LBA65 - KRYSTAL-7: Efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation

Background

Adagrasib (ada) is an irreversible KRAS^G12C inhibitor selected for favorable properties, including long half-life (23 hrs), dose-dependent PK, and CNS penetration. Optimized noncovalent binding affinity and minimized cysteine reactivity associated with ada are hypothesized to limit off-target effects in the liver and other organ sites. Preliminary ada plus pembrolizumab (pembro) data showed a manageable safety profile and encouraging clinical activity. We report updated efficacy and safety in more patients (pts) treated with ada plus pembro in KRYSTAL-7 (NCT04613596).

Methods

In the phase 2 KRYSTAL-7 study, pts with treatment-naïve KRAS^G12C-mutated advanced NSCLC received concurrent ada 400 mg orally BID plus pembro 200 mg intravenously Q3W. Study objectives included efficacy (investigator-assessed objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], and overall survival), and safety.

Results

As of 19 June 2023, 148 pts had received ada plus pembro (median follow-up 8.7 months). Median age was 67 years, 48% were female, 39%/61% were ECOG PS 0/1. In pts with PD-L1 ≥50% (median follow-up 10.1 months), ORR was 63% (32/51 pts), disease control rate was 84%. Median DOR was not reached (NR; 95% CI 12.6–not estimable [NE]); median PFS was NR (95% CI 8.2–NE). In all pts, treatment-related adverse events (TRAEs) of any grade (gr) occurred in 94% (139/148) of pts; 55% gr3, 9% gr4, 1% gr5. TRAEs led to both ada and pembro discontinuation in 4% of pts (6% discontinued ada alone, 11% discontinued pembro alone). No pt discontinued both drugs due to ALT/AST increase or hepatic TRAEs; 1 pt discontinued ada and 3 pts discontinued pembro due to liver transaminase elevation. Additional efficacy and safety analyses will be presented.

Conclusions

After longer follow-up, concurrent ada plus pembro continued to have encouraging preliminary efficacy in pts with PD-L1 ≥50% and a manageable safety profile. These findings support initiation of a phase 3 trial evaluating concurrent ada plus pembro vs pembro for treatment-naïve pts with KRAS^G12C-mutated NSCLC and PD-L1 ≥50% (NCT04613596).

Clinical trial identification

NCT04613596.

Editorial acknowledgement

KRYSTAL-7 was sponsored by Mirati Therapeutics, Inc. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Victoria Eyre-Book, PhD, of Ashfield MedComms, an Inizio company, and funded by Mirati Therapeutics, Inc.

