Review Article

Oncol Res Treat Received: September 8, 2019

Accepted: January 11, 2020
DOI: 10.1159/000506080 Published online: March 6, 2020

Metastatic Colorectal Carcinoma after Second

Progression and the Role of Trifluridine-Tipiracil
(TAS-102) in Switzerland
Alexander Siebenhüner a Sara De Dosso b Alexander Meisel c
Anna Dorothea Wagner d Markus Borner e
a Clinic
for Medical Oncology and Hematology, Universitätsspital Zürich and University of Zurich, Zurich,
Switzerland; b Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland; c Hematology and Oncology,
Clinic for Internal Medicine, Stadtspital Waid, Zurich, Switzerland; d Département d’oncologie, CHUV, Lausanne,
Switzerland; e ONCOCARE at the Engeriedspital, Bern, Switzerland

Keywords es published data and their impact for FTD/TPI as well for
Refractory colorectal cancer · Lonsurf · Trifluridine-tipiracil · regorafenib and rechallenge chemotherapy in clinical prac-
Tas-102 · Rechallenge · Regorafenib · Second progression tice settings of refractory situations of colorectal cancer.
© 2020 The Author(s)
Published by S. Karger AG, Basel

Abstract
Background: Metastatic colorectal carcinoma (mCRC) is one
of the most prevalent types of cancer worldwide. After tu- Introduction
mor progression with first- and second-line treatment, triflu-
ridine (FTD) and tipiracil (TPI) has been shown to be a treat- Colorectal cancer (CRC) is the third most common
ment option. Summary: Data from a pivotal phase 3 trial (RE- type of cancer worldwide, accounting for 10.6% of all can-
COURSE) and an ongoing phase 3b trial (PRECONNECT) have cer cases [1]. In Switzerland, about 4,000 new patients are
shown that, in mCRC patients who experienced disease pro- diagnosed with CRC every year, which is 11% of all cancer
gression after 2 lines of standard therapy, treatment with diagnoses [2]. The majority of diagnoses are staged in a
FTD/TPI is safe and efficacious. Other third-line options in- metastatic setting. At that stage most tumors are inoper-
clude regorafenib, rechallenge with previous treatment able and systemic treatment is recommended. Generally,
lines or personalized approaches based on comprehensive metastatic colorectal carcinoma (mCRC) patients receive
molecular profiling. Randomized trials or sequential studies multiple lines of therapy during their history of disease
aiming for the right treatment sequence or predefined sub- [3]. However, in Switzerland, management of mCRC is
types for FTD/TPI or regorafenib as well for rechallenge are challenging, as no Switzerland-specific guidelines for
missing. However, FTD/TPI as well as regorafenib are recom- mCRC treatment have been established until now. Thus,
mended by the current ESMO, German S3, and National Swiss physicians use international recommendations for
Comprehensive Cancer Network (NCCN) guidelines in the mCRC as listed in ESMO, German S3, and National Com-
same situation, thus offering physicians a number of alterna- prehensive Cancer Network (NCCN) guidelines, which
tives for the treatment of mCRC patients after the second vary in nuances from each other [3–5]. Basically, the es-
progression. Key Message: This narrative review summariz- tablishment of treatment recommendations with ongoing

