Cost-effectiveness of trifluridine/tipiracil for previously treated metastatic colorectal cancer in England and Wales

Background Treatment options at third-line and beyond for patients with late-line metastatic colorectal cancer (mCRC) are limited, and outcomes are poor with best supportive care (BSC). This study investigated the cost-effectiveness of trifluridine/tipiracil and regorafenib relative to BSC alone in patients with mCRC who have been previously treated with, or are not considered candidates for, standard chemotherapies. Materials and Methods A partitioned survival model was constructed to assess the lifetime costs and benefits accrued by patients. Clinical data were derived from the pivotal phase III (Randomized, Double-Blind, Phase 3 Study of TAS-102 plus Best Supportive Care [BSC] versus Placebo plus BSC in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapies [RECOURSE]) and supporting phase II (J003-10040030) randomized controlled trial of trifluridine/tipiracil + BSC versus placebo + BSC, as well as the phase III Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy (CORRECT) randomized controlled trial of regorafenib, and were extrapolated to estimate lifetime outcomes. Costs were taken from published sources, and health effects sourced from previous mCRC studies. Results Trifluridine/tipiracil was associated with a 0.27 incremental life year versus BSC alone, which corresponds to a 0.17 quality-adjusted life year gain. The incremental cost of treatment with trifluridine/tipiracil was £8,479, resulting in an incremental cost-effectiveness ratio of £51,194 per quality-adjusted life year gained. Trifluridine/tipiracil was shown to dominate regorafenib (improve outcomes with reduced costs). Sensitivity analyses showed principal areas of uncertainty were survival estimates and patient utility. Conclusions The results show that trifluridine/tipiracil is more clinically and cost-effective than regorafenib, with clinical outcomes greatly exceeding those for patients treated with BSC alone. Based on the results of the analysis, trifluridine/tipiracil offers an important new treatment option for patients with mCRC maintaining good performance status at the end of life

The impact of prior platinum therapy on survival in patients with metastatic urothelial cancer receiving vinflunine

Background: A phase III trial demonstrated an overall survival advantage with the addition of vinflunine to best supportive care (BSC) in platinum-refractory advanced urothelial cancer. We subsequently examined the impact of an additional 2 years of survival follow-up and evaluated the influence of first-line platinum therapy on survival. Methods: The 357 eligible patients from the phase III study were categorised into two cohorts depending on prior cisplatin treatment: cisplatin or non-cisplatin. Survival was calculated using the Kaplan–Meier method. Results: The majority had received prior cisplatin (70.3%). Survival was higher in the cisplatin group (HR: 0.76; CI 95% 0.58–0.99; P=0.04) irrespective of treatment arm. Multivariate analysis including known prognostic factors (liver involvement, haemoglobin, performance status) and prior platinum administration did not show an independent effect of cisplatin. Vinflunine reduced the risk of death by 24% in the cisplatin-group (HR: 0.76; CI 95% 0.58–0.99; P=0.04) and by 35% in non-cisplatin patients (HR: 0.65; CI 95% 0.41–1.04; P=0.07). Interpretation: Differences in prognostic factors between patients who can receive prior cisplatin and those who cannot may explain the survival differences in patients who undergo second line therapy. Prior cisplatin administration did not diminish the subsequent benefit of vinflunine over BSC

Status of the Stardust ISPE and the Origin of Four Interstellar Dust Candidates

Some bulk properties of interstellar dust are known through infrared and X-ray observations of the interstellar medium. However, the properties of individual interstellar dust particles are largely unconstrained, so it is not known whether individual interstellar dust particles can be definitively distinguished from interplanetary dust particles in the Stardust Interstellar Dust Collector (SIDC) based only on chemical, mineralogical or isotopic analyses. It was therefore understood from the beginning of the Stardust Interstellar Preliminary Examination (ISPE) that identification of interstellar dust candidates would rest on three criteria - broad consistency with known extraterrestrial materials, inconsistency with an origin as secondary ejecta from impacts on the spacecraft, and consistency, in a statistical sense, of observed dynamical properties - that is, trajectory and capture speed - with an origin in the interstellar dust stream. Here we quantitatively test four interstellar dust candidates, reported previously [1], against these criteria

