Pretreated Metastatic Gastric Cancer Research Articles

Impact of muscle mass loss on outcomes in advanced or metastatic gastric cancer patients receiving a second-line treatment.

Sarcopenia is a frequent disorder among cancer patients. It commonly leads to muscle mass wasting and poor clinical outcomes, even though it is rarely recognized and often undertreated. The relationship between skeletal muscle depletion and chemotherapy toxicity or postoperative complications is well known. The aim of the present study was to analyze the impact of sarcopenia on clinical outcomes of pretreated metastatic gastric cancer (GC) patients. 88 pretreated GC patients were retrospectively analyzed. Patients were divided into two groups according to their skeletal mass index (SMI): sarcopenic patients with low SMI (≤39 cm2/m2 for women and ≤55 cm2/m2 for men) and non-sarcopenic patients with normal/high SMI value. The two groups were compared according to outcomes and adverse events. Progression-free survival (PFS) was significantly higher in patients with normal/high SMI than in those with low SMI (6 vs. 3.5 months, respectively; HR 0.52). Similarly, the overall response rate (ORR) was higher in the subgroup with normal/high SMI (41% vs. 20%; p=0.02). Overall survival (OS) was not significantly different, but multivariate analysis demonstrated that both SMI and performance status were associated with OS. In the sarcopenic group, the patients treated in the second line with paclitaxel and ramucirumab regimen showed a better outcome profile. Overall, adverse events (AEs) were more frequent in the group of patients with low SMI (p<0.0001). Early recognition of sarcopenia may contribute to personalizing second or further lines of treatment in advanced GC and to weigh up the potential risk of serious toxicities.

O-4 Trifluridine/tipiracil (TAS-102) with or without bevacizumab in patients with pretreated metastatic esophago-gastric adenocarcinoma (mEGA): A Danish randomized trial (LonGas)

Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) prolongs survival in patients with heavily pretreated metastatic gastric cancer (Shitara, Lancet Oncol 2018). The randomized Danish Lonsurf trial showed that a combination of FTD/TPI and bevacizumab prolonged PFS and OS in patients with chemo-refractory metastatic colorectal cancer (Pfeiffer, Lancet Oncol 2020). Inspired by these results, we designed the present investigator-initiated randomized trial testing FTD/TPI and bevacizumab in patients with pretreated mEGA. The main inclusion criteria were histologically confirmed mEGA, previous therapy with a fluoropyrimidine and platinum, PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m2/dose bid from days 1-5 and 8-12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. A total of 96 patients were needed to show an increase in progression-free survival (PFS – primary endpoint) from 2.0 months to 4.0 months. To ensure at least 96 evaluable patients we included 103 patients. Here we report efficacy and safety data of all randomized patients (intention-to-treat population). 103 pretreated patients with mEGA were randomized from October 2019 to September 2021 at 4 Danish University Hospitals. Baseline characteristics were (arm A/arm B): median age 66/64 years, females 19%/22%; PS 0 47%/44%, median number of metastatic sites 2/2, at least 2 prior lines of therapy 42%/42%. Baseline characteristics including blood tests were well balanced. There was no significant difference in PFS (6 months PFS 28% vs 40%, 12 months PFS 6% vs18%, median PFS 3.7 vs 3.9 months; HR 0.71, p=0.11), median OS (9.0 vs 9.9 months; HR 0.86, p=0.53), response rate (2% vs 6%; p=0.35) or disease control rate (47% vs 56%; p=0.43)b. Therapies were well tolerated with adverse events as expected and with no significant difference in severe toxicity. Neutropenia ≥ grade 3 was observed in 49%/46% of patients, but only febrile neutropenia in 8%/10%. Other severe adverse events were fatigue 4%/10% and nausea 6%/6%. In patients with pretreated mEGA, FTD/TPI + bevacizumab did not improve efficacy compared with FTD/TPI monotherapy in patients previously treated with fluoropyrimidine and platinum. Both regimens produced encouraging PFS and OS and both regimens were well tolerated with adverse events as expected. Compared to the heavily pretreated patients in TAGS, only 42% of patients in LonGas had received at least 2 lines of therapy. This may account for the unexpected long PFS in patients receiving FTD/TPI monotherapy.

Clinical features as potential prognostic factors in patients treated with nivolumab for highly pretreated metastatic gastric cancer: a multicenter retrospective study

BackgroundAlthough nivolumab (anti-programmed cell death-1 antibody) is a promising approach for advanced gastric cancer (AGC), the response rate remains limited. The aim of this multicenter retrospective study was to determine if clinical features could serve as prognostic factors of the efficacy of nivolumab in patients with AGC.MethodsFifty-eight patients with AGC who were treated with nivolumab as a third or later line from October 2017 to December 2018 at any of five clinical sites were enrolled in the study. The correlation between the best overall response and clinical features was investigated. Overall survival and progression-free survival after initiation of nivolumab were calculated and clinical features that could be predictors of the prognosis were sought.ResultsThe disease control rate (DCR) for nivolumab was 36.2% and was significantly correlated with performance status (p = 0.021), metastasis to one organ (p = 0.006), and grade 2 or higher immune-related adverse events (p = 0.027). There was also a significant association between response to nivolumab and ability to receive subsequent chemotherapy (p = 0.022). In the analysis of overall survival, the following variables were identified as being significantly associated with a poor outcome: Eastern Cooperative Oncology Group performance status ≥1, prior treatment with trastuzumab, no immune-related adverse events, lack of a response to nivolumab, and inability to receive subsequent chemotherapy.ConclusionThe findings of this study suggest that nivolumab may be ineffective for AGC in patients with poor performance status and those with a history of treatment with trastuzumab.