karger@karger.com © 2020 The Author(s) Dr. med. Alexander Siebenhüner

www.karger.com/ort Published by S. Karger AG, Basel Clinic for Medical Oncology and Hematology, Universitätsspital Zürich
Rämistrasse 100
This article is licensed under the Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International License (CC BY- CH–8091 Zurich (Switzerland)
NC-ND) (http://www.karger.com/Services/OpenAccessLicense). alexander.siebenhuener @ usz.ch
Usage and distribution for commercial purposes as well as any dis-
tribution of modified material requires written permission.
updates presented in these guidelines has led to an overall conditions, confirms the advantages of FTD/TPI as a fa-
improvement in the clinical outcome of mCRC patients vorable treatment for refractory mCRC [10]. A prelimi-
[6]. Different combinations of chemotherapies with or nary analysis of data from 462 patients showed that pa-
without biologicals or monotherapy regimens or even im- tients on FTD/TPI had a median progression-free surviv-
munotherapies based on the molecular profile as well the al (PFS) of 2.8 months, disease control was achieved in
location of the tumor drives the choice of first- and sec- 37% of the patients, and their performance status deterio-
ond-line treatment regimens for mCRC [3–5]. These rated to ECOG performance status ≥2 after a median of
strategies have resulted in improvement of overall surviv- only 8.7 months [10]. The safety profile of the therapy was
al (OS) of mCRC patients, i.e., from 19 months to over 3 acceptable and consistent with that found in the RE-
years in the last decade [7]. As mCRC patients tend to live COURSE study – a pivotal phase 3 trial comparing the ef-
longer with the tumor, a larger group of patients should ficacy of FTD/TPI to that od placebo for the treatment of
be assessed for third or refractory lines of treatment. In refractory CRC and mCRC in heavily pretreated patients
cases of refractory mCRC that has not responded favor- (ECOG performance status 0–1) [11, 12]. The RECOURSE
ably to first- and second-line treatments, an oral combina- study demonstrated that FTD/TPI treatment successfully
tion drug, i.e., trifluridine-tipiracil (FTD/TPI, Lonsurf®), prolonged the median OS by about 2 months (Fig. 2) and
or an oral multikinase inhibitor, i.e., regorafenib, as well PFS (2 vs. 1.7 months) with an acceptable toxicity profile
as rechallenge of chemotherapy with or without a former- [11, 12]. The most frequently observed side effects with
ly used antibody regimen are valid options presented in FTD/TPI were neutropenia (32.4%), asthenia (24.3%),
ESMO and NCCN recommendations [3, 5]. The recom- anemia (21.6%), and diarrhea (18.9%) [12]. A retrospec-
mendation level in the guidelines of the NCCN and ESMO tive analysis showed that neutropenia could be a good sur-
ranks these options equally, whereas S3 has reassessed the rogate marker for adequate dose exposure [13]. Further-
ranking of regorafenib with a weaker recommendation more, all of the subgroups in the patient data set, including
compared to other options such as FTD/TPI or rechal- the geographical subsets, the KRAS mutation-based sub-
lenge. This mainly affects mCRC patients in Germany as sets, etc., benefited from FTD/TPI treatment [11, 12]. A
regorafenib is not directly available in that country [3–5]. number of phase 1/2 studies have also shown that the
The other oral drug for refractory mCRC is FTD/TPI. combination of FTD/TPI and bevacizumab can lead to a
It is a combination of: (a) the thymidine-based nucleoside positive clinical outcome. A recent study demonstrated
analog FTD, which has been reported to act through in- that the addition of bevacizumab to an FTD/TPI treat-
hibition of thymidylate synthase and incorporation into ment regimen had a tolerable toxicity profile and led to a
the DNA, ultimately leading to DNA damage and cell prolonged median PFS (from 2.6 to 5.9 months, 95% CI
death, and (b) the TPase inhibitor TPI, which prevents 0.28–0.92; p < 0.03) and median OS (from 7.3 to 10.3
the rapid degradation of FTD, thus elongating its short months, 95% CI 0.18–0.99; p < 0.05) [14]. This study was
half-life. As a result, FTD/TPI remains in the body longer inspired by a phase 1/2 multicenter Japanese study (C-
and can therefore be administered at a lower dose. Since TASK FORCE), which also showed similar results [15].
the mode of action of FTD/TPI is significantly different Neutropenia (72%) and leucopenia (44%) were the most
from that of fluorouracil (5-FU) (Fig. 1), it has been common adverse effects observed in this study [15]. Fur-
shown to have considerable efficacy in 5-FU-refractory thermore, a phase 2 trial, i.e., RAMTAS, is currently as-
patients [8]. In June 2015, Servier and Taiho Pharmaceu- sessing the efficacy of the combination of an anti-VEGFR
tical obtained an exclusive license for FTD/TPI under the antibody, ramucirumab, and FTD/TPI [16].
name Lonsurf® [9] for Japan, the USA, the EU, and Swit- Several compassionate use programs of FTD/TPI
zerland. It has been licensed for adult mCRC patients who across Europe, the USA, and Asia have been conducted
have already been treated with available first- and and in summary they underline the efficacy and safety of
­second-line therapies such as fluoropyrimidine (5-FU/ FTD/TPI in a real-world population with refractory
capecitabine)-, oxaliplatin- and irinotecan-based chemo- mCRC [17–21].
therapy and anti-VEGF therapy and for RAS wild-type
mCRC patients treated with anti-EGFR therapy [3–5].
Rechallenge Therapy: an Alternative after a Second
Progression
Studies Favoring FTD/TPI Treatment for mCRC
Patients Rechallenge therapy, i.e., administration of a previous-
ly given regimen of chemotherapy with or without the
A preliminary analysis of the data from the ongoing same antibodies (e.g., bevacizumab or anti-EGFR related
multicenter phase 3b study PRECONNECT, designed to to a molecular tumor profile), may be an option for se-
evaluate the safety and efficacy of FTD/TPI in real-life lected patients [22].

