TAS-102 Research Articles

Utilization of TAS-102 (TAS) or regorefenib (Rego) among commercially insured refractory metastatic colorectal cancer (R-mCRC) patients.

e23121 Background: R-mCRC is the time period after use of fluoropyrimidine, oxaliplatin, and irinotecan and usually in conjunction with biological therapies. Several agents are efficacious during R-mCRC with high level evidence for survival improvement. We describe access and utilization of therapeutics in this state using claims data. Methods: This is a retrospective cohort study using the Optum’s de-identified Clinformatics® Data Mart Database (2013-2020). We identified patients (pts) with mCRC after 2014; the metastasis date was set as the index date. Pts were required to have a continuous enrollment for 6 months pre- and 18 months post-index to ensure they were potentially in the refractory setting. Eligible pts were required to have utilization of standard therapies after diagnosis of metastatic disease. Those who switched from FOLFOX to FOLFIRI or vice versa were classified as refractory. The use of either TAS or Rego was identified during the entire follow-up period. Baseline characteristics were compared between patients who received TAS or Rego and those who did not using Chi-Squared test/T-test. We conducted multivariate logistic regressions to evaluate the factors associated with patients’ access to TAS or Rego. Results: 6,233 pts with mCRC identified, 53.7% male, and 70.4% white. FOLFOX was the dominant treatment in the 1L setting (60.1%). 9.7% received either TAS or Rego, with 4.8% taking Rego first and 4.9% receiving TAS first. Recipients of TAS or Rego were younger (mean age of 62.8 vs. 66.5, p < 0.001) and had fewer comorbidities (e.g. myocardial infarction was associated with reduced probability of receiving either TAS or Rego (p < 0.05)). More were enrolled in preferred provider organization in pts using these agents (45% vs. 37.5%, p < 0.001). In the multivariate analysis, Asian pts had a higher likelihood of using late-line therapies (OR = 1.53, p < 0.05). Among 707 pts who switched from FOLFOX to FOLFIRI or vice versa (R-mCRC), 29.8% received late-line therapy (15.7% TAS followed by Rego). The trends were similar among these patients. The TAS or Rego recipients were younger than the non-recipients (mean age of 60.6 vs. 63.8, p < 0.001), had fewer comorbidities, and enrolled in preferred provider organization (47.5% vs. 38.5%, p < 0.05). Conclusions: While front line therapy for mCRC is relatively homogenous, there is significant heterogeneity in transitioning and receiving later lines of therapy. This claims level analysis highlights the disparities in access to later lines of therapy. Further analyses for characterization of the patterns of care and disparities are underway.

Phase IB/II first line panitumumab, irinotecan, trifluridine/tipiracil in RAS wild-type patients with metastatic colorectal cancer: PIT study.

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

BackgroundKRAS 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.MethodsIn 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.ResultsAfter 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.ConclusionsIn 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.)

Prognostic Value of TACE With Irinotecan-loaded Drug-eluting Beads (DEBIRI) in Patients With Liver Metastases from Unresectable Colorectal Cancer.

The standard of care for patients with colorectal cancer and liver metastases, who fail to respond to systemic chemotherapy has not yet been established. Therefore, we investigated the prognostic value of transarterial chemoembolization (TACE) using irinotecan-loaded drug-eluting beads (DEBIRI) in treating liver metastases due to colorectal cancer. Forty-six patients with colorectal cancer and unresectable liver metastases, who received systemic chemotherapy beyond the third line at our hospital between July 2014 and April 2020 were analyzed. They were divided into two groups: 1) Seventeen patients who received TACE with DEBIRI, and 2) twenty-nine patients who did not receive TACE. The median age was 68 years (range=37-85 years), and the male-to-female ratio was 29:17. The primary sites were the cecum in six cases, ascending colon in seven cases, transverse colon in two cases, descending colon in three cases, sigmoid colon in 14 cases, and rectum in 14 cases. All patients had received at least two prior systemic chemotherapy regimens including oxaliplatin-based and irinotecan-based regimens, and trifluridine tipiracil hydrochloride (38 patients) or regorafenib (12 patients) as the third line or beyond (overlap). Median survival was 272 days overall, 416 days in the TACE group, and 229 days in the non-TACE group, with significantly better survival in the TACE group (p=0.0126). TACE with DEBIRI may improve the prognosis of patients with liver metastases from unresectable colorectal cancer. We suggest that TACE with DEBIRI should be highly considered, especially in patients in whom liver metastasis may be a prognostic factor.

Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer

BackgroundIn 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.MethodsWe 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).ResultsA 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).ConclusionsAmong 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.)

Trifluridine–tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study

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. 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. 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. 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. Servier International Research Institute, Suresnes, France.

436TiP COLSTAR: Randomized, open-label, multicentre, phase III study comparing futuximab/modotuximab plus trifluridine/tipiracil to trifluridine/tipiracil in KRAS/NRAS and BRAF wild type (wt) metastatic colorectal cancer (mCRC) previously treated with both standard and anti-EGFR treatment

Approved treatments for 3rd-line mCRC are limited and outcomes remain poor. Trifluridine/tipiracil (TT) is a standard of care option for patients previously treated/not considered candidates for available therapies. Futuximab/modotuximab (FuMo) is a biological composed of a 1:1 mixture of two monoclonal antibodies, futuximab and modotuximab, that bind to non-overlapping epitopes on the extracellular domain (ECD) of EGFR. FuMo has demonstrated activity in RAS/BRAF wt mCRC EGFR-pretreated patients in the Sym004-05 phase II study. Anti-EGFR Mabs have been safely combined with TT. COLSTAR (NCT05223673) is a randomized, open-label, phase III study comparing FuMo + TT with TT alone with a safety lead-in (SLI) part. Main eligibility criteria include KRAS/NRAS (exons 2, 3 and 4) and BRAF wt (V600E mutation) (double negative; DN) assessed by centralized analysis of ctDNA at screening, and previous treatment with at least 2 regimens including fluoropyrimidine, irinotecan, oxaliplatin, at least one anti-VEGF (bevacizumab, aflibercept, ramucirumab, regorafenib) and at least one anti-EGFR mAb (cetuximab or panitumumab) for ≥4 months. Randomization will be done in a 1:1 ratio to TT (35 mg/m2 BID on days 1-5 and days 8-12 of a 28-day cycle) or to the same dose of TT + FuMo (9 mg/kg loading dose on day 1 of cycle 1 followed by 6 mg/kg weekly). Stratification will be done according to performance status (ECOG 0 vs 1), previous regimens of treatment (2 vs ≥3), and EGFR ECD mutations (presence vs absence). Approximately 25 patients will be enrolled in the SLI part and 500 in the randomized part of the study. Primary objectives are: safety and tolerability of FuMo + TT according to CTCAE v5.0 (part 1) and superiority of the combination in terms of OS in the DN population (part 2). The key secondary endpoint is OS in the triple-negative (KRAS/NRAS, BRAF, and EGFR-ECD wt) population (part 2). A group sequential design with 3 interim analyses (IA) will allow to stop the trial prematurely for futility at each IA as well as for efficacy at last IA. NCT05223673. Institut de Recherches Internationales Servier.

Prognostic Value of Sarcopenia in Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil.

Sarcopenia is common in metastatic colorectal cancer (mCRC), increases the risk of treatment-related toxicity and reduces survival. Trifluridine/tipiracil (TT) chemotherapy significantly improved survival in refractory mCRC patients, but the prognostic and predictive role of pretherapeutic sarcopenia and variation in the skeletal muscle index (SMI) during this treatment has not been investigated so far. In this retrospective, observational study, clinical data on mCRC patients treated with TT at six cancer centres in Poland were collected. Computed tomography (CT) scans acquired at the time of initiation of TT (CT1) and on the first restaging (CT2), were evaluated. SMI was assessed based on the skeletal muscle area (SMA) at the level of the third lumbar vertebra. Progression-free survival (PFS) and overall survival (OS) were calculated from the treatment start. Neither initial sarcopenia nor ≥5% skeletal mass loss (SML) between CT1 and CT2 had a significant effect on PFS in treated patients (p = 0.5526 and p = 0.1092, respectively). In the multivariate analysis, reduced OS was found in patients with ≥5% SML (HR: 2.03 (1.11–3.72), p = 0.0039). We describe the prognostic role of sarcopenia beyond second line treatment and analyze other factors, such as performance status, tumor histological differentiation or carcinoembryonic antigen level that could predict TT treatment response.

