) | 2 (1.6) | 2 (1.7) | 1 (1.0) | 1 (1.1) |
Psychotic effects, n (%) | 4 (2.7) | 0 | 2 (1.7) | 2 (2.0) | 0 |
Conclusions
In the 3-year follow up from the CROWN study, the incidence of CNS AEs did not increase over time. Long-term analysis confirmed that CNS AEs remained manageable and LOR dose reductions did not impact IC efficacy.
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
A. Bearz: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Takeda, BMS, Pfizer, AstraZeneca. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly, GSK, Janssen, Medical T, MSD, Pfizer, Puma, Sanofi, Merck Serono, Peptomyc, Regeneron, Syneos Health, F. Hoffman La Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Eli Lilly, Medscape, MSD, Peervoice, Pfizer, Springer, Touch Medical, Amgen, F. Hoffman La Roche, Janssen, Medical Trends, Merck Serono; Financial Interests, Personal, Invited Speaker, Independent: Grifols; Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, Daiichi Sankyo, Exelixis Inc., Merck KG, Janssen Cilag International NV, GSK, AbbVie Deutschland GmbH & Co KG, Novartis Pharmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim, Pfizer S.L.U., Amgen Inc, BMS, Mirati Therapeutics Inc.; Non-Financial Interests, Leadership Role, President: SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member: ESMO, ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Leadership Role, Member: IASLC. J. Mazieres: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, MSD, Daiichi, Novartis, Amgen; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Lilly, Merck; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Pierre, Fabre, BMS; Non-Financial Interests, Personal and Institutional, Principal Investigator: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Sanofi, Pfizer, Merck. T. Bauer: Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Lilly, Bayer; Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Lilly, Bayer, AZ; Financial Interests, Personal and Institutional, Speaker’s Bureau: Lilly, Bayer, BMS; Financial Interests, Personal and Institutional, Funding: Pfizer; Financial Interests, Personal and Institutional, Principal Investigator: Pfizer, Lilly, Bayer, AZ, BMS; Financial Interests, Personal and Institutional, Research Grant: Lilly, Bayer, AZ, BMS. A. Polli: Financial Interests, Personal, Full or part-time Employment: Pfizer. R. Messina: Financial Interests, Personal and Institutional, Full or part-time Employment: Pfizer. H. Thurm: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. D. Thomaidou: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. T.S.K. Mok: Financial Interests, Personal, Invited Speaker: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly; Financial Interests, Personal, Advisory Board: AbbVie, Acea Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly. B.J. Solomon: Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Roche, Novartis, AstraZeneca, Amgen, BMS, Merck, GSK, Takeda, BeiGene, Janssen; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Roche, Novartis, AstraZeneca, Amgen, BMS, Merck, GSK, Takeda, BeiGene, Janssen. All other authors have declared no conflicts of interest.