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Clinical Trial
. 2024 Jun 3;14(6):982-993.
doi: 10.1158/2159-8290.CD-24-0217.

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer

Rona Yaeger  1 , Nataliya V Uboha  2 , Meredith S Pelster  3 , Tanios S Bekaii-Saab  4 , Minal Barve  5 , Joel Saltzman  6 , Joshua K Sabari  7 , Julio A Peguero  8 , Andrew Scott Paulson  9 , Pasi A Jänne  10 , Marcia Cruz-Correa  11 , Kenna Anderes  12 , Karen Velastegui  12 , Xiaohong Yan  12 , Hirak Der-Torossian  12 , Samuel J Klempner #  13 , Scott E Kopetz #  14
Affiliations
Clinical Trial

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer

Rona Yaeger et al. Cancer Discov. .

Abstract

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance.

Significance: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.

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Conflict of interest statement

R. Yaeger reports grants and personal fees from Mirati Therapeutics; grants from Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Boundless Bio; personal fees from Zai Lab, Loxo@Lilly, and Revolution Medicine; and other support from Amgen outside the submitted work. N. Uboha reports grants and personal fees from Ispen and Arcus; grants from Gilead and EMD Serono; personal fees from AstraZeneca, Astellas, Bristol Myers Squibb, Eli Lilly, Elevation Oncology, Strata, and personal fees from Eisai outside the submitted work. M.S. Pelster reports grants and other support from Arcus Biosciences, CytomX, and Elevation Oncology; grants from Actuate Therapeutics, Agenus, Astellas, BeiGene, BioNTech, Bristol Myers Squibb, Codiak Biosciences, Compass Therapeutics, Eisai, Exelixis, Gilead, HiberCell, Immune-Onc Therapeutics, Impact Therapeutics, Leap Therapeutics, Novartis, OncXerna Therapeutics, Panbela Therapeutics, Revolution Medicines, Surface Oncology, SQZ Biotechnologies, Tachyon Therapeutics, Translational Genomics, TransThera Sciences, ZielBio, 1200 Pharma; and grants from Bristol Myers Squibb during the conduct of the study; other support from AstraZeneca, Daiichi Sankyo, EMD Serono, Ipsen Biopharmaceuticals, Jazz Pharmaceuticals, Pfizer, SeaGen, and other support from Stemline Therapeutics outside the submitted work. T.S. Bekaii-Saab reports research funding (to institution) from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Eli Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and Bristol Myers Squibb; consulting (to institution) from Servier, Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA, and Merck; consulting (to self) from Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, BeiGene, Kanaph, AstraZeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine; Sanofi; GSK, and Xilio; IDMC/DSMB from The Valley Hospital, Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan, and 1Globe; is a scientific advisory board member for Imugene, Immuneering, Xilis, Replimune, Artiva, and Sun Biopharma; royalties: from UptoDate; in addition, T.S. Bekaii-Saab has patent for Human PD1 peptide vaccines and uses thereof (WO/2018/183488) licensed to Imugene; and a patent for Methods and compositions for the treatment of cancer cachexia (WO/2019/055687) licensed to Recursion. M. Barve reports personal fees from Tempus Labs and personal fees from Texas Oncology outside the submitted work. J.K. Sabari reports personal fees from AstraZeneca, Abbvie, Genentech, and F. Hoffmann-La Roche; grants and personal fees from Janssen, Loxo Lilly, Mirati, and Regeneron; personal fees from Jazz, Pfizer, Sanofi Genzyme, and personal fees from Takeda during the conduct of the study. J.A. Peguero reports grants and non-financial support from Mirati outside the submitted work. A.S. Paulson reports other support from Mirati during the conduct of the study; and other support from Mirati outside the submitted work; in addition, A.S. Paulson has an immediate family member employed by Day One Biopharmaceuticals; has stock ownership in Actinium; has received honoraria from Curio Science and Cardinal Health; has advisory role or received consulting fees from Amgen, Bristol Myers Squibb, Ipsen, Advanced Accelerator Applications, Incite, Exelixis, Pfizer, QED Therapeutics, Lilly Pharmaceuticals, Mirati, HutchMed, Astellas, Aadi, EMD Serono, AstraZeneca, Servier, Novartis, Array, Bayer, Jazz Pharmaceuticals, Takeda, Seagen, Agenus, Ideo Oncology; has received institutional research funding from Buzzard Pharmaceuticals, Ipsen, Bristol Myers Squibb, Exelixis, HutchMed, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, Incyte, Deciphera, G1 Therapeutics, Zentalis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Seattle Genetics, Sotio, Innovative Cellular Therapeutics Co., Regenxbio, Gilead Sciences, Gritstone Bio, BioNTech SE, Novartis, TransThera Biosciences, ITM Oncologics, Inspirna; and has received travel, accommodations, expenses from Pfizer, Camurus, Mirati Therapeutics, Nucana, and AADi. P.A. Jänne reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, and Takeda Oncology; personal fees from Pfizer, F. Hoffmann-La Roche/Genentech, Chugai Pharmaceuticals, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Alllorion Therapeutics, Accutar Biotech, AbbVie, Mone Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics, Blueprint Medicines; and personal fees from Mirati Therapeutics during the conduct of the study; grants from Revolution Medicines, and grants from PUMA outside the submitted work; in addition, P.A. Jänne has a patent for EGFR mutations issued and licensed to Lab