PD-8 Regorafenib with TAS-102 in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY)

The oral fluoropyrimidine TAS-102 (TAS) and the multi-kinase inhibitor regorafenib (REGO) both show efficacy as single agents in the treatment of refractory metastatic CRC patients (pts). The REMETY trial was conducted to determine a recommended phase II dose (RP2D) of their combination and to increase efficacy in this third-line setting.

Economic evaluation of trifluridine/tipiracil (TT) versus nivolumab (N) in patients with advanced/metastatic gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in Canada.

376 Background: Systemic treatment options in pre-treated patients with advanced/metastatic GC and GEJC have historically been limited especially in the third line or more. Recent potential advances in the therapeutic landscape of this patient population include TT (TAGS study) and immune checkpoint inhibitors (ICI) such as N (ATTRACTION-2 study). There is an anticipated budgetary impact on healthcare systems within the context of these potentially funded options. An economic evaluation can be instrumental in choosing a regimen if survival and quality of life are felt to be comparable. Methods: A cost minimization analysis was performed in Canadian dollars ($) comparing TT and N respectively in advanced de novo and relapsed GC/GEJC cases diagnosed in 2017 and subsequently treated in the third line in Canada. Direct costs including drug acquisition costs, supportive medications, transfusions, laboratory tests, physician visits, pharmacy and nursing time (health resource utilization-HRU) costs were calculated utilizing Ontario data. Direct costs for treatable adverse events G3/4 &gt; 5% were incorporated. The analysis assumed complete drug delivery and the number of target patients was derived from constructed schema. Results: Compared to TT, the use of N was associated with a higher direct cost by a difference of $2.63 million (M) in the third line for GC and GEJC in Canada, principally reflecting a greater drug acquisition cost.The direct costs ranged (IQR) from 3.65M - 10.62M for TT to 3.3M – 15.69 M for N. N also had a greater HRU cost at 2.7 times that of TT and this was 64% of the direct costs for N excluding drug cost versus 42% of the direct non drug costs for TT. Supportive care (GCSF and transfusions) were 34% of the direct cost for TT excluding drug cost. A sensitivity analysis was performed. Conclusions: N generated a higher direct cost both for drug acquisition cost and other direct costs especially in HRU. Despite the increased cost of supportive care for adverse events related to TT, the direct non drug costs were less for this option. The use of biomarkers predictive of response may reduce the potential cost burden of the use of ICIs.

Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).

158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categories were used to define DLTs if they occurred during the first 2 treatment cycles: any grade ≥3 non-hematologic toxicity (except vomiting, nausea, non-significant lab abnormalities), grade ≥3 hematological toxicities, grade ≥3 bleeding. Tumor response was assessed Q8W as per RECIST1.1. EudraCT 2016-001968-11; NCT03305913. Results: All observed toxicities were consistent with safety profile of individual IMPs. 6 pts were enrolled into each DL1 and DL2 (n=12 in total). One DLT was observed in 1/6 pts in DL1; 2 DLTs in 2/6 pts in DL2. All DLTs were only grade 3 hypertension was well manageable, causality was attributed to REGO. No DLT resulted in treatment discontinuation. Results indicate a RP2D of 25mg/m² TAS-102 BID + 120mg REGO daily. No remissions were observed. Overall disease control rate (DCR) after 8 weeks was promising with 58.3% (DCR of 33.3% for DL1 and 83.3% in DL2) and remarkably better as historical data with 41/44% for REGO/TAS102 alone, respectively (Lancet 2013/NEJM 2015). Conclusions: Toxicities of REGOTAS were consistent with safety profiles of REGO and TAS alone. No additional DLTs were attributed to REGOTAS. Thus, the risk-benefit assessment of REGOTAS was positive. DCR was clinically quite meaningful. Mature PFS and OS will be presented at the meeting. Clinical trial information: NCT03305913. [Table: see text]

Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: an exploratory analysis

BackgroundThe choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes.MethodsThis post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with <3 metastatic sites at randomisation (low tumour burden) and ≥18 months from diagnosis of metastatic disease to randomisation (indolent disease) were included in the good prognostic characteristics (GPC) subgroup; the remaining patients were considered to have poor prognostic characteristics (PPC).ResultsGPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the trifluridine/tipiracil and placebo arms. GPC patients receiving trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p<0.0001) and progression-free survival (3.3 vs 1.9 months; HR (95% CI) 0.56 (0.46 to 0.67), p<0.0001) than PPC patients receiving trifluridine/tipiracil (n=273). Improvements in survival were irrespective of age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), KRAS mutational status, and site of metastases at randomisation. In the trifluridine/tipiracil arm, time to deterioration of ECOG PS to ≥2 and proportion of patients with PS=0–1 discontinuing treatment were longer for GPC than for PPC patients (7.8 vs 4.2 months and 89.1% vs 78.4%, respectively).ConclusionLow tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.

Temporary loss of consciousness during cetuximab treatment of a patient with metastatic colon cancer: a case report

BackgroundAnti-epidermal growth factor receptor (EGFR) antibody is widely used for the treatment of patients with metastatic colorectal cancer. Hypomagnesemia is a comparatively frequent adverse event of this drug, which is likely overlooked because it occurs later in treatment without symptoms. Furthermore, hypomagnesemia and hypomagnesemia-induced corrected QT (QTc) prolongation may lead to loss of consciousness (LOC), the onset of which is not generally considered associated with the treatment of anti-EGFR antibody because of its rare occurrence. Here, we present a colorectal cancer patient treated with anti-EGFR antibody, who suffered LOC during treatment while severe hypomagnesemia or QTc prolongation was not observed.Case presentationA 69-year-old man with metastatic colon cancer was treated with cetuximab (anti-EGFR antibody) plus irinotecan as third-line chemotherapy. His serum magnesium level gradually decreased, and grade 2 hypomagnesemia (a serum magnesium level of 0.9 mg/dL) was observed at the 12th administration of cetuximab. In light of this development, intravenous supplementation of 20 mEq magnesium sulfate began with careful blood monitoring despite the lack of clinical symptoms. Electrocardiogram (ECG) showed prolonged QT or corrected QT (QTc) intervals (grade 1). His serum magnesium level remained at 0.9 mg/dL, and no hypomagnesemia symptoms were observed by the 17th administration of cetuximab. After the treatment, however, he suddenly lost consciousness without symptoms related to infusion or allergic reactions. Circulatory collapse following dermatological reactions and respiratory events were not evident. Intravenous supplementation of magnesium sulfate was administered again. He awakened 2 min after the onset of temporary LOC without any other symptoms related to hypomagnesemia, such as lethargy, tremor, tetany, and seizures. No other etiology outside of the low level of serum magnesium was confirmed in further examinations. Cetuximab was discontinued, and his serum magnesium level returned to a level within the normal range after 6 weeks. Because of tumor progression, regorafenib and TAS-102 (trifluridine tipiracil hydrochloride) were introduced sequentially for 6 months. Five months after the final treatment of TAS-102, he died of his primary disease, which reflected a survival period of 4 years and 6 months since the beginning of treatment.ConclusionsThis case report reminds clinicians that LOC can be induced without severe hypomagnesemia or QTc prolongation, during anti-EGFR antibody treatment for metastatic colorectal cancer even while under carefully monitored magnesium supplementation.

The safety and efficacy of trifluridine-tipiracil for metastatic colorectal cancer: A pharmacy perspective.

The pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, and place in therapy of trifluridine-tipiracil are reviewed. Trifluridine-tipiracil is an oral antineoplastic agent consisting of trifluridine (a trifluorothymidine, a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor), at a molar ratio of 1:0.5. Tipiracil blocks the degradation of trifluridine by thymidine phosphorylase, which improves the bioavailability of trifluridine and allows for oral administration. A Phase III study comparing trifluridine-tipiracil versus placebo in metastatic colorectal cancer (mCRC) patients refractory to or intolerant of standard therapy (n = 800) showed a benefit in overall survival (the primary endpoint) and progression-free survival compared with placebo. The most common grade ≥ 3 adverse events in trifluridine-tipiracil groups in Phase II and III trials were neutropenia, anemia, and leukopenia. The recommended dose of trifluridine-tipiracil is 35 mg/m2 twice a day after meals in a 28-day cycle comprising 2 weeks of 5 days of treatment and 2 days of rest (days 1-5 and 8-12 [every] 28 days), followed by 2 weeks of rest. Trifluridine-tipiracil is approved for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antivascular endothelial growth factor biological therapy and, if RAS wild-type, an antiepidermal growth factor receptor therapy. Trifluridine-tipiracil is a new treatment option for patients with mCRC who have received at least 2 prior lines of standard chemotherapy (including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an antiepidermal growth factor receptor antibody in patients with KRAS wild-type tumors). Ongoing trials are investigating trifluridine/tipiracil in combination with other anticancer agents for mCRC and its use in other malignancies, such as metastatic gastric cancer.

The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer

ABSTRACTIntroduction: TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free survival (PFS), and overall survival (OS) as compared with placebo in patients with refractory mCRC.Areas covered: This manuscript aims to review the clinical development of TAS102 in CRC, with a particular focus on safety, and to provide some perspective regarding its role in clinical practice. A literature search was conducted of MEDLINE and EMBASE databases for published studies (January 2004–December 2016) using the search terms TAS102, trifluridine–tipiracil, metastatic or advanced CRC, clinical trial, toxicity, safety, pharmacology, pharmacokinetics, and therapy.Expert opinion: TAS102 significantly improves survival of patients with refractory mCRC and has manageable toxicity. An expanding role in the treatment of CRC is expected for TAS102 in the near future, as its favorable safety profile makes TAS102 a suitable drug to be combined with other cytotoxic and targeted agents.

Trifluridine-Tipiracil for Previously Treated Metastatic Colorectal Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf®), to submit evidence for the clinical and cost effectiveness of T/T compared with best supportive care (BSC) for metastatic colorectal cancer (third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company’s submission (CS), the ERG report and the development of the NICE guidance for the use of this drug in England and Wales by the appraisal committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of T/T based upon the CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE) showed that T/T resulted in a significant increase in overall survival [OS; hazard ratio (HR) 0.67, 95% CI 0.58–0.78] and progression-free survival (PFS; HR 0.46, 95% CI 0.40–0.53). The AC considered the survival benefit of T/T clinically meaningful although relatively small. The ERG highlighted that none of the participants in the phase II trial and approximately half of the RECOURSE participants (394 of 800) were from Europe, which might limit the applicability of the study findings to the NHS. Moreover, the ERG’s critical assessment of the company’s economic evaluation highlighted a number of concerns that resulted in 11 adjustments to the company’s base-case analysis. The ERG adjustments that had the largest impact were using the RECOURSE trial data only (instead of the pooled evidence), fixing errors and violations and using the utilities from the CORRECT trial (identified in the literature review) only. The ERG preferred to use the RECOURSE trial data only given the suboptimal methodology used by the company to pool the evidence. However, since there were no fundamental arguments to prevent the two trials from being pooled, the ERG also presented its base-case analysis based on the pooled effectiveness estimates. The company base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032 per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392 per QALY gained based on the RECOURSE trial only and pooled evidence, respectively. Since the AC concluded that the most plausible ICER was £49,392 per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as a cost effective use of NHS resources.

