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Regorafenib and trifluridine/tipiracil in real clinical practice

 Department of Pharmacy, University Hospital Complex of Vigo, Álvaro Cunqueiro Hospital, Vigo, Pontevedra, Spain

Date of Submission07-Sep-2020
Date of Decision20-Dec-2020
Date of Acceptance22-Jan-2021
Date of Web Publication15-Oct-2021

Correspondence Address:
Nerea García-Beloso,
Hospital Pharmacy Service, Álvaro Cunqueiro Hospital, University Hospital Complex of Vigo, 36213 Vigo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1316_20

 > Abstract 

Background: Colorectal cancer is the ninth leading cause of death in Spain. The latest therapeutic developments in the advanced stages of this disease are the oral drugs trifluridine/tipiracil and regorafenib.
Objective: Results of clinical trials (CTs) are not in real conditions and therefore, we want to study the effectiveness and the safety profile in the usual clinical practice and compare it with the bibliography.
Materials and Methods: A retrospective and unicentric study was carried out in a health area of 500,000 inhabitants. Patients who started treatment with regorafenib and/or trifluridine/tipiracil were included from the date of marketing until June 2019. Patient-related variables, pathology, effectiveness, and treatment toxicity were collected. The statistical analysis was carried out with the PSPP program.
Results: Fifty-four patients were analyzed. Men accounted for 59.3% of patients. Regorafenib was the treatment for 22.2% of patients and 77.8% received trifluridine/tipiracil. The reason for the drug's suspension was the disease progression in 85.2% of patients. No patient had a full response and 3.2% achieved partial response. The median progression-free survival time in treatments with regorafenib was 2.5 months (95% confidence interval [CI]: 0.0–5.4) and the overall survival time was 3.1 months (95% CI: 0.0–6.7), while in treatments with trifluridine/tipiracil, these data were, respectively, 2.8 (95% CI: 2.5–3.2) and 5.7 months (95% CI: 3.8–7.6). Side effects occurred in 91.7% of patients treated with regorafenib and in 100% of treated with trifluridine/tipiracil. Hematological adverse reactions were, on average, 0.4 ± 0.5/patient with regorafenib and 1.5 ± 0.9 with trifluridine/tipiracil. General (77.8%) and gastrointestinal disorders (50%) were common with both drugs.
Conclusions: The effectiveness results of standard clinical practice are lower than those described in CTs and in the literature. The toxicity profile does reproduce what is described in the bibliography.

Keywords: Colorectal cancer, effectiveness, real-world data, regorafenib, trifluridine/tipiracil

How to cite this URL:
García-Beloso N, Romero-Ventosa EY, Gayoso-Rey M, López-López A, Robles-Torres D, de Castro NM, Piñeiro-Corrales G. Regorafenib and trifluridine/tipiracil in real clinical practice. J Can Res Ther [Epub ahead of print] [cited 2022 Jun 25]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=328259

 > Introduction Top

Colorectal cancer metastatic (mCRC) is a pathology with a high incidence.[1] It is the ninth cause of death in Spain,[2],[3] and 20%–25% of patients are initially diagnosed with mCRC.[4] Fluorouracil/leucovorin monotherapy was the standard therapy.[5] The addition of oxaliplatin and irinotecan and monoclonal antibodies increased the overall survival (OS).[1]

The latest advances correspond to oral drugs regorafenib and trifluridine / tipiracil. Both drugs are indicated in the treatment of patients with mCRC that have been previously treated or are not considered candidates for treatment with therapies.[6],[7]

Regorafenib[8] and trifluridine/tipiracil[9] were associated with grade 3/4 adverse reactions (ARs) such as hand–foot syndrome, fatigue and diarrhea with regorafenib; and neutropenia, anemia, and thrombocytopenia with trifluridine/tipiracil.

Patients who need treatment in standard clinical practice may not share the same characteristics as the population selected in clinical trials (CT). Therefore, this study aims to analyze the survival and safety profile of these new oral drugs in the usual clinical practice.

 > Materials and Methods Top

Study design

An observational, retrospective and unicentric study was conducted in a health-care area of 500,000 inhabitants, in which there is a third level hospital. Patients who started treatment with regorafenib and trifluridine/tipiracil were included, from the date of marketing of the drugs (regorafenib: September 24, 2013; trifluridine/tipiracil: June 1, 2016) to June 2019.