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Disclosure

M.C. Garassino: Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, AstraZeneca, MSD, MSD Italia, Srl, GrupoPacifico-Secretaria Tenica ICAPEM/AstraZeneca, S.O.S.S.r.l, Medscape, ecancer, Roche, Bayer, Janssen, Pfizer, Celgene, Amgen, Blueprint, Sanofi, IPSEN Bioscience, Novartis, Exelixis, Spectrum Pharmaceuticals, Merck Serono, Merck, BMS, Otsuka, Incyte, Turning Point Therapeutics, Daiichi Sankyo, AstraZeneca S.p.A, MedImmune LCC, GSK, AstraZeneca AB, Merck KGaA; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati Therapeutics, Inc., Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGenius; Non-Financial Interests, Personal, Principal Investigator: Pfizer, Eli Lilly, MSD, Instituto Nazionale dei Tumori, GOIRC Sant'Orsola Malpighi - Bologna (Alma Mater Studiorum Universita Bologna), Istituto dei Tumori Pascale - Napoli, Gustave-Roussy Parigi Lipi Trial, O Spedali Civili Brescia, ETOP; Non-Financial Interests, Personal, Member: AIOM, WCLC, IPOP, TUTOR, AIOT, EMA SAG; Non-Financial Interests, Personal, Leadership Role: Women for Oncology Italy, AIOT, ESMO; Financial Interests, Personal, Other: AstraZeneca, MSD, Janssen, GSK, Pfizer, Seattle Genetics, AstraZeneca UK; Non-Financial Interests, Personal, Other: ASCO, AACR, ESMO; Other, Personal, Other: Pfizer, Roche, AstraZeneca, Merck. R. Jotte: Financial Interests, Personal, Advisory Board: Mirati Therapeutics, Inc.. J. Laskin: Financial Interests, Personal, Invited Speaker: Roche Canada, Jazz Pharmaceuticals, AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer, Eli Lilly, Takeda; Financial Interests, Institutional, Research Grant: Roche Canada. F. de Marinis: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, BMS, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, BMS, Novartis. C. Aguado: Non-Financial Interests, Personal, Invited Speaker: MSD, Bristol Myers Squibb, Novartis; Non-Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Sanofi, Pierre Fabre; Non-Financial Interests, Personal, Principal Investigator: Mirati Therapeutics, Inc., MSD, AstraZeneca. F.B. Badin: Non-Financial Interests, Personal, Writing Engagement: BMS, Jazz; Other, Personal, Speaker’s Bureau: BMS, Merck, Jazz, Pfizer, Lilly, Regeneron, EMD Serono, Janssen. I. Chmielewska: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Roche, MSD, Pfizer; Financial Interests, Personal, Advisory Board: Amgen, BMS; Financial Interests, Personal, Principal Investigator: Roche, Amgen, Mirati; Financial Interests, Personal, Other, Travel: Pfizer, Takeda. M.J. Hochmair: Financial Interests, Personal, Invited Speaker: AstraZeneca, Amgen, MSD, Boehringer Ingelheim, Lilly, Takeda, Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Amgen, Boehringer Ingelheim, Lilly, Takeda, Roche, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, MSD, Boehringer Ingelheim, Lilly, Takeda, Roche. S. Lu: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Hansoh; Financial Interests, Personal, Speaker’s Bureau: AstraZenca, Roche, Hansoh; Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Hutchinson MediPharma, ZaiLab, GenomiCare, Novartis, Yuhan Corporation, Menarini, Mirati, Daiichi Sankyo, D3 Bio, Simcere, Takeda, Roche, MediPharma; Financial Interests, Institutional, Research Grant: AstraZeneca, Hutchinson, BMS, Heng Rui, BeiGene, Roche, Hansoh. E. Nadal: Financial Interests, Personal, Invited Speaker: Roche, BMS, MSD, Boehringer Ingelheim, Lilly, Pfizer, Sanofi, AstraZeneca, Takeda, Amgen, Qiagen, Janssen; Financial Interests, Personal, Advisory Board: Roche, BMS, MSD, Boehringer Ingelheim, Lilly, Janssen, Pfizer, Merck Serono, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Sanofi, Qiagen, Janssen; Financial Interests, Institutional, Funding: Roche, BMS, Merck Serono; Financial Interests, Personal, Advisory Role: Pfizer, Roche. G. Ostoros: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Roche; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Roche. E. Felip: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Eli Lilly, Roche, Janssen, MSD, Pfizer, Sanofi, Takeda, Medscape, Peervoice, TouchOncology, Daiichi Sankyo, Exelixis, GSK, AbbVie, Novartis, Bayer, Boehringer Ingelheim, Amgen, Mirati, Merck, AstraZeneca AB, Merck KGaA; Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Roche, GSK, Janssen, Merck, Novartis, Peptomyc, Pfizer, Sanofi, Takeda, MSD; Non-Financial Interests, Personal, Member: ESMO, ETOP; Non-Financial Interests, Personal, Leadership Role: SEOM; Financial Interests, Personal, Other, Grant for oncology innovation: Merck; Financial Interests, Personal, Other: Fundacion Merck Salud. A.I. Spira: Financial Interests, Personal, Invited Speaker: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, BMS, Bayer; Financial Interests, Personal, Advisory Board: Incyte, Amgen, Novartis, Mirati, Gritstone Oncology, Jazz, Takeda, Janssen, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Array Biopharma, AstraZeneca/Medimmune, Merck, BMS, Blueprint Medicines; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Research Grant: LAM Therapeutics, Regeneron, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharma, BMS, Loxo, Arch, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen, Mirati, Rubius, Synthekine, Mersana, Blueprint, Alkermes, Revolution Medicines. C.M. Lane: Financial Interests, Personal, Full or part-time Employment: Mirati; Financial Interests, Personal, Stocks/Shares: Mirati. J. He: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc.. R. Chao: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics, Inc.. P.A. Jänne: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai, Eli Lilly, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda, Mirati, Transcenta, Silicon, Syndax, Nuvalent, Bayer, Eisai, Allorion, Accutar Biotech, AbbVie, Monte Rosa, Scorpion, Merus, Frontier, Hongyun Biotechnology, Duality Biologics; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties: Lab Corp; Financial Interests, Personal, Research Grant: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda. All other authors have declared no conflicts of interest.