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Trifluridine/tipiracil (FTD/TPI) with or without bevacizumab is an effective treatment for metastatic colorectal cancer (mCRC). As this agent is mainly excreted via the kidney, we aimed to evaluate the impact of renal impairment (RI) on the early development of severe neutropenia, a dose-limiting toxicity and whose development reflects better treatment outcomes, in patients with mCRC treated with FTD/TPI. Patients with mCRC receiving FTD/TPI ± bevacizumab (n = 100) were divided into the RI group (creatinine clearance [CCr] < 90 mL/min) or control group (CCr ≥ 90 mL/min), and retrospectively evaluated. Severe neutropenia during the first two cycles occurred in 57.6% and 34.2% of patients in the RI and control groups, respectively, which was significantly different (P = 0.03) and met our primary endpoint. Furthermore, the incidence during the first cycle also differed significantly (52.5% in the RI group and 17.1% in the control group, P = 0.0004). Multivariate logistic regression analysis suggested that baseline RI and neutropenia were significant risk factors for early severe neutropenia (adjusted odds ratio and 95% confidence interval: 3.07, 1.24-7.59, P = 0.02 for RI, and 9.76, 1.08-88.11, P = 0.04 for neutropenia). In conclusion, our study suggested that patients with RI can exhibit early severe neutropenia during real-world FTD/TPI treatment for mCRC., (© 2024. The Author(s).)

Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumour efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study., Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS)., Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p = 0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven per cent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhoea, nausea, and vomiting)., Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard-of-care therapy is warranted., Clinical Trial Registration: ClinicalTrials.gov NCT04109924., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment., Methods: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m 2 twice daily on days 1-5) and irinotecan (150-165 mg/m 2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose., Results: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m 2 twice daily, irinotecan 150 mg/m 2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m 2 twice daily, irinotecan 150 mg/m 2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m 2 twice daily, irinotecan 165 mg/m 2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m 2 twice daily and irinotecan 150 mg/m 2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease., Conclusion: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation., (© The Author(s) 2024. Published by Oxford University Press.)

Background: TAS-102 (Lonsurf ® ) is an oral fluoropyrimidine consisting of a combination of trifluridine (a thymidine analog) and tipiracil (a thymidine phosphorylation inhibitor). The drug is effective in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan and oxaliplatin. This study is a real-world analysis, investigating the interplay of genotype/phenotype in relation to TAS-102 sensitivity., Methods: Forty-seven consecutive mCRC patients were treated with TAS-102 at the National Cancer Institute of Naples from March 2019 to March 2021, at a dosage of 35 mg/m 2 , twice a day, in cycles of 28 days (from day 1 to 5 and from day 8 to 12). Clinical-pathological parameters were described. Activity was evaluated with RECIST criteria (v1.1) and toxicity with NCI-CTC (v5.0). Survival was depicted through the Kaplan-Meyer curves. Genetic features of patients were evaluated with Next Generation Sequencing (NGS) through the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit., Results: Median age of patients was 65 years (range: 46-77). Forty-one patients had 2 or more metastatic sites and 38 patients underwent to more than 2 previous lines of therapies. ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) was 2 in 19 patients. The median number of TAS-102 cycles was 4 (range: 2-12). The most frequent toxic event was neutropenia (G3/G4 in 16 patients). There were no severe (> 3) non-haematological toxicities or treatment-related deaths. Twenty-six patients experienced progressive disease (PD), 21 stable disease (SD). Three patients with long-lasting disease control (DC: complete, partial responses or stable disease) shared an FGFR4 (p.Gly388Arg) mutation. Patients experiencing DC had more frequently a low tumour growth rate (P = 0.0306) and an FGFR4 p.G388R variant (P < 0.0001). The FGFR4 Arg388 genotype was associated with better survival (median: 6.4 months) compared to the Gly388 genotype (median: 4 months); the HR was 0.25 (95% CI 0.12- 0.51; P = 0.0001 at Log-Rank test)., Conclusions: This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings., (© 2024. The Author(s).)

Background: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001)., Methods: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0., Results: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D 2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%., Conclusions: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© The Author(s) 2023. Published by Oxford University Press.)