2 Oncol Res Treat Siebenhüner/De Dosso/Meisel/Wagner/

DOI: 10.1159/000506080 Borner
Fig. 1. Mechanism of action of FTD/TPI.
FTD/TPI shows a different mechanism of
action compared to 5-FU-based fluoropy-
rimidines. Adapted from Lenz et al. [8].

A possible explanation for the efficacy of such a rechal- irinotecan in the refractory setting [23]. Several other
lenge strategy is that mCRC comprises heterogeneous tu- studies like OPTIMOX 2, COIN, or NORDIC IV under-
mor clones. Therefore, the first- and second-line treat- line the concept of rechallenge even using a different che-
ment do not entirely address this heterogeneity. Even motherapy backbone in these patients [24]. Interestingly,
clones that were suppressed do not completely disappear these highly selected patient benefit from this third-line
during the initial treatment and can initiate disease pro- strategy. A precondition is that no RAS or BRAF mutation
gression at a later point. Since the number of cytostatic was detected by liquid biopsy prior to rechallenge therapy
agents available for mCRC therapy is limited, resumption [25].
of treatment with the same chemotherapeutic agents can The fact that a median OS of up to 18 months was
represent a treatment continuum. achieved in the REVERSE study [26] – which is long-
This rechallenge concept especially attracts the situa- er than that observed after treatment with licensed sec-
tion if more than 6 months have elapsed since the last use ond-line treatments such as aflibercept-FOLFIRI [27] –
of this specific regimen. In a prospective study with strongly supports the idea that this is a highly selective
mCRC patients who presented, at the first stage, a re- patient group. A benefit of rechallenge with an anti-EGFR
sponse to aEGFR but developed resistance over time were antibody was demonstrated by biomarkers and evidence
rechallenged with the aEGFR antibody cetuximab plus of the EGFR wild-type clone [25]. Moreover, excellent re-

Treatment Landscape in mCRC After Oncol Res Treat 3

Second Progression DOI: 10.1159/000506080
 Fig. 2. OS of refractory mCRC patients. Patients treated with FTD/TPI showed a clear OS advantage compared
to the placebo group. All of the patients showed a benefit from the treatment apart from those who had only 2
prior regimens. Adapted from Mayer et al. [12].

4 Oncol Res Treat Siebenhüner/De Dosso/Meisel/Wagner/

DOI: 10.1159/000506080 Borner
Fig. 3. Toxicity comparison between FTD/
TPI and regorafenib. Adapted from Tour­
nigand [38].

