Abstract
Background
Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) have been reported to exhibit resistance to various cytotoxic agents, including fluorouracil. A preclinical study showed that trifluridine, a key active component of FTD/TPI, retained antitumor activity in 5-FU-refractory dMMR CRC cell lines. However, the efficacy of trifluridine/tipiracil (FTD/TPI), with or without bevacizumab, in patients with MSI-H/dMMR mCRC remains poorly understood.
Objectives
This study aimed to evaluate the clinical efficacy and safety of FTD/TPI, with or without bevacizumab, specifically in patients with MSI-H/dMMR mCRC.
Design
A retrospective, multicenter observational study was conducted across 10 hospitals in Japan.
Methods
We identified patients with MSI-H/dMMR mCRC treated with FTD/TPI as second- or later-line therapy between June 2012 and January 2023. All eligible patients were divided into two groups: FTD/TPI monotherapy (FT group) and FTD/TPI combined with bevacizumab (FTB group); the safety and efficacy of the two groups were compared. Whole-exome sequencing (WES) was performed on available samples to explore genomic features associated with treatment response of FTD/TPI.
Results
The objective response rate (ORR) was 16.7% (95% confidence interval [CI], 3.6–41.4); median progression-free survival (PFS) was 5.5 months, and median overall survival (OS) was 11.8 months in the overall cohort. Although the median PFS was similar between the two groups (5.6 months in the FTB group and 5.2 months in the FT group, p=0.34), the ORR (22.2% vs. 11.1%, p=0.53), disease control rate (DCR; 88.9% vs. 55.6%, p=0.77) and median OS (18.9 months in the FTB group and 7.1 months in the FT group, p=0.18) were numerically better in the FTB group. WES revealed diverse genomic alterations, including those affecting DNA double-strand break repair-related genes, but no clear genomic biomarkers predictive of treatment response were identified.
Conclusions
FTD/TPI, with or without bevacizumab, demonstrated favorable antitumor activity in patients with MSI-H/dMMR mCRC. These findings suggest that FTD/TPI-based treatment may represent a potentially useful treatment option for this rare population, although further studies are warranted.
Keywords: metastatic colorectal cancer, microsatellite instability, DNA mismatch repair, FTD/TPI, with or without bevacizumab
Introduction
The proportion of metastatic colorectal cancer (mCRC) patients with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) has been reported to be approximately 3%–5%.1,2 Currently, immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have shown a durable response and have become standard treatments for mCRC with MSI-H/dMMR.3–5 However, some patients treated with ICIs exhibit primary resistance3,4 or discontinue treatment due to Grade ≥3 adverse events,3–5 highlighting the need for an alternative therapeutic option. Regarding chemotherapeutic agents and molecular-targeted drugs other than ICIs, responses in MSI-H/dMMR CRC have been considered limited or inconsistent compared to those observed in microsatellite stable (MSS) CRC. Numerous studies have evaluated adjuvant chemotherapy for CRC with MSI-H/dMMR, showing that the efficacy of 5-fluorouracil (5-FU)-based adjuvant chemotherapy is limited.6,7 Prospective observational studies on patients with MSI-H/dMMR mCRC have reported that adding irinotecan (CPT-11) or oxaliplatin (L-OHP) to 5-FU-based chemotherapy provides no significant benefit over 5-FU monotherapy. 8 A preclinical study revealed that dMMR CRC cell lines exhibit resistance to 5-FU; however, trifluridine, the key active component of FTD/TPI, retains its antitumor activity in these refractory cell lines. 9
Furthermore, these patients have been reported to exhibit differential responsiveness to molecular-targeted agents, particularly anti-EGFR and anti-vascular endothelial growth factor (VEGF) antibodies. 10 Although the response to anti-EGFR therapy has been reported to be inferior in this population, no significant difference in the response to bevacizumab has been observed between mCRC patients with MSI-H/dMMR and those with MSS. 10
Recently, based on results from prospective phase III trials,11,12 FTD/TPI, with or without bevacizumab, has been established as a standard later-line therapy for mCRC; however, data on mCRC patients with MSI-H/dMMR remain insufficient. Therefore, this study aimed to retrospectively evaluate the efficacy of FTD/TPI, with or without bevacizumab, in patients with MSI-H/dMMR mCRC. Furthermore, based on reports13,14 of an association between double-strand DNA break (DSB) repair-related gene mutations and favorable therapeutic efficacy of FTD/TPI, we conducted whole-exome sequencing (WES) to analyze these baseline alterations in MSI-H/dMMR tumors and correlate them with clinical outcomes.
