Long-Term Progression-Free Survival of a Pre-Treated Patient with Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil

In 2020, 10% of all newly diagnosed malignancies were colorectal cancers (CRCs), with more than 1.9 million cases worldwide [1]. CRC remains the second leading cause of cancer-related deaths [2], and development of metastases significantly decreases overall survival (OS). In patients with metastatic CRC (mCRC), the 5-year survival rate is less than 15% [3]. Although in the last 2 decades novel therapeutic regimens, optimized surgical interventions, and more sensitive diagnostic approaches have increased the median OS from 15 to 30 months [3‒5], patients with refractory mCRC or intolerance to standard treatment have an unmet medical need [6]. For these patients, the novel oral anti-tumor agent trifluridine/tipiracil (sometimes known as TAS-102 or by its tradename Lonsurf^®), which combines the antineoplastic thymidine-based nucleoside analog trifluridine with the thymidine phosphorylase inhibitor tipiracil hydrochloride, was shown to improve survival while maintaining a manageable toxicity profile [7‒10].

Here, we report the case of a male patient with KRAS-mutated mCRC who received trifluridine/tipiracil after failure of standard treatment with FOLFIRI plus bevacizumab and FUFA plus bevacizumab. The treatment resulted in progression-free survival (PFS) over 31 months, which by far exceeds the survival results observed in clinical trials.

In May 2012, a 60-year-old male was newly diagnosed with an adenocarcinoma located in the descending colon. The pathologic finding after left hemicolectomy revealed an UICC stage II adenocarcinoma pT3 pN0(0/14) L0 V0 R0 and a KRAS mutation in exon 2. The patient’s medical history included a non-insulin-dependent diabetes mellitus type 2a (treated with metformin 1,000 mg, twice daily) and chronic obstructive pulmonary disease (untreated) due to his cigarette consumption (25 pack years). In June 2013, a sessile serrated adenoma was endoscopically removed and, in July 2014, the patient underwent laparoscopic surgery for the treatment of an obstructive ileus due to adhesions.

In October 2016, 4 years after first CRC diagnosis, the patient displayed pulmonal and hepatic metastatic lesions in radiologic imaging and an elevated carcinoembryonic antigen (CEA) level of 9.0 μg/L in the serum. The histologic analysis of liver lesion biopsy confirmed colorectal metastatic spread consistent with the previously resected KRAS-mutated adenocarcinoma of the colon. Considering the histologic results, first-line chemotherapy with FOLFIRI (irinotecan 180 mg/m², folinic acid 400 mg/m², 5-fluorouracil bolus 400 mg/m², 5-fluorouracil 2,400 mg/m² continuous infusion for 42 h, scheme repeated every 2 weeks) and bevacizumab (5 mg/kg body weight, repeated every 2 weeks) was initiated in November 2016. In January 2017, after only 4 cycles of FOLFIRI plus bevacizumab, radiologic assessment revealed a partial response according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 [11]. Therefore, treatment was continued and 12 cycles of FOLFIRI plus bevacizumab were completed in order to strengthen partial remission. Metastatic surgery was not an option due to disseminated lung nodules in both lungs as well as several liver metastases in both lobes with the largest in segment 6. However, dexamethasone given as premedication for better chemo-tolerability impaired insulin sensitivity and worsened the patient’s diabetes leading to medicinal insulin-dependency. Therefore, and due to ongoing treatment response, therapy was de-escalated to FUFA (folinic acid 400 mg/m², 5-fluorouracil 2,400 mg/m² continuous infusion for 42 h, scheme repeated every 2 weeks) plus bevacizumab as maintenance treatment. Again, after 12 cycles of FUFA plus bevacizumab, pulmonal progression was observed in November 2017. Additionally, an infection of the port catheter occurred requiring anti-infective treatment with intravenous antibiotics and explantation of the catheter. Thus, chemotherapy had to be suspended in December 2017. In January 2018, after a new port catheter was implanted, the patient again started systemic chemotherapy rechallenge with FOLFIRI plus bevacizumab upon progression [12]. He received 18 more cycles of this drug regimen until October 2018 and achieved disease control (stable disease [SD]). In parallel to the previously applied strategy, de-escalation to maintenance FUFA plus bevacizumab followed. However, after only seven cycles of FUFA plus bevacizumab disease progressed and re-escalation to FOLFIRI plus bevacizumab failed after only one cycle because the patient developed oral and anal mucositis grade 3 according to CTCAE criteria [13]. Besides port catheter infection and mucositis, no further grade ≥3 toxicities were observed while on FOLFIRI plus bevacizumab. All applied treatment sequences are precisely illustrated in Figure 1.

After failure of FOLFIRI and bevacizumab, molecular pathologic analysis of metastatic tumor tissue was obtained from the latest liver biopsy. It revealed mismatch repair-proficiency, HER2-negativity (IHC score 0), BRAF wild-type status, and a KRAS mutation in exon 2 (C:34G>A). Lack of actionable drug targets excluded a targeted therapeutic approach.

