We read with great interest the article published by Wakabayashi and colleagues,1 a phase II study that evaluated the role and clinical impact of intrapatient dose escalation of biweekly trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) in metastatic colorectal cancer (mCRC).
With the aim of translating these data into clinical practice, we believe that some aspects would deserve discussion. In a previous report, van de Haar and colleagues2 identified codon-specific KRAS mutations as predictive biomarkers for survival associated with FTD–TPI treatment of mCRC. In this analysis, the authors used real-world discovery and validation cohorts along with a reanalysis of data from the practice-changing phase III RECOURSE trial3 and highlighted that FTD–TPI did not result in any meaningful improvement in overall survival in patients with KRAS G12 mutations.
Conversely, patients with KRAS G13 mutations or wild-type KRAS had clear overall survival benefit. Interestingly, the poor overall survival of patients with KRAS G12 mutations after treatment with FTD–TPI was not driven by specific prognostic effects, since survival of these mCRC patients was similar to overall survival of patients with KRAS wild-type disease in the placebo group of the landmark RECOURSE trial.
Thus, the favorable overall survival of patients with KRAS G13 mutations who received FTD–TPI was driven by a strong treatment effect, since these patients had a poor prognosis in the placebo group of the RECOURSE trial. To better understand whether intrapatient dose escalation of FTD/TPI plus BEV may overcome these effects, Wakabayashi and colleagues1 should provide additional data, especially in terms of codon-specific data on KRAS status among patients of this phase II trial. These data could be particularly important to allow an independent post hoc analysis of the link between various KRAS mutations and overall survival associated with intrapatient dose escalation of FTD/TPI plus BEV.
We invite the authors to share their view on these remarks.
Acknowledgments
Funding
None declared.
Disclosure
The authors have declared no conflicts of interest.
References
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