Advances in colorectal cancer research from 2017 annual meeting of Chinese Society of Clinical Oncology

There are several progresses in colorectal cancer research from 2017 annual meeting of Chinese Society of Clinical Oncology (CSCO). (1) Phase Ⅲ multi-center trial FRESCO and TERRA study have showed domestic new drug Fruquintinib and Japanese oral combination anti-cancer drug TAS-102 significantly improved overall survival (OS) comparing to placebo in third-line metastatic colorectal cancer (mCRC) patients. (2) Preoperative neoadjuvant chemotherapy with mFOLFOXIRI and selective radiotherapy or concomitant boost neoadjuvant chemoradiotherapy (nCRT) followed by one cycle of XELOX, can improve short-term outcome for locally advanced rectal cancer, and clinical and pathological features can be used to predict complete response following nCRT. (3) In asymptomatic elderly population, the specificity of septin9 methylation detection in plasma cfDNA as colorectal cancer screening is low, but the probability of negative predictions as non-colorectal cancer is high. And integrated signature of the gut microbiome and metabolome serves as diagnostic biomarkers in patients with colorectal cancer. (4) Immunoscore system predicts prognosis after liver metastasectomy in colorectal metastases, and the immune signature difference between right and left colon cancer could explain the difference of targeted therapy. Key words: Colorectal neoplasms; Third-line treatment; Neoadjuvant chemoradiation; Screening; Immune signature

P-332 - Trifluridine tipiracil (TAS 102) in patients with stage IV pretreated colorectal neoplasm: an experience from Rimini City Hospital

P-332 - Trifluridine tipiracil (TAS 102) in patients with stage IV pretreated colorectal neoplasm: an experience from Rimini City Hospital

Efficacy and safety of regorafenib compared to TAS-102 for metastatic colorectal cancer: A systematic review and network meta-analysis.

735 Background: Recent studies have shown regorafenib and TAS-102 (TAS) to be superior to placebo (P) in refractory metastatic colorectal cancer (mCRC). However, no studies have directly compared both drugs. Giving the lack of therapeutic options for these patients,, a systematic review to compare the efficacy and safety of regorafenib compared with TAS was performed, using indirect comparison methods. Methods: A systematic review using PubMed, Medline, Embase, Scopus and Cochrane database to identify published and unpublished studies up to November 2015 for randomized controlled trials (RCTs) for patients with metastatic colorectal cancer, involving regorafenib or TAS was performed. Data including overall survival (OS), progression-free survival (PFS) and toxicity were extracted. Pairwise direct meta-analyses (regorafenib versus placebo and TAS versus placebo) and indirect comparison (regorafenib versus TAS) using network meta-analyses methods (R package “netmeta”) to preserve randomization were performed using random effects. Results: 914 citations were initially identified among which 3 RCTs fulfilled eligibility criteria (CORRECT, CONCUR and RECOURSE trials) involving 1.764 patients (regorafenib: 641, TAS: 534, Placebo: 589). Subgroups of patients (1.659) who had not received prior regorafenib or TAS-102 were used to performed meta-analyses for efficacy. In indirect comparison, there were no statically differences observed between regorafenib and TAS-102 in overall survival (HR 0.96 95% CI 0.56-1.55 p = 0.082) and progression-free survival (HR HR 0.85 95% CI 0.40-1.80 p = 0.0182). In addition, there were no differences in objective response rate and disease control between both drugs. However, regorafenib has statistically more all grade toxicity (risk difference (RD) 0.31 CI 0.25-0.38 p = 0.001) and toxicity grade 3-5 (RD 0.22 CI 0.13-0.31 p &lt; 0.001) compared to TAS. Conclusions: In this indirect comparison, regorafenib and TAS appeared to have similar efficacy. However, regorafenib has more toxicity compared to TAS. Post-approval real world data focusing on the comparative toxicity of regorafenib and TAS is warranted.

Efficacy and safety of regorafenib compared to TAS-102 for refractory metastatic colorectal cancer.

e15010Background: Recent studies have shown Regorafenib (R) and TAS-102 (TAS) to be superior to placebo (P) in refractory metastatic colorectal cancer (mCRC). However, no studies have directly comp...