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Clinical Trial
. 2024 Jan;30(1):271-278.
doi: 10.1038/s41591-023-02696-8. Epub 2023 Dec 5.

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial

Jayesh Desai  1 , Guzman Alonso  2 , Se Hyun Kim  3 , Andres Cervantes  4 , Thomas Karasic  5 , Laura Medina  6 , Einat Shacham-Shmueli  7 , Rasha Cosman  8 , Alejandro Falcon  9 , Eelke Gort  10 , Tormod Guren  11 , Erminia Massarelli  12 , Wilson H Miller Jr  13 , Luis Paz-Ares  14 , Hans Prenen  15 , Alessio Amatu  16 , Chiara Cremolini  17 , Tae Won Kim  18 , Victor Moreno  19 , Sai-Hong I Ou  20 , Alessandro Passardi  21 , Adrian Sacher  22 , Armando Santoro  23 , Rafal Stec  24   25 , Susanna Ulahannan  26   27 , Kathryn Arbour  28 , Patricia Lorusso  29 , Jia Luo  30 , Manish R Patel  31 , Yoonha Choi  32 , Zhen Shi  32 , Sandhya Mandlekar  32 , Mark T Lin  32 , Stephanie Royer-Joo  32 , Julie Chang  32 , Tomi Jun  32 , Neekesh V Dharia  32 , Jennifer L Schutzman  32 ; GO42144 Investigator and Study Group; Sae-Won Han  33
Affiliations
Clinical Trial

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial

Jayesh Desai et al. Nat Med. 2024 Jan.

Abstract

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

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Conflict of interest statement

