Impact of KRASG12 mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: Post hoc analysis of the phase III SUNLIGHT trial
Open accessAbstract
Background In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRAS G12 mutational status on OS in SUNLIGHT. Patients and methods In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRAS G12 mutation in the overall population and in patients with RAS -mutated tumors. Results Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRAS G12 mutation and 88 with a non- KRAS G12 RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRAS G12 mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRAS G12 mutation versus those with a non- KRAS G12 RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRAS G12 mutational status. Among patients with a KRAS G12 mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRAS G12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). Conclusions The presence of a KRAS G12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRAS G12 status.
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In post hoc analysis of SUNLIGHT, FTD/TPI plus bevacizumab resulted in better overall survival compared to FTD/TPI alone in both RAS mutant and RAS wild-type groups; mOS was 10.1 vs 7.1 months for mRAS and 11.4 vs 7.4 months for wtRAS.
“The post hoc analysis of the Phase III SUNLIGHT trial demonstrated that FTD/TPI plus bevacizumab treatment resulted in better overall survival compared to FTD/TPI alone in both the RAS mutant and RAS wild-type groups; the median OS (mOS) was 10.1 months vs. 7.1 months for mRAS and 11.4 months vs. 7.4 months for wtRAS, respectively [47].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [47]
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- Authors
- Tabernero, J., Taieb, J., Fakih, M., Prager, G. W., Van Cutsem, E., Ciardiello, F., Mayer, R. J., Amellal, N., Skanji, D., Calleja, E., & Yoshino, T.
- Affiliations
- Vall d'Hebron Institute of Oncology (ES)
- City Of Hope National Medical Center (US)
- Medical University of Vienna (AT)
- University of Campania "Luigi Vanvitelli" (IT)
- Dana-Farber Cancer Institute (US)
- Institut de Recherches Internationales Servier (France) (FR)
- Taiho Oncology (United States) (US)
- National Cancer Center Hospital East (JP)
- Corresponding author
- Tabernero, J.
- ORCID
- Venue
- ESMO Open
- Publisher
- Elsevier BV
- Published
- 2024-03
- Volume
- 9
- Issue
- 3
- Pages
- 102945
- ISSN
- 2059-7029 (ISSN-L)
- PMC
- PMC10944099
- OpenAlex
- W4392639095
- Cited by
- 18
- References
- 30
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 2
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ESMO Open (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- Servier Institute
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- metastatic colorectal cancer, trifluridine/tipiracil, bevacizumab, overall survival, RAS mutations, prognostic factors, combination chemotherapy, predictive biomarkers, anti-VEGF therapy, first-line therapy, neutropenia
- MeSH terms
- Bevacizumab, Adult, Colonic Neoplasms, Humans, Mutation, Pyrrolidines, Thymine, Trifluridine, Uracil, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Frontotemporal Dementia
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