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Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial

Nature Medicine volume 30, pages 265–270 (2024)Cite this article

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Abstract

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg−1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib–panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883.

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Fig. 1: Study schema.
Fig. 2: Patient disposition.
Fig. 3: Activity of sotorasib therapy in the dose-expansion cohort.

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Data availability

Qualified researchers may request data from Amgen clinical studies. Complete details are available at https://www.amgen.com/science/clinical-trials/clinical-data-transparency-practices/clinical-trial-data-sharing-request. Source data are provided with this paper.

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Acknowledgements

We thank the patients and their families for participating in this trial. We thank T. Harrison of Amgen Inc. and J. Martucci of Amgen Inc. for operational planning assistance, K. Price (all while employed by Amgen Inc.) and A. Joshi of Cactus Life Sciences (part of Cactus Communications) for medical writing support, S. Dastidar of Cactus Life Sciences (part of Cactus Communications) for editorial assistance and R. Dawson of Cactus Life Sciences (part of Cactus Communications) for graphics assistance. This study received support from the following grants to D.S.H.: MD Anderson Cancer Center Support Grant (National Institutes of Health and National Cancer Institute P30 CA016672), Clinical Translational Science Award 1UL1 TR003167, Cancer Prevention Research Institute of Texas (CPRIT) Precision Oncology Decision Support Core (RP150535) and Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy. This study was sponsored and funded by Amgen Inc.

Author information

Author notes

  1. These authors contributed equally: Yasutoshi Kuboki, Marwan Fakih, John Strickler, Rona Yaeger.

Authors and Affiliations

  1. National Cancer Center Hospital East, Kashiwa, Japan

    Yasutoshi Kuboki

  2. City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Marwan Fakih

  3. Duke University Medical Center, Durham, NC, USA

    John Strickler

  4. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Rona Yaeger

  5. Aichi Cancer Center Hospital, Nagoya, Japan

    Toshiki Masuishi

  6. UC Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Edward J. Kim

  7. University of Chicago, Chicago, IL, USA

    Christine M. Bestvina

  8. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Scott Kopetz & David S. Hong

  9. Sarah Cannon Research Institute, Nashville, TN, USA

    Gerald S. Falchook

  10. University of Pennsylvania, Philadelphia, PA, USA

    Corey Langer

  11. University of Michigan, Ann Arbor, MI, USA

    John Krauss

  12. Huntsman Cancer Institute, Salt Lake City, UT, USA

    Sonam Puri

  13. Amgen Inc., Thousand Oaks, CA, USA

    Panli Cardona, Emily Chan, Tracy Varrieur, Lata Mukundan, Abraham Anderson & Qui Tran

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Contributions

E.C. contributed to the design and conception of the study. Y.K., M.F., J.S., R.Y., T.M., E.J.K., C.M.B., S.K., G.S.F., C.L., J.K., S.P. and D.S.H. contributed to patient data collection. All authors contributed to data analysis and interpretation. All authors contributed to the writing and editing of the manuscript and approved the final version for submission to the journal. All authors are accountable for all aspects of the work.

Corresponding author

Correspondence to David S. Hong.

