Trifluridine/Tipiracil Plus Bevacizumab for Vulnerable Patients With Pretreated Metastatic Colorectal Cancer: A Retrospective Study (WJOG14520G)

Abstract Background Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable). Methods We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab. Results The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed. Conclusion Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.


Introduction
Colorectal cancer is the third most diagnosed cancer type and the second leading cause of cancer-related death worldwide. 1he standard of care for first-and second-line treatment of unresectable metastatic colorectal cancer (mCRC) has been a doublet (or triplet) chemotherapy regimen consisting of a fluoropyrimidine and either oxaliplatin or irinotecan (or all these cytotoxic agents) plus a molecularly targeted agent.However, a substantial proportion of patients is unsuitable for full-dose standard chemotherapy as a result of various factors including an older age, the presence of comorbidities, a poor performance status, a low tumor burden, and patient preference.Several clinical trials have been conducted for first-line treatment of patients who are not candidates for intensive therapy.1][12] However, little is known about second or later lines of treatment for vulnerable patients, some of whom may have become intolerant of intensive therapy after first-line treatment.
Trifluridine/tipiracil (FTD/TPI) is an orally administered combination of a thymidine-based nucleic acid analog (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride).A phase III study (RECOURSE) revealed a significant survival benefit of FTD/TPI compared with placebo for patients with refractory mCRC. 13][16][17] The SUNLIGHT phase III trial recently showed the superiority of FTD/TPI plus bevacizumab over FTD/TPI alone in patients previously treated with a fluoropyrimidine, oxaliplatin, and irinotecan, offering a new standard therapy for this population. 18Given its relatively low frequency of nonhematologic toxicities, the efficacy and safety of the combination of FTD/TPI plus bevacizumab have also been evaluated in patients unsuitable for intensive therapy.The SOLSTICE phase III trial was thus designed to examine the superiority of FTD/TPI plus bevacizumab over capecitabine plus bevacizumab as first-line treatment for these patients. 19Although FTD/TPI plus bevacizumab failed to achieve superiority, this regimen showed similar efficacy to capecitabine plus bevacizumab with no new safety concerns, suggesting that FTD/TPI plus bevacizumab might be a feasible option for subsequent treatment of this population.Given the lack of data addressing this clinical question, we have now retrospectively investigated the efficacy and safety of FTD/TPI plus bevacizumab for vulnerable patients with previously treated mCRC in the clinical practice setting.

Study Design and Patient Selection
West Japan Oncology Group (WJOG) 14520G (TWILIGHT) is a multicenter, retrospective, observational study of FTD/ TPI plus bevacizumab as second-or later-line treatment for vulnerable patients with mCRC who are intolerant of intensive chemotherapy.The main inclusion criteria were as follows: (1) histologically confirmed colorectal adenocarcinoma, (2) age of ≥20 years, (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, (4) previous treatment with chemotherapy for unresectable disease (but excluding patients with a history of having received all key cytotoxic agents: a fluoropyrimidine, oxaliplatin, and irinotecan), (5) treatment with FTD/TPI plus bevacizumab between May 2014 and October 2020, and (6) intolerance of intensive therapy (defined as full-dose combination chemotherapy with a fluoropyrimidine and either oxaliplatin or irinotecan) as a result of medical condition.Patients deemed unsuitable for intensive therapy simply because of a low tumor volume or personal preference were excluded.
The study protocol was approved by the WJOG Protocol Review Committee and the institutional review board of each participating institution, and it complied with the provisions of the Declaration of Helsinki as well as Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. 20Consent to participation was obtained via an opt-out form on the website of WJOG and each participating institution.This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000044136).

Treatment and Assessments
All patients were treated with the combination of FTD/TPI and bevacizumab.The approved dosage and administration of FTD/TPI in Japan were 35 mg/m 2 orally twice daily on days 1 to 5 and 8 to 12 every 4 weeks.Bevacizumab was administered intravenously at a dose of 5 mg/kg every 2 weeks.Dose reductions and schedule modifications were instituted at the discretion of the physician.
Efficacy was assessed on the basis of overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), objective response rate (ORR), and disease control rate (DCR).
OS was calculated from the initiation of treatment to death from any cause, PFS from the initiation of treatment to disease progression or death from any cause, and TTF from the initiation of treatment to the last administration of FTD/TPI or disease progression.OS, PFS, and TTF were evaluated by the Kaplan-Meier method.Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1).ORR was defined as the proportion of patients whose best response was a complete response or a partial response, and DCR as the proportion of patients whose best response was a complete response, a partial response, or stable disease.

Patient Characteristics
A total of 96 patients from 26 institutions was registered between July 2021 and January 2022.Given that 3 patients who did not meet the inclusion criteria were excluded, 93 patients were evaluated for the analysis.The baseline characteristics of these 93 patients are summarized in Table 1.The median age was 79 years (range, 21-90 years), 10 (11%) patients had an ECOG performance status of 2, and 32 (34%) patients had tumors known to be wild-type for RAS.Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and poor performance status in 19 (20%) patients (Table 2).
With regard to prior treatment for metastatic disease, 93 (100%) patients received a fluoropyrimidine, whereas 46 (49%) and 14 (15%) patients received oxaliplatin and irinotecan, respectively.Although BRAF mutation and microsatellite instability, high/mismatch repair, deficient status were detected in 1 and 3 patients, respectively, no patient had previously received a BRAF inhibitor or an immune checkpoint inhibitor.FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as thirdor fourth-line treatment in 19 (20%) patients.The proportions of patients with RAS mutation-positive tumors (70% vs. 37%), who received oxaliplatin for pre-or postoperative treatment (18% vs. 0%), or who received oxaliplatin or irinotecan in first-line treatment (61% vs. 32%) were numerically higher for the second-line setting than for the third-or fourthline setting.Thirty-three patients had no history of either oxaliplatin or irinotecan treatment for metastatic disease, 31 (94%) of whom were aged 75 years or older.

