Although KRAS was once considered an untargetable mutation, KRAS inhibitors are now approved for the treatment of KRAS-mutated non–small cell lung cancer (NSCLC) and are emerging as a potential option for the treatment of KRAS G12C–mutated colorectal cancer in combination with other therapies.
Pooled results of the phase I/II KRYSTAL-1 trial showed clinical benefit in terms of response rates and duration of disease control with the combination treatment of the KRAS G12C inhibitor adagrasib plus cetuximab in a cohort of patients with metastatic, heavily pretreated KRAS G12C–mutated colorectal cancer.1 The new findings were presented at the 2024 Annual Meeting of the American Association for Cancer Research (AACR) by lead author Scott Kopetz, MD, PhD, Professor and Associate Vice-President of Translational Integration at The University of Texas MD Anderson Cancer Center. The data were published simultaneously in Cancer Discovery, a journal of the AACR.2
For the primary endpoint, the rate of objective response was 34%, and the median duration of response was 5.8 months. The disease-control rate (complete or partial response and stable disease) was 85.1%. The median progression-free survival was 6.9 months, and the median overall survival was 15.9 months for these difficult-to-treat patients.
Scott Kopetz, MD, PhD
“Treatment options are limited for previously treated patients with KRAS G12C–mutated colorectal cancer. Although there is some encouraging single-agent activity of adagrasib in KRAS G12C–mutated colorectal cancer, it was important to continue finding ways to mitigate resistance,” stated Dr. Kopetz.
“The population of patients with KRAS-mutated colorectal cancer faces a poor prognosis. The combination [adagrasib/cetuximab] shows clinically meaningful benefit both in response rates and duration of disease control, along with an encouraging safety profile. Adagrasib plus cetuximab may be a new potential standard of care for patients with previously treated KRAS G12C–mutated colorectal cancer. Our study builds upon the progress made with KRAS G12C inhibitors and underscores the importance of ongoing research to define and expand treatment options for patients with colorectal cancer,” Dr. Kopetz stated.
Based on the preliminary results of KRYSTAL-1, the U.S. Food and Drug Administration has granted Breakthrough Therapy designation to this combination.
Study Background
KRAS G12C mutations are reported in about 4% of all colorectal cancers and are associated with shorter progression-free survival and overall survival when treated with standard chemotherapy.
Adagrasib is a selective and irreversible KRAS G12C inhibitor, which can penetrate the central nervous system. Dr. Kopetz explained that preclinical evidence suggested that cancer cells develop resistance to KRAS G12C inhibition by upregulating EGFR activity. Thus, he and his research team hypothesized that dual blockade of KRAS G12C and EGFR could overcome that resistance.
“In preclinical studies, we found that combining a KRAS G12C inhibitor with an EGFR inhibitor [such as cetuximab] could mitigate this adaptive resistance. The KRYSTAL-1 trial was conducted to evaluate this strategy in patients,” Dr. Kopetz explained.
KRYSTAL-1 Trial
KRYSTAL-1 is a multiple expansion cohort phase I/II trial designed to test the efficacy and safety of adagrasib alone or in combination with other anticancer therapies in patients with solid tumors that harbor a KRAS G12C mutation. The cohort that was the focus of Dr. Kopetz’ presentation at the AACR meeting included 94 heavily pretreated patients with unresectable or metastatic KRAS G12C–mutated colorectal cancer who were treated with adagrasib plus cetuximab in phase I or II. Participants had a median age of 57 years, and 53% were female. The median prior number of lines of systemic therapy was three (range = 1–9). About 50% of patients had an ECOG performance status of 0. Median follow-up was 11.9 months.
Although the study reported by Dr. Kopetz was not designed to compare the use of adagrasib monotherapy vs the combination of adgrasib plus cetuximab, he noted the combination appeared to result in better outcomes compared with adagrasib monotherapy—that is, the 34% objective response rate observed in this cohort in KRYSTAL-1 compared with objective response rates of around 20% in similar cohorts of patients with monotherapy.