The inclusion criteria were as follows: over 18 years of age, diagnosis of nonresectable mCRC, previous treatments with fluoropyrimidine, irinotecan, oxaliplatin, and anti-vascular endothelial growth factor antibody (bevacizumab), or anti-epidermal growth factor receptor (cetuximab or panitumumab) for patients who had mutated KRAS gene. In addition, patients should have a performance status (PS) from 0 to 2.

This study has been approved by the Ethics Committee of Galicia (registration code 2019/451).

Treatment was prescribed under routine clinical practice. Regorafenib at standard doses of 160 mg once daily for 3 weeks, followed by 7 days without treatment. Trifluridine/tipiracil at 35 mg/m2 every 12 h on days 1–5, and on days 8–12 followed by a 14-day rest period. In both cases, this regimen is repeated every 4 weeks. Patients were treated until they had unacceptable toxicity, disease progression, or death.

Following standard practice, patients underwent computed axial tomography (CT) every 3 months in order to evaluate tumor responses to therapy, in accordance with the Response Evaluation Criteria Solid Tumors (RECIST).[10]


Variables were obtained from the patient's electronic clinical record and from the electronic prescription program of the pharmacy service.

Patient-related and pathology-related variables were collected: date of birth, gender, diagnosis and date, adenocarcinoma location, PS, KRAS mutation, drug and dosage, treatment line number, and prior and subsequent treatments. Efficacy-related variables were also collected: disease control rate according to RECIST criteria; progression and date; and if applicable, the death date. The safety variables collected were discontinuations of treatment, dose reductions or suspensions, presence or absence of kidney failure, development of high blood pressure, elevation of transaminases and/or bilirubin, electrolyte disturbances, infections, bleeding events, hand-foot syndrome, gastrointestinal (GI) disorders, and hematological AR.

Mann–Whitney U test was used in order to compare means. In case of dichotomous variables, the probability was calculated by means of the Chi-square test or Fisher's exact test in case any value had a frequency under 5.

The OS was defined as the length of time between the start of treatment and the patient's death. Progression-free survival (PFS) was defined as the length of time from the start of treatment to disease progression. The OS and PFS curves were estimated by a Kaplan–Meier estimator, and the log-rank test was used for comparisons. Results were considered statistically significant when P < 0.05. Statistical analysis of the data was carried out with the Statistical Package for the Social Sciences (SPSS), version 20 for Windows, IBM.

 > Results Top


Patient characteristics are summarized in [Table 1]. We analyzed 54 mCRC patients, 12 of whom received (22.2%) treatment with regorafenib and 42 (77.8%) trifluridine/tipiracil. Men accounted for 59.3% of patients, with an average age at diagnosis of 60 ± 10.4 years, and 35 (67.3%) had PS = 1. We have found 22 (40.7%) patients with wild-type KRAS gene.
Table 1: Patients' characteristics

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Regarding pathology, 35 (64.8%) had a colon location. The types of metastasis and previous therapies are detailed in [Table 2], and we must highlight that the most common metastases were in the liver (43 patients, 79.6%); and as previous therapies: 54 patients (100%) received fluoropyrimidines, 53 (98.2%) received irinotecan, and 50 patients (92.6%) received oxaliplatin.
Table 2: Type of metastasis and prior therapies

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Drug exposure

In the regorafenib group, 50% (n = 6) was treated in the 4th or subsequent line, compared to 30.9% (n = 13) in the trifluridine/tipiracil group. In the regorafenib group, 5 patients (41.7%) started treatment at reduced doses; and during treatment, 5 patients (41.7%) required a reduction or discontinuation of treatment due to an AR. In the case of trifluridine/tipiracil, 2 patients (4.8%) started at reduced doses, and 24 patients (57.1%) needed reduction or discontinuation also due to an AR. The average length of treatment with regorafenib was 56.5 (RIC: 73.5; 15.25-88.75) days, the suspension due to disease progression occurred in 11 patients (97.7%) and due to toxicity in 1 (8.3%). With trifluridine/tipiracil, the average length was 81.0 (RIC: 35; 63.0-98.0) days, and the reasons for the suspension were disease progression in 35 patients (92.1%) and toxicity in 3 patients (7.9%). After the withdrawal of regorafenib, 5 patients (41.7%) received a subsequent line of treatment, and in the case of trifluridine/tipiracil, 16 patients (38.1%).