Corp. M. Cruz-Correa reports grants from Mirati during the conduct of the study; other support from Pan American Center for Oncology Trials; grants from Pfizer, AbbVie, Bristol Myers Squibb, Merck, Genentech, Huyabio, Janssen, Natera, and grants from SeaGen outside the submitted work; is a governing board member of the American Association for Cancer Institute; and is an executive board member of Precision Oncology Alliance. K. Anderes reports personal fees from Mirati Therapeutics outside the submitted work. H. Der-Torossian reports other support from Mirati Therapeutics/BMS outside the submitted work. S.J. Klempner reports personal fees from Astellas, Novartis, Amgen, Pfizer, Natera, AstraZeneca, Sanofi-Aventis, Daiichi-Sankyo, Mersana, Merck, and personal fees from Bristol Myers Squibb outside the submitted work; and is an NCCN Guideline committee member (no compensation). S.E. Kopetz reports other support from Lutris, Frontier Medicines, Xilis, Navire, Genentech, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Eli Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, other support from Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GSK, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol Myers Squibb-Medarex, Amgen, Tempus, other support from Foundation Medicine, Harbinger Oncology, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics, Accademia Nazionale Di Medicina, Tachyon Therapeutics, Sanofi, Biocartis, Guardant Health, Array BioPharma, F. Hoffmann-La Roche/Genentech, EMD Serono, MedImmune, Novartis, Amgen, Eli Lilly, and other support from Daiichi Sankyo outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1. Efficacy outcomes with adagrasib plus cetuximab in previously treated patients with KRASG12C-mutated unresectable or metastatic CRC. A, Best change in tumor volume from baseline (n = 86; excludes eight patients without any postbaseline scans). B, Treatment duration (n = 32; only subjects with tumor response are displayed). C, Changes from baseline in sum of target lesion diameters over time for patients with tumor response. D, PFS. E, OS. Data as of June 30, 2023 (median follow-up: 11.9 months). Responses and PFS assessed by BICR per RECIST version 1.1. aOnly patients with objective tumor responses are displayed (n = 32). bTime to first maintained dose reduction due to any cause. BICR, blinded-independent central review; BID, twice daily; CI, confidence interval; CRC, colorectal cancer; DOR, duration of response; OS, overall survival; PFS, progression-free survival; QD, once daily.
Figure 1.
Efficacy outcomes with adagrasib plus cetuximab in previously treated patients with KRASG12C-mutated unresectable or metastatic CRC. A, Best change in tumor volume from baseline (n = 86; excludes eight patients without any postbaseline scans). B, Treatment duration (n = 32; only subjects with tumor response are displayed). C, Changes from baseline in sum of target lesion diameters over time for patients with tumor response. D, PFS. E, OS. Data as of June 30, 2023 (median follow-up: 11.9 months). Responses and PFS assessed by BICR per RECIST version 1.1. aOnly patients with objective tumor responses are displayed (n = 32). bTime to first maintained dose reduction due to any cause. BICR, blinded-independent central review; BID, twice daily; CI, confidence interval; CRC, colorectal cancer; DOR, duration of response; OS, overall survival; PFS, progression-free survival; QD, once daily.
Figure 2. Subgroup analyses of ORR (in FAS per BICR) for patients with KRASG12C-mutated unresectable or metastatic CRC receiving adagrasib plus cetuximab. Data as of June 30, 2023 (median follow-up: 11.9 months). BICR, blinded-independent central review; CI, confidence interval; CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FAS, full analysis set; ORR, objective response rate.
Figure 2.
Subgroup analyses of ORR (in FAS per BICR) for patients with KRASG12C-mutated unresectable or metastatic CRC receiving adagrasib plus cetuximab. Data as of June 30, 2023 (median follow-up: 11.9 months). BICR, blinded-independent central review; CI, confidence interval; CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FAS, full analysis set; ORR, objective response rate.
Figure 3. KRASG12C ctDNA clearance in previously treated patients with KRASG12C-mutated unresectable or metastatic CRC receiving adagrasib plus cetuximab (n = 15). Response according to BICR. BICR, blinded independent central review; C, cycle; CRC, colorectal cancer; ctDNA, circulating tumor DNA; D, day; ND, not detected.
Figure 3.
KRAS G12C ctDNA clearance in previously treated patients with KRASG12C-mutated unresectable or metastatic CRC receiving adagrasib plus cetuximab (n = 15). Response according to BICR. BICR, blinded independent central review; C, cycle; CRC, colorectal cancer; ctDNA, circulating tumor DNA; D, day; ND, not detected.
Figure 4. Acquired genomic alterations in previously treated patients with KRASG12C-mutated unresectable or metastatic CRC receiving adagrasib plus cetuximab; alterations present at EOT, that were not present at baseline. CNA, copy number alteration; EOT, end of therapy; SNV, single nucleotide variant.
Figure 4.
Acquired genomic alterations in previously treated patients with KRASG12C-mutated unresectable or metastatic CRC receiving adagrasib plus cetuximab; alterations present at EOT, that were not present at baseline. CNA, copy number alteration; EOT, end of therapy; SNV, single nucleotide variant.
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