514MO - Acquired mechanisms of resistance to first-line (1L) osimertinib with or without platinum-based chemotherapy (CT) in EGFR-mutated (EGFRm) advanced NSCLC: Preliminary data from FLAURA2

Background

Osimertinib (osi) is the preferred 1L treatment (tx) for patients (pts) with EGFRm advanced NSCLC; however, most pts will develop progressive disease (PD) due to tx resistance. The phase III, open-label, randomised FLAURA2 (NCT04035486) study demonstrated a significant PFS benefit with 1L osi + CT vs osi monotherapy in EGFRm advanced NSCLC. A safety run-in (SRI) assessed safety of the combination prior to the randomised phase. We report preliminary results for the pre-specified, exploratory analysis of acquired mechanisms of resistance to osi ± CT in pts.

Methods

Pts with treatment-naïve, EGFRm advanced NSCLC received osi + CT (osi 80 mg once daily [QD] + pemetrexed 500 mg/m² + cisplatin 75 mg/m² or carboplatin AUC5 every 3 weeks [Q3W] for 4 cycles, followed by osi 80 mg QD + pemetrexed 500 mg/m² Q3W) or osi monotherapy (80 mg QD) until PD/discontinuation criterion. Plasma ctDNA samples collected at baseline and PD up to 15 Dec 2022 were analysed using next-generation sequencing (Guardant Health, GuardantOMNI™).

Results

138 matched baseline and PD plasma samples were evaluable for analysis (10 from the SRI [osi + CT] and 128 from the randomised part [osi + CT, n=51; osi, n=77]). Of these, 126 had EGFRm ctDNA detected at baseline (osi + CT, n=53; osi, n=73). Resistance mechanisms were broadly similar across tx arms, although numerically fewer pts with acquired EGFR C797S and MET amplification were detected in the osi + CT arm than the osi monotherapy arm (Table). No novel resistance mechanisms were detected specifically in pts on the osi + CT arm.

Conclusions

Acquired resistance mechanisms to 1L osi monotherapy were consistent with previous data (Chmielecki Nat Commun. 2023). Osi + CT resulted in similar resistance mechanisms to osi monotherapy, and should not impact subsequent targeted second-line tx options. This analysis was enriched with pts who had early progression; further follow-up is required. Table: 514MO

ND, not detected. *Alterations detected at PD that were not detected at baseline (for an individual pt). †Includes plasma samples from pts in SRI and randomised parts of FLAURA2. ‡One pt had only acquired RB1 loss with preexisting TP53 mutation (unconfirmed tSCLC)

Clinical trial identification

FLAURA2, NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Donna Tillotson 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

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 KGA. J.P. Robichaux: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Licencing Fees or royalty for IP, Inventor on patents held by UT MD Anderson Cancer Center licenced to SP for treatment of EGFR/HER2 exon 20 mutant cancers: UT MD Anderson Cancer Center and Spectrum Pharmaceuticals; Financial Interests, Personal, Other, Inventor on patent held by UT MDACC regarding EGFR mutation subtypes and methods of treatment (no monetary exchange): UT MD Anderson Cancer Center; Financial Interests, Personal, Stocks/Shares: AstraZeneca. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. S. Kim: Non-Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Norvasc, Takeda, Terrapex, Yuhan; Non-Financial Interests, Personal, Funding: Yuhan; Non-Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim. T.M. Kim: Non-Financial Interests, Personal, Advisory Board: Boryung, Janssen, Novartis, Takeda, Regeneron; Financial Interests, Personal, Advisory Role: AstraZeneca, Boryung, Hanmi, IMBDx, Janssen, Novartis, Takeda, Sanofi, Regeneron, Roche/Genentech, Samsung Bioepis; Non-Financial Interests, Personal, Coordinating PI: Regeneron; Financial Interests, Personal, Local PI: ABBVIE, AstraZeneca, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche Ltd/Genentech, Inc, Hanmi, Janssen, Novartis, Regeneron, Sanofi, Takeda, and Yuhan. K. Kobayashi: Financial Interests, Personal, Financially compensated role, Board Chairman: NPO North East Japan Study Group; Financial Interests, Personal, Speaker’s Bureau, Speaker Fees: AstraZeneca, Takeda Pharmaceutical Co., Daiichi Sanko Pharmaceutical Co., Boehringer Ingelheim. 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. S. Sugawara: Financial Interests, Institutional, Local PI: AnHeart, AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, MSD K.K, Nippon Boehringer Ingelheim, Ono Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Kyowa Kirin, Lilly, Merck, MSD K.K, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka, Pfizer, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, TOWA PHA. N. Yanagitani: Financial Interests, Personal, Advisory Board: Pfizer Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor, Lecture Fees: Taiho, MSD, Ono, Bristol Myers Squibb, Novartis, Pfizer Inc.,Chugai co., Eli Lilly and Company, Boehringer Ingelheim, Bayer AG. A. Markovets, Y. Rukazenkov: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. P. Bhetaryia: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Poole: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly, Takeda. R.J. Hartmaier: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Other, Personal, Other: Inventor on patent: US11066709B2 (no fees or royalties); Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.C. Yang: Financial Interests, Institutional, Advisory Board, My institute received fee for my role as advisory board: AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan Pharmaceuticals, Janssen, Puma Technology, Gilead, GSK, Dizal Pharmaceutica; Financial Interests, Personal, Coordinating PI: AstraZeneca, MSD, Dizal Pharmaceutical; Non-Financial Interests, Personal, Member: ASCO, ESMO, IASLC; Financial Interests, Personal, Research Funding: AstraZeneca, Roche; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Takeda, Yuhan Pharmaceuticals, Janssen, Dizal Pharmaceutical. All other authors have declared no conflicts of interest.