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Competing interests

Y.K.: honoraria—Bristol-Myers Squibb Japan, Lilly Japan, Taiho Pharmaceutical; consulting or advisory role—Amgen, Boehringer Ingelheim, Takeda; research funding—AbbVie (institution), Amgen (institution), Astellas Pharma (institution), AstraZeneca (institution), Boehringer Ingelheim (institution), Chugai Pharma (institution), Genmab (institution), GlaxoSmithKline (institution), Incyte (institution), Janssen Oncology (institution), Lilly (institution), Merck Serono (institution), Ono Pharmaceutical (institution), Taiho Pharmaceutical (institution), Takeda (institution), Hengrui (institution), Novartis Pharma (institution); travel, accommodations, expenses—Amgen. M.F.: grants or contracts—Amgen (institution), Agenus Bio (institution), Verastem (institution), Genentech/imCORE (institution); consulting fees (payments made to self)—AstraZeneca, Bristol-Myers Squibb, Bayer, Incyte, Pfizer, Taiho Oncology; participation in a data safety monitoring board or an advisory board (payments made to self)—Bayer, Eisai Oncology, Entos, Merck, Mirati Therapeutics, Nouscom, Roche/Genentech, Seattle Genetics, Xenthera Inc.; receipt of equipment, materials, drugs, medical writing, gifts or other services—Bristol-Myers Squibb (study-related drugs provided to institution). J.S.: consultant or advisory role—AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Natera, Pfizer, Pionyr Immunotherapeutics, Roche/Genentech, Seagen, Silverback Therapeutics, Taiho Pharmaceutical, Takeda, Viatris, Zentalis; research funding or contracted research—AbbVie (institution), Amgen (institution), AStar D3 (institution), Bayer (institution), BeiGene (institution), Curegenix (institution), Daiichi-Sankyo (institution), Eli Lilly (institution), Erasca (institution), Leap Therapeutics (institution), Roche/Genentech (institution), Seagen (institution), Silverback Therapeutics (institution). R.Y.: honoraria—Zai Lab; consulting or advisory role—Mirati Therapeutics, Amgen Inc.; research funding—Array BioPharma (institution), Boehringer Ingelheim (institution), Mirati Therapeutics (institution), Pfizer (institution), Daiichi-Sankyo (institution). T.M.: honoraria—Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharma, Daiichi-Sankyo, Lilly, Merck Serono, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda, Yakult Honsha, MSD, Nippon Kayaku; research funding—Amgen (institution), Boehringer Ingelheim (institution), CMIC (institution), Daiichi-Sankyo (institution), Lilly Japan (institution), MSD (institution), Novartis (institution), Ono Pharmaceutical (institution), Pfizer (institution), Syneos Health (institution). E.J.K.: grants or contracts—NGM (institution), Erytech (institution), Fibrogen (institution), Eureka (institution), Merck (institution), Bristol-Myers Squibb (institution), Astellas (institution), Boston Biomedical (institution), AstraZeneca (institution), Celgene (institution), Halozyme (institution), Samumed (institution), Epicentrx (institution), MedImmune (institution), BeiGene (institution), Theriva Biologics (institution); consulting fees—Eisai (self), Taiho (self), Lilly (self), Relay (self); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events—Eisai (speaker), Seagen (speaker); monitoring board or advisory board—Lilly (self), Relay (self); stock or stock options—ROMTech. C.M.B.: consulting or advisory role—AbbVie (institution), AstraZeneca, Bristol-Myers Squibb/Celgene, Clinical Care Options, Creative Educational Concepts, Curio Science, CVS, Daiichi-Sankyo, EMD Serono, Genentech, Janssen, Jazz Pharmaceuticals, Medical Learning Institute, MJH Holdings, Novartis, Novocure, OncLive Clinical Congress Consultants, Sanofi/Regeneron, Seagen, Takeda, Targeted Oncology, Tempus; speakers’ bureau—Merck; research funding—Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb. S.K.: stock and other ownership interests—Frontier Medicines, Iylon, Lutris, Navire, Xilis; consulting or advisory role—AbbVie, Accademia Nazionale di Medicina (ACCMED), Amal Therapeutics, Amgen, AstraZeneca/MedImmune, Bayer Health, Bicara Therapeutics, Black Diamond Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb/Medarex, Cardiff Oncology, Carina Biotech, CureTeq, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Foundation Medicine, Frontier Medicines, Genentech, Genomic Health, Gilead Sciences, GlaxoSmithKline, HalioDx, Harbinger Oncology Inc., Holy Stone Healthcare, Inivata, Ipsen, Iylon, Jacobio, Jazz Pharmaceuticals, Johnson & Johnson/Janssen, Lilly, Lutris, Merck, Mirati Therapeutics, NeoGenomics Laboratories, Novartis, Numab, Ono Pharmaceutical, Pfizer, Redx Pharma, Repare Therapeutics, Replimune, Servier, Taiho Pharmaceutical, Takeda, Tempus, Xilis, Zentalis; research funding—Amgen, Array BioPharma, Biocartis, Daiichi-Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, Sanofi. G.S.F.: royalties (self)—Wolters Kluwer (2014–present); advisory role (to institution)—AbbVie (2022), Fujifilm (2018), Silicon (2020, 2021), Navire (2021), Turning Point (2021), Predicine (2021), Inspirna (2021), Regeneron (2021), Jubilant (2022), BostonGene (2022), Teon (2022), Merck (2022), Sanofi (2023), BridgeBio (2023); advisory role (self)—EMD Serono (2010, 2011); speaker’s honorarium for continuing medical education—Total Health Conferencing (2019), Rocky Mountain Oncology Society (2020); travel (self, for work and/or research related to institution)—Amgen (2022), Bristol-Myers Squibb (2015), EMD Serono (2011, 2012, 2013), Fujifilm (2018), Millennium (2013), Sarah Cannon Research Institute (employer, at least once yearly), Synthorx/Sanofi (2022); research funding (to institution, for any trial for which G.S.F. has been the primary investigator (ever) or subinvestigator (minimum last 4 years))—3-V Biosciences, Abbisko, AbbVie, ABL Bio, ADC Therapeutics, Accutar, Agenus, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, Bayer, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Ingelheim, Celgene, Celldex, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, Immunitas, ImmunoGen/MacroGenics, Incyte, Jacobio, Jazz, Jounce, Jubilant, Kineta, Kolltan, Loxo/Bayer, MedImmune, Merck, Metabomed, Millennium, Mirati, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire/BridgeBio, NGM Bio, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, Pyxis, RasCal, Regeneron, Relay, Rgenix, Ribon, Roche, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tallac, Tarus, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, University of Texas MD Anderson Cancer Center, Vegenics, Xencor, Zhuhai Yufan. C.L.: honoraria—AstraZeneca, Genentech/Roche, Lilly/ImClone, Merck, Takeda Science Foundation; consulting or advisory role—Abbott Biotherapeutics, ARIAD, AstraZeneca, Bayer/Onyx, Bristol-Myers Squibb, Cancer Support Community, Celgene, Clarient, Clovis Oncology, Genentech/Roche, Gilead Sciences, Lilly/ImClone, Merck, Novocure, Pfizer, Regeneron, Takeda; research funding—Advantagene (institution), Amgen, ARIAD (institution), AstraZeneca, Celgene (institution), Clovis Oncology (institution), Genentech/Roche (institution), GlaxoSmithKline (institution), Incyte, Inovio Pharmaceuticals (institution), Johnson & Johnson/Janssen, Lilly, Merck (institution), Stem CentRx (institution), Trizell (institution). J.K.: Bristol-Myers Squibb, Hutchison Medipharma/Syneos Health, Sumitomo Dainippon/Paraexel, Tempest Therapeutics, Merck/NSABP (National Surgical Adjuvant Breast and Bowel Project) Foundation, Ignyta/Qintiles, Tempest Therapeutics/ICON, AstraZeneca/NSABP Foundation, AbbVie, Bristol-Myers Squibb/Mayo Clinic, MedImmune, Pfizer, Daiichi-Sankyo/Syneos Health, Xencor, Amgen Inc., Merck, Gilead Sciences, Janssen. S.P.: honoraria—Aptitude Health (institution), IntegrityCE; consulting or advisory role—AstraZeneca (institution), G1 Therapeutics, Jazz Pharmaceuticals (institution), Pfizer; travel, accommodations, expenses—Dava Oncology. P.C.: employee and stockholder—Amgen Inc.; patents, royalties, other intellectual property—Amgen. E.C.: employee and stockholder—Amgen Inc. T.V.: employee and stockholder—Amgen Inc. L.M.: employee and stockholder—Amgen Inc. A.A.: employee and stockholder—Amgen Inc. Q.T.: employee and stockholder—Amgen Inc. D.S.H.: stock and other ownership interests—MolecularMatch, OncoResponse, Telperian; consulting or advisory role—Acuta, Adaptimmune, Alkermes, Alphasights, Amgen, AUM Biosciences, Axiom Biotechnologies, Baxter, Bayer, Boxer Capital, Bridgebio, COG, Cor2Ed, Cowen, EcoR1 Capital, Genentech, Gennao Bio, Gerson Lehrman Group, Gilead Sciences, GroupH, Guidepoint Global, HCW Precision, Immunogen, Infinity Pharmaceuticals, Janssen, Liberum, MedaCorp, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, Precision Oncology Experimental Therapeutics, Prime Oncology, RAIN, STCube, Takeda, Tavistock Life Sciences, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, ZIOPHARM Oncology; research funding—AbbVie (institution), Adaptimmune (institution), Adlai Nortye (institution), Amgen (institution), AstraZeneca (institution), Bayer (institution), Bristol-Myers Squibb (institution), Daiichi-Sankyo (institution), Deciphera (institution), Eisai (institution), Endeavor BioMedicines (institution), Erasca Inc. (institution), F. Hoffmann LaRoche (institution), Fate Therapeutics (institution), Genentech (institution), Genmab (institution), Ignyta (institution), Infinity Pharmaceuticals (institution), Kite, a Gilead Company (institution), Kyowa (institution), Lilly (institution), Loxo (institution), MedImmune (institution), Merck (institution), Mirati Therapeutics (institution), Mologen (institution), National Cancer Institute (institution), Navire (institution), Novartis (institution), Numab (institution), Pfizer (institution), Pyramid Biosciences (institution), Seagen (institution), Takeda (institution), TCR2 Therapeutics (institution), Teckro (institution), Turning Point Therapeutics (institution), VM Pharma (institution); travel, accommodations, expenses—American Association for Cancer Research, American Society of Clinical Oncology, Bayer Schering Pharma, Genmab, Society for Immunotherapy of Cancer, Telperian.

