Trifluridine 1% eye drops

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.

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Abstract Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 ( KRAS G12 ) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS G12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS / RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial ( n = 800 patients) and found that KRAS G12 mutations ( n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRAS G12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo ( n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRAS G13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo ( n = 60; HR = 0.29; 95% CI = 0.15–0.55; P &lt; 0.001). In isogenic cell lines and patient-derived organoids, KRAS G12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS G12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

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The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

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For patients with metastatic colorectal cancer (mCRC) that is refractory to standard chemotherapy, a recommended standard-of-care treatment in the third-line setting is trifluridine/tipiracil (FTD/TPI) alone or in combination with bevacizumab; other treatment options include fruquintinib or regorafenib. The safety profiles of FTD/TPI and bevacizumab as individual agents are well characterized. Common adverse events (AEs) associated with FTD/TPI include neutropenia, anemia, nausea, and diarrhea, and AEs frequently observed with bevacizumab include hypertension, proteinuria, hemorrhage, venous thromboembolism, and gastrointestinal perforation. Approval of the combination of FTD/TPI plus bevacizumab for the treatment of patients with refractory mCRC in the United States and Europe was based on results from the phase III SUNLIGHT trial. There is clinical value in developing a specific set of recommendations for the prevention or management of the key AEs associated with the combination regimen to inform clinical care and improve patient benefit. In this review, we summarize the safety profile of combination treatment with FTD/TPI plus bevacizumab in patients with refractory mCRC who were enrolled in the SUNLIGHT trial, with a focus on the key AEs of neutropenia, anemia, nausea or vomiting, diarrhea, fatigue, hypertension, and hemorrhage. In addition, we provide recommendations for the management or prevention of these key AEs in clinical practice, based on published literature and expert opinions on effective strategies.

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IntroductionTrifluridine-tipiracil (FTD/TPI) is approved as monotherapy and in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC). This UK real-world retrospective analysis aimed to evaluate the use of granulocyte colony stimulating factor (G-CSF) to prevent FTD/TPI induced neutropenia in patients with mCRC.MethodsRetrospective data were collected across five UK Healthcare sites. Consecutive patients with mCRC having received at least 2 cycles of FTD/TPI in addition to G-CSF administered as primary or secondary prophylaxis were included. The study assessed the timing and duration of G-CSF treatment, incidence of neutropenia, and subsequent dose delays/reductions. Time on FTD/TPI treatment, Progression free Survival (PFS), and Overall Survival (OS) were also calculated for this patient cohort.ResultsThe data set included 55 mCRC patients in total; 25 receiving primary prophylaxis, and 30 receiving secondary prophylaxis. 68% of G-CSF prophylaxis commenced on day 15, with 99% initiated between days 14 and 22. Following G-CSF use, 25% of patients experienced a dose delay and 18% a dose reduction due to neutropenia. 14.5% of patients reported grade ≥3 neutropenia. In patients receiving primary prophylaxis a mean of 18.4 weeks of FTD/TPI were completed, whereas in those receiving secondary prophylaxis the mean was 28.8 weeks. Primary prophylaxis patients exhibited a median PFS of 3 months, and a median OS of 9.7 months. In secondary prophylaxis patients the median PFS was 7.2 months and the median OS 17.5 months.ConclusionG-CSF prophylaxis reduced the incidence of neutropenia, improved dose intensity, and extended PFS and OS in this real-world study of mCRC patients on FTD/TPI. G-CSF prophylaxis was commonly administered as a 5-day course of filgrastim starting on day 15.