sponse rates (i.e., 21%) and disease control rates (i.e., the second line and an interval of at least 6 months be-
54%) were reported in the CRICKET study, but the me- tween the first anti-EGFR therapy and the anti-EGFR re-
dian PFS was relatively short (i.e., 1.9 months in RAS- challenge. However, molecular retesting is recommended
mutated patients and 3.9 months in KRAS wild-type pa- for anti-EGFR re-challenge therapy. In addition, a posi-
tients) [25]. tive effect on PFS was observed only in KRAS wild-type
Rechallenge with oxaliplatin in mCRC can be an op- patients [25].
tion in the refractory setting that can achieve tumor con- To date, there has been no direct comparison between
trol, PFS, and OS benefits [28, 29]. In this setting, how- rechallenge with a chemotherapy doublet and FTD/TPI
ever, patients should be monitored carefully for neuro- or regorafenib. However, recent data suggest that the
toxicity, hypersensitivity, and allergic reactions [28]. timely use of FTD/TPI or regorafenib in early phases of
Rechallenge with an oxaliplatin-based chemotherapy can refractory mCRC is superior to renewed exposure to a
therefore represent an option for the treatment of refrac- chemotherapy doublet or anti-EGFR therapy with regard
tory mCRC and it is therefore listed in the joint ESMO to the time to treatment failure and OS duration [22].
[3], German S3 [4] and NCCN [5] guidelines. Rechal- Furthermore, FTD/TPI and regorafenib were evaluated
lenge with a chemotherapy combination such as FOL­ in large-scale phase 2 and 3 studies in mCRC after a sec-
FOX or FOLFIRI, however, has not been studied prospec- ond progression. Thus, these treatment options are now
tively [22]. the preferred choice after a second progression and
Overall, the evidence for the success of a rechallenge should be given prior to rechallenge therapy [22]. More-
strategy with cetuximab or bevacizumab with or without over, a randomized phase 2 study compared cetuximab
chemotherapy such as oxaliplatin and irinotecan is lim- with regorafenib after prior treatment with fluoropyrim-
ited. The results of such studies must be interpreted with idines, irinotecan, and oxaliplatin [26]. This sequential
caution due to the small sample sizes and a lack of appro- treatment regimen resulted in a markedly longer OS
priate controls [22]. Further prospective clinical trials are compared to that of the reverse sequence (17.4 vs. 11.6
warranted before this option can routinely be considered months, HR = 0.61) [26]. Apart from the danger of dete-
in clinical practice. Factors that support the rechallenge rioration of the performance status over time, these re-
strategy in mCRC patients are a long duration of response sults indicate that regorafenib and, by analogy, FTD/TPI
to a first-line anti-EGFR therapy, a good general perfor- should be used prior to rechallenge therapy with cetux-
mance status, the duration of the treatment response in imab.

Treatment Landscape in mCRC After Oncol Res Treat 5

Second Progression DOI: 10.1159/000506080
 The Safety and Quality-of-Life Profiles of FTD/TPI Various Aspects to be Considered and Individualized
and Regorafenib Impact Treatment Decisions Concepts