Background/aim: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC., Patients and Methods: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29)., Results: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999)., Conclusion: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRAS G12 mutational status on OS in SUNLIGHT., Patients and Methods: In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRAS G12 mutation in the overall population and in patients with RAS-mutated tumors., Results: Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRAS G12 mutation and 88 with a non-KRAS G12 RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRAS G12 mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRAS G12 mutation versus those with a non-KRAS G12 RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRAS G12 mutational status. Among patients with a KRAS G12 mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRAS G12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81)., Conclusions: The presence of a KRAS G12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRAS G12 status., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Trifluridine (FTD) and tipiracil (TPI) hydrochloride tablets (TAS-102) were used for the treatment of patients with metastatic rectal cancer that was resistant to conventional chemotherapy drugs. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous determination of TPI, FTD, and the metabolite 5-trifluoromethyluracil (FTY) of FTD in human plasma. The plasma samples were prepared by protein precipitation. The chromatography separation was performed using ACE Excel 3 AQ (100 × 2.1 mm i.d., 1.7 µm, ACE, England) column protected by a security guard cartridge (4.0 × 2.0 mm i.d., 5 µm, Phenomenex, USA) with a gradient elution of 0.05% acetic acid in water and methanol at a flow rate of 0.35 mL/min. The MS/MS analysis was performed by using multiple reaction monitoring with the segmented polarity (positive for TPI: m/z 243.1→183.0, and negative for FTD: m/z 295.1→252.0 and FTY: m/z 178.9→158.9) electrospray ionization mode. The segmented polarity mode was designed to achieve two advantages: better sensitivity and simultaneous determination of the analytes with different ion polarities. The calibration ranges were as follows: 1.00-250 ng/ for TPI, 8.00-8000 ng/mL for FTD and 5.00-1250 ng/mL for FTY. The selectivity, accuracy, precision, matrix effect, recovery, carryover, dilution integrity and stability test results meet ICH acceptance criteria. The method was evaluated using the RGB model and successfully applied to a clinical study in patients with solid tumors. For TPI, FTD and FTY, the maximum plasma concentration was 137-147 ng/mL, 6160-6240 ng/mL and 724-725 ng/mL, respectively; the plasma elimination half-life was 1.69-1.78 h, 1.70 h, and 3.09-3.14 h, respectively, after an oral administration of 60 mg TAS-102., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m 2 ) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered potential competing interests: Dr Nakanishi reports personal fees from Taiho Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, and Daiichi Sankyo Company, Ltd, outside the scope of the submitted work. Dr Kodera reports grants and personal fees from Taiho Pharmaceutical Co, Ltd, Chugai Pharma, MSD, Nihon Kayaku, Yakult, Lilly Japan, Ono Pharmaceutical Co, Ltd, Covidien, Daiichi Sankyo Company, Ltd, Tsumura, Johnson & Johnson, and Abbvie; grants from Takeda, Kaken Pharma, EA Pharma, Otsuka, Sanofi, Abbot, Bayer, and Pfizer; and personal fees from Miyarisan, Amgen, and Olympus, outside the scope of the submitted work. Dr Ando reports grants and personal fees from Chugai Pharmaceutical Co, Ltd, Kyowa Kirin Co, Ltd, Nippon Kayaku Co, Ltd, Yakult Honsha Co, Ltd, Ono Pharmaceutical Co, Ltd, Taiho Pharmaceutical Co, Ltd, Novartis Pharma KK, Daiichi Sankyo Company, Ltd, and Eisai Co, Ltd; personal fees from Eli Lilly Japan KK, Bayer Holding Ltd, Sawai Pharmaceutical Co, Ltd, MSD KK, Astellas Pharma Inc., Otsuka Holdings Co, Ltd, Sanwa Kagaku Kenkyusho Co, Ltd, Hisamitsu Pharmaceutical Co, Inc., SymBio Pharmaceuticals, Aptitude Health, and Alfresa Pharma Corporation; and grants from BeiGene, Ltd, outside the scope of the submitted work. Dr Murotani reports personal fees from Taiho Pharmaceutical Co, Ltd, outside the scope of the submitted work. The other authors declare that no financial or material support was received for this study.

Objectives: The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available., Methods: The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs)., Results: There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events., Conclusion: TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Hypoxic regions in solid tumors are highly resistant to drugs and thus represents an obstacle in drug discovery. Currently, however, there are technical barriers in sampling human hypoxic tumors and examining drug delivery with high sensitivity and accuracy. Herein, we present a new platform combining functional endoscopy and highly sensitive liquid chromatography-mass spectrometry (LC-MS) to assess drug delivery to hypoxic regions. Because oxygen saturation endoscopic imaging (OXEI), a functional endoscopy, can evaluate lesions and hypoxia in real-time by simultaneously acquiring a pseudocolor map of oxygen saturation and conventional endoscopic images, this platform can be used to evaluate drug delivery with human samples from hypoxic regions. As the first clinical application of this platform, the relationship between hypoxic regions and the concentration of trifluridine (FTD) incorporated into DNA was evaluated in patients with advanced gastric cancer treated with FTD/tipiracil (FTD/TPI; n = 13) by obtaining and analysis of tissue samples by OXEI and LC-MS and vascular maturity index by CD31/α-SMA staining ex vivo. The results showed that the concentration of FTD was significantly higher in the normoxic region than in the hypoxic region (P < 0.05) and there were significantly more immature vessels in hypoxic regions than in normoxic regions (P < 0.05). These results indicate that the platform was sufficiently sensitive to evaluate differences in drug anabolism in different oxygenic regions of human tumor tissue. This new platform allows quantitative drug analysis in hypoxic regions and is expected to initiate a new era of drug discovery and development., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy., Methods: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response., Results: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab., Conclusions: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.)., (Copyright © 2023 Massachusetts Medical Society.)

