Using two independent real-world datasets from three countries and an independent validation cohort based on the global, double-blind, placebo-controlled, phase III RECOURSE study, a group of researchers demonstrated that codon-specific KRAS mutations predict overall survival (OS) benefit for patients with metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil. Specifically, KRASG12 mutations identified patients who experienced no clinically relevant survival benefit from trifluridine/tipiracil, while the remaining population, including patients with KRASG13-mutated tumours, had substantial benefit. The RECOURSE study showed only a modest OS benefit of trifluridine/tipiracil versus placebo in the general, unselected population with mCRC.
The results offer a framework to (re)assess the risk–benefit profile of trifluridine/tipiracil according to codon-specific KRAS mutations. Given that KRAS testing is routinely performed in the molecular work-up of all patients with CRC to guide anti-EGFR treatment, the findings can be readily adopted in the clinic according to Prof. Emile E. Voest of The Netherlands Cancer Institute in Amsterdam, the Netherlands and Prof. Nicola Valeri of the Imperial College London, Hammersmith Hospital, and The Institute of Cancer Research in London, UK who published the results on 2 March 2023 in the Nature Medicine.
The authors wrote in the background that trifluridine/tipiracil, a combination of nucleoside analogue trifluridine and a thymidine phosphorylase inhibitor tipiracil, is approved for patients with heavily pretreated mCRC. Although durable responses to trifluridine/tipiracil have been observed in some patients with mCRC, the median OS benefit in the general population with mCRC is modest, only 1.8 months, highlighting the unmet need for patient selection.
Detection of KRAS hotspot mutations is a critical step in the diagnostic work-up of mCRC as RAS/RAF mutations predict clinical resistance to anti-EGFR treatment. KRAS mutations are found in 44% of patients with mCRC, most frequently occurring at codon G12 (28% of patients) or codon G13 (8% of patients). Although KRASG12 and KRASG13 mutations are regarded as a single entity in clinical practice guidelines, they have different biochemical properties and display tissue- and treatment-specific mutational patterns.
Given the lack of genomic biomarkers and the limited clinical benefit of trifluridine/tipiracil in unselected patients with mCRC, the investigators harnessed the power of whole-genome somatic profiles coupled with patient outcomes to identify biomarkers of response and resistance to trifluridine/tipiracil. Key findings were then validated in a real-world cohort of patients with mCRC treated with trifluridine/tipiracil and in a phase III RECOURSE study.
Particularly, using whole-genome analysis of 37 patients with mCRC treated with trifluridine/tipiracil, the authors identified KRASG12 mutations as a potential biomarker of resistance. Next, they collected real-world data of 960 patients with mCRC receiving trifluridine/tipiracil and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF-mutated subgroup.
They next analyzed the data of the global, double-blind, placebo-controlled, phase III RECOURSE study performed in 800 patients and found that KRASG12 mutations were predictive biomarkers for reduced OS benefit of trifluridine/tipiracil versus placebo (unadjusted interaction p = 0.0031, adjusted interaction p = 0.015). For patients with KRASG12 mutations in the RECOURSE study, OS was not prolonged with trifluridine/tipiracil versus placebo (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.73–1.20; p = 0.85). However, patients with KRASG13-mutated tumours showed significantly improved OS with trifluridine/tipiracil versus placebo (HR 0.29, 95% CI 0.15–0.55; p < 0.001).
Furthermore, in isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to trifluridine-based genotoxicity.
The authors concluded that their results show that KRAS mutational analysis, a standard-of-care test already implemented worldwide, can identify patients with KRASG12-mutated mCRC who are unlikely to benefit from treatment with trifluridine/tipiracil, avoiding unnecessary side effects and rationalising the use of resources for healthcare systems. They reported the first proof of genomics-based precision medicine for a chemotherapy in mCRC, which has the potential to substantially improve patient selection for treatment with trifluridine/tipiracil.
The authors acknowledged Servier for sharing the RECOURSE study dataset. They acknowledged the Hartwig Medical Foundation, the Centre for Personalised Cancer Treatment, and all participating centres for the generation of the discovery dataset. They acknowledged the Memorial Sloan Cancer Center for generating the data used in this manuscript. They also acknowledged the statistics department of the Netherlands Cancer Institute for support with the analyses. They acknowledged Andrea Bardelli and his team for sharing the isogenic SW48 models.
van de Haar J, Ma X, Ooft SN, et al. Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer. Nature Medicine; Published online 2 March 2023. DOI: https://doi.org/10.1038/s41591-023-02240-8