Subsequent Chemotherapy
Of

Discussion
Our retrospective study has shown that treatment with the combination of FTD/TPI and bevacizumab was associated with a median OS and PFS of 18.6 and 6.3 months, respectively, and with moderate toxicity for vulnerable patients with previously treated mCRC.These data are similar to those for the recent TRUSTY phase III trial, which investigated the noninferiority of FTD/TPI plus bevacizumab in comparison with full-dose combination therapy with a fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. 21In the present study, although 80% of patients were treated in the second-line setting, there was no significant difference in efficacy between the second-line and the third-or fourth-line settings.
4][5][6] However, few data regarding second-or later-line treatment have been available to date.We recently reported real-world data for treatment sequencing in vulnerable patients with mCRC in a multicenter retrospective survey. 22In this survey, among 195 vulnerable patients who progressed on first-line therapy consisting of "less-intensive regimens" (defined as a fluoropyrimidine with or without biologics, reduced-dose doublet regimens with or without biologics, or anti-EGFR monotherapy), 74 (38%) individuals received less-intensive regimens as second-line treatment, achieving a median OS and PFS of 13.7 and 5.5 months, respectively.Interestingly, there was no survival difference between patients received a fluoropyrimidine with or without biologics versus those received reduced-dose doublet regimens with or without biologics in the second-line setting as well as the first-line setting, suggesting that the addition of oxaliplatin or irinotecan is not always necessary for elderly or vulnerable patients with mCRC in second-line treatment and beyond.Furthermore, for patients who are never able to use oxaliplatin or irinotecan, the second-line treatment after the first-line fluoropyrimidine with or without biologics must be the best supportive care, of which the prognosis was shown ), malignant disease (n = 4), cardiac disease (n = 3), metabolic disease (n = 1), mental disease (n = 1), paralysis due to poliomyelitis (n = 1), and postchemotherapy for lymphoma (n = 1).

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The Oncologist, 2024, Vol. 29, No. 3 to be dismal (3.5 months). 22In this regard, our data thus offer an important treatment option for those population, given that the efficacy of FTD/TPI plus bevacizumab in the present study appears to be better than that of second-line lessintensive regimens in our previous study, although the patient backgrounds differed between the 2 studies.The present study excluded patients who were ineligible for intensive therapy because of a low tumor burden or patient preference, with such individuals tending to have a good prognosis, although the SOLSTICE trial included these patients. 19n the Japanese treatment guidelines, 11 "vulnerable patients" are defined as those who are considered intolerant of firstline combination therapy with oxaliplatin or irinotecan.The inclusion criteria for the present study were established on the basis of this definition.Some vulnerable patients might receive FTD/TPI plus bevacizumab after first-line treatment with a less intensive regimen, whereas others might become vulnerable after progression on first-line intensive therapy with oxaliplatin or irinotecan.To evaluate the efficacy and safety of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC, we adopted criteria that excluded patients with a history of having received all key cytotoxic  agents (a fluoropyrimidine, oxaliplatin, and irinotecan) but which included those intolerant of intensive therapy as a result of medical condition.Despite the worse background of patients in our study compared with those in the first-line SOLSTICE trial and the second-line TRUSTY trial, the present study showed a good efficacy and acceptable safety profile for FTD/TPI plus bevacizumab.These findings suggest that FTD/TPI plus bevacizumab can be a preferred regimen in second or later lines of treatment for vulnerable patients with mCRC.
Our study has several limitations.First, it was retrospective in design and included a relatively small number of patients.Given that the vulnerable patients were highly heterogeneous, it might also have been affected by selection bias.Furthermore, the patients were treated with various drug doses and treatment schedules for the FTD/ TPI and bevacizumab combination therapy.Second, the impact of subsequent chemotherapies including doublet regimens on the OS could not be evaluated because of the luck of sufficient data.Third, it was difficult to evaluate the efficacy of FTD/TPI plus bevacizumab for the vulnerable patients with previously treated mCRC in our study because of the lack of appropriate reference data, such as outcome of chemotherapy or best supportive care in such patients.We conducted our multicenter retrospective survey and previously reported the reference data to address this deficiency. 22Prospective comparative studies will be needed to fully resolve this issue.Finally, all patients enrolled in the present study were Japanese.However, no ethnic differences in the efficacy or safety of FTD/TPI plus bevacizumab between Japanese and Western patients have been described previously. 13,23

Conclusion
Our retrospective study has revealed a promising clinical activity with acceptable toxicity of FTD/TPI plus bevacizumab mostly as second-line treatment for vulnerable patients with previously treated mCRC who are intolerant of intensive therapy, and it, therefore, indicates that this regimen is a possible treatment option for such patients.

Table 1 .
Characteristics of the study patients.

Table 2 .
Reasons for intolerance of intensive therapy in the study patients.

Table 3 .
Adverse events in the study patients (n = 93).