Based on results of prior trials (TAGS, REGARD, RAINBOW), the combination of ramucirumab beyond progression with TAS-102 (trifluridine/tipiracil) seems to be promising in advanced esophagogastric adenocarcinoma (EGA). In this multicenter, non-randomized, open-label, investigator-initiated pilot trial, ramucirumab-pretreated patients with metastatic EGA received a maximum of 4 cycles of ramucirumab (8 mg/kg i.v. on day 1 and 15, Q2W) plus TAS-102 (35 mg/m 2 p.o. bid on day 1-5 and day 8-12; Q2W). Primary endpoint was tolerability and toxicity, defining a positive trial if the SAE rate according to CTCAE 5.0 will increase <30% (up to 55%) compared to historical results from TAGS trial (SAE rate 43%). Secondary endpoints were further evaluation of safety and assessment of efficacy according to tumor response and overall and progression-free survival (OS/PFS). Twenty patients, 20% gastric and 80% GEJ cancers and 55% with ECOG 0 were enrolled. In total, nine SAEs were reported in 25% [95% CI: 8.7-49.1] of the patients, all without relationship to the systemic therapy. The median OS and PFS were 9.1 months [5.4-10.1] and 2.9 months [1.7-4.8], respectively. In addition, a disease control rate of 45% was obtained. The trial showed a favorable safety profile with a numerically lower incidence of SAEs for the combination of ramucirumab with TAS-102 compared to historical TAGS trial. Furthermore, the combination demonstrated efficacy in the beyond progression setting and therefore warrants further evaluation in a randomized trial compared to TAS-102 alone., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Several studies have reported an association between severe neutropenia and long-term survival in patients treated with trifluridine-tipiracil (TAS-102). Because some of these studies failed to address immortality time bias, however, their findings should be interpreted with caution. Additionally, the association between severe neutropenia and survival in patients receiving TAS-102 in combination with bevacizumab (Bmab) remains unclear., Patients and Methods: We conducted a single-center retrospective cohort study in patients with colorectal cancer who received Bmab + TAS-102. We compared overall survival (OS) between patients who developed grade ≥ 3 neutropenia during the treatment period and those who did not. To account for immortal time bias, we used two approaches, time-varying Cox regression and landmark analysis., Results: Median OS was 15.3 months [95% CI: 14.1-NA] in patients with grade ≥ 3 neutropenia and 10.0 months [95% CI: 8.1-NA] in those without. In time-varying Cox regression, onset grade ≥ 3 neutropenia was significantly related to longer survival after adjustment for age and modified Glasgow Prognostic Score. Additionally, 30-, 60-, 90-, and 120-day landmark analysis showed that grade ≥ 3 neutropenia was associated with longer survival after adjustment for age and modified Glasgow Prognostic Score, with respective HRs of 0.30 [0.10-0.90], 0.65 [0.30-1.42], 0.39 [0.17-0.90], and 0.41 [0.18-0.95]., Conclusion: We identified an association between long-term survival and the development of severe neutropenia during the early cycle of Bmab + TAS-102 using an approach that addressed immortality time bias., (© 2023. The Author(s).)

Background: Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy., Methods: We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients., Results: Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups., Conclusions: Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit., (© 2023. Springer Nature Limited.)