Materials and methods
Study population
This multicenter, non-interventional, retrospective study was conducted at 10 institutions in Japan: (1) NHO Osaka National Hospital, (2) Saitama Cancer Center, (3) NHO Nagoya Medical Center, (4) St. Marianna University School of Medicine, (5) Kindai University Faculty of Medicine, (6) Shizuoka Cancer Center, (7) Hokkaido University Hospital, (8) National Cancer Center Hospital, (9) National Cancer Center Hospital East, and (10) Aichi Cancer Center Hospital.
Patients with MSI-H/dMMR mCRC who received FTD/TPI, with or without bevacizumab, for the first time between June 1, 2012, and January 31, 2023, were included in this study. The MSI status was determined by a polymerase chain reaction (PCR)-based assay, and the MMR status was evaluated by immunohistochemistry (IHC) of MMR proteins to assess MMR expression. The inclusion criteria were as follows: (1) unresectable adenocarcinoma of the colon or rectum with MSI-H/dMMR; (2) Eastern Cooperative Oncology Group performance status of 0–2; (3) prior history of at least one fluoropyrimidine-containing chemotherapy regimen; and (4) adequate organ function. Patients were eligible regardless of the number of prior chemotherapy lines. Patients were followed up from the initiation of FTD/TPI treatment until death, loss to follow-up, or the data cut-off date (January 31, 2023), using electronic medical records.
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and was reviewed and approved by the central Institutional Review Board of NHO Osaka National Hospital (approval number: ONH23004). In accordance with the ethical guidelines for multicenter retrospective studies in Japan, the study protocol was subsequently accepted and formally approved for implementation by the institutional heads or relevant administrative authorities at each participating center. Therefore, separate IRB reviews were not required at the other participating institutions. Patient confidentiality was maintained, and the requirement for informed consent was waived due to the retrospective nature of the study, with an opt-out method provided on the institutional websites. This study was registered with the UMIN Clinical Trials Registry (UMIN000051378).
Treatment
In the FTD/TPI monotherapy (FT) group, FTD/TPI 35 mg/m2 was administered orally twice daily on days 1–5 and 8–12, every 28 days; the FTD/TPI + bevacizumab (FTB) group received bevacizumab (5 mg/kg, intravenously) alongside FTD/TPI on days 1 and 15, every 28 days. Bevacizumab was administered via a 30-min intravenous infusion before FTD/TPI. Treatment courses were repeated every 28 days until disease progression, patient refusal, or unacceptable toxicity. The treatment dose, including the initial dose and treatment schedule, was modified at the physician’s discretion based on the toxicity profiles. The use of bevacizumab was not mandatory in this study because it included patients treated before FTD/TPI + bevacizumab became a standard therapy; the decision to administer bevacizumab with FTD/TPI was left to the physicians’ discretion.
All data were extracted from patients’ medical charts into a specific electronic case report form.
Statistical analysis
All clinical data were retrospectively obtained from medical records. Each patient’s tumor response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1, 15 with computed tomography scans performed every 2 to 3 months until disease progression or loss to follow-up. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. PFS was defined as the time from the initiation of FTD/TPI, with or without bevacizumab, to the date of death from any cause or detection of disease progression, whichever occurred first. OS was defined as the time from the initiation of FTD/TPI, with or without bevacizumab, to the date of death from any cause. All statistical comparisons were exploratory because of the limited sample size. Survival outcomes, including OS and PFS, were compared between groups using the log-rank test, and categorical variables were analyzed using Fisher’s exact test. Calculated p-values were interpreted descriptively. Due to the exploratory nature of this study and the rarity of the target population, all eligible patients who met the inclusion criteria were included and categorized into two groups for comparison: the FTD/TPI monotherapy group (FT group) and the FTD/TPI plus bevacizumab group (FTB group). During chemotherapy, adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
