Survival Benefit of Crossover Administration of Regorafenib and Trifluridine/Tipiracil Hydrochloride for Patients With Metastatic Colorectal Cancer: Exploratory Analysis of a Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study (REGOTAS)

Background: The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study. Patients and Methods: We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD). Results: A total of 550 patients (cohort A, n = 252; cohort B, n = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9–10.9 months) vs. 5.2 months (95% CI, 4.4–6.0 months), P < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47–0.72; P < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B. Conclusions: Our study revealed prolonged survival in patients treated with REG and TFTD. Therefore, all active agents, including REG and TFTD, should be made available to mCRC patients.

Background: The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study.
Patients and Methods: We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD).
Results: A total of 550 patients (cohort A, n = 252; cohort B, n = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9-10.9 months) vs. 5.2 months (95% CI, 4.4-6.0 months), P < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47-0.72; P < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B.
The strategic availability of the active ingredients FU, OX, and IRI for all mCRC patients suitable for systemic chemotherapy maximizes OS (11). However, there are few reports of the benefits of using both REG and TFTD as a salvage therapy to improve OS in mCRC patients (12).
We previously reported the REGOTAS study, which was a multicenter, large cohort, observational study, showed no significant difference in OS between treatment using REG and TFTD in patients with mCRC. The present study compared patients treated using both REG and TFTD with those treated with either REG or TFTD alone in the REGOTAS study to assess the effects of exposure to REG and TFTD on OS in patients with mCRC who received FU, OX, IRI, and bevacizumab, as well as anti-EGFR antibody (in patients with wild type KRAS/NRAS tumors).

Patients
The present study retrospectively examined the clinical records of patients with mCRC treated with later-line chemotherapy comprising REG or TFTD during the period from June 1, 2014 to November 30, 2015 in the participating institutions. All patients were registered in the REGOTAS study, which is described in detail elsewhere (13). The main eligibility criteria were: (1) histologically confirmed colorectal adenocarcinoma; (2) no prior treatment using REG and TFTD; (3) previous treatment with FU, OX, IRI, bevacizumab, and anti-EGFR antibody (in patients with wild type KRAS/NRAS tumors); (4) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2; and (5) adequate organ function. The present study was approved by the ethics committees at each institution and was in accordance with the guidelines for biomedical research specified in the Declaration of Helsinki. The REGOTAS study was registered with the University Medical Information Network (number UMIN000020416). The requirement for informed consent was waived due to the retrospective design of this study.

Statistical Analysis
The exploratory primary endpoint was OS of all patients stratified by exposure to REG and/or TFTD as follows: cohort A (both REG and TFTD) and cohort B (either REG or TFTD). The following pretreatment clinical data and baseline laboratory values were used in the analysis as covariates: age, sex, body mass index, ECOG PS, primary tumor site, surgery on primary tumor, RAS status, metastatic tumor site (liver metastasis, lung metastasis, lymph node metastasis, peritoneal dissemination, and bone metastasis), number of metastatic sites, pathologic type, time from initiation of first-line chemotherapy to initiation of later-line treatment, serum albumin, serum aspartate transaminase (AST), serum C-reactive protein (CRP), and serum carcinoembryonic antigen (CEA). Each cutoff value of quantitative data was set with reference to that of albumin, AST, CRP, AST, and CEA in the REGOTAS study (13).
OS was defined as the time from the start of initial REG or TFTD to death or last follow-up. Quantitative data are expressed as median and interquartile range (IQR). The Mann-Whitney U-test was used to compare the continuous variables, and Fisher's exact test was performed to compare the categorical variables. Survival curves were estimated using the Kaplan-Meier method, and differences between the groups were tested by the log-rank test. Hazard ratios (HRs) were estimated using the Cox proportional hazard model. OS was analyzed using univariate and multivariate Cox regression analyses. The backward selection method was conducted for the selection of factors retained (P < 0.2) in the multivariate analysis. The predictive factor for OS between each group was explored using subgroup analyses with the multivariate Cox model including interaction terms.
A 1:1 matching using the propensity score (propensity score-matched dataset) was performed as a sensitivity analysis. Patients in the two groups were matched by a difference of propensity score within 0.05. The propensity score was calculated with a multivariate logistic regression model including 19 prognostic variables (Supplementary Table 1). All P-values < 0.05 were considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).

Efficacy
The median follow-up at the time of analysis was 17.3 months [95% confidence interval (CI), 16.1-18.0 months]. The median OS for all patients was 6.8 months (95% CI, 3.4-11.5 months), and 418 (76%) patients had died. The median follow-up was significantly longer in cohort A compared with cohort B (17.6 vs. 15.2 months, respectively; P < 0.001). The median OS was significantly greater in cohort A compared with cohort B [9.6 (95% CI, 8.9-10.9) months vs. 5.2 months (95% CI, 4.4-6.0 months), respectively; P < 0.001] (Figure 2A). There was no significant difference in OS between patients receiving REG followed by TFTD and TFTD followed by REG in cohort A [10.5 months (95% CI, 9.2-12.2 months) vs. 9.4 months (95% CI, 8.3-10.8 months), P = 0.52] (Figure 2B). Table 2 shows the results of univariate and multivariate analyses for OS. In these analyses, the factors significantly  In the subgroup analysis adjusted using the multivariate Cox model, cohort A demonstrated consistently better trends in almost all subgroups examined compared with cohort B (Figure 3).