Four Interstellar Dust Candidates from the Stardust Interstellar Dust Collector

In January 2006, the Stardust sample return capsule returned to Earth bearing the first solid samples from a primitive solar system body, Comet 81P/Wild2, and a collector dedicated to the capture and return of contemporary interstellar dust. Both collectors were approx. 0.1 sq m in area and were composed of aerogel tiles (85% of the collecting area) and aluminum foils. The Stardust Interstellar Dust Collector (SIDC) was exposed to the interstellar dust stream for a total exposure factor of 20 sq m/day. The Stardust Interstellar Preliminary Examination (ISPE) is a consortium-based project to characterize the collection using nondestructive techniques. The goals and restrictions of the ISPE are described . A summary of analytical techniques is described

<i>mito</i>-QC illuminates mitophagy and mitochondrial architecture <i>in vivo</i>

Autophagic turnover of mitochondria, termed mitophagy, is proposed to be an essential quality-control (QC) mechanism of pathophysiological relevance in mammals. However, if and how mitophagy proceeds within specific cellular subtypes in vivo remains unclear, largely because of a lack of tractable tools and models. To address this, we have developed “mito-QC,” a transgenic mouse with a pH-sensitive fluorescent mitochondrial signal. This allows the assessment of mitophagy and mitochondrial architecture in vivo. Using confocal microscopy, we demonstrate that mito-QC is compatible with classical and contemporary techniques in histochemistry and allows unambiguous in vivo detection of mitophagy and mitochondrial morphology at single-cell resolution within multiple organ systems. Strikingly, our model uncovers highly enriched and differential zones of mitophagy in the developing heart and within specific cells of the adult kidney. mito-QC is an experimentally advantageous tool of broad relevance to cell biology researchers within both discovery-based and translational research communities

Phase II study of an all-oral combination of vinorelbine with capecitabine in patients with metastatic breast cancer

Purpose: Combination of intravenous (i.v.) vinorelbine and capecitabine was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience and to prolong infusion-free survival, we investigated in first-line treatment a regimen combining oral vinorelbine and capecitabine in a phase II study. Patients and methods: Fifty-two patients (median age, 60 years) with MBC received the combination consisting of oral vinorelbine 60 mg/m2 on days 1, 8 and 15 plus capecitabine 1,000 mg/m2 bid given from day 1 to day 14 in an open-label, multicentre phase II study [the recommended doses were established in a phase I study (Nol\ue9 et al. in Ann Oncol 17:332-339, 2006)]. Cycles were repeated every 3 weeks. Results: Seventy-nine percent of the patients had received prior adjuvant chemotherapy and 81% presented with visceral involvement. The median number of administered cycles per patient was 7 (range 1-18). Twenty-three responses were documented and validated by an independent panel review, yielding response rates of 44.2% (95% CI, 30.5-58.7) in the 52 enrolled patients and 54.8% (95% CI, 38.7-70.2) in the 42 evaluable patients. Median progression-free survival and median overall survival were 8.4 and 25.8 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, only one patient having experienced febrile neutropenia. Other frequently reported adverse events included, fatigue, nausea, vomiting, diarrhoea and constipation, stomatitis and hand-foot syndrome, which were rarely severe. Conclusions: This regimen combining oral vinorelbine with capecitabine is effective and manageable in the first-line treatment of MBC. Oral vinorelbine on days 1, 8 and 15 with capecitabine from days 1 to 14 every 3 weeks represents a convenient option which offers an all-oral treatment to the patients and prolongs their infusion-free survival

Trifluridine/tipiracil plus bevacizumab for third-line management of metastatic colorectal cancer: SUNLIGHT study design

Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

International audienceBackground: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann-la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods: In 14-day cycles, patients received FTD/TPI 35 mg/m 2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m 2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC