LBA57 - Adagrasib (ADA) vs docetaxel (DOCE) in patients (pts) with KRASG12C-mutated advanced NSCLC and baseline brain metastases (BM): Results from KRYSTAL-12

Background

Pts with KRAS ^G12C-mutated NSCLC and BM have poor prognosis. ADA, a KRAS^G12C inhibitor, significantly improved progression-free survival (PFS) and objective response rate (ORR) vs DOCE in pts with previously treated KRAS ^G12C-mutated advanced NSCLC in the phase 3 KRYSTAL-12 trial (NCT04685135). In CNS evaluable pts, intracranial ORR was improved in pts with baseline BM receiving ADA (40%) vs DOCE (11%). We report efficacy and safety outcomes in pts with and without baseline BM from KRYSTAL-12.

Methods

Pts with KRAS ^G12C-mutated locally advanced/metastatic NSCLC who had previously received both platinum-based chemotherapy and anti-PD(L)1 therapy were randomized 2:1 to receive ADA (600 mg BID orally) or DOCE (75 mg/m² Q3W IV). Pts with treated, neurologically stable baseline BM were eligible. BM were identified using an independent CNS imaging charter and neuroradiologist review. Exploratory analyses included systemic efficacy (ORR, PFS, duration of response, assessed per RECIST v1.1) and safety by baseline BM, and intracranial efficacy (assesed per CNS-adapted RECIST v1.1) in pts with baseline BM, all by blinded independent central review.

Results

Of 453 randomized pts, 114 (25.2%) had baseline BM (ADA n = 78; DOCE n = 36); baseline characteristics were similar across treatment and BM groups. Systemic efficacy outcomes (median follow-up 7.2 months) were improved with ADA vs DOCE, regardless of BM status. Treatment-related adverse events (TRAEs) were reported in 93.5% and 85.7% of pts with BM receiving ADA and DOCE, respectively. TRAEs led to discontinuation of ADA and DOCE in 6.5% and 17.1% of pts with BM, respectively. Additional intracranial efficacy and safety data will be presented. Table: LBA57

Efficacy by baseline BM in KRYSTAL-12

DOR, duration of response; NE, not estimable.

Conclusions

In pts with previously treated KRAS ^G12C-mutated advanced NSCLC, ADA demonstrated improved efficacy outcomes vs DOCE, including in pts with baseline BM, consistent with benefits observed in all randomized pts in KRYSTAL-12.

Clinical trial identification

NCT04685135.

Editorial acknowledgement

Third-party medical writing support, under the direction of the authors, was provided by Jessica Traynor, PhD, of Ashfield MedComms, an Inizio company, and was funded by Mirati Therapeutics, a Bristol Myers Squibb company.

Legal entity responsible for the study

Mirati Therapeutics, a Bristol Myers Squibb company.

Funding

Mirati Therapeutics, a Bristol Myers Squibb company.