All patients experienced side effects consistent with the safety profile of each drug. Low-grade adverse events were reported in 72.3% of patients, and grade 3 or higher treatment-related adverse events were reported in 27.7% of patients. No grade 5 treatment-related adverse events were reported. About 30% of patients required dose reductions of adagrasib because of adverse events, and 6.4% required dose reductions of cetuximab. Eight patients (8.5%) discontinued cetuximab because of side effects, but no discontinuations of adagrasib were reported as a result of adverse events.
In an exploratory analysis, baseline KRAS G12C mutations were found in the circulating tumor DNA of 69 of 83 patients tested, with 83% concordance between paired tumor samples. This suggests liquid biopsies could be used to identify patients most likely to benefit from the combination therapy.
Dr. Kopetz noted that limitations of the study include its single-arm, open-label design.
The combination of adagrasib plus cetuximab is now recommended by the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology®.3 The phase III KRYSTAL-10 trial is comparing adagrasib plus cetuximab vs standard-of-care chemotherapy as second-line treatment of KRAS G12C–mutated colorectal cancer.4
Expert Point of View
“The results of KRYSTAL-1 highlight further exciting advances in the management of KRAS G12C–mutant colorectal cancers. Although further evaluation in a phase III trial is certainly warranted, the combination of adagrasib plus cetuximab appears to be well tolerated and shows promising clinical activity in this phase I/II trial,” said Mark O’Hara, MD, Assistant Professor of Hematology/Oncology at the Hospital of the University of Pennsylvania Perelman School of Medicine, Philadelphia.
Mark O’Hara, MD
“The population of KRAS G12C–mutant colorectal cancer—while a relatively small percentage of patients with colorectal cancer—has an overall poor prognosis, and the results of this trial highlight an important advance in improving outcomes for these patients…. The meaningful response and disease control rates and progression-free and overall survival in the KRYSTAL-1 trial provide support for this combination in the refractory setting and provide further evidence that molecular testing for all patients with metastatic colorectal cancer is essential for achieving the best possible treatment options,” Dr. O’Hara stated.
DISCLOSURE: The study was funded by Mirati Therapeutics. Dr. Kopetz has ownership interests in Lutris Pharma, Iylon Precision Oncology, LLC, Frontier Medicines, Xilis, and Navire Pharma; serves as a consultant for Genentech/Roche, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris Pharma, Jacobio Pharmaceuticals, Pfizer, Repare Therapeutics, NeoGenomics Laboratories/Inivata, GSK, Jazz Pharmaceuticals, Iylon Precision Oncology, LLC, Xilis, AbbVie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier Pharmaceuticals, Carina Biotech, Bicara Therapeutics, Endeavor Biomedicines, Numab Therapeutics AG, Johnson & Johnson/Janssen Pharmaceuticals, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol Myers Squibb/Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Health, Takeda Pharmaceuticals, Cureteq, Zentalis, Pharmaceuticals, Blackstone Therapeutics, Accademia Nazionale di Medicina, and Tachyon Therapeutics; and has received research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, AstraZeneca/MedImmune, Novartis, Eli Lilly and Company, and Daiichi Sankyo. Dr. O’Hara has served as a consultant or advisory board member for Alligator, Natera, Strike, and Merus; and has received institutional research funding from BMS, Merck, Celldex, Genmab, Natera, HiberCell, PsiOxus, and AstraZeneca.
REFERENCES
1. Kopetz S, Uboha NV, Klempner SJ, et al: KRYSTAL-1: Pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer harboring a KRAS G12C mutation. 2024 AACR Annual Meeting. Abstract CT013. Presented April 8, 2024.
2. Yaeger R, Uboha NV, Pelster MS, et al: Efficacy and safety of adagrasib plus cetuximab in patients with KRAS G12C–mutated metastatic colorectal cancer. Cancer Discov 14:1-12, 2024.
3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. Accessed April 11, 2024.
4. Klempner SJ, Weiss J, Pelster M, et al: KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer harboring a KRAS G12C mutation. Ann Oncol 33(suppl 7):S1391, 2022.
