512MO - FLAURA2: Safety and CNS outcomes of first-line (1L) osimertinib (osi) ± chemotherapy (CTx) in EGFRm advanced NSCLC

Background

In FLAURA2 (NCT04035486), osi, a 3rd gen CNS-active EGFR-TKI, combined with platinum-pemetrexed (osi-CTx) showed a statistically significant improvement vs osi-monotherapy (osi-mono) in PFS per investigator (HR 0.62 [95% CI 0.49–0.79], p<0.001) with a manageable and tolerable safety profile. Addition of CTx did not affect osi exposure. 76% of pts completed 4 CTx cycles; median duration of pemetrexed exposure was 8.3 mos. 40% of FLAURA2 pts had baseline CNS metastases (mets); we report exploratory analyses of CNS efficacy by CNS blinded independent central review (BICR; conducted by neuroradiologist). Updated safety data will be reported.

Methods

Eligible pts (≥18 y [Japan: ≥20] with EGFRm advanced NSCLC, no prior tx for advanced NSCLC; asymptomatic CNS mets not requiring steroids or stable >2 wks after definitive tx/steroids allowed) were randomised 1:1 to 1L osi-CTx or osi-mono until progression/discontinuation. Brain imaging (MRI preferred) was performed in all pts at baseline + progression, and at scheduled assessments until progression for pts with baseline CNS mets. CNS endpoints (modified RECIST 1.1) included CNS PFS, CNS response and CNS DoR by CNS BICR. Safety was assessed by CTCAE v5. Data cutoff: 3 Apr 2023.

Results

Of 557 pts randomised, 118/279 (osi-CTx) and 104/278 (osi-mono) were included in the CNS BICR full analysis set (cFAS; pts with ≥1 measurable and/or non-measurable lesion); 40/118 (osi-CTx) and 38/104 (osi-mono) were included in the CNS evaluable for response set (cEFR; pts with ≥1 measurable lesion). Demographics were balanced across tx arms. CNS efficacy is shown (table). Safety profile was similar in the cFAS and overall population. The safety and tolerability profile during the course of tx will be described.

Conclusions

In FLAURA2, pts with CNS mets in the osi-CTx arm had a clinically meaningful reduction in the risk of CNS progression, with high CNS ORR (and high CR) and durable responses, with a manageable and tolerable safety profile. Table: 512MO

*Analysed using stratified (cFAS; by race, WHO PS and EGFRm test method) or unstratified (cEFR) log-rank test. CR, complete response; DoR, duration of response; NC, not calculable; NR, not reached; ORR, objective response rate; PFS, progression-free survival

Clinical trial identification

NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP) guidelines (https://www.ismpp.org/gpp-2022).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, AbbVie, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Non-Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, AbbVie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Mirati Therapeutics, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly and Company, Ignyta, Takeda Oncology, Novartis, Voronoi, SFJ Pharmaceuticals, Biocartis, LOXO Oncology, PUMA, Sanofi, Transcenta, Daiichi Sa; Financial Interests, Personal, Other, Dr. Jänne is a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Takeda Oncology, PUMA, Astellas Pharmaceuticals, Daiichi Sankyo ; Financial Interests, Personal, Royalties, Post marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp: Lab Corp. C.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Pfizer, Novartis, GSK, Merck KGA, Roche, Janssen, and MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Roche, Merck KGaA. K. Laktionov: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad, Pfizer; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Other: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad. T. Kato: Financial Interests, Personal, Full or part-time Employment: Lilly (family member); Financial Interests, Institutional, Funding: AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Chugai Pharma, Daiichi Sankyo, Haihe Biopharma, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Takeda, Turning Point Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer; Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, GSK, Janssen, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Takeda, Taiho Pharmaceutical. L. Jiang: Non-Financial Interests, Personal, Local PI: Shanghai Chest Hospital, Shanghai Jiao Tong University, PR China. B. Chewaskulyong: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca. S. Lucien Geater: Financial Interests, Personal, Advisory Board: Pfizer, MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Roche, Novartis, MSD; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim. F.A. Shepherd: Financial Interests, Personal, Invited Speaker, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune, Squibbb, Lilly, Roche Canada, Pfizer; Financial Interests, Personal, Advisory Role, Honoraria: AstraZeneca. K. Tanaka: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, BMS, MSD, Merck; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca. D. Ghiorghiu, E. Armenteros Monterroso, X. Huang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.C. Yang: Financial Interests, Personal, Other, Personal fees: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb; Financial Interests, Personal, Research Grant: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Other: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, Puma Technology, Gi. All other authors have declared no conflicts of interest.