The role of biomarker in later-line treatment for metastatic colorectal cancer
Trifluridine/tipiracil (FTD/TPI) is an oral drug that inhibits thymidylate synthase, interfering with DNA synthesis (1). FTD/TPI monotherapy demonstrated efficacy for overall survival in heavily treated metastatic colorectal cancer (mCRC) in the RECOURSE trial with a hazard ratio (HR) of 0.68 [95% confidence interval (CI): 0.58–0.81] against the placebo (1). FTD/TPI is widely used as the standard later-line treatment worldwide (2-4), and its efficacy and safety have been reproduced in real-world data (RWD) (5,6). Regorafenib is also a late-line treatment option, and it remains an important clinical question whether FTD/TPI or regorafenib should be administered first. As administration of all active drugs has been shown to improve survival of mCRC (7,8), information on predictive biomarkers is helpful for patient selection and for improving prognosis.
Neutropenia is considered a predictive factor for the efficacy of FTD/TPI (9,10). However, it is difficult to identify during drug selection. In mCRC, the difference in drug response, depending on the RAS/BRAF/microsatellite instability (MSI) status, as well as primary tumor location, is an area of interest. FTD/TPI has shown similar antitumor effects regardless of the KRAS mutation status (11). There are few reports that evaluate the effect of each BRAF mutation and MSI status in a large number of patients, including those with RWD. In the article of Martínez-Pérez et al. (12), the BRAF V600E mutant was a predictive biomarker and microsatellite stable (MSS) was a prognostic factor, in addition to the previously reported biomarkers. As for the MSI status, FTD/TPI has shown antitumor effects regardless of MSI status in preclinical models (13). It is interesting that the antitumor effects of FTD/TPI differed depending on the MSI status in RWD. However, the number of MSI-H patients in the present study was small, and future analysis in a larger cohort is needed.
Recently, later-line treatment for mCRC has been further advanced. The addition of bevacizumab to FTD/TPI showed good treatment efficacy in several phase 2 trials (14-16) and in a randomized phase 2 trial (17). Moreover, the SUNLIGHT trial demonstrated that the addition of bevacizumab to FTD/TPI significantly prolonged overall survival compared with FTD/TPI monotherapy (18,19). The FRESCO-2 study also showed the superiority of fruquintinib monotherapy compared with the best supportive care with a HR of 0.662 (95% CI: 0.549–0.8000) (20,21). Randomized phase 3 clinical trials of the combination therapy, with immune checkpoint inhibitors targeting MSS mCRC, are ongoing (Table 1). Biomarkers will become increasingly beneficial in the near future as more treatment options are expected to become available.
|Checkpoint inhibitor||Study treatment groups||Primary endpoint||Trial identifier|
|Pembrolizumab||Pembrolizumab + lenvatinib versus SOC (regorafenib or FTD/TPI)||OS||NCT04776148 (LEAP-017)|
|Favezelimab/pembrolizumab||Favezelimab/pembrolizumab versus SOC (regorafenib or FTD/TPI)||OS||NCT05064059 (MK-4280A-007)|
|Nivolumab/relatlimab FDC||Nivolumab/relatlimab FDC versus SOC (regorafenib or FTD/TPI)||OS||NCT05328908 (RELATIVITY-123)|
MSS, microsatellite stable; mCRC, metastatic colorectal cancer; SOC, standard of care; FTD/TPI, trifluridine/tipiracil; OS, overall survival; FDC, fixed dose combination.
Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2023-01/coif). TK reports honoraria received from Bristol Myers-Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, Yakult Honsha, Takeda Pharmaceutical. KY reports honoraria received from Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Lilly, Sanofi, Ono Pharmaceutical, MSD, Bristol Myers Squibb; and institutional research funding from Taiho Pharmaceutical. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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