No patient had a complete response according to RECIST criteria, and only one (3.2%) of the patients with trifluridine/tipiracil reached a partial response. Disease control rates are recorded in [Table 3].
Table 3: Disease control rate according to Response Evaluation Criteria Solid Tumors criteria

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The median of PFS in the regorafenib group was 2.5 months (95% confidence interval [CI]: 0.0–5.4) and the median OS was 3.1 months (95% CI: 0.0–6.7), while in the trifluridine/tipiracil group, the survival data were 2.8 months (95% CI: 2.5–3.2) and 5.7 months (95% CI: 3.8–7.6), respectively [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Figure 1: Regorafenib: Progression-free survival Kaplan–Meier curve

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Figure 2: Regorafenib: Overall survival Kaplan–Meier curve

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Figure 3: Trifluridine-tipiracil: Overall survival Kaplan–Meier curve

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Figure 4: Trifluridine-tipiracil: Progression-free survival Kaplan–Meier curve

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There are no significant differences in OS among patients treated with regorafenib or trifluridine/tipiracil [Figure 5]. Medians were 3.1 months (95% CI: 0.0–6.7) versus 5.7 months (95% CI: 3.8–7.6); P = 0.073. There are also no differences in PFS when comparing both drugs [Figure 6]: regorafenib 2.5 months (95% CI: 0.0–5.4) versus trifluridine 2.9 months (95% CI: 2.5–3.2); P = 0.259.
Figure 5: Overall survival regorafenib versus trifluridine-tipiracil

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Figure 6: Progression-free survival regorafenib versus trifluridinetipiracil

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[Table 4] summarizes the ARs described in patients during treatment. They were reported in 11 patients (91.7%) with regorafenib and 42 patients (100%) trifluridine/tipiracil. The mean number of hematological ARs associated with treatment per patient was 0.42 ± 0.51 with regorafenib and 1.48 ± 0.86 with trifluridine/tipiracil, and of nonhematological ones was 2.33 ± 1.44 and 2.26 ± 1.29, respectively.
Table 4: Safety

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Among nonhematological ARs, with both drugs, the most common were general disorders (asthenia and fatigue), GI (diarrhea, nausea, and vomiting), and elevation of hepatic transaminases and/or bilirubin; and among the hematological ARs, anemia.

The drug had to be withdrawn due to toxicity in 1 case (8.3%) in the regorafenib group, and in 3 cases (7.9%) in the group of trifluridine/tipiracil.

 > Discussion Top

This study contributes to improving the knowledge about the effectiveness and safety of regorafenib and trifluridine/tipiracil in mCRC patients in real clinical practice.

In our sample, patients treated with both regorafenib and trifluridine/tipiracil have had lower OS than those obtained in CTs (CORRECT:[8] 6.4 months for regorafenib and RECOURSE:[9] 7.1 months for trifluridine/tipiracil) which led to their authorization.[8],[9] Also in the CONCUR study,[11] the OS was higher than that of our study and that of the regorafenib approval trial, perhaps due to the difference in how pretreated patients are, which usually happens in actual clinical practice.

However, PFS data are slightly higher in our study than those obtained in CTs (1.9 months[8] and 2.0 months[9]). But these data are not comparable, the response and tumor progression were evaluated radiologically (computed axial tomography) every 8 weeks in the trials, while they were evaluated every 12 weeks in our study. In those 4 weeks, there may have been undetected progesses. Therefore, there is a possibility that there would be a progression in our patients between weeks 0 and 12 would not have been detected until radiological evaluation.

Other retrospective studies describing the effectiveness and safety of these drugs in standard clinical practice have been published. They are three studies of smaller sample size than our study and where they find OS higher than ours for both drugs. In the study of Sueda et al.[12] 37 patients were analyzed, and the OS for regorafenib and trifluridine/tipiracil was 5.8 months and 6.3 months, respectively. Tanaka et al.[13] included 44 patients and described a 9.1-month OS (regorafenib) and a 9.3-month OS (trifluridine/tipiracil). Chiang et al.[14] evaluated the OS in 22 patients treated with regorafenib and 6 with trifluridine/tipiracil, obtaining, respectively, 5.7 and 5.4 months. These results higher than ours may be due to the small sample size, and to the patients' ethnicity. The latter study[14] also evaluated the relationship between eligibility for treatment according to the inclusion and exclusion criteria of CTs and the OS, where 25% of ineligible patients received third-line active treatment, obtaining a worse OS than those eligible for the trial. This clearly indicates that actual practice sometimes differs from CTs.