J.D. served as a consultant for BeiGene, Pierre Fabre, Bayer, GSK, Merck, Boehringer Ingelheim, Roche/Genentech, Daiichi Sankyo Europe, Novartis, Pfizer, Ellipses Pharma, Axelia Oncology and Amgen; and reports funding to their institution from Roche, GSK, Novartis, BeiGene, Lilly, Bristol Myers Squibb, AstraZeneca/MedImmune and Amgen. S.H.K. was a consultant on the advisory boards for Pfizer, Daiichi, Takeda and Astellas; and reports funding to their institution from Ono Pharma and Eisai Korea. A.C. received institutional research funding from Genentech, Merck Serono, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Natera and Fibrogen and advisory board or speaker fees from AbbVie, Amgen, Merck Serono, GlaxoSmithKline and Roche. T.K. has received honoraria from Incyte, Pfizer, Ipsen, AstraZeneca/MedImmune, Taiho Oncology, Elevar Therapeutics and Nucorion; and reports funding to their institution from Taiho Pharmaceutical, H3 Biomedicine, Bristol Myers Squibb, Lilly, Tempest Therapeutics, Xencor, Genentech, Incyte and Totus Medicines. L.M. has received travel and accommodation fees from Sevier, Novartis, Janssen, Bristol Myers Squibb; is on the speaker’s bureau for Novartis; has received research funding from AstraZeneca; and reports funding to their institution from Bristol Myers Squibb, AstraZeneca, Abbvie, Genmab, Nelum, Numab and Precision Medicine. E.S. reports funding to their institution from Amgen, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Lutris Pharma, MSD, Novartis and Pangea Pharma. R.C. reports funding to their institution from Abbvie, AkesoBio, AcroImmune, ALX Oncology, Arcus, Ascendis Pharma, Amgen, ARIAD Pharmaceuticals, Array BioPharma, AstraZeneca, Bayer, Beigene, Biosplice Therapeutics, Bristol Myers Squibb, Blueprint Medicines Corporation, Boehringer, Boston Biomedical, BridgeBio, Carina Biotech, CBT Pharmaceuticals, Celgene, Corvus Pharmaceuticals, GSK, CSTONE Pharmaceuticals, Daichii Sankyo, Duality, DynamiCure, ENB Therapeutics, EtiraRX, Exelisis, Five Prime Therapeutics, Foghorn Therapeutics, Fortrea, Fusion Pharmaceuticals, GC Cell, Genentech, Gilead, Grey Wolf Therapeutics, Henlius, Biotech, ICON, IDEAYA Biosciences, Immunocore, Incyte, Innovent Biologics, InxMed, Janssen, Linnaeus Therapeutics, Lilly, Loxo, MacroGenics, Merck, Merrimack Pharmaceuticals, MSD, Moderna, Multitude Therapeutics, Myeloid Therapeutics, Nektar Therapeutics, Neoleukin Therapeutics, Novartis, NuvOx Pharma, Pfizer, QBiotics, Regeneron, Relay Therapeutics, Roche, Sanofi, Seagen, Starpharma, SERVIER AFFAIRES MÉDICALES, Takeda, TigerMed, ViroCure, Virogin Biotech, Xencore and Xennials Therapeutics. A.F. has received consultation fees from Seagen, Roche, Pfizer, Novartis, AstraZeneca, GSK and Esteve; and is on the speaker’s bureau for Seagen, Roche, Pfizer, Novartis, Lilly, AstraZeneca, Pierre Fabre, Daiichi, Gilead and Eisai. T.G. reports honoraria to their institution from Pierre Fabre. W.H.M is on the advisory boards of and has received consulting fees from Merck, Bristol Myers Squibb, Roche, GSK, Novartis, Amgen, Mylan, EMD Serono and Sanofi; is on the speaker’s bureau of and has received honoraria from Bristol Myers Squibb, Merck, Roche, GSK, Novartis, Amgen, Mylan, EMD Serono and Sanofi; reports grants paid to their institution from Merck, Canadian Institutes of Health Research, CRS, Terry Fox Research Institute, Samuel Waxman Cancer Research Foundation and Canadian Cancer Society Research Institute; and reports clinical trial support to their institution from Merck, MiMic, Astellas, Bristol Myers Squibb, Novartis, GSK, Incyte, Pfizer, Sanofi, Ocellaris Pharma, Alkermes, Genentech, Array, Exelixis, VelosBio, Esperas Pharma, Seagen, AstraZeneca and Roche. E.M. was an advisory board consultant for Lilly, Janssen Scientific Affairs, Bristol Myers Squibb, Daiichi Sankyo, AbbVie Consulting, Mirati Therapeutics, Fusion Pharmaceuticals, Iovance Biotherapeutics, Sanofi and Gilead; and was on the speaker’s bureau for AstraZeneca, Lilly, Takeda Pharmaceuticals and Mirati Therapeutics. L.P. has received consulting fees from Lilly, MSD, Roche, PharmaMar, Merck KgaA (Darmstadt, Germany), AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati, GSK, Janssen, Takeda, Regeneron and Sanofi; grants or contracts from MSD, AstraZeneca, Bristol Myers Squibb and Pfizer; and is on the speaker’s bureau and has received honoraria from AstraZeneca, Janssen, Merck, Mirati and Sanofi. H.P. has received honoraria from Amgen, Roche, Sanofi, AstraZeneca and Bayer. C.C. has received honoraria for speaker or advisory roles from Bayer, Roche, Merck Serono, Amgen, Servier, Mirati, Pierre Fabre, MSD, Nordic Pharma and Takeda; and research grants from Bayer, Servier, Merck and Amgen. T.W.K. reports funding to their institution from Genentech. V.M. has received consulting fees from Roche, Bayer, Bristol Myers Squibb, Janssen, Syneos, Affimed and AstraZeneca; and reports funding to their institution from Achilles, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Arcus, Ascendis Pharma, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer, Beigene, Biomea, BioInvent International AB, BMS, Boheringer, Boston Therapeutics, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Therapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Relay Therapeutics, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics and Upsher-Smith. S.I.O. has received consulting fees from Pfizer, Janssen, Daiichi Sankyo, Lilly and AnHeart Therapeutics; reports funding to their institution from Pfizer, Mirati, Revolution Medicine, Nuvalent, Janssen and Genentech/Roche; and reports ownership of MBrace Therapeutics and Blossomhill Therapeutics. A.P. has received consulting fees from Amgen, Bayer, Merck, Servier and Pierre Fabre; and travel, accommodation and expenses from Pierre Fabre and Bayer. A. Sacher is a consultant and on the advisory board for Genentech-Roche and AstraZeneca; and is an institutional research and clinical trial principal investigator for AstraZeneca, Amgen, Genentech-Roche, Merck, Lilly, Pfizer, Bristol Myers Squibb, GSK, Spectrum, Iovance and CRISPR Therapeutics. A. Santoro is on the advisory board for Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer and MSD; is a consultant for Sanofi and Incyte; and is on the speaker’s bureau for Takeda, Bristol Myers Squibb, Roche, Abbvie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayers and MSD. R.S. has been a lecturer for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech, Gilead, Merck, MSD, Moderna, Novartis, Pfizer, Roche, Sanofi and Takeda. S.U. is on the advisory board for Eisai, AstraZeneca and IgM Biosciences; and reports funding to their institution from AbbVie, Adlai Nortye, ArQule, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ciclomed, Erasca, Evelo Biosciences, Exelexis, G1 Therapeutics, GSK, IGM Biosciences, Incyte, Isofol, Klus Pharma, Macrogenics, Merck, Mersana Therapeutics, OncoMed Pharmaceuticals, Pfizer, Regeneron, Revolution Medicines, Synermore Biologics, Takeda, Tarveda Therapeutics, Tesaro, Tempest, and Vigeo Therapeutics. K.A. has received personal financial compensation for advisory board participation from Amgen, Novartis, AstraZeneca, G1 Therapeutics and Sanofi-Genzyme; and reports financial support to their institution for conduct related to clinical trials from Genentech, Mirati and Revolution Medicines. P.L. has served on the advisory boards of Abbvie, GenMab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Zentalis Pharmaceuticals, Molecular Templates, STCube Pharmaceuticals, Bayer, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials and Actuate Therapeutics; has served on the data safety monitoring board for Agios, Five Prime, Halozyme and Tyme; and has served as a consultant for Roche-Genentech, SOTIO, SK Life Science and Roivant Sciences. J.L. reports honoraria from Targeted Oncology, Physicians’ Education Resource, VJ Oncology, CancerGRACE and Community Cancer Education; advisory board participation from AstraZeneca and Astellas; research support to their institution from Erasca, Genentech, Kronos Bio, Novartis and Revolution Medicines; personal fees from Erasca, Blueprint Medicines and Daiichi Sankyo; and reports that a patent filed by Memorial Sloan Kettering Cancer Center related to multimodal features to predict response to immunotherapy (PCT/US2023/115872) is pending. M.R.P. is on the leadership board of ION Pharma; has received honoraria from Janssen Oncology; has a consulting or advisory role at Olema Pharmaceuticals, Daiichi Sankyo/UCB Japan and Accutar Biotech; and reports funding to their institution from Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Celgene, CicloMed, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Lilly, Evelo Therapeutics, Genentech/Roche, Gilead Sciences, GSK, H3 Biomedicine, Hengrui Therapeutics, Hutchison MediPharma, Jacobio, Janssen, Klus Pharma, Kymab, Loxo, LSK Biopartners, Lycera, Macrogenics, Merck, Millenium, Mirati Therapeutics, Moderna Therapeutics, Pfizer, Prelude Therapeutics, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences, Vigeo, ORIC Pharmaceuticals, Artios, Treadwell Therapeutics, Mabspace, IgM Biosciences, Puretech, BioTheryX, Black Diamond Therapeutics, NGM Biopharmaceuticals, Novartis, Nurix, Relay Therapeutics, Samumed, Silicon Therapeutics, TeneoBio, Zymeworks, Olema, Adagene, Astellas, NGM, Accutar Biotech, Compugen, Immunogen, Blueprint Pharmaceuticals, Bicycle Therapeutics, Cullinan Oncology, Erasca, Immune-Onc Therapeutics, Immunitas, Jazz Pharmaceuticals, Pionyr, Revolution Medicines, Step Pharma, Syndax, Synthorx, Xencor, Bristol Myers Squibb/Celgene, Incytes, Kineta, Hotspot Therapeutics, Conjupro Biotherapeutics and Allorion Therapeutics. Y.C., Z.S., S.M., M.T.L., S.R.J., J.C., T.J., N.V.D. and J.L.S. are employees of Genentech and are Roche stockholders. S.W.H. has received honoraria from IMBdx and Ono Pharmaceutical; and reports funding to their institution from IMBdx, Hanmi, Loxo, Roche, Genentech, Mirati Therapeutics, Turnstone Bio, Arcus Biosciences, MSD, BeyondBio, Jeil Pharmaceutical, Janssen, Seagen, Lilly, MedImmune and Leap Therapeutics. The other authors declare no completing interests.