Currently, there are only limited data available on the As the treatment options for mCRC patients are evolv-
optimal therapy sequence involving FTD/TPI and rego- ing rapidly, several guidelines [3–5] recommend discussing
rafenib. The key question is whether FTD/TPI or rego- the available treatment approaches within a multidisci-
rafenib should be administered first, and this was inves- plinary tumor board (MDT) consisting of experts in their
tigated indirectly in PRECONNECT [10, 30]. A post hoc field of treatment. This could also include individualized
subgroup analysis showed that the sequence of treatment concepts. For oligometastatic liver disease, for instance,
with FTD/TPI and regorafenib did not affect the efficacy ESMO guidelines list various ablative modalities like stereo-
of the following treatment regimen [30]. In addition, tactic ablative body radiotherapy and radiofrequency abla-
there is no evidence to suggest that either of the 2 treat- tion as well as hyperthermic intraperitoneal chemotherapy
ment options leads to better efficacy. Recent data from for peritoneal disease, and nodal dissection. Surgical proce-
the RETAS study confirms that both agents can be ad- dures have also been expanded beyond the resection of
ministered in sequence [31]. Without a direct head-to- maximally 3 liver metastases by novel methods like 2-step
head comparison, the sequence of administration re- associating liver partition and portal vein ligation for staged
mains a clinical decision. hepatectomy (ALPPS) for highly selected cases after discus-
The authors of the PRECONNECT study concluded sion in an MDT. These scenarios highlight the complexity
that the safety and quality-of-life profiles are important of an individualized concept using surgical or intervention-
aspects to be considered when treating mCRC patients al steps in addition to the systemic options [3].
after a second progression. It is important to note that Tumor heterogeneity and clonal evolution add to the
FTD/TPI has presented a favorable toxicity profile in complexity of treating refractory mCRC. Therefore, rebi-
comparison to regorafenib [30]. This also enables pa- opsy of the primary or metastases should be considered
tients to receive further treatment lines in future. [25, 35]. However, this will rather be a topic of future
With FTD/TPI, toxicities in the first 1–2 months are clinical trials and not part of clinical routine as the thera-
mostly hematological. For instance, neutropenia, anemia, peutic consequences are still unclear.
and thrombocytopenia can occur quickly. In a study by Kasi After anti-EGFR regimens have been exhausted in RAS
et al. [32], it was observed that neutropenia induced by wild-type mCRC, extended molecular testing should be
FTD/TPI treatment was associated with a better prognosis taken into account at the latest in the refractory setting.
in patients with refractory mCRC. Thus, the extent of neu- Currently several commercial platforms are available for
tropenia in such patients can be instrumental in dose ad- comprehensive tumor profiling, which detects various
justments as well as in predicting treatment outcomes [32]. subtypes within a certain tumor entity. For mCRC the
Toxicities associated with regorafenib, on the other hand, available molecularly driven therapies include BRAF- and
can be more severe (Fig. 3). Regorafenib is mostly associ- Her-2-directed therapies as well as immune checkpoint
ated with hand-and-foot syndrome, fatigue (which also inhibition for DNA-mismatch-repair-deficient tumors as
might be observed after treatment with FTD/TPI, but in a well rare mutations (e.g., POLE mutations). This extended
milder form), liver toxicity, and hypertension. As these molecular testing might also uncover very rare but highly
complaints usually occur in the first 1–2 weeks, patients on targetable mutations or alterations like NTRK fusions
regorafenib need to visit the clinic once a week during the which allow treatment with highly selective drugs like en-
first month. Patients exhibiting pronounced fatigue at this trectinib or larotrectinib [36]. Within ongoing trials con-
stage should be monitored regularly [33]. sidering early use of targeted treatments like BRAF-mu-
Another factor affecting treatment decisions after a tated mCRC, extended molecular testing will be more fo-
second progression is the impact of treatment on the cused on the primary diagnosis of mCRC in the future. In
quality of life of the patient. The PRECONNECT study summary, treatment of mCRC will be become more com-
shows that more than 20% of patients receiving FTD/TPI plex in the future and, besides an MDT, treatment possi-
had improved EORTC Quality-Of-Life Core Question- bilities including expanded molecular profile testing
naire Core-30 (QCQ-C30) scores, and more than half of should be discussed in a molecular tumor board.
the patients (58.5%) showed no deterioration in their
quality of life [34]. Furthermore, the ECOG performance
status was maintained after treatment with FTD/TPI Future Perspectives
compared to placebo [2, 10–12, 30]. With regorafenib,
clinical studies have demonstrated that the quality of life A variety of treatment options depicted in the different
did not deteriorate in patients treated with regorafenib guidelines are currently available to physicians treating
compared to placebo [22, 33]. patients with mCRC. While the development of these