Another retrospective study but of a larger sample[15] analyzed 200 patients treated with regorafenib and trifluridine/tipiracil, reaching PFS of 2.1 and 2.1 months, and OS of 6.7 and 6.5 months, respectively. Its PFS is very similar to ours, but not its OS, as was the case when compared to our data with those in CTs.

Because not all patients treated with these drugs have observed beneficial effects, studies have been conducted that look for prognostic factors to use these treatments in patients who may actually benefit. Moriwaki et al.[16] conducted a retrospective study of 489 patients and obtained a 7.7-month OS with regorafenib and a 7.4-month OS with trifluridine/tipiracil (extensive study and with results similar to CTs). They divided patients into three groups according to a number of prognostic factors, resulting in significant differences in OS. The OS in patients treated with regorafenib with the worst prognostic factors was 3.3 months, compared to 12.6 months in the group with the best prognostic factors. In the case of trifluridine/tipiracil, the mean was 2.8 and 15.4 months, respectively. This is a very important difference between groups, indicating that research should follow the selection of patients by prognostic or biomarking factors, to treat the patients who will benefit most from these treatments. REBACCA[17] is a retrospective cohort study of 654 patients where they related a high PS, short time since diagnosis, initial regorafenib dose <160 mg, >3 metastatic sites, liver metastases, and KRAS mutations, with worse survival. The median OS was 5.6 months, but in the subgroup analysis, low-risk ones obtained an OS of 9.2 months, those at an average risk obtained 5.2 months, and those at high risk obtained an OS 2.5 months. Fernández Fernandez Montes et al.[18] made a retrospective study on the prognostic factors that may improve the therapeutic approach with trifluridine/tipiracil. A total of 160 patients were analyzed and there was a 2.75-month PFS and an OS of 7.64 months, establishing three groups according to the presence of negative prognostic factors, with low negative prognosis (OS: 8.43 months); intermediate (OS: 5.05 months); or high (OS: 1.90 months). The authors conclude that having PS = 2, multiple metastatic sites, platelets >350,000/μl, alkaline phosphatase >500 IU/l, and carcinoembryonic antigen >10 ng/ml are worse prognostic factors in patients treated with trifluridine/tipiracil. For our study, we included mostly patients with PS 0–1, being a positive prognostic factor. However, the other factors studied were not recorded in our study since it was not designed to select patients by risk group.

The OS in our study is lower than that described in other studies of standard clinical practice. This result could be due to the treatment initiation at reduced regorafenib doses (described as a negative survival prognostic factor) occurred in nearly half of the patients in our study. The possibility that a reduced dose of regorafenib may have had a negative impact on the results may be an option or may be a confounding factor, since the phase II study ReDOS[19] suggests that treatment results can be maintained at lower doses. Regarding the reasons for reducing the initial dose, we must highlight the following:

  1. Due to the advanced age of the patient, the doctor considered that it was necessary to see tolerance
  2. Due to the frailty of the patient (according to medical criteria in patients with comorbidities even though it is not described in this way in the drug's technical data shee.”

The worse prognosis found with respect to some studies may be due to comorbidities not registered in the study in real-life patients (they are not as selected patients as those in CTs); the percentage of patients treated in the first or second line in our study was lower than CTs, the patients of our study had a PS worse than in CTs, underreported ARs in real life, in addition to other factors already mentioned, such as the initiation of treatment with reduced doses or different times used in the radiological evaluation of the response.

There is no CT comparing regorafenib against trifluridine/tipiracil, nor any indirect comparison in the literature consulted. Several studies[15],[20] compared both drugs, concluding that there were no differences in either PFS or OS. In our case, we have not obtained significant differences between both drugs either, but it should be noted that the group that received regorafenib is quite smaller. More studies would be needed to verify both drugs directly or indirectly with a more appropriate methodology.

In terms of safety, as a retrospective study, variables could not be recorded in the same way as other published studies, making comparisons with respect to ARs difficult. However, we have observed the same as in the subgroup analysis of a meta-analysis:[21] hematological ARs in the trifluridine/tipiracil group are larger than those in the regorafenib group. Meanwhile, the presence of nonhematological AR was higher in the regorafenib group than in the trifluridine/tipiracil one.

The most common ARs obtained in our study with regorafenib have been general disorders (fatigue and asthenia), followed by elevation of hepatic transaminases and/or bilirubin, GI disorders, and anemia. In the pivotal CT,[8] the most common ones were fatigue (with a high percentage (47%) if compared to ours) and hand–foot syndrome (with a high percentage (47%) compared to ours). We must note that some ARs in our study are collected by group as in the case of GI disorders, while in CTs, they are collected individually: diarrhea, nausea, constipation, and vomiting; and that's why our percentage seems to be higher.

