549O - Adagrasib with or without cetuximab in patients with KRASG12C-mutated colorectal cancer (CRC): Analysis of tumor biomarkers and genomic alterations

Background

Adagrasib (ada) is a KRAS^G12C inhibitor with favorable properties including 23 hr half-life, dose-dependent PK, and CNS penetration. KRAS^G12C inhibitor resistance may occur in CRC via EGFR reactivation, and a dual EGFR/KRAS^G12C blockade may be necessary to effectively treat KRAS^G12C-mutated CRC. In phase 1/2 cohorts of KRYSTAL-1 (NCT03785249), ada was well tolerated as monotherapy (mono) and in combination with cetuximab (cetux) in patients (pts) with KRAS^G12C-mutated CRC who were previously treated with chemotherapy, with a higher response (46%) and longer median progression-free survival (6.9 months) for ada + cetux.

Methods

Pts with previously treated KRAS^G12C-mutated CRC received ada mono (600 mg BID) or ada (600 mg BID) + cetux (400 mg/m² then 250 mg/m² QW or 500 mg/m² Q2W). Exploratory analyses in both cohorts included mechanisms of acquired KRAS^G12C resistance and correlation of plasma ctDNA clearance and baseline tumor IHC-assessed EGFR expression with response. Plasma was collected at baseline, cycle (C) 2 day (D) 1, C4D1, and end of treatment (EOT). Acquired genomic alterations were characterized for pathogenicity and defined as absent at baseline and present at EOT.

Results

At data cutoff (16 June 2022), 44 pts had received ada and 32 ada + cetux. A total of 27 pts in the ada cohort and 11 in the ada + cetux cohort had paired plasma samples at baseline and EOT. Acquired genomic alterations were observed in 81% (22/27) and 73% (8/11) of pts on ada and ada + cetux, respectively, and included mutations, copy number changes, and fusions. Mutant allele frequency clearance of >95% by C2 occurred in 55% (16/29) and 88% (14/16) of pts on ada and ada + cetux, respectively. Preliminary data suggest a relationship between tumor EGFR expression and response to ada + cetux.

Conclusions

Exploratory analyses suggest diverse mechanisms of acquired resistance in pts treated with ada mono and in combination with cetux, and a greater depth of ctDNA response in pts treated with ada + cetux. Ada + cetux is being investigated in 2L CRC in the phase 3 KRYSTAL-10 trial (NCT04793958).

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 Victoria Eyre-Brook, PhD, 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

M.S. Pelster: Financial Interests, Institutional, Research Grant: Arcus Biosciences, Astellas, Codiak Biosciences, CytomX, Eisai, Gritstone Oncology, HiberCell, Immune-Onc Therapeutics, OncXerna Therapeutics, Surface Oncology, SQZ Biotechnologies, TransThera Sciences, ZielBio, BeiGene, BioNTech, Bristol Myers Squibb, Compass Therapeutics, Gilead, Novartis, Panbela Therapeutics, Revolution Medicines, Translational Genomics, 1200 Pharma, Agenus; Financial Interests, Institutional, Advisory Role: AstraZeneca, Bayer, Novartis, SeaGen, CytomX, Daiichi Sankyo, Ipsen, Pfizer. R. Yaeger: Financial Interests, Personal, Invited Speaker: ZaiLab; Financial Interests, Personal, Advisory Board: Array Biopharma/Pfizer, Mirati Therapeutics, Natera; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim, Mirati Therapeutics, Daiichi Sankyo. S.J. Klempner: Financial Interests, Personal, Advisory Board: Astellas, Bristol Myers Squibb, Merck, Eli Lilly, Exact Sciences, Mersana, Pieris, Daiichi Sankyo, AstraZeneca, Novartis, Coherus, Sanofi-Aventis; Financial Interests, Personal, Stocks/Shares: MBrace Therapeutics; Financial Interests, Institutional, Research Grant: Leap Therapeutics, Astellas, SU2C-AACR; Non-Financial Interests, Personal, Principal Investigator: Leap, Astellas, Arcus; Non-Financial Interests, Personal, Other: NCCN, Debbie's Dream Foundation. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology, AnHeart Therapeutics; Financial Interests, Personal, Ownership Interest: MBrace Therapeutics, BlossomHill Therapeutics; Financial Interests, Institutional, Local PI: Pfizer, Mirati, JNJ/Jassen, Merus, Revolution Medicine, Nuvalent. A.I. Spira: Financial Interests, Personal, Invited Speaker: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer; Financial Interests, Personal, Advisory Board: Incyte, Amgen, Novartis, Mirati Therapeutics, Inc., 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; 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, Inc., Rubius, Synthekine, Mersana, Blueprint Medicines, Alkermes, Revolution Medicines. P.A. Jänne: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Inc., Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties: Lab Corp; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. N.V. Uboha: Financial Interests, Personal, Advisory Board: QED, Ipsen, Incyte, AstraZeneca, Pfizer, Boston Gene, Grail, Astellas, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Taiho Inc, Ipsen, EMD Serono. Y.A. Gaffar: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, AstraZeneca, Rigel Pharmaceuticals, Seagen, Exelixis, BeiGene. C.P. Paweletz: Financial Interests, Personal, Speaker’s Bureau: Bio-Rad; Financial Interests, Personal, Stocks/Shares: XSphera Biosciences; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Bicycle Therapeutics, Transcenta, Bicara Therapeutics, AstraZeneca, Intellia Therapeutics, Janssen Pharmaceuticals, Mirati Therapeutics, Array Biopharma, Bristol Myers Squibb, Takeda, KSQ Therapeutics, IMPACT Therapeutics; Financial Interests, Personal, Other, Consulting fees: DropWorks, XSphera Biosciences. L. Alejandro, T. Kheoh, K. Anderes, H. Der Torossian: 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. J. Weiss: Financial Interests, Personal, Advisory Board: AstraZeneca, EMD Serono, Genentech, G1 Therapeutics, Jounce Therapeutics, AbbVie, Nanobiotix, Eli Lilly, Blueprint Medicines, Pfizer, Saatchi Wellness, Jazz Pharmaceuticals, Boehringer Ingelheim, Regeneron, Genmab, SDP Oncology, BeiGene; Financial Interests, Personal, Stocks/Shares: Nektar, Vesselon, Achilles Therapeutics, Nuvalent, Lyell Immunopharma, En Fuego Therapeutics. All other authors have declared no conflicts of interest.