Background: Trifluridine/tipiracil (TAS-102) is an anticancer drug for metastatic colorectal cancer (CRC). This study aimed to analyze the effects and risk factors about effects of TAS-102 in real-world patients with metastatic CRC (the EROTAS-R study)., Methods: This study retrospectively analyzed 271 patients aged ≥ 20 years who underwent TAS-102 for metastatic CRC at nine related institutions from 2014 to 2021. Therapeutic results of TAS-102 + bevacizumab (Bev) and TAS-102, effect predictors, adverse events (AE), and AE predictors were examined., Results: The backgrounds of all cases were as follows: average age, 66.7 ± 10.9 years; male ratio, 59.5%; performance status (PS) 0/1/2, 43.5%/50.6%/5.9%; and tumor site right/left, 25.5%/74.5%. The therapeutic results of 109 cases receiving TAS-102 + Bev and 162 cases receiving TAS-102 were as follows: disease control rate, 53.2% vs. 28.0% (p < 0.01); progressive free survival (PFS), 6.2 vs. 4.2 months (p < 0.01); and overall survival (S), 11.8 vs. 9.3 months (p = 0.03). Multivariate analysis for effect-related factors (odds ratio (OR), 95%confidence interval (CI)) showed the following: PS1 + 2 (0.257, 0.134-0.494, p < 0.01) and a combination of Bev (3.052, 1.598-5.827, p < 0.01). The rates of grade 3 AE for TAS-102 + Bev and TAS-102 were 53.2% and 48.8%, respectively (p = 0.47). Various AE predictors were as follows: male sex (p = 0.69), age ≥ 75 years (p = 0.59), PS1 + 2 (p = 0.20), body surface area < 1.53 m 2 (p = 0.26), eGFR < 50 ml/min (p = 0.02), and AST ≥ 50 IU/L (p = 0.64)., Conclusion: A better OS and PFS comparing TAS-102 + Bev to TAS-102 for CRC was achieved in a large number of real-world patients., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma., Methods: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m 2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70., Discussion: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer., Trial Registration: jRCTs041220120., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard therapies for refractory metastatic colorectal cancer (mCRC). No results of large real-world data directly comparing FTD/TPI + bevacizumab (BEV) with FTD/TPI or REG monotherapy have been reported. We evaluated the efficacy and safety of FTD/TPI + BEV in a real-world setting., Materials and Methods: This retrospective study used a Japanese claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Eligible patients were aged 20 years and over with a diagnosis of mCRC, and received their first dose of FTD/TPI or REG from 2014 to 2021. The primary endpoint was overall survival (OS) in a propensity score matching (PSM) population in which PSM was carried out by matching using a 1 : 1 ratio for the FTD/TPI + BEV group and the control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were carried out using the inverse probability treatment weighted (IPTW) approach and the analysis in the all eligible population. Secondary endpoints included time to treatment discontinuation (TTD), incidence of adverse events, and post-treatment., Results: Eligible population was 2369 for the FTD/TPI + BEV group and 9318 for the control group. The PSM population was 1787 for each group. Median OS (mOS) was longer in the FTD/TPI + BEV group compared to the control group [17.0 versus 11.6 months, hazard ratio (HR) = 0.70, P < 0.001] in the PSM population. Similarly, mOS was longer for the FTD/TPI + BEV group compared to that for the control group in IPTW analyses and in the all eligible population (both HRs = 0.68). Median TTD was 3.3 months for the FTD/TPI + BEV group and 1.8 months for the control group in the PSM population (P < 0.001)., Conclusions: Real-world data showed that FTD/TPI + BEV was significantly associated with OS and TTD compared to FTD/TPI or REG. In clinical practice, FTD/TPI + BEV can be a favorable regimen for refractory mCRC., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN))., Materials and Methods: We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study., Results: We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023)., Conclusion: A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Background/aim: The phase III TAGS trial of trifluridine/tipiracil showed a survival benefit compared with placebo as a third- or later-line treatment in patients with advanced gastric cancer (AGC), in which only a few patients had a history of previous treatment with immune checkpoint inhibitors., Patients and Methods: We retrospectively reviewed consecutive patients with AGC who received trifluridine/tipiracil monotherapy as third- or later-line chemotherapy at our institution. Clinical outcomes were assessed in both overall population and patients with previous anti-PD-1 therapies., Results: A total of 60 patients were included in this study. Eastern Cooperative Oncology Group performance status was 0, 1, and 2 in 37%, 52%, and 12% of patients, respectively. Median number of previous treatment regimens was 4 (range=2-7). Forty-nine (82%) patients had previously received anti-PD-1 therapies. In the overall population, the most common grade 3 or higher treatment-related adverse events were neutropenia (37%), anemia (32%) leukopenia (20%), thrombocytopenia (8%), and anorexia (7%). The frequencies of grade 3 or higher events were not increased among patients with previous anti-PD-1 therapies, and no delayed onset immune-related adverse events occurred. In the overall population, objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were 4%, 42%, and 1.8 months, respectively. Efficacy results in patients with previous anti-PD-1 therapies (ORR 5%, DCR 47%, and median PFS 2.1 months) were almost comparable with those in the overall population., Conclusion: Trifluridine/tipiracil monotherapy after exposure to anti-PD-1 therapies showed manageable safety profile and anti-tumor activity in AGC patients., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer., Methods: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting., Findings: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group)., Interpretation: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population., Funding: HUTCHMED., Competing Interests: Declaration of interests AD reports support for the present manuscript from HUTCHMED; grants or contracts from HUTCHMED, Guardant Health, Natera, AAA/Novartis, Eisai, and Crinetics; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from HUTCHMED, Personalis, AAA/Novartis, Crinetics, and Voluntis. SL reports support for the present manuscript from HUTCHMED; grants or contracts from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb; consulting or advisory fees from Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and MSD; and speakers' bureau fees from Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, and MSD. RG-C reports support for the present manuscript to their institution from HUTCHMED; grants for investigator-initiated clinical trials from Pfizer, Bristol Myers Squibb, and MSD; consulting fees from AAA/Novartis, Advanz Pharma, Amgen, Bayer, Bristol Myers Squibb, Boerhringer Ingelheim, Esteve, HUTCHMED, Ipsen, Merck, Midatech Pharma, MSD, Pierre Fabre, Roche, and Servier; and support for attending meetings or travel from AAA/Novartis, Esteve, Ipsen, Merck, MSD, and Roche. EE reports grants or contracts to their institution from Amgen, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Bayer, Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; support for attending meetings or travel from Amgen, Array BioPharma, Bristol Myers Squibb, Merck Serono, Roche, Sanofi, and Servier; participation on a data safety monitoring or advisory board for Amgen, Bayer, F Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; and a paid or unpaid leadership or fiduciary role with the American Society of Clinical Oncology, European Society for Medical Oncology, and Sociedad Española de Oncología Médica. TY reports grants or contracts to their institution from Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex Corporation, Chugai Pharmaceutical, and Nippon Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD. ASo reports consulting fees and attending meetings or travel support from HUTCHMED; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Servier, MSD, Bristol Myers Squibb, Amgen, Merck, Bayer, Sanofi, and Pierre Fabre; and participation on a