Safety and Toxicity
Safety and toxicity are shown in Table 3. There was no significant difference in incidence of grade ≥3 hematologic toxicities between cohorts A and B, except for anemia (5 vs. 11%, respectively; P = 0.019). Additionally, for nonhematologic toxicities, incidence of grade ≥3 anorexia was higher in cohort B than cohort A (2 vs. 8%, respectively; P = 0.001), whereas the incidence of hand-foot skin reaction was higher in cohort A than cohort B (13 vs. 4%, respectively; P < 0.001).

Sensitivity Analysis
A total of 201 patients per group were matched by propensity score. Patients' characteristics were well-balanced between the two groups (Supplementary Table 2), and the median OS was found to be significantly longer in cohort A compared with that of cohort B [9.3 months (95% CI, 8.2-10.5 months) vs. 5.3 months (95% CI, 4.8-6.7 months), P < 0.001] as in the observational dataset (Supplementary Figure 1). The incidence of grade ≥3 toxicity was also similar to that in the observational dataset, except for the incidence of hand-foot skin reaction (Supplementary Table 3).

DISCUSSION
To the best of our knowledge, this is the first study to report the beneficial effects of the crossover administration of REG and TFTD on survival of patients with chemorefractory mCRC. Although increased exposure to standard chemotherapy agents, such as FU, OX, and IRI, and molecular targeting agents, including bevacizumab and anti-EGFR antibodies, contribute to a prolongation of OS (11,14), our findings suggested that making all key active agents, including REG and TFTD, available could further improve OS in mCRC patients. It has not previously been shown that treatment with both REG and TFTD contributes to longer OS compared with use of either REG or TFTD alone in patients with chemorefractory mCRC. The CORRECT trial did not include patients who had previously received TFTD, and the RECOURSE trial included only 18% of patients who had previously received REG (9, 10). Furthermore, details of post-study treatments were not reported in either of these phase III studies. Our findings indicated that treatment with both REG and TFTD improved OS compared with use of either REG or TFTD alone in mCRC patients who were refractory or intolerant to standard chemotherapy, irrespective of the subgroup. While the optimal sequential order of REG and TFTD therapy remains unclear, there was no significant difference in OS between the patients in cohort A who received TFTD followed by REG or REG followed by TFTD. These data support the findings from an Italian retrospective study in which patients received both REG and TFTD that showed that the median OS was 12.8 months (95% CI, 10.2-14.4 months) for REG followed by TFTD and 10.3 months (95% CI, 8.7-14.4 months) for TFTD followed by REG (15).
The differences observed in patients' characteristics indicate the requirement for both REG and TFTD to be made available to patients with chemorefractory mCRC. In the present study, patients with ECOG PS 1 or 2, peritoneal dissemination, albumin <3.5 g/dL, AST ≥40 IU/L, or CRP ≥1 mg/dL had fewer chances to receive both REG and TFTD. The consistent efficacy of crossover administration of REG and TFTD irrespective of the subgroup highlights that exposure to both REG and TFTD contributes to improved OS in patients with poor prognostic factors. It is important to note that the nature of this analysis may have led to an inherent bias. In particular, patients who live longer have a greater opportunity to be treated with more lines of chemotherapies. Furthermore, patients with poor ECOG PS or a shorter life expectancy may have been excluded from receiving the salvage-line chemotherapy of REG and/or TFTD. Therefore, we only analyzed patients who were refractory or intolerant to standard chemotherapies [FU, OX, IRI, bevacizumab, and anti-EGFR antibody (if the patients had wild type KRAS/ NRAS tumor)] in order to minimalize the inherent bias. Multivariate analysis of prognostic factors also demonstrated that crossover administration of REG and TFTD was independently associated with significant OS prolongation. In addition, subgroup analysis adjusted by the multivariate Cox model revealed that cohort A consistently demonstrated better trends in almost all subgroups examined compared with cohort B. These findings highlight the importance of making active agents, including REG and TFTD, available to all patients.
However, while making these active agents available is a valuable treatment strategy, the OS of these patients remains unsatisfactory and warrants further improvement. A promising efficacy of TFTD with bevacizumab was previously reported in a phase I-II trial (C-task force) (16), and was recently replicated in retrospective and prospective studies (17,18). In addition, the combination of REG with nivolumab showed manageable toxicities and encouraging antitumor activity in microsatellite stable mCRC patients (19). We believe that these combination therapies are effective strategies to prolong OS in patients with chemorefractory mCRC. The present study had some limitations that should be considered when interpreting the results. First, this was a non-randomized retrospective study with a limited sample size. Second, all patients enrolled in this study were Japanese. However, the absence of ethnic differences in the analysis of the efficacy of REG and TFTD in the phase III trials could enable the results to be applied to all patients, regardless of ethnicity (9,10,20,21).

CONCLUSIONS
Our multicenter retrospective study revealed the survival benefits of crossover administration of REG and TFTD. Our findings highlight the importance of making all active agents, including REG and TFTD, available to patients with mCRC. Frontiers in Oncology | www.frontiersin.org

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by National Cancer Center Hospital East and each participating facilities. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.