A groundbreaking combination therapy involving adagrasib (Krazati) alongside cetuximab (Erbitux) has demonstrated substantial efficacy and tolerability in individuals with advanced or metastatic colorectal cancer (mCRC) carrying KRAS G12C mutations. These encouraging results were unveiled through pooled analysis findings from the phase 1/2 KRYSTAL-1 trial (NCT03785249), presented at the esteemed American Association for Cancer Research (AACR) 2024 Annual Meeting.
Lead study author, Dr. Scott Kopetz, Professor of Gastrointestinal Medical Oncology and Associate Vice President of Translational Integration at The University of Texas MD Anderson Cancer Center, Houston, emphasized the clinical significance of the adagrasib and cetuximab combination. He stated, “Adagrasib and cetuximab demonstrated clinically meaningful activity…in these patients, and the safety profile was consistent with what was previously known.” This revelation marks a potential shift in the treatment paradigm for patients with previously treated metastatic KRAS G12C–mutant colorectal cancer.
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A Novel Therapeutic Approach: Adagrasib and Cetuximab Combination
KRAS G12C mutations are associated with poor prognostic outcomes, affecting approximately 3% to 4% of all colorectal cancer cases. Adagrasib, an irreversible KRAS G12C inhibitor with a 23-hour half-life and central nervous system penetration, has emerged as a promising therapeutic agent. Previous trials demonstrated notable efficacy of adagrasib monotherapy, prompting further exploration of combination therapies.
KRYSTAL-1 Trial Design and Key Findings
The KRYSTAL-1 trial enrolled patients with unresectable or metastatic KRAS G12C–mutated CRC and an ECOG performance status of 0 or 1. The combination regimen consisted of adagrasib administered twice daily alongside cetuximab, with dose adjustments based on patient response and tolerability.
Pooled analysis of the phase 1 and 2 cohorts revealed a confirmed objective response rate (ORR) of 34.0% and a disease control rate of 85.1%. The median duration of response (DOR) was recorded at 5.8 months, showcasing the sustained efficacy of the combination therapy.
Implications for Clinical Practice and Regulatory Approval
Current guidelines from the National Comprehensive Cancer Network recommend adagrasib plus cetuximab or panitumumab for patients with previously treated KRAS G12C–mutant CRC. The positive outcomes observed in the KRYSTAL-1 trial underscore the potential incorporation of this combination into standard clinical practice.
Furthermore, the FDA has accepted a supplemental new drug application for priority review regarding the approval of adagrasib plus cetuximab based on the KRYSTAL-1 findings. With an action date set for June 21, 2024, this development holds promise for expanding treatment options for patients with metastatic colorectal cancer harboring KRAS G12C mutations.
Safety Profile and Future Directions
In terms of safety, the combination therapy demonstrated manageable adverse effects, with dose adjustments and interruptions effectively mitigating treatment-related issues. Dr. Kopetz highlighted the need for further research to optimize the utilization of this combination therapy across different patient populations and treatment settings.
The ongoing phase 3 KRYSTAL-10 trial aims to compare adagrasib/cetuximab with conventional chemotherapy regimens in patients with second-line KRAS G12C–mutant metastatic CRC, providing valuable insights into the long-term efficacy and safety of this innovative therapeutic approach.
Conclusion
The groundbreaking findings from the KRYSTAL-1 trial underscore the potential of adagrasib in combination with cetuximab as a transformative therapeutic option for patients with previously treated metastatic KRAS G12C–mutant colorectal cancer. As we await regulatory decisions, ongoing research endeavors continue to explore the optimal integration of this combination therapy into clinical practice, offering hope for improved outcomes and enhanced quality of life for patients battling this challenging disease.
References
- 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 (CRC) harboring a KRASG12C mutation. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT013.
- Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov. Published April 8, 2024. doi:10.1158/2159-8290.CD-24-0217
- Yaegar R, Weiss J, Pelster M, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Eng J Med. 2023;388(1):44-54. doi:10.1056/NEJMoa2212419
- US Food and Drug Administration (FDA) accepts supplemental new drug application for Krazati (adagrasib) in combination with cetuximab as a targeted treatment option for patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) for priority review. News release. Bristol Meyers Squibb. February 20, 2024. Accessed April 8, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-KRAZATI-adagrasib-in-Combination-with-Cetuximab-as-a-Targeted-Treatment-Option
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