data safety monitoring or advisory board for Bristol Myers Squibb, Pierre Fabre, Amgen, HUTCHMED, MSD, and Servier. JY reports support for the present manuscript and consulting fees from HUTCHMED, Ipsen, Crinetics, Amgen, Chiasma, Advanced Accelerator Applications, and Novartis. PG-A reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events; and support for attending meetings or travel from and participation on a data safety monitoring or advisory board for Amgen, Merck, Roche, Sanofi, Servier, Lilly, and Pierre Fabre. AS-B reports lecture or educational event fees from Amgen, Bayer, Guardant Health, Merck, Sanofi, and Servier; and advisory board fees from Amgen, Bayer, Novartis, and Servier. TS reports grants or contracts from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Daiichi Sankyo, Chugai Pharmaceutical, and Yakult Honsha; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, and Daiichi Sankyo. VR reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Servier, and Pierre Fabre; and meetings or travel support from Merck, Bayer, Amgen, Vifor Pharma, and Accord Healthcare. JTo reports consulting fees and honoraria for lectures and presentations from Eisai, Roche, Merck, Servier, Amgen, Novartis, MSD, and Bristol Myers Squibb. GC reports consulting fees to their institution from and participation on a data safety monitoring or advisory board for Bristol Myers Squibb; support for attending meetings or travel from HUTCHMED; and research funding to their institution from HUTCHMED, Servier, Bayer, Isofol, Merck Serono, Bristol Myers Squibb, AstraZeneca, Pharmacyclics, Regeneron, Morphosys, and Incyte. ASP reports support for the present manuscript to the institution from HUTCHMED; grants or contracts for clinical trials to their institution from Ipsen, Bristol Myers Squibb, Exelixis, HUTCHMED, Taiho, Lilly, AstraZeneca, Incyte, Deciphers, G1 Therapeutics, Zentalkis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Sotio, and Innovations Cellular Therapeutics; educational event fees from Ideo Oncology, and MJH Life Sciences; travel support from Pfizer; participation on a data safety monitoring or advisory board for Amgen, Bristol Myers Squibb, Eisai, Ipsen, AAA, Exelixis, Pfizer, QED, Lilly, Mirati, HUTCHMED, Astellas, Incyte, AADi, Stromatis, EMD, and Serono; holding stock or stock options in Aptose, Actinium, and Alexion; and payment for medical writing services from Bayer, Ipsen, HUTCHMED, and Exelixis. TM reports grants or contracts to the institution from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer Ingelheim, Pfizer, Cimic Shift Zero, and Eli Lilly; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and Bristol Myers Squibb. CC reports consulting fees from Merck, Pierre Fabre, Servier, Amgen, and Nordic Pharma; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Roche, Servier, MSD, Merck, and Pierre Fabre; payment for expert testimony from Bayer, Servier, Pierre Fabre, and Merck; support for attending meetings or travel from Amgen; and participation on a data safety monitoring or advisory board for Amgen and Mirati. FG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to their institution from AstraZeneca, Roche, and MSD; and support for attending meetings or travel from MSD. ASh reports grants or contracts to their institution from HUTCHMED, Merck, INHIBRx, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, Bristol Myers Squibb, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi Sankyo, Lilly, and Jacobio; advisory board fees from Regeneron/Sanofi, Pfizer, and Catalyst Pharmaceuticals; and speaker fees from OncLive, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, and ASCO Advantage. HSH reports consulting fees from Merck, Processa, and TRIGR; lecture fees from Natera; and participation on a data safety monitoring or advisory board for Genentech and Seattle Genetics. JKr reports support for the present manuscript to their institution from Syneos Health/HUTCHMED; grants or contracts to their institution from Genentech, Bristol Myers Squibb, Amgen, Isofol Medical, Novartis, Tempest Therapeutics, MedImmune/AstraZeneca, AbbVie, MedImmune, Icon, and Turning Point Therapeutics; and participation on a data safety monitoring board for Amgen (Codebreak 300 trial, NCT05198934). MD reports support for the present manuscript from HUTCHMED; research grants from Roche, Keocyt, and Bayer; advisory board consulting fees from Boehringer, Roche, Merck Serono, Daiichi Sankyo, Rafael, Bayer, Agenus, Terumo, Pierre Fabre, and Servier; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Merck Serono, Bayer, Amgen, Pierre Fabre, Servier, Roche, Merck Serono, and MSD; support for attending meetings from Servier, Pierre Fabre, and Roche; participation on a data safety monitoring or advisory board for Roche and Pancan; and a personal conflict of interest with Sandoz. AE reports payments for advisory boards from Amgen, Merck, and Ewopharma; and lectures or educational events from Amgen, Merck, Ipsen, and Ewopharma. SK reports personal and institutional grants or contracts from Bristol Myers Squibb, Lilly, and Roche; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Amgen, Servier, Lilly, Merck Serono, Roche, MSD, and Pierre Fabre; consulting fees from Novartis and Incyte; support for attending meetings or travel from Pierre Fabre, Lilly, Amgen, Bristol Myers Squibb, Roche, and Merch Serono; and participation on a data safety monitoring board or advisory board for Novartis. EVC reports grants or contracts to their institution from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Novartis, Roche, and Servier; and consulting fees from AbbVie, ALX, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks. DA reports support for the present manuscript from his institution; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Roche, Sanofi, Servier, Sirtex, and Terumo; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Roche, Sanofi, Servier, Sirtex, Terumo, and CME providers Art Tempi, PriME Oncology, Medscape, and TRM Oncology; congress travel support from AstraZeneca; remunerated advisory board fees from Sanofi; non-remunerated advisory board fees from Oncolytics; and a paid or unpaid role with the European Society for Medical Oncology, European Organisation for Research in Treatment of Cancer, and Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. SN, ZY, WRS, and MK report employment and holding stock or stock options with HUTCHMED. JTa reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; educational collaboration fees from Imedex/HMP, Medscape Education, MJH Life Sciences, and PeerView Institute for Medical Education and Physicians Education Resource; and holding stock or stock options in Oniria Therapeutics. CE reports support for the present manuscript from HUTCHMED; grants or contracts from Elevar, Merck, Pfizer, and Gritstone; and consulting fees from Bayer, GlaxoSmithKline, Halio Dx, and Boston Scientific. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background/aim: Irinotecan and trifluridine/tipiracil (FTD/TPI) are fourth-line treatment options after third-line nivolumab for advanced gastric cancer (AGC). However, the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab remains unclear. This study aimed to evaluate the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab., Patients and Methods: We identified 137 AGC patients treated with nivolumab as third-line treatment in our institute between October 2017 and July 2021. Of these, we recruited 19 AGC patients who initiated irinotecan and 23 AGC patients who initiated FTD/TPI in the fourth-line setting until September 2021., Results: The median overall survival was 5.83 months for irinotecan and 6.31 months for FTD/TPI. Median time-to-treatment failure was 2.07 months for irinotecan and 1.64 months for FTD/TPI. While the frequency of all-grade diarrhea was higher in irinotecan (36% vs. 17%), grade ≥3 neutropenia tended to be higher in FTD/TPI (21% vs. 35%)., Conclusion: Irinotecan and FTD/TPI may be clinically useful as fourth-line treatments after nivolumab., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment., Methods: TRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment., Discussion: The aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment., Trial Registration: EudraCT 2018-002936-26; NCT04059562., (© 2023. The Author(s).)