The most common AR in our study with trifluridine/tipiracil would be the one called general disorders (fatigue, asthenia, and pain). It should be noted that in the usual clinical practice, it is difficult to differentiate between fatigue caused by a drug or the progression of the disease itself, so the percentage may differ between studies. In the pivotal CT of trifluridine/tipiracil,[9] the most common ARs were hematological (leukopenia 77% and anemia 77%), as in our study. Among the nonhematological ARs are nausea (48%), which we included as part of the GI disorders and that is why it is a little higher in our study.

As for the need for treatment reductions or discontinuations, the results of our study differ from what is described in the literature. In the CT on regorafenib[8] and in another study[12] 67% and 65.2% of patients required dose modification, compared to only 14% in CT on trifluridine/tipiracil[9] or 14.3% in Sueda et al.[12] In our study, reductions in patients treated with trifluridine/tipiracil were greater than when treated with regorafenib, contrary to what would be expected. This difference may be due to the fact that almost half of the patients in our sample started at reduced doses of regorafenib. In addition, the length of treatment was also longer in the case of trifluridine/tipiracil, giving more time to the appearance of ARs.

The main limitations of this study are its retrospective nature, which is unicentric and with a reduced sample size, although all patients diagnosed with mCRC in the center and treated with these drugs were included. “It must be taken into account that it is a study of small sample size that does not allow to draw robust conclusions. However, it reproduces what is described in the clinical trials of drug approval and what is described in other retrospective studies.” In addition, being a retrospective study, it is difficult to collect variables from the medical record such as ARs. In the usual clinical practice, the grades of the ARs are not collected, being forced to collect them only qualitatively. In addition, the study is not designed to compare both drugs, as it should be done using another methodology such as an indirect comparison or it would even be necessary to conduct prospective studies comparing this third (or subsequent) line of treatment.

 > Conclusions Top

In our sample of patients, the effectiveness results of real clinical practice are lower than those described in the CTs. With respect to other studies of real clinical practice, we have also obtained lower results. As for drug safety, the toxicity profile does reproduce those values with respect to CTs and to other clinical practice studies. Although our main objective was not the comparison between regorafenib and trifluridine/tipiracil, according to our results, there does not seem to be any differences between them, neither in effectiveness nor regarding ARs. It is necessary to evaluate the position of both drugs comparatively between them and the search for biomarkers that allow us to find a population in which this pharmacotherapy is more effective.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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Therapeutic Positioning Report PT / V1 / 04032015. Ministry of Health, Social Services and Equality. Available from: https://www.aemps.gob.es/medicamentosUsoHumano/informesPublicos/docs/IPT-regorafenib-Stivarga.pdf. [Last accessed on 2019 Feb 25].  Back to cited text no. 4
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386-422.  Back to cited text no. 5
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.  Back to cited text no. 10
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Sueda T, Sakai D, Kudo T, Sugiura T, Takahashi H, Haraguchi N, et al. Efficacy and safety of regorafenib or TAS-102 in patients with metastatic colorectal cancer refractory to standard therapies. Anticancer Res 2016;36:4299-306.  Back to cited text no. 12
Tanaka A, Sadahiro S, Suzuki T, Okada K, Saito G, Miyakita H. Retrospective study of regorafenib and trifluridine/tipiracil efficacy as a third-line or later chemotherapy regimen for refractory metastatic colorectal cancer. Oncol Lett 2018;16:6589-97.  Back to cited text no. 13
Chiang CL, Choi HC, Lam KO, Chan BY, Lee SF, Yeung SY, et al. Real-world treatment patterns and outcomes in refractory metastatic colorectal cancer. Asia Pac J Clin Oncol 2019;15 Suppl 2:5-13.  Back to cited text no. 14
Masuishi T, Taniguchi H, Hamauchi S, Komori A, Kito Y, Narita Y, et al. Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison. Clin Colorectal Cancer 2017;16:e15-e22.  Back to cited text no. 15
Moriwaki T, Fukuoka S, Masuishi T, Takashima A, Kumekawa Y, Kajiwara T, et al. Prognostic scores for evaluating the survival benefit of regorafenib or trifluridine/tipiracil in patients with metastatic colorectal cancer: An exploratory analysis of the REGOTAS study. Int J Clin Oncol 2020;25:614-21.  Back to cited text no. 16
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