Translational research
WES was performed on DNA extracted from archived formalin-fixed, paraffin-embedded (FFPE) sample of the tumor. Genomic DNA was extracted from the tumor sample using the SureSelect Target Enrichment System and SureSelect XT Reagent Kit (Agilent Technologies Japan). The enriched libraries were sequenced as 150-bp paired‐end reads on a NovaSeq (Illumina, San Diego, CA, USA) at TAKARA Bio (Shiga, Japan). After removing adapters and low-quality reads, the sequences were aligned to the NCBI human genome reference assembly hg19 using the Burrows-Wheeler Aligner algorithm. After duplicate removal and local realignment, the Genome Analysis Toolkit (GATK) was used to call single-nucleotide variations and short insertions/deletions. Variants were annotated using ANNOVAR. Variants with an allele frequency above 1% in each sample were selected and further annotated using the Catalog of Somatic Mutations in Cancer, ClinVar, and the dbSNP database.16–18 The functional classification of each mutation followed the interpretation, reporting standards, and guidelines recommended by the Association for Molecular Pathology, the American Society of Clinical Oncology, and the College of American Pathologists. 19
Results
Patient characteristics
The patient characteristics at the initiation of FTD/TPI, with or without bevacizumab, are shown in Table 1. A total of 18 patients (9 in the FT group and 9 in the FTB group) met the inclusion criteria and were included in the analysis. All patients had measurable lesions; tumors were more commonly located on the right side in both groups, and more than half of the patients had received three or more prior lines of treatment. Anti–PD-1 therapy had been administered to seven patients in the FT group and three patients in the FTB group. BRAF V600E mutations were identified in three patients in the FTB group and four in the FT group (total, n = 7). Of note, one patient in the FT group had not undergone baseline PCR testing, but WES analysis successfully identified the BRAF V600E mutation in this case. Since this mutation carries the same clinical significance as those detected via PCR, this patient was included in the entire cohort. RAS mutations were identified in 2 patients in the FTB group and 2 in the FT group (total, n = 4).
Table 1.
Patient characteristics.
| | All (n = 18) | FTB (n = 9) | FT (n = 9) |
|---|---|---|---|
| Age, Median (range) | 70 (35-80) | 70 (44-80) | 70 (35-79) |
| Sex, Male/Female | 10/8 | 5/4 | 5/4 |
| ECOG PS, 0/1/2 | 7/11/0 | 5/4/0 | 2/7/0 |
| Primary tumor location, Left/Right | 6/12 | 3/6 | 3/6 |
| Pathology, Grade 1/2/3 | 3/8/7 | 0/4/5 | 3/4/2 |
| Metastatic sites, Peritoneal/Liver/Lung/Lymph | 11/8/11/9 | 4/3/7/5 | 7/5/4/4 |
| No. of metastatic sites, 1-2/3- | 8/10 | 4/5 | 4/5 |
| No. of previous treatment, 1/2/3- | 2/4/12 | 1/2/6 | 1/2/6 |
| Previous treatment | |||
| Fluoropyrimidine/Irinotecan/Oxaliplatin | 18/15/17 | 9/9/8 | 9/6/9 |
| Anti-VEGF monoclonal antibody | 18 | 9 | 9 |
| Anti-EGFR monoclonal antibody | 12 | 6 | 6 |
| BRAF inhibitor therapy | 4 | 2 | 2 |
| Prior use of anti-PD-1 therapy, Yes/No | 10/8 | 3/6 | 7/2 |
| Assessment of MSI status, PCR/IHC | 16/2 | 7/2 | 9/0 |
| BRAF V600E status, Mutant/Wild | 7/11 | 3/6 | 4/5 |
| RAS status, Mutant/Wild | 4/14 | 2/7 | 2/7 |
PS, performance status; PD-1, Programmed cell death 1; MSI, microsatellite instability; PCR, polymerase chain reaction; IHC, immunohistochemistry.
Survival time and efficacy of FTD/TPI, with or without bevacizumab
The median duration of follow-up was 11.3 months. In the overall population, the ORR and DCR were 16.7% (95% confidence interval [CI], 3.6–41.4) and 72.2% (95% CI, 46.5–90.3), respectively. The FTB group had higher ORR (22.2% vs. 11.1%, p = 0.53) and DCR (88.9% vs. 55.6%, p = 0.77) than the FT group (Table 2). The median PFS for all patients was 5.5 months (95% CI: 2.6–6.4), with no significant difference observed between the FT and FTB groups (5.2 vs. 5.6 months; p = 0.34; Figure 1). The median OS was 11.8 months in the overall population; notably, the FTB group had a longer median OS than the FT group, though this did not reach statistical significance (18.9 vs. 7.1 months; p = 0.18; Figure 2).
Table 2.