Disclosure

F. Barlesi: Financial Interests, Institutional, Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, Bayer, Amgen, Eisai Europe, Sanofi, Mirati, a Bristol Myers Squibb Company; Financial Interests, Personal, Other, Travel, accommodation, expenses: Roche/Genentech; Financial Interests, Institutional, Research Funding: Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Pierre Fabre, AbbVie, Amgen, Bayer, Boehringer Ingelheim, Eisai, Lilly, Ipsen, Innate Pharma, Novartis, Merck Serono, MSD Oncology, Pfizer, Sanofi/Aventis, Takeda. M. Duruisseaux: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, GSK, Merck Sharp & Dohme, Sanofi, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Merus, Amgen, Guardant, Pfizer, Roche, Gamamabs Pharma; Financial Interests, Personal, Research Funding: Takeda, NanoString, Eli Lilly, Blueprint. L. Doucet: Financial Interests, Personal, Advisory Board: Takeda; Non-Financial Interests, Institutional, Coordinating PI: Dizal; Non-Financial Interests, Institutional, Principal Investigator: Merck Sharp & Dohme, Takeda, Tango, Bristol Myers Squibb, Mirati Therapeutics, a Bristol Myers Squibb company, Novartis, Nucana, Gilead, Regeneron, Inhatarget; Financial Interests, Personal, Speaker’s Bureau: Amgen. O.J. Juan Vidal: Financial Interests, Institutional, Research Funding: AstraZeneca (Spain); Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Roche/Genentech, AstraZeneca, Pfizer, Eli Lilly, Takeda, Janssen, Novartis. Y. Kim: Financial Interests, Personal, Advisory Role: AstraZeneca, Johnson & Johnson, Merck Sharp & Dohme, Takeda, Yuhan, Boehringer Ingelheim, Pfizer, Amgen; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Johnson & Johnson, Merck Sharp & Dohme, Takeda, Yuhan, Boehringer Ingelheim, Pfizer, Amgen; Financial Interests, Institutional, Research Funding: AstraZeneca. M.R. García Campelo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Roche, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Roche, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda; Non-Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Roche, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Sanofi, Pfizer; Non-Financial Interests, Personal, Member of Board of Directors: SEOM, GECP. S. Lu: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Hutchinson MediPharma, ZaiLab, GenomiCare, Novartis, Yuhan Corporation, Menarini, Mirati Therapeutics, a Bristol Myers Squibb company, Daiichi Sankyo, D3 Bio, Simcere, Takeda, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal, Leadership Role, Independent director and board member: Innovent Biologics, Inc; Financial Interests, Personal, Research Funding: AstraZeneca, Hutchinson MediPharma, Bristol Myers Squibb, Heng Rui, BeiGene, Roche, Hansoh; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Hansoh; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb. E. Felip: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Roche, Genmab, Gilead Sciences, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; Non-Financial Interests, Personal, Leadership Role: SEOM; Non-Financial Interests, Personal, Member: Member of the Scientific Advisory Committee for Hospital Universitari Parc Tauli, ETOP IBCSG Partners Member of the Scientific Committee; Financial Interests, Personal, Other, Grant for oncology innovation: Merck; Financial Interests, Personal, Officer: Fundacion Merck Salud; Financial Interests, Personal, Other, Travel, acommodations, expenses: AstraZeneca, Janssen, Roche; Financial Interests, Personal, Other: GRIFOLS; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda. G. Lo Russo: Financial Interests, Personal, Advisory Board: Merck Sharp and Dohme, Takeda, Amgen, Eli Lilly, Bristol Myers Squibb, Roche, Novartis, Sanofi, AstraZeneca, GSK, Janssen Oncology, Pierre Fabre, Merck, Regeneron, Pfizer, Bayer, BeiGene, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Merck Sharp & Dohme, Amgen, Eli Lilly, Bristol Myers Squibb, Roche, Novartis, Sanofi, AstraZeneca, GSK, Merck, Regeneron, Pfizer, Bayer, BeiGene; Financial Interests, Institutional, Local PI: Merck Sharp & Dohme, Amgen, Eli Lilly, Bristol Myers Squibb, Roche, Novartis, Sanofi, AstraZeneca, GSK, Merck, Regeneron, Pfizer, Bayer, BeiGene; Non-Financial Interests, Personal, Non financial benefits: Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Novartis, AstraZeneca, Sanofi; Other, Personal, Other: Merck Sharp & Dohme, Takeda, Amgen, Eli Lilly, Bristol Myers Squibb, Roche, Novartis, Sanofi, Pfizer, AstraZeneca, GSK, Bayer; Financial Interests, Personal, Research Grant: Merck Sharp & Dohme; Financial Interests, Personal, Speaker, Consultant, Advisor: Merck Sharp & Dohme, Takeda, Amgen, Eli Lilly, Bristol Myers Squibb, Roche, Novartis, Sanofi, AstraZeneca, GSK, Janssen, Pierre Fabre, Merck, Regeneron, Pfizer, Bayer, BeiGene, Daiichi Sankyo. M. Reck: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bristol Myers Squibb, Biontech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GSK, Merck Sharp & Dohme, Mirati Therapeutics, a Bristol Myers Squibb company, Pfizer, Regeneron, Sanofi, Roche, Seagen; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bristol Myers Squibb, Biontech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GSK, Merck Sharp & Dohme, Mirati Therapeutics, a Bristol Myers Squibb company, Pfizer, Regeneron, Sanofi, Roche, Seagen; Financial Interests, Personal, Other, DMSB: Daiichi Sankyo, Sanofi; Financial Interests, Institutional, Research Funding: Boehringer Ingelheim, Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, GSK, Lilly, Mirati Therapeutics, a Bristol Myers Squibb company, Merck Sharp & Dohme, Merck, Novartis, Regeneron, Sanofi, Roche, Seagen. Y. Zhang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. N. Hu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. M.F. Michenzie: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, a Bristol Myers Squibb company, Bristol Myers Squibb. T.S.K. Mok: Financial Interests, Personal, Advisory Role: AbbVie, Acea Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before 1/1/19), Aveo Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, BI, Blueprint Medicines Corporation, Bristol Myers Squibb, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG's Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd., Gilead Sciences, Inc., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Ilumina, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd, Lilly, Lunit USA, Inc., Loxo-Oncology, Lucence Health Inc., Medscape LLC/ WebMD, Medtronic, Merck Serono, Merck Sharp & Dohme, Mirati, a Bristol Myers Squibb Company, MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/ Diagnostics/ Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Simcere of America Inc., Simcere Zaiming, Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, Xencor Inc., Yuhan Corporation; Financial Interests, Personal, Leadership Role: AstraZeneca PLC, HutchMed, Aurora; Financial Interests, Institutional, Research Funding: AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery; Financial Interests, Personal, Stocks or ownership: Alentis Therapeutics AG, AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, Lunit Inc.. All other authors have declared no conflicts of interest.