6 Oncol Res Treat Siebenhüner/De Dosso/Meisel/Wagner/

DOI: 10.1159/000506080 Borner
treatment options has improved the overall clinical out- needs. Such biomarkers will also play an important pre-
come for such patients, the lack of a definitive and well- dictive role to better guide physicians in choosing the
established treatment recommendation represents a chal- most effective treatment regimen. Lastly, study models
lenge for physicians. Especially for Swiss oncologists this can potentially determine the optimal treatment sequence,
is a relevant factor, as there are no Swiss-specific guide- as large randomized studies will hardly be feasible for de-
lines for the management or treatment of mCRC in Swiss termining the most effective sequence of treatments.
patients that also includes the availability of these drugs in In conclusion, FTD/TPI and regorafenib provide sim-
the country as well regulatory affairs. This might be coun- ilar advantages in the treatment of refractory mCRC.
terproductive for prolongation of OS or for improvement
of general clinical outcomes for patients. The relevance of
creating Switzerland-based recommendations regarding Acknowledgment
treatment sequences in relation to clinical, tumor biologi-
We thank our collaborators for their comments and inputs for
cal, and regulation-based factors is of high interest.
preparation of the final version of this paper. These persons con-
Furthermore, an alternative approach would be to tributed equally: Daniel Helbling, Rahel Odermatt, Thomas Wind-
combine FTD/TPI with rechallenge therapy as a treat- er, and Philippe von Burg.
ment option after a second progression. The APOLLON
study evaluated the combination of FTD/TPI with an an-
ti-EGFR antibody and this led to considerable improve- Statement of Ethics
ment in the PFS (5.8 months) and response rate (37%)
with an acceptable safety profile [37]. However, this study Ethical approval was not necessary as this is a review.
had a limited data set as it included only patients without
prior anti-EGFR treatment. Although the result appears
promising, further analysis will be needed before a conclu- Disclosure Statement
sion can be drawn on this combinatorial approach [37]. A.S. has received consulting honoraria from Amgen, Bayer,
BMS, Eisai, IPSEN, Lilly, Merck, MSD, Novartis, Pfizer, Roche,
Sanofi, and Servier and travel grants from Amgen, BMS, IPSEN,
Conclusions Roche, and Servier.
S.D. has received consulting honoraria from Amgen, Bayer,
BMS, IPSEN, Lilly, Merck, BMS, Novartis, Pfizer, Roche, Sanofi,
Treatment of mCRC in refractory settings remains a and Servier, and travel grants from Amgen, BMS, IPSEN, Roche
challenging field, with several options such as FTD/TPI, and Servier.
regorafenib, and rechallenges equally recommended in A.M. has provided a consulting/advisory role for Astellas, Jans-
the updated guidelines [4, 5, 22]. There is currently no sen, MSD, Roche, Celgene, Novartis, Vifor, Sanofi, Amgen, and
Merck, has received research funding from Bayer (Personal) and
evidence to suggest a better efficacy of either treatment.
MERCK (Inst), has intellectual property interests relating to Mer-
However, tolerability and the quality of life of patients are ck (not related to this report), has been paid to provide expert tes-
also important factors to consider when choosing a treat- timony for Sanofi and has reported travel/accommodation/other
ment option after a second progression. Toxicity and im- expenses paid for by Amgen, Astellas, Janssen, Servier, Sanofi,
pact on quality of life assessments for either regorafenib Roche, and Boehringer Ingelheim.
A.D.W. has received travel support from Ipsen, Abbvie, and
or FTD/TPI treatment options have shown that FTD/TPI
Sanofi, and honoraria or consultation fees from Bayer, BMS, Mer-
has a favorable safety profile. Neither of the 2 treatments ck, Servier, and Lilly. She is coordinating investigator 55 of the
has any impact on the quality of life of the patient. EORTC 1203 trial, which is supported by an educational grant
The strategy of giving FTD/TPI or regorafenib prior to from Roche to EORTC.
rechallenge therapy allows for as many treatment lines as M.B. has nothing to disclose.
possible to achieve the maximal prolongation of OS in the
patients [3, 4]. Based on the conducted studies FTD/TPI
Funding Sources
or regorafenib may be chosen earlier, although most of
the study patients were treated after failure of at least 2 This research did not receive any specific grant from funding
treatment lines. Rechallenge therapy, on the other hand, agencies in the public, commercial, or not-for-profit sector. H+O
may be given in highly selected cases, i.e., in RAS wild- Communication AG supported to generate the figures of this pub-
type patients who have shown a sustained benefit of ther- lication.
apy in an earlier line with disease control.
However, there is still a need for innovative treatments
Author Contributions
to supplement the currently available options. Moreover,
new biomarkers are needed to facilitate the development All of the authors designed this study, analyzed the data, wrote
of more tailored treatments to match individual patient this paper, and gave final approval of the submitted version.

Treatment Landscape in mCRC After Oncol Res Treat 7

Second Progression DOI: 10.1159/000506080
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DOI: 10.1159/000506080 Borner