Efficacy.
| Response | All | FTB (n = 9) | FT (n = 9) |
|---|---|---|---|
| CR | 0 | 0 | 0 |
| PR | 3 | 2 | 1 |
| SD | 10 | 6 | 4 |
| PD | 5 | 1 | 4 |
| ORR (%) | 16.7 | 22.2 | 11.1 |
| (95% CI) | (3.6-41.4) | (2.8-60.0) | (0.3-48.2) |
| DCR (%) | 72.2 | 88.9 | 55.6 |
| (95% CI) | (46.5-90.3) | (51.8-99.7) | (21.2-86.3) |
CR, complete response; PR, partial response; SD stable disease; PD, progressive disease; ORR, overall response rate; DCR, disease control rate; CI, confidencial interval.
Figure 1.
Progression-free survival (PFS) in the overall population (a) and in the FTB and FT groups (b).
Figure 2.
Overall survival (OS) in the overall population (a) and in the FTB and FT groups (b).
Furthermore, we presented clinical outcomes according to prior ICI therapy in Supplemental Table 1 and Supplemental Figure 1. Of the 18 patients, 10 had prior exposure to ICI therapy, whereas 8 had no prior ICI exposure. Given the potential imbalance in prior ICI exposure between the FTB and FT groups, exploratory subgroup analyses were conducted to evaluate the clinical outcomes according to ICI status (Supplemental Table 1 and Supplemental Figure 1). There were no significant differences in the objective response rate (ORR) between patients with and without prior ICI therapy (0% vs. 25%, p = 0.13, Supplemental Table 1). Furthermore, prior ICI exposure did not significantly impact median PFS (4.7 months vs. 5.3 months; p = 0.90), though OS was significantly superior in patients with no prior ICI exposure compared to those with prior ICI exposure (23.0 months vs. 6.6 months; p = 0.01; Supplemental Figure 1).
Subsequent treatment after FTD/TPI, with or without bevacizumab
Following FTD/TPI, with or without bevacizumab, 11 patients (4 in the FT group and 7 in the FTB group) received subsequent treatment (Table 3). Notably, four of the seven patients in the FTB group received ICI therapy for the first time, while none in the FT group did. No patients received combination therapy with anti-CTLA-4.
Table 3.
Subsequent treatment.
| Subsequent treatment | All (n = 18) | FTB (n = 9) | FT (n = 9) |
|---|---|---|---|
| Regorafenib | 5 | 2 | 3 |
| 5-FU-based chemotherapy | 2 | 1 | 1 |
| Anti-PD-1 inhibitor therapy | 4 | 4 | 0 |
| Best supportive care | 7 | 2 | 5 |
PD-1, Programmed cell death 1.
Safety
The common Grade 3 or higher adverse events were primarily hematologic toxicities (Table 4). Neutropenia was observed in 77.8% of patients in both groups, while anemia occurred in 33.3% of the FT group and 22.2% of the FTB group. Thrombocytopenia (11.1%), fatigue (11.1%), and anorexia (11.1%) were observed only in the FTB group, whereas febrile neutropenia (22.2%) was observed in the FT group.
Table 4.
Safety.
| Adverse events (grade 3 ≤) | All (n = 18) | FTB (n = 9) | FT (n = 9) |
|---|---|---|---|
| Neutropenia | 14 (77.8%) | 7 (77.8%) | 7 (77.8%) |
| Leukopenia | 7 (38.9%) | 2 (22.2%) | 5 (55.6%) |
| Anemia | 5 (27.8%) | 2 (22.2%) | 3 (33.3%) |
| Thrombocytopenia | 1 (5.6%) | 1 (11.1%) | 0 (0.0%) |
| Febrile neutropenia | 2 (11.1%) | 0 (0.0%) | 2 (22.2%) |
| Fatigue | 1 (5.6%) | 1 (11.1%) | 0 (0.0%) |
| Anorexia | 1 (5.6%) | 1 (11.1%) | 0 (0.0%) |
| Diarrhea | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Hypertension | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Mutational profile of patients
WES was performed on 11 of the 18 patients using pre-treatment archived surgical specimens. Overall, 93 variants were identified in the WES data. FGFR4 mutations were detected in 8 (72.7%) of these 11 patients. Regarding BRAF status, a total of 7 patients were confirmed via WES to harbor mutations (Figure 3). Of these 7 BRAF-mutated patients, 5 exhibited tumor shrinkage (Cases No. 5, 7, 8, 14, and 15; Figure 3).