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Nature Medicine thanks Thierry André, Jorge Barriuso, Andres Cervantes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Cmax and AUC0–24 on Day 1 and Day 8 following oral administration of 960 mg sotorasib QD in Japanese vs US patients.

The lower and upper hinges represent the first and third quartiles (the 25th and 75th percentiles). The upper whisker extends from the hinge to the largest value no further than 1.5 * IQR (inter-quartile range) from the hinge. The lower whisker extends from the hinge to the smallest value at most 1.5 * IQR of the hinge. Data beyond the end of the whiskers represents outliers. Day 1: Japan, n=9; United States, n=37. Day 8: Japan, n=8, United States, n=34–35. AUC0–24h, area under the concentration-time curve from time 0 to 24 h after dose; Cmax, maximum observed drug concentration.

Extended Data Fig. 2 Mean (+SD) plasma concentration on Day 1 and Day 8 following oral administration of 960 mg sotorasib QD.

The black line represents mean (+SD) average sotorasib plasma concentration for the overall population. Red and blue lines represent mean (+SD) average sotorasib plasma concentration for Japanese and US patients, respectively. The inset shows results for Japanese vs United States sites. Day 1: Japan, n=9; United States, n=36–37. Day 8: Japan, n=8; United States, n=32–37. SD, standard deviation.

Extended Data Fig. 3 Survival according to tumor location.

Kaplan-Meier curves of (A) progression-free survival and (B) overall survival, according to right-sided vs left-sided tumor. Vertical lines indicate censoring. For the PFS curve, disease progression or death (whichever occurs earlier) is an event. For the OS curve, death is an event. CI, confidence interval; CRC, colorectal cancer; NE, not estimable; OS, overall survival; PFS, progression-free survival.

Extended Data Fig. 4 Survival according to baseline genomic co-alterations.

Kaplan-Meier curves of (A) PFS according to BRAF alterations, and (B) PFS according to ARID1A mutations. Vertical lines indicate censoring. PFS, progression-free survival.

Supplementary information

Supplementary Information

Supplementary Methods, list of sites and their laboratories and imaging facilities that screened and/or enrolled patients into this study, additional information on patients enrolled in this study and Supplementary Tables 1–8.

Reporting Summary

Supplementary Data

Statistical data for Supplementary Tables 2–6.

Source data

Source Data

Statistical source data for Tables 1–3 and Figs. 2 and 3.

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Kuboki, Y., Fakih, M., Strickler, J. et al. Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial. Nat Med 30, 265–270 (2024). https://doi.org/10.1038/s41591-023-02717-6

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