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•Patients with mCRC benefit from third-line treatment with FTD/TPI irrespective of KRASG12 mutational status.•OS is improved in patients receiving FTD/TPI plus bevacizumab versus FTD/TPI, independently of KRASG12 mutational status.•KRAS mutations are not predictive of clinical outcomes with FTD/TPI as monotherapy or in combination with bevacizumab. BackgroundIn 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 KRASG12 mutational status on OS in SUNLIGHT.Patients and methodsIn 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 KRASG12 mutation in the overall population and in patients with RAS-mutated tumors.ResultsOverall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12 RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 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 KRASG12 mutation versus those with a non-KRASG12 RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 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 KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81).ConclusionsThe presence of a KRASG12 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 KRASG12 status. 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 KRASG12 mutational status on OS in SUNLIGHT. 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 KRASG12 mutation in the overall population and in patients with RAS-mutated tumors. Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12 RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 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 KRASG12 mutation versus those with a non-KRASG12 RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 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 KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). The presence of a KRASG12 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 KRASG12 status.

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Abstract Trifluridine/Tipiracil (FTD/TPI, TAS102) has been approved for the treatment of patients with colorectal cancer (CRC) for its promising anticancer activity enabled by its incorporation into double strands during DNA synthesis. However, the mechanisms underlying the anticancer targets of FTD/TPI remain not fully understood. Here we report our observation of the activation of ferroptosis in CRC by FTD/TPI. Mechanistically, FTD/TPI directly promotes the ubiquitination and degradation of MDM2, thereby stabilizing the p53. Nuclear accumulation of p53 subsequently downregulates SLC7A11 expression, leading to ferroptosis. Furthermore, we observed that FTD/TPI combined with sulfasalazine (SAS), a system Xc – inhibitor, works in a synergistic manner to induce ferroptosis and further inhibit the proliferation of CRC cells. Finally, we confirmed the synergistic effect of SAS and FTD/TPI on patient-derived organoids in vitro and patient-derived xenograft mouse models in vivo. Our findings are the first to reveal that FTD/TPI induces ferroptosis via the p53-SLC7A11 axis and that SAS enhances the sensitivity and therapeutic effect of FTD/TPI. These findings suggest that the synergistic effect of FTD/TPI and SAS may represent a new therapeutic strategy for patients with CRC.

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• An eco-friendly, green chemistry approach was employed using the AGREE scale calculator to ensure sustainability. • The Quality by Design (QbD) methodology, utilizing Analytical Quality by Design (AQbD) tools, was applied to develop a high-performance thin-layer chromatography (HPTLC) method with robust quality attributes. • The method was optimized using Central Composite Design (CCD) under Response Surface Methodology (RSM) for chromatographic parameters. • The validation of the developed HPTLC method was conducted as per ICH Q2 (R1) guidelines, confirming excellent linearity, low limits of detection (LOD) and quantification (LOQ), and high precision (%RSD < 2%). • The environmental impact of the method was evaluated using the ComplexGAPI, AGREE, Eco-Scale, and BAGI tools, yielding high green metrics and confirming minimal environmental impact. Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, necessitating efficient treatment strategies and accurate analytical methods. This study presents a green analytical approach using a Quality by Design (QbD)-assisted high-performance thin-layer chromatography (HPTLC) method for the simultaneous quantification of trifluridine (TRI) and tipiracil (TIP) in pharmaceutical formulations. Chromatographic parameters were optimized using a Central Composite Design (CCD) under Response Surface Methodology (RSM), with solvent volume and chamber saturation time identified as critical factors. The optimized method yielded reliable Rf values of 0.64 for TIP and 0.91 for TRI. Validation per ICH Q2 (R1) guidelines confirmed excellent linearity (R² = 0.9944 for TIP and R² = 0.9988 for TRI), low detection limits (0.0011 µg/mL for TIP and 0.0022 µg/mL for TRI), and high precision (intra-day %RSD <0.74, inter-day %RSD <0.92). Robustness testing demonstrated minimal variability in Rf values (%RSD <0.28). Environmental sustainability was assessed using ComplexGAPI, AGREE, and BAGI tools. The developed method achieved an AGREE score of 0.81, an Eco-Scale score of 86, and a BAGI score of 80, highlighting its eco-friendliness and practical applicability. This study demonstrates an efficient, precise, and environmentally sustainable analytical method for TRI and TIP quantification, aligning with green chemistry principles and ensuring minimal environmental impact.

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