Figure 3.
Mutation landscape of the top 26 genes in 11 samples.
Moreover, gene alterations in the DNA damage repair pathway, cases No. 5, 15, and 17, which carried mutations in ERCC5, BRCA2, and MSH6, demonstrated mild tumor regression. In contrast, case No. 13, despite harboring the same genetic alterations in MSH6, BRCA2, and ERCC5, showed no measurable tumor shrinkage.
Furthermore, alterations in FANCE and CHEK2 were observed in case No. 12, who achieved partial response, whereas mutations in CCND2, ATM, RB1, and RAD50 were identified in cases No. 3, 5, 7, and 17 with stable disease.
Discussion
This study evaluated the efficacy and safety of FTD/TPI, with or without bevacizumab, in mCRC patients with MSI-H/dMMR. Our findings suggest that FTD/TPI, particularly when combined with bevacizumab, shows favorable antitumor activity in mCRC patients with MSI-H/dMMR. Notably, the observed efficacy in this cohort —specifically the ORR and DCR—were comparable, if not superior, to those reported in previous clinical trials involving MSS/pMMR populations.11,12 Furthermore, the PFS results in the FT group in this study were longer than those reported in previous studies.12,20 These findings suggest that MSI-H/dMMR status may not be linked to resistance to FTD/TPI, unlike its association with 5-FU or anti-EGFR drugs. A preclinical study has also demonstrated that FTD/TPI exerts cytotoxic effects in CRC cell lines regardless of MMR status, unlike 5-FU. 9 While 5-FdU (a metabolite of 5-FU) inhibits cell proliferation via an MMR-dependent pathway in MMR-proficient cells, this recognition mechanism is lost in MMR-deficient cells, thereby failing to induce cell death. 9 In contrast, FTD is incorporated into DNA at concentrations far exceeding those of 5-FU. Consequently, FTD/TPI exerts its antitumor effects by directly inducing DNA dysfunction, independent of the presence or absence of MMR function. 9 Furthermore, while MMR-deficient cells often exhibit high thymidylate synthase (TS) expression leading to 5-FU resistance, FTD/TPI overcomes this challenge by exerting its antitumor effect primarily through direct DNA incorporation rather than TS inhibition. 21 Therefore, FTD/TPI is expected to provide favorable therapeutic efficacy in this population through this distinct mechanism. 9 Additionally, the combination with bevacizumab further enhances this effect, as anti-VEGF antibodies have been shown to increase trifluridine accumulation and phosphorylation within tumors. 22 In the current study, the FTB group showed a higher response rate and longer OS than the FT group. The prolonged OS observed with the addition of bevacizumab is consistent with the findings from a previous phase III study 11 ; however, PFS in the FTB group was comparable to that reported in that study. The survival prolongation observed in the FTB group may be attributed to subsequent therapies, particularly ICIs, as a greater proportion of patients in this group were ICI-naïve at baseline and later received ICIs after treatment discontinuation. Conversely, in our study, 10 patients had received prior ICI therapy; among them, three demonstrated tumor shrinkage, suggesting potential clinical benefit even in those with disease progression during prior ICI therapy. Regarding the subgroup analysis by prior ICI exposure, although no significant differences were observed in ORR or PFS regardless of prior ICI exposure status, the significant OS benefit observed in patients with no prior ICI exposure suggests a substantial impact of subsequent therapies (23.0 vs. 6.6 months, p=0.01; Supplemental Figure 1). Importantly, OS in this study was defined as survival from the initiation of FTD/TPI ± bevacizumab. The marked OS prolongation in the ICI-naïve group reflects a historical bias related to the timing of regulatory approvals for ICIs in Japan where these patients successfully received newly approved ICIs as subsequent later-line therapies.
In terms of safety, neutropenia was the most frequently observed Grade ≥3 adverse event, consistent with previous trials of FTD/TPI, with or without bevacizumab, in later-line settings.11,12 The incidence of non-hematologic adverse events, including anorexia and fatigue (each 11.1%), was higher in the FTB group; nevertheless, the treatment was well tolerated by all patients. In this study, although Grade ≥3 neutropenia occurred frequently (77.8%), the incidence of FN was limited in the FTB group. This safety profile may be partly explained by proactive management in clinical practice, including the use of G-CSF support and individualized treatment modification.