Background: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival., Methods: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability)., Results: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67)., Conclusions: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC)., Methods: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m 2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33., Results: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; P noninferiority  = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%)., Conclusions: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC., Clinical Trial Registration: JapicCTI-173618, jRCTs031180122., (© 2023. The Author(s).)

Background/aim: Although combination chemotherapy with trifluridine/tipiracil (TAS-102) and bevacizumab (BEV) is highly effective for metastatic unresectable colorectal cancer (mCRC), this combination chemotherapy often induces nausea and vomiting. To identify risk factors for nausea and vomiting, we investigated the occurrence of nausea and vomiting in mCRC patients treated with TAS-102 and BEV., Patients and Methods: Study patients with mCRC received TAS-102 and BEV between March 2016 and December 2021. The status of nausea, vomiting, and antiemetic measures in each course were investigated, and factors involved in the occurrence of nausea and vomiting were analysed by logistic regression analysis., Results: Data from 57 patients were analysed. The incidence rates of nausea and vomiting during the overall period were 57.9% and 17.5%, respectively. Nausea and vomiting were frequent not only in the early courses but also after the sixth course. Multivariate logistic regression analysis showed that the experience of nausea and vomiting in previous treatment with other agents was significantly associated with nausea and vomiting with TAS-102 and BEV., Conclusion: The experience of nausea and vomiting in previous treatment was associated with increased risk for nausea and vomiting in mCRC patients treated with TAS-102 and BEV., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment., Methods: In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892., Findings: Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5-17·1), the hazard ratio for progression-free survival for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75-1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1-10·9) with trifluridine-tipiracil plus bevacizumab versus 9·3 months (8·9-9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [<1%]), anaemia (60 [14%] vs 16 [4%]), and hand-foot syndrome (none vs 61 [15%]). Nine deaths (five in the trifluridine-tipiracil plus bevacizumab group and four in the capecitabine plus bevacizumab group) were treatment related., Interpretation: First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the two treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population., Funding: Servier International Research Institute, Suresnes, France., Competing Interests: Declaration of interests TA reports attending advisory board meetings and receiving consulting fees from AstraZeneca, Astellas, Bristol Myers Squibb, Gritstone Oncology, GamaMabs Pharma Sa, GlaxoSmithKline, Haliodx, Kaleido Oncology, Merck & Co, Pierre Fabre, Seagen, Servier, and Transgène; honoraria from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck & Co, Pierre Fabre, Roche, Ventana, Sanofi, and Servier; and support for meetings from Bristol Myers Squibb, Merck & Co, and Servier. AF reports advisory roles and honoraria from Amgen, Bayer, Bristol, Daiichi Sankyo, Incyte, Lilly, Merck & Co, Merck Sharp & Dohme, Pierre-Fabre, Roche, and Servier; and financial support for clinical studies from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Roche, Sanofi, and Servier. FM reports consultancy and advisory roles with AstraZeneca and Boehringer Ingelheim; participation in speakers' bureaus with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F Hoffmann-La Roche/Genentech, and Takeda; research funding from Biocad; payment for travel and accommodation expenses from Boehringer Ingelheim, Pfizer, Sanofi, and Takeda; and other relationships (educational activities) with AstraZeneca, Bristol Myers Squibb, F Hoffmann-La Roche/Genentech, Merck Sharp & Dohme, and Pfizer. EP-M reports attending advisory boards for Amgen, Roche, Merck, Servier, Ipsen, and Sanofi; and payment for travel expenses from Roche, Ipsen, Merck, and Sanofi. TC reports consultancy and advisory roles with Novartis; participation in speakers' bureaus for Ipsen and Janssen-Cilag; and receiving payment for travel and accommodation expenses from Sanofi and Pfizer. PA, LM, RF, and NA are employees of Servier. MPS reports receiving lecture and meeting fees from Amgen, Servier, and Merck Serono. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Extrahepatic disease progression limits clinical efficacy of Yttrium-90 ( 90 Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer., Methods: Sequential lobar TARE using 90 Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE., Results: A total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%)., Conclusions: The combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver., Trial Registration: ClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015)., (© 2022. The Author(s).)

