8MO - Adagrasib (MRTX849) in patients with advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC): Preliminary analysis of mutation allele frequency

Background

KRAS^G12C mutations occur in ∼14% of NSCLC adenocarcinomas. Adagrasib (ada), a KRAS^G12C inhibitor, was selected for favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system penetration. In the KRYSTAL-1 registrational phase II Cohort A, ada showed clinical activity with manageable tolerability in patients (pts) with previously treated KRAS^G12C-mutated NSCLC.

Methods

Pts with previously treated KRAS^G12C-mutated NSCLC received ada 600 mg orally BID. Study objectives included objective response rate [ORR], progression-free survival [PFS], overall survival [OS], safety and exploratory correlative analyses. An exploratory analysis of clinical response for pts with detectable circulating tumor (ct) DNA at baseline, cycle 2 day 1, and cycle 4 day 1 (C4D1), who comprise the mutation allele frequency clearance (MAFC)-evaluable population, was also performed; KRAS^G12C ctDNA was assessed by digital droplet polymerase chain reaction.

Results

At data cutoff, 15 Oct 2021, Cohort A included 116 pts (median follow-up 12.9 months): median age 64 years, 56% female, median 2 prior systemic therapies. ORR by blinded independent central review (BICR) was 42.9%, disease control rate 79.5%, median PFS 6.5 months (95% CI 4.7–8.4) and, with longer follow-up (cutoff 15 Jan 2022), median OS 12.6 months (95% CI 9.2–19.2). Any grade treatment-related adverse events (TRAEs) occurred in 97% of pts (most commonly [>40%] diarrhea [63%], nausea [62%], vomiting [47%], and fatigue [41%]), and Grade 3–4 TRAEs in 43% (most commonly [≥5%] serum lipase increase [6%] and anemia [5%]). Two grade 5 TRAEs occurred; 8 (7%) TRAEs led to discontinuation. In MAFC-evaluable pts (n = 35), ORR by BICR was 60% (21/35) and all responses correlated with MAFC >90% by C4D1.

Conclusions

Ada showed promising efficacy and manageable tolerability in previously treated pts with KRAS^G12C-mutated NSCLC. Additional analyses are needed to further evaluate whether clinical response with ada correlates with MAFC in ctDNA. A phase III trial evaluating ada monotherapy vs docetaxel in previously treated pts with KRAS^G12C-mutated NSCLC is ongoing (NCT04685135).

Clinical trial identification

NCT03785249.

Editorial acknowledgement

KRYSTAL-1 was sponsored by Mirati Therapeutics, Inc. Third-party medical writing support, under the direction of the authors, was provided by Rebecca Benatan, BSc, of Ashfield MedComms, an Inizio company, and was funded by Mirati Therapeutics, Inc.

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Disclosure

P.A. Jänne: Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; Financial Interests, Institutional, Funding: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Revolution Medicines, Takeda Oncology, Daiichi Sankyo; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Novartis, Biocartis, Takeda Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Allorion Therapeutics, Accutar Biotech, AbbVie, Bayer, Eisai, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology. A. Spira: Financial Interests, Personal, Invited Speaker: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol-Myers Squibb, Bayer; 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 Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Alkermes, Revolution Medicines; Financial Interests, Personal, Advisory Role: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Array Biopharma, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb, Blueprint Medicines. G.J. Riely: Financial Interests, Personal, Advisory Board: Mirati Therapeutics, Novartis, Takeda, Eli Lilly, Rain Therapeutics, Merck; Financial Interests, Institutional, Research Grant: Mirati Therapeutics, Roche, Novartis, Takeda, Eli Lilly, Rain Therapeutics, Merck; Financial Interests, Personal, Principal Investigator: Mirati Therapeutics, Roche, Novartis, Takeda, Eli Lilly, Rain Therapeutics, Merck. S. Gadgeel: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Genentech/Roche, Bristol Myers Squibb, Pfizer, Eli Lilly, Mirati Therapeutics, Blueprint, Daiichi Sankyo, Janssen, GSK, Merck; Financial Interests, Personal, Other, Data safety monitoring board: AstraZeneca. R. Heist: Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Novartis, Eli Lilly, Regeneron, Sanofi, Claim, EMD Serono; Financial Interests, Institutional, Research Grant: AbbVie, Agios, Corvus, Daiichi Sankyo, Eli Lilly, Mirati Therapeutics, Novartis, Erasca, Exelixis, Turning Point. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche, DAVA Oncology, JNJ/Janssen; Financial Interests, Personal, Speaker's Bureau: Pfizer; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Elevation Oncology; Financial Interests, Personal, Advisory Role: Elevation Oncology. M.L. Johnson: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera, CytomX, Daiichi Sankyo, EcoR1, Editas Medicines, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, GSK, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Eli Lilly, Merck, Mirati Therapeutics, Oncorus, Regeneron, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics. J. Sabari: Financial Interests, Personal, Invited Speaker: Medscape, MJHS Onclive, Clinical Care Options; Financial Interests, Personal, Advisory Role: AstraZeneca, Genentech, Janssen, Mirati Therapeutics, Pfizer, Sonfi Genzyme, Takeda. K. Velastegui: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics. J.G. Christensen: Financial Interests, Personal, Advisory Board: Bridge Biosciences; Financial Interests, Personal, Officer: Mirati Therapeutics; Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics. W. Yang: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics. K. Anderes: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics. R. Chao: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics. C. Paweletz: Financial Interests, Personal, Research Grant: Daiichi Sankyo, Bicycle Therapeutics, Transcenta, Bicara Therapeutics, AstraZeneca, Intellia Therapeutics, Janssen Pharmaceuticals, Mirati Therapeutics, Array Biopharma, Bristol Myers Squibb, Takeda Pharmaceutical Company, KSQ Therapeutics, IMPACT Therapeutics; Financial Interests, Personal, Other, Consulting: DropWorks, XSphera Biosciences; Financial Interests, Personal, Speaker's Bureau: Bio-Rad; Financial Interests, Personal, Stocks/Shares: XSphera Biosciences.