LBA24 - KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation

Background

KRAS^G12C mutations occur in 3–4% of CRC and are associated with shorter PFS and OS with standard chemotherapy. Adagrasib (ada), a selective and irreversible KRAS^G12C inhibitor, is optimized for a long half-life (23 h), dose-dependent PK, and CNS penetration. Durable inhibition of KRAS^G12C may be important in CRC, due to signaling pathways creating susceptibility to feedback reactivation of RAS. Preclinical data suggest dual EGFR/KRAS^G12C blockade may enhance inhibition of KRAS-dependent signalling and overcome adaptive feedback.

Methods

KRYSTAL-1 (NCT03785249) is a multicohort Ph 1/2 study evaluating safety and efficacy of ada in patients (pts) with KRAS^G12C-mutated advanced solid tumors. Ada (600 mg BID) and ada + cetuximab (cetux; 400 mg/m² followed by 250 mg/m² QW or 500 mg/m² Q2W) were evaluated in pts with previously treated CRC, in Ph 2 and 1b cohorts, respectively. Responses were investigator assessed.

Results

As of Jun 16 2022, 44 pts received ada and 32 pts received ada + cetux. In the ada mono cohort (median follow-up 20.1 mo), median age was 59 yrs, 50% were female, median prior lines of systemic therapy was 3, 52% and 48% were ECOG PS 0 and 1, respectively. In 43 pts evaluable for efficacy, ORR was 19% (8/43), and DCR was 86% (37/43). Median DOR was 4.3 mo (95% CI 2.3–8.3) and median PFS was 5.6 mo (95% CI 4.1–8.3). In the ada + cetux cohort (median follow-up 17.5 mo), median age was 60 yrs, 53% were female, median prior lines of systemic therapy was 3, 44% and 56% were ECOG PS 0 and 1, respectively. In 28 pts evaluable for efficacy, ORR was 46% (13/28) and DCR was 100% (28/28). Median DOR was 7.6 mo (95% CI 5.7–NE) and median PFS was 6.9 mo (95% CI 5.4–8.1). Gr 1–2 and 3–4 TRAEs occurred in 59% and 34% of pts, respectively, in the ada cohort, and 84% and 16% of pts, respectively, in the ada + cetux cohort. No Gr 5 TRAE occurred.

Conclusions

Adagrasib is well tolerated as monotherapy and with cetuximab. Both showed clinical activity in heavily pretreated pts with KRAS^G12C-mutated CRC, with more sustained responses with the combination. Adagrasib + cetuximab is being investigated in 2L CRC in the Phase 3 KRYSTAL-10 trial (NCT04793958).

Clinical trial identification

NCT03785249.

Editorial acknowledgement

Third-party medical writing support, under the direction of the authors, was provided by Victoria Eyre-Brook 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

S.J. Klempner: Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Eli Lilly, Merck, Bristol Myers Squibb, Astellas, Daiichi Sankyo, Pieris; Financial Interests, Personal, Advisory Board, One Time Advisory Board: Natera; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1: Mersana, Sanofi-Aventis; Financial Interests, Personal, Stocks/Shares, Stock Ownership: Turning Point Therapeutics; Financial Interests, Personal, Stocks/Shares, Early investor, company is not public: MBrace; Financial Interests, Institutional, Invited Speaker, National PI for trial: Leap Therapeutics; Financial Interests, Personal and Institutional, Invited Speaker, Local PI for trial, also served on advisory board as noted above: Astellas; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker, Trial PI: Silverback; Non-Financial Interests, Advisory Role, Medical-Scientific Advisory Board Member: Debbies Dream Foundation; Non-Financial Interests, Advisory Role, Member of Scientific Advisory Board: Hope for Stomach Cancer; Non-Financial Interests, Other, Member of Gastric and Esophageal NCCN Guideline Committees: NCCN. J. Weiss: Financial Interests, Advisory Board: Genmab, AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, AbbVie, Rakuten Medical, Nanobiotix, Azitra, Lilly, Blueprint Medicines, Pfizer, Jazz Pharmaceuticals, Boehringer Ingelheim, Regeneron; Financial Interests, Stocks/Shares: Nektar, Vessalon. M. Pelster: Financial Interests, Institutional, Principal Investigator: Arcus Biosciences, Astellas, Codiak Biosciences, CytomX, Gritstone Oncology, HiberCell, Immune-Onc Therapeutics, Surface Oncology, SQZ Biotechnologies, ZielBio; Financial Interests, Institutional, Advisory Role: Bayer, Novartis, AstraZeneca. A. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, 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. M. Barve: Financial Interests, Stocks/Shares: Texas Oncology Physician Associates; Financial Interests, Funding: Mary Crowley Cancer Research. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Elevation Oncology; Financial Interests, Institutional, Invited Speaker: Pfizer, Mirati, JNJ/jassen, Merus. T.A. Leal: Financial Interests, Advisory Board: Daiichi Sankyo, Beyond Spring Pharmaceuticals, BMS, Merck, Takeda, Genentech, Invision First Lung, AstraZeneca, Novocure, Jazz Pharmaceuticals, EMD Serono, Boehringer Ingelheim, Blueprint Medicines. T. Bekaii-Saab: Financial Interests, Advisory Board: Replimune Artiva, Imugene, Immuneering, Xilis, Sun Biopharma; Financial Interests, Research Grant: BMS, Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer; Financial Interests, Other, Data monitoring committees: Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan, 1Globe; Financial Interests, Other, Inventions/patents: WO/2018/183488: human PD-1peptide vaccines and uses thereof –Licensed to Imugene, WO/2019/055687: methods and compositions for the treatment of cancer cachexia –Licensed to Recursion; Financial Interests, Advisory Role: Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merck, Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, AstraZeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine. J.G. Christensen: Financial Interests, Advisory Board: Bridge Biosciences; Financial Interests, Officer: Mirati Therapeutics; Financial Interests, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Stocks/Shares: Mirati Therapeutics. T. Kheoh: Financial Interests, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Stocks/Shares: Mirati Therapeutics. K. Velastegui: Financial Interests, Full or part-time Employment: Mirati Therapeutics. H. Der Torossian: Financial Interests, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Stocks/Shares: Mirati Therapeutics. R. Yaeger: Financial Interests, Advisory Board: Array Biopharma/ Pfizer, Mirati Therapeutics, Natera; Financial Interests, Research Grant: Array Biopharma/ Pfizer, Boehringer Ingelheim, Mirati Therapeutics.