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., Competing Interests: None

Background: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment., Patients and Methods: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m 2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function., Results: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function., Conclusions: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities., (Copyright © 2022. Published by Elsevier Ltd.)

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73-3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

Introduction: Regorafenib (R) and trifluridine/tipiracil (FTD/TPI) are of proven efficacy in metastatic colorectal cancer (mCRC) patient's refractory to standard therapies. However, it remains unclear which drug should be administered first., Patients and Methods: This French observational study was prospectively conducted in 11 centers between June 2017 and September 2019. All consecutive patients with chemorefractory mCRC and receiving FTD/TPI and/or R were eligible. The aim was to evaluate the efficacy and tolerability of FTD/TPI and/or R in real-world setting with adjusted analysis., Results: A total of 237 mCRC patients (25% R and 75% FTD/TPI) were enrolled. As compared to R, FTD/TPI patients were significantly older and with more metastatic sites. Median OS and PFS were respectively 6.2 and 2.4 months in the FTD/TPI and 6.6 and 2.1 months in the R group. After matching 46 paired patients according to a propensity score, a trend to a longer OS (P = .58), and a significantly longer PFS (P = .048) were observed in the FTD/TPI group. In the 24% of patients receiving the R/T or T/R sequence, median OS from first treatment was similar. Tolerability profiles were similar to published data and dose reductions were more frequent in the R group., Conclusion: Efficacy and safety results in this real-world prospective study are in line with phase III trials. In a matched population, PFS was significantly longer in the FTD/TPI group. Despite a limited number of patients, clinical outcomes seemed similar in patients treated with the T/R or R/T sequence., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer, but their efficacies are limited. We investigated the combination of FTD/TPI and irinotecan for such patients., Methods: Patients who were refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) and treated with irinotecan (100 [Level 1] or 125 [Level 2] mg/m 2 on days 1 and 15) and FTD/TPI (35 mg/m 2 /dose, twice daily, on days 1-5 and 8-12 [Level A] or on days 1-5 and days 15-19 [Level B]) of a 28-day cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D); the secondary endpoint was the disease control rate (DCR)., Results: Eleven patients were enrolled: 2 at Level 1A, 3 at Level 1B, and 6 at Level 2B. DLTs occurred in 2/2 patients at Level 1A and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved a partial response, and the DCR was 72.7% (95% CI, 39.0%-94.0%). The median progression-free survival and overall survival periods were 3.0 months (95% CI, 0.92-not reached) and 10.2 months (95% CI, 2.2-not reached), respectively., Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B; this level was associated with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation of the efficacy of RP2D treatment is necessary., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results., Methods: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m 2 orally twice daily on days 1-5 and 8-12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m 2 orally twice daily on days 1-14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS., Results: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings., Conclusions: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy., Clinical Trial Information: NCT02743221 (clinicaltrials.gov)., (© 2022. The Author(s).)

Background: Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age., Methods: In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m 2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years., Results: Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51-0.89), 0.73 (95% CI 0.52-1.02), and 0.67 (95% CI 0.33-1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]., Conclusions: The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments., (© 2021. The Author(s).)