Thus, in July 2019, after failure of FOLFIRI plus bevacizumab, the therapy regimen was changed to trifluridine/tipiracil. At that point, the patient rejected oxaliplatin-based therapies due to the advanced risk of adverse events (especially neuropathy) limiting his quality of life (QoL). The patient worked as a car mechanic and wished to maintain an independent lifestyle, especially regarding his passion to restore vintage cars, and being able to travel. He strongly preferred oral therapy and the preceding port catheter infection strengthened this wish. Additionally, worsening of mucositis that was most likely caused by infusional 5-fluorouracil-containing regimen had to be avoided at all costs. Also, due to KRAS mutation, anti-EGFR therapy was not an option. Thus, we decided to begin treatment with trifluridine/tipiracil that also made dexamethasone-containing antiemetics, which had worsened his diabetes before, obsolete. At that time of second-line treatment initiation, the patient presented with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and exhibited a CEA level of 6.9 μg/L.

On treatment with trifluridine/tipiracil, stabilization of disease was observed from July 2019 to January 2022 (in total 31 months). The pulmonal regression was confirmed by computed tomography scans (Fig. 2a), whereas SD was achieved in the liver (Fig. 2b; therefore, overall SD according to RECIST criteria). Furthermore, CEA levels slightly decreased from 6.9 μg/L to 5.6 μg/L. The patient maintained his QoL and was fully able to pursue his work as a car mechanic. The only safety issue was a symptomatic anemia grade 3 with a minimum hemoglobin of 6.7 g/dL, which was adequately managed with erythrocyte transfusion every 4–6 months (in total 4 times 2 erythrocyte transfusions while on trifluridine/tipiracil). A ferritin level of 804 μg/L (normal range <250 μg/L) and a transferrin saturation of 36% ruled out iron deficiency or bleeding anemia. With regard to hematologic toxicity from cycle five onward, asymptomatic neutropenia grade 3 intermittently occurred. No other side effects grade ≥3 occurred, and no hospitalization was required while on trifluridine/tipiracil illustrating the manageable toxicity profile.

However, from October 2021 onward the CEA level increased from 7.6 μg/L to 32.2 μg/L in January 2022 and further to 46.1 μg/L in February 2022 (Fig. 2c). Radiologic imaging confirmed pulmonary and hepatic disease progression. As a next step, a comprehensive individual molecular diagnosis (next-generation sequencing of tumor tissue) was to be performed. On this basis, discussion of further treatment options in a molecular tumor board is planned.

Trifluridine/tipiracil is approved as monotherapy for the treatment of adult patients with mCRC who were previously treated with or who are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies as well as anti-VEGF and -EGFR agents. The mode of action is distinct to fluoropyrimidines such as 5-fluorouracil, which makes it an attractive compound for the treatment of 5-fluorouracil-resistant tumors [14]. Trifluridine interferes with cell proliferation and leads to cell death by incorporation into the DNA. The combination with tipiracil enhances bioavailability of the substance by inhibition of the trifluridine degrading activity of the thymidine phosphorylase [15].

In this report, we describe a 67-year-old male patient with KRAS-mutated mCRC and metachronous liver and lung metastasis who failed prior 5-fluorouracil- and irinotecan-containing regimens, but then showed long-term disease control for 31 months on single-agent trifluridine/tipiracil given as second-line treatment. After in a total of 30 months of disease stabilization with FOLFIRI plus bevacizumab and maintenance with FUFA plus bevacizumab as well as rechallenge with FOLFIRI plus bevacizumab, the patient was not able to receive oxaliplatin-based therapies due to several reasons: (1) worsening of ongoing mucositis that had occurred on infusional 5-fluorouracil-containing regimen, (2) avoidance of QoL-limiting adverse events such as neuropathy, especially with regard to the patient’s profession as a car mechanic and his passion to restore vintage cars, (3) no option of anti-EGFR agents due to a KRAS-mutated tumor, (4) oral therapy at the patient’s desire to travel and to maintain an independent lifestyle, (5) no need for dexamethasone-containing antiemetic pre-treatment that had caused insulin-dependent diabetes before.

When comparing toxicity profiles in our patient, first-line treatment with FOLFIRI plus bevacizumab and FUFA plus bevacizumab caused a life-threatening grade 4 infection, worsening of diabetes with insulin-dependency, and compromised QoL due to painful mucositis. On second-line trifluridine/tipiracil, anemia occurred as single but easily manageable side effect.

