KRYSTAL-10: A randomized phase 3 study of adagrasib (MRTX849) in combination with cetuximab vs chemotherapy in patients with previously treated advanced colorectal cancer with KRASG12C mutation

Background KRAS G12C mutation occurs in 3-4% of colorectal cancer (CRC) and is associated with poor prognosis. KRAS is a key mediator of the RAS/MAPK signaling cascade and promotes cellular growth and proliferation. Cetuximab, an EGFR-inhibiting monoclonal antibody, is indicated as monotherapy or in combination with chemotherapy for the treatment of KRAS wild-type metastatic CRC. However, in patients (pts) with KRAS G12C mutation, EGFR antibodies lack clinical activity, and no targeted therapy has been approved in this population, presenting a large unmet need for new treatments. Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRAS G12C that irreversibly and selectively binds to KRAS G12C and locks it in its inactive state. Adagrasib was optimized for favorable PK properties, including oral bioavailability, long half-life (∼24 h), and extensive tissue distribution. Initial results from the Phase 1b KRYSTAL-1 study demonstrated encouraging antitumor activity and tolerability of adagrasib monotherapy (600 mg BID). In pretreated pts with CRC harboring KRASG12C mutation who had received a median of 4 prior lines of therapy, 17% (3/18) had confirmed objective responses and the disease control rate (DCR) was 94% as of the August 2020 data cutoff. Despite this observed activity of KRAS G12C inhibition, reactivation of RAS/MAPK pathway signaling may occur through adaptive feedback mediated by EGFR, which is expressed in a variety of human tumors including CRC. These observations indicate that combined treatment of adagrasib with cetuximab may enhance inhibition of KRAS-dependent signaling to overcome adaptive feedback and improve clinical outcomes. Preclinical data in KRAS G12C human xenograft CRC mouse models suggest synergistic activity of adagrasib and cetuximab. These data, along with initial feasibility and efficacy signals seen in KRYSTAL-1, support further evaluation of the combination. Trial design Open-label, randomized Phase 3 study. Methods KRYSTAL-10 (NCT04793958) is a global, open-label, randomized Phase 3 study evaluating the efficacy and safety of adagrasib (600 mg BID) in combination with cetuximab (500 mg/m2 Q2W) vs chemotherapy in pts with CRC harboring a KRAS G12C mutation who have progressed on or after treatment with a standard first-line fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan. Pts randomized to the chemotherapy control arm will receive FOLFIRI or mFOLFOX6 depending on their first-line treatment regimen; a VEGF/VEGFR inhibitor may be used in combination with chemotherapy at the investigator’s discretion. Dual primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include safety, objective response rate (ORR) per RECIST 1.1, duration of response (DOR), plasma PK parameters of adagrasib, and patient-reported outcomes (PROs). The study will also explore correlations between tumor biomarkers, gene alterations (at baseline and upon treatment resistance), and efficacy. Approximately 420 pts will be randomized 1:1 to receive adagrasib in combination with cetuximab or chemotherapy. Randomization will be stratified by region (United States/Canada vs all other countries) and time to disease progression after beginning first-line treatment (This study will be enrolling at sites in North America, South America, Europe, Asia, and Australia. Clinical trial identification NCT04793958. Editorial acknowledgement Writing and editorial assistance were provided by Rohan Gidvani of Axiom Healthcare Strategies, funded by Mirati Therapeutics, Inc. Legal entity responsible for the study Mirati Therapeutics, Inc. Funding Mirati Therapeutics, Inc. Disclosure J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); Advisory / Consultancy: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. J. Bendell: Honoraria (Institution): Gilead, Genentech, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, ARMO, Ipsen, Merrimack, Oncogenex, FORMA, Arch Oncology, Prelude Therap., Phoenix Bio, Cyteir, Molecular Partners, Innate, Torque, Tizona, Janssen, Tolero, Translational Drug Devel., Amgen, Seattle Genetics, Moderna Therap., Tanabe Research, Beigene, Continuum Clinical, Agios, Bicycle, Relay, Evelo, Pfizer, Piper Biotech, Samsung Bioepios, Fusion Therap.; Research grant / Funding (institution): Gilead, Genentech, BMS,Five Prime, Lilly, Merck, MedImmune, Celgene, EMDSerono, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP,TG Therapeutics, AstraZeneca, BI Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, Scholar Roch, NGMBio, Stemcentrx, Beige, AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Bicycle, Zymeworks, Relay, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Oncology,Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, Imclone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus, Seattle Genetics, Tempest, Shattuck Labs, Synthorx, RevloutionMed.R. Corcoran: Honoraria (self): AstraZeneca, Chugai (last 2018), Guardant Health, Shire (last 2016); Advisory / Consultancy: AbbVie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, LOXO, Merrimack, Mirati Therapeutics, Natera, Navire, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, Zikani Therapeutics; Leadership role: Scientific Advisory Board/Equity Holder: Avidity Biosciences, C4 Therapeutics, Erasca, Kinnate Biopharma, nRichDx, Remix Therapeutics, and Revolution Medicines; Research grant / Funding (self): Research Funding Asana (ended 2019), AstraZeneca (ended 2019), Lilly, and Sanofi (ended 2018). S. Kopetz: Advisory / Consultancy: Roche, Redx Pharma, Jacobio, Merck, Navire Pharma, Holy Stone, Biocartis, Natera, Karyopharm Therapeutics, Repare Therapeutics, Genentech, Lilly, AstraZeneca/MedImmune, EMD Serono, Daiichi Sankyo, Amal Therapeutics, Boehringer Ingelheim, Bayer Health, Lutris, Pfizer, Amgen, Pierre Fabre, Symphogen, Novartis, Boston Biomedical, Ipsen, HalioDx. M. Davis: Full / Part-time employment: Mirati Therapeutics, Inc. J. Christensen: Leadership role: Mirati Therapeutics, Mirati Therapeutics; Shareholder / Stockholder / Stock options: Mirati Therapeutics, Mirati Therapeutics; Full / Part-time employment: Mirati Therapeutics, Mirati Therapeutics, Mirati Therapeutics; Spouse / Financial dependant: Mirati Therapeutics, Mirati Therapeutics, Mirati Therapeutics. A. Chi: Full / Part-time employment: Mirati Therapeutics. T. Kheoh: Shareholder / Stockholder / Stock options: Mirati Therapeutics; Full / Part-time employment: Mirati Therapeutics. R. Yaeger: Advisory / Consultancy: Natera; Research grant / Funding (institution): Pfizer, Mirati Therapeutics, Boehringer Ingelheim. The other author has declared no conflicts of interest.