Introduction: Trifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted., Methods: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). A validated questionnaire, EORTC QLQ-C30, was employed to assess HRQoL. Secondary endpoints included OS, PFS and safety., Results: Of 194 eligible patients, 185 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. On the other hand, treatment with FTD/TPI was associated with maintained HRQoL. Median OS was 6.9 months [95% confidence interval (CI) 6.1-8.2 months] and median PFS was 2.5 months (95% CI 2.1-2.9 months). The most frequent treatment-emergent adverse events were neutropenia (27.6%) and anaemia (22.7%). Febrile neutropenia occurred in 1.1%., Conclusions: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression but also with maintained HRQoL., Competing Interests: Disclosure LW reports receiving honoraria for talks from Roche; MK reports receiving fees for serving on advisory boards and travel support from Servier; MW reports receiving fees for serving on advisory boards from Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Celgene, Gilead, Hexal, Janssen, Lilly, Medac, Novartis, Roche and SANOFI; HP reports being an employee of PiTri Studien GmbH and receiving fees for serving on advisory boards and travel support from Roche Pharma AG, Bristol-Myers Squibb, Pfizer, Bayer, Novartis, MSD, Takeda, Janssen-Cilag, Rönsberg, Ingress-Health, Gilead, Amgen, Alexion, Abbvie and Uniklinik Freiburg; JH, TR and AK report being employees of Servier Deutschland GmbH. VH reported receiving honoraria from Merck, Roche, Celgene, AMGEN, Sanofi, Lilly, SIRTEX, Boehringer-Ingelheim, Taiho, Servier; consulting of Merck, Roche, AMGEN, Sanofi, SIRTEX, Servier, Celgene, Boehringer-Ingelheim, Halozyme, MSD, BMS; research funding for the institution of Merck, Roche, AMGEN, SIRTEX, Servier, Celgene, Boehringer-Ingelheim, Shire and Travel accommodation expenses from Merck, Roche, AMGEN, SIRTEX, Servier, Shire, MSD, BMS. All other authors have declared no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The RECOURSE trial supported trifluridine/tipiracil as a treatment option in metastatic colorectal cancer (mCRC). Subsequent analysis demonstrated that low tumour burden and indolent disease are good prognosis factors improving progression-free survival (PFS) and overall survival (OS). This study aimed to evaluate the impact of prognosis group in the OS, PFS and safety of trifluridine/tipiracil in patients with mCRC., Methods: Single-centre, retrospective, and observational study of patients with mCRC who started trifluridine/tipiracil between February 2018 and July 2019. Patients were divided into good prognosis characteristics (GPC) [low tumour burden (less than 3 metastasis site) and indolent disease (≥18 months from first metastasis diagnosis)] and poor prognostic characteristics (PPC) group [high tumour burden (3 or more metastasis sites) and/or aggressive disease (<18 months since the first metastasis diagnosis)]., Results: Median age was 67 years (48-82), 67.3% of the patients were male, and 65.3% had stage IV disease at baseline. Overall, median OS was 7.5 months (95%CI:5.7-9.3). Twenty-two patients (44.9%) presented GPC and 29 (59.1%) had PPC. GPC patients had longer median OS [11.4 (95%CI:6.2-16.7)] versus 3.9 months [(95%CI: 3.3-4.6),p < 0.0001] and PFS [4.9 (95%CI:3.0-6.9) versus 2.6 months (95%CI:2.2-2.8),p < 0.0001]. These differences were more pronounced in GPC patients with no liver metastasis. Grade ≥3 adverse events incidence didn't vary between GPC and PPC subgroups., Conclusion: Our study validates the improved trifluridine/tipiracil efficacy in patients with GPC in comparison with PPC while maintaining a well-tolerated safety profile. Indolent disease, low tumour burden and the absence of liver metastasis were shown to be good prognosis factors influencing sustained response to trifluridine/tipiracil., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study., Patient and Methods: We performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom., Results: A total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR <5 and CEA <200 had favorable prognostic (HR: 0.52 and 0.39, P≤ .001) and predictive value (OR: 4.1 and 6.7, P< .05). Development of grade 3 neutropenia predicted treatment response (OR: 0.32, P< .001). Following treatment with trifluridine/tipiracil 41% were referred for phase I trial or rechallenged with chemotherapy., Conclusion: Trifluridine/tipiracil is well tolerated in refractory mCRC patients with comparable efficacy and toxicity profile to that of the phase III RECOURSE. Pretreatment NLR and CEA could serve as potential markers for patient selection, while treatment-induced grade 3 neutropenia predicted response. Prospective validation is needed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance., Methods: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m 2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m 2 twice daily., Results: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs., Conclusion: FTD/TPI is safe and tolerable at the recommended 35 mg/m 2 dose in patients with mild/moderate RI and at the reduced 20 mg/m 2 dose in patients with severe RI., Trial Registration: NCT02301117, registration date: November 21, 2014., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer., Methods: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m 2 , days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations., Results: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036)., Discussion: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug., Trial Registration Number: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network)., (© 2021. The Author(s).)

Background: We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy., Methods: APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety., Results: Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m 2 twice daily; days 1-5 and 8-12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8-45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5-6.5), 14.1 months (95% CI 12.2-19.3), 37.0% (95% CI 24.3-51.3), 81.5% (95% CI 68.6-90.8), and 5.8 months (95% CI 4.29-6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred., Conclusion: Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice., Patients and Methods: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region., Results: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18)., Conclusion: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)