Figures

Fig. 1
Fig. 1. Patient disposition.
Patient disposition for all 29 patients that were enrolled and received divarasib plus cetuximab.
Fig. 2
Fig. 2. Antitumor activity for all patients.
a, Waterfall plot showing the best percentage decrease from baseline in the tumor burden (defined as the sum of the longest diameters of all target lesions) in all 29 patients. b, Swimmer plot showing the time on study treatment, best response, and reason for treatment discontinuation for all 29 patients. c, Spider plot of the percentage changes from baseline in sum of tumor diameters over time in all 29 patients.
Fig. 3
Fig. 3. Duration of response and PFS for KRAS G12C inhibitor-naive patients.
a, Kaplan–Meier plot for duration of response for the 16 KRAS G12C inhibitor-naive patients who experienced a CR or PR. b, Kaplan–Meier plot for median PFS for all 24 KRAS G12C inhibitor-naive patients.
Fig. 4
Fig. 4. Biomarker analysis of ctDNA.
a, Shown is the KRAS G12C VAF at baseline (C1D1) and early treatment time points (C1D15, C3D1) among patients with a detectable KRAS G12C mutation from cfDNA at C1D1 (n = 20 shown, each line represents one patient). Two patients with missing C1D15 plasma samples are not shown in the plot. Box-and-whisker plots at each time point in each indication show the median (center line) with the minima and maxima box boundaries representing the 25th and 75th percentiles; whiskers represent the minimum and maximum values of the data that are within 1.5 times the interquartile range under the 25th and over the 75th percentiles. b, Shown are putative genetic mechanisms of acquired resistance to divarasib plus cetuximab combination treatment among 14 patients who had an EoT visit before 01 May 2023. Each row represents one patient with the first four columns describing assigned divarasib dose, best response, PFS, prior KRAS G12C inhibitor use and subsequent columns indicating acquired genomic alterations at EoT.
Extended Data Fig. 1
Extended Data Fig. 1. Mean (SD) Plasma Concentration-Time Profiles of Divarasib as a Single Agent and in Combination with Cetuximab Following Multiple Doses.
Multiple-dose pharmacokinetic profile of divarasib was obtained on either C1D8 or C2D1 from blood samples collected over an 8 hour period following administration of divarasib 400 mg QD (n = 76 patients)1 or divarasib 400 mg QD plus 250 mg/m2 of cetuximab QW (n = 21 patients). Time (hr) is shown as nominal time and the error bars represent standard deviation around the mean divarasib plasma concentration (ng/mL) measured at each time point during the 8 hour post-dose interval.
See this image and copyright information in PMC

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