In the current study, patients experienced tumor shrinkage after FTD/TPI treatment, with or without bevacizumab, regardless of the BRAF V600E mutation status, which is widely recognized as a negative prognostic factor in mCRC patients. 23 In this study, a total of 7 out of 18 patients (38.9%) were confirmed to harbor BRAF V600E mutations. While this overall frequency appears numerically higher than previous reports,1,3 it may partly reflect our cohort’s age profile. According to a recent large database analysis, 24 BRAF mutations are highly enriched in late-onset (≥50 years) dMMR/MSI-H colorectal cancer (54.7%). When restricting our analysis to patients aged 50 and older, BRAF mutations were confirmed in 7 out of 15 patients (46.7%), a trend that is consistent with the previous report. 24 On the other hand, regarding FGFR4 alterations, the frequency observed in our study was higher than that in prior report. 25 This higher frequency is likely attributable to sample bias resulting from the limited sample size (n = 11) of this exploratory analysis. In a previous report evaluating the relationship between BRAF V600E mutation status and the tumor microenvironment among MSI-H/dMMR patients, 26 alterations in genes involved in DSB repair, such as ATM and BRCA2, were identified in approximately 10%–12% of MSI-H/dMMR tumors with BRAF V600E mutations. Given that these alterations occur regardless of BRAF V600E mutation status, the genomic instability arising from DSB repair deficiencies—which are the primary targets of FTD/TPI—may contribute to its therapeutic efficacy independent of BRAF status. Further investigation is needed to determine the efficacy of FTD/TPI for MSI-H/dMMR tumors with BRAF V600E mutations.
Several previous studies have reported an association between DSB–related genes and the therapeutic efficacy of FTD/TPI.13,14 Mechanistically, FTD is incorporated into DNA, inducing DSBs and activating the DNA damage response. 13 Given that MSI-H/dMMR tumors harbor multiple genomic alterations in genes associated with DSB repair, this mechanism may also contribute to the observed efficacy of FTD/TPI.14,27,28 However, the WES results in the present study did not clearly demonstrate this relationship, likely due to the limited number of patients evaluated. Therefore, further evaluation in a larger cohort is warranted.
To our knowledge, this is the first study to evaluate the clinical efficacy of FTD/TPI with or without bevacizumab exclusively in patients with MSI-H/dMMR mCRC. However, several limitations should be noted. First, the retrospective nature of the study and the small sample size may limit the generalizability of the findings. Second, while the study period spanned the transition before and after ICIs became the standard of care, more than half of our patients (n=10, 55.6%) had received prior ICI therapy. Importantly, our subgroup analysis indicated that the efficacy of FTD/TPI ± bevacizumab was consistent regardless of prior ICI exposure (Supplemental Table 1 and Supplemental Figure 1). These results suggest that FTD/TPI remains a relevant treatment option even in the current clinical era where ICIs are used in earlier lines of therapy. Furthermore, we acknowledge that the limited sample size and retrospective multicenter design of this study may have contributed to some numerical imbalance in the observed frequencies of BRAF and FGFR4 alterations compared to broader populations. Finally, all patients were Japanese; however, prior studies such as RECOURSE and TERRA have shown no major differences in efficacy or safety by ethnicity, suggesting that these results may apply to broader populations.12,20
Conclusion
FTD/TPI, with or without bevacizumab, demonstrated favorable antitumor activity and acceptable toxicity in patients with MSI-H/dMMR mCRC, including those previously treated with ICIs. The observed clinical outcomes were comparable to, and possibly more favorable than those reported in previous clinical trial cohorts that predominantly consisted of MSS populations. Our findings support further prospective studies to validate the role of FTD/TPI with or without bevacizumab in this population and may assist clinicians in selecting appropriate treatment strategies for MSI-H/dMMR mCRC in clinical practice.
Supplemental material
Supplemental Material for Trifluridine/tipiracil with or without bevacizumab in microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: A retrospective observational study by Hiroko Hasegawa, Rin Inamoto, Keiji Sugiyama, Naoki Izawa, Seiichiro Mitani, Takeshi Kawakami, Satoshi Yuki, Hidekazu Hirano, Saori Mishima, Tetsutaro Hamano and Toshiki Masuishi in Therapeutic Advances in Medical Oncology.