Nevertheless, treatment with trifluridine/tipiracil achieved disease control for an outstanding 31 months. This therapeutic effect is encouraging, since PFS of the described patient was considerably longer compared to median PFS and OS data from several clinical phase 3 studies and real-world settings (median PFS <5 months, median OS <9 months) [7, 9, 10, 16‒18]. In earlier treatment lines, trifluridine/tipiracil is currently under investigation as a novel chemotherapy backbone for monoclonal antibodies (Table 1). All studies, even if not statistically designed for non-inferiority, showed a comparable efficacy of trifluridine/tipiracil as the comparator.

For example, in the phase 3 SOLSTICE trial (NCT03869892), mCRC patients who are not fit for intensive chemotherapy (independent of RAS status) were randomized to receive either first-line trifluridine/tipiracil plus bevacizumab or capecitabine plus bevacizumab. Results of a first interim analysis were presented recently [23, 24]. Even though it was a negative study, PFS (9.4 months in trifluridine/tipiracil arm; 95% CI [9.1–10.9] vs. 9.3 months in capecitabine arm; 95% CI [8.9–9.8]) and OS (19.74 months in trifluridine/tipiracil arm; 95% CI [18.04–22.40] vs. 18.59 months in capecitabine arm; 95% CI [16.82–21.39]) were comparable in both treatment arms, suggesting that first-line trifluridine/tipiracil plus bevacizumab is not inferior but similarly active compared to capecitabine plus bevacizumab in frail mCRC patients. Further, the German phase 2 FIRE-8 study (NCT05007132) was recently initiated and aims to compare treatment efficacy between trifluridine/tipiracil in combination with either panitumumab or bevacizumab in frail and untreated patients with RAS wild-type mCRC [19]. The study is actively recruiting patients in 40 German centers.

In the described case, trifluridine/tipiracil treatment was extremely well tolerated and exceeded expectations with regard to treatment efficacy and toxicity profile. Severe neutropenia grade ≥3 was described as a surrogate efficacy endpoint for trifluridine/tipiracil [29, 30]. Recently, Giuliani et al. [31] reported 33 long-term survivors of mCRC treated with trifluridine/tipiracil and identified neutropenia, ECOG performance status, and overall response rate as predictive factors. Our presented patient fulfilled all three predictive criteria as he developed intermittent neutropenia grade ≥3, was in ECOG performance status 1 at treatment start and showed partial response to at least the lung metastasis. According to previous reports on QoL on trifluridine/tipiracil in clinical trials [32‒34], our patient’s QoL was fully maintained in both his private and his work life.

On trifluridine/tipiracil, our patient did not require antiemetics, did not experience serious adverse events and no hospitalization occurred while on trifluridine/tipiracil. The oral treatment conveniently made infusions obsolete and allowed extended traveling and handicraft work on his vintage cars.

Based on the experience with our presented patient, we suggest that trifluridine/tipiracil is a feasible and effective treatment option in earlier but not necessarily last lines of therapy for mCRC patients who are not considered candidates for doublet or triplet chemotherapy. Besides its efficacy, it is associated with maintained QoL and a manageable toxicity profile. Considering increasing age of mCRC patients and their wish for maintaining an independent lifestyle, further research on the use of trifluridine/tipiracil in earlier lines of systemic mCRC therapy is warranted.

The authors thank all medical colleagues and nursing staff who contributed to the successful oncologic treatment of the presented patient. Also, we thank the patient and his family for allowance to publish his medical history within this present case report.

This single case report did not require ethical approval in accordance with local/national guidelines. The reported patient has signed written informed consent to publish his case (including publication of images) and agreed to the publication of his case and medical history in a national or international peer-reviewed journal. The published case report includes evidence that medical treatment was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Within the presented case report, all authors but Timo Reisländer have no conflicts of interest to disclose. Timo Reisländer is an employee of Servier Deutschland GmbH.

Outside the submitted manuscript, Gerlinde M. Michl received honoraria for advisory boards and travel support from Roche, MSD, Servier, BMS, Sobi, and Merck. Florian Vogt holds a reader function for the Bayer AG. Marlies Michl received honoraria for talks and advisory boards from SIRTeX, Roche, MSD, Servier, BMS, and Merck, and travel support from SIRTeX, Amgen, MSD, BMS, Sobi, and Merck.

The publication of the present manuscript was funded by Servier Deutschland GmbH.

Gerlinde M. Michl, Timo Reisländer, and Marlies Michl wrote the manuscript. Gerlinde M. Michl and Marlies Michl treated the patient as the oncologists in charge. Andreas Nouriani was the gastroenterologist in charge who performed several endoscopies and performed ultrasound-guided liver biopsy. Marcus Kremer conducted pathological investigations on various tumor tissue specimen including immunohistochemistry, provided the pictures, and reviewed the manuscript. Florian Vogt was the clinical radiologist in charge, provided the radiological pictures, and reviewed the manuscript. Roland Ladurner was the surgeon in charge where oncologic hemicolectomy took place and the port catheter was implanted, and he reviewed the manuscript. Thus, all authors substantially contributed to the patient’s diagnosis, his treatment, and/or writing of the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.