Supplemental Material for Trifluridine/tipiracil with or without bevacizumab in microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: A retrospective observational study by Hiroko Hasegawa, Rin Inamoto, Keiji Sugiyama, Naoki Izawa, Seiichiro Mitani, Takeshi Kawakami, Satoshi Yuki, Hidekazu Hirano, Saori Mishima, Tetsutaro Hamano and Toshiki Masuishi in Therapeutic Advances in Medical Oncology.
Acknowledgments
The authors would like to thank the clinical research office at 22 CEMIT for assistance with data management and Enago for English language editing.
Author contributions: Hiroko Hasegawa: Conceptualization; Data curation; Formal analysis; Funding acquisition; Resources; Supervision; Visualization; Writing – review & editing. Rin Inamoto: Conceptualization; Data curation; Writing – review & editing. Keiji Sugiyama: Conceptualization; Data curation; Writing – review & editing. Naoki Izawa: Conceptualization; Data curation; Writing – review & editing. Seiichiro Mitani: Conceptualization; Data curation; Writing – review & editing. Takeshi Kawakami: Conceptualization; Data curation; Writing – review & editing. Satoshi Yuki: Conceptualization; Data curation; Writing – review & editing. Hidekazu Hirano: Conceptualization; Data curation; Writing – review & editing. Saori Mishima: Conceptualization; Data curation; Writing – review & editing. Tetsutaro Hamano: Formal analysis; Visualization. Toshiki Masuishi: Conceptualization; Funding acquisition; Supervision; Writing – review & editing.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Taiho Pharmaceutical Co., Ltd., Japan.
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors N.I., S.M., S.Y., S.M., T.H., and T.M. declare the following financial interests/personal relationships that may be considered potential competing interests. All other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. N.I.: Honoraria for lectures, presentations, and speaker bureaus from Taiho. S.M.: Research funding from Caris Life Science; and honoraria for lectures, presentations, and speaker bureaus from MSD, Daiichi Sankyo Co. Ltd., Ono Pharmaceutical Co. Ltd., Novartis, Takeda Pharmaceutical Co. Ltd., Bristol-Myers Squibb. S.Y.: Honoraria for lectures, presentations, and speaker bureaus from MSD, Daiichi Sankyo, Ono, Amgen, Boehringer-Ingelheim, Eli Lilly, Takeda, Chugai, Merck Bio Pharma, Taiho, Bristol-Myers Squibb. S.M.: Honoraria for lectures, presentations, and speaker bureaus from Takeda Pharmaceutical Co. Ltd., and Taiho.; and Institutional research funding from Boehringer-Ingelheim. T.H.: Honoraria for lectures, presentations, and speaker bureaus from Kyorin Pharmaceutical Co. Ltd. and Meiji seika Pharmaceutical Co. Ltd.; and Consulting fees from Chugai Pharmaceutical Co. Ltd. T.M.: Institutional research funding from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer-Ingelheim, Pfizer, Cimic Shift Zero, Eli Lilly, Abbvie and Merck biopharma. ; and honoraria for lectures, presentations, and speaker bureaus from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, Bristol-Myers Squibb, Nippon Kayaku, MSD, Takeda, Guardant Health, and Amgen.
Supplemental material: Supplemental material for this article is available online.
ORCID iD
Hiroko Hasegawa https://orcid.org/0000-0001-8330-5245
Ethical considerations
The study protocol was approved by the central Institutional Review Board (approval number: ONH23004) and was conducted in accordance with the ethical principles of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of the study; however, patients were given the opportunity to opt out of the use of their clinical data for research purposes. This study was registered with the UMIN Clinical Trials Registry (UMIN000051378).
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.*
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Material for Trifluridine/tipiracil with or without bevacizumab in microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: A retrospective observational study by Hiroko Hasegawa, Rin Inamoto, Keiji Sugiyama, Naoki Izawa, Seiichiro Mitani, Takeshi Kawakami, Satoshi Yuki, Hidekazu Hirano, Saori Mishima, Tetsutaro Hamano and Toshiki Masuishi in Therapeutic Advances in Medical Oncology.
Supplemental Material for Trifluridine/tipiracil with or without bevacizumab in microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: A retrospective observational study by Hiroko Hasegawa, Rin Inamoto, Keiji Sugiyama, Naoki Izawa, Seiichiro Mitani, Takeshi Kawakami, Satoshi Yuki, Hidekazu Hirano, Saori Mishima, Tetsutaro Hamano and Toshiki Masuishi in Therapeutic Advances in Medical Oncology.
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.*