Real-World Data of Trifluridine/Tipiracil for Patients With Advanced Gastric Cancer: A Multi-Institutional Retrospective Study.

A trial with trifluridine/tipiracil (FTD/TPI) versus placebo in patients with heavily pretreated metastatic gastric cancer showed that FTD/TPI is effective with manageable toxicity in these patients. However, real-world data on the effects of FTD/TPI in patients with advanced gastric cancer (AGC) are limited. We retrospectively collected and analyzed the clinicopathological data of patients with AGC who received FTD/TPI monotherapy at our institutions (Kobe City Medical Center General Hospital, Osaka Red Cross Hospital, Himeji Red Cross Hospital, and Kansai Medical University Hospital) between September 2019 and July 2021. Tumor responses were evaluated based on the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method. A total of 53 patients were included in the study. The median age was 70 (range, 37-85) years; 39 patients (74%) were men; the numbers of patients with Eastern Cooperative Oncology Group performance status scores of 0, 1, and 2 were 10 (19%), 39 (74%), and 4 (8%), respectively; and 27 patients (51%) had diffuse-type histology. A total of 29 patients (56%) had ascites. Prior nivolumab therapy was administered to 49 patients (92%). The response rate and disease control rate (DCR) were 2% and 35%, respectively. The median progression-free survival was 2.4 months, and OS was 5.8 months. Patients with ascites exhibited significantly shorter OS (8.6 vs 4.7 months, P = .0291) than those without ascites, and DCR (54% vs 18%, P = .0055) was significantly worse in patients with ascites. There was no significant difference in the frequency of adverse events of grade 3 or higher between patients with and without ascites. In a real-world setting, FTD/TPI has similar effectiveness as late-line chemotherapy for patients with AGC, including those who previously had received nivolumab.

Cost-effectiveness of trifluridine/tipiracil against nivolumab for heavily pretreated metastatic gastric cancer in Japan.

ObjectiveNivolumab and trifluridine/tipiracil have significantly improved the overall survival of patients with heavily pretreated metastatic gastric cancer in different placebo-controlled phase III trials. Accordingly, nivolumab and trifluridine/tipiracil have been approved and recommended for patients with heavily pretreated metastatic gastric cancer in Japan. The aim of this study was to assess the cost-effectiveness of trifluridine/tipiracil against nivolumab.MethodsA partitioned survival model, which consisted of three health states, namely, ‘pre-progression,’ ‘post-progression,’ and ‘death,’ was constructed. Efficacy and safety data were derived from the TAGS and ATTRACTION-2 trials. Costs were estimated based on the standard clinical pathway and national insurance fee schedules. One-way and probabilistic sensitivity analyses were performed. The threshold value was set to JPY 7 500 000 (USD 68 182) for each quality-adjusted life-year.ResultsThe expected median overall survival and progression-free survival were 5.59 and 1.99 months for trifluridine/tipiracil and 5.26 and 1.55 months for nivolumab, respectively. The quality-adjusted life-year and expected costs per patient were 0.4379 and JPY 2 054 625 (USD 18 678) for trifluridine/tipiracil and 0.5295 and JPY 5 018 148 (USD 45 620) for nivolumab, respectively. The expected median progression-free survival and overall survival were equivalent with trifluridine/tipiracil and nivolumab, whereas the expected quality-adjusted life-year with trifluridine/tipiracil was slightly lower than that with nivolumab. However, trifluridine/tipiracil reduced the total treatment cost by JPY 2 963 523 (USD 26 996) compared with that of nivolumab. The incremental cost-effectiveness ratio of nivolumab versus trifluridine/tipiracil was JPY 32 352 489 (USD 294 113) per quality-adjusted life-year gained.ConclusionsTrifluridine/tipiracil was more cost-effective than nivolumab for patients with heavily pretreated metastatic gastric cancer.

Changes in the therapeutic landscape of oesophago-gastric cancers.

This article reviews recent randomised clinical trials on systemic treatment of oesophago-gastric cancers in the perioperative and metastatic setting. Adding nivolumab to first-line chemotherapy improved survival in patients with metastatic gastric/gastro-oesophageal junction/oesophageal adenocarcinoma with PD-L1 combined positive score (CPS) ≥ five in a global trial and progression-free survival in metastatic gastric/gastro-oesophageal junction cancers in an Asian trial. The addition of pembrolizumab to first-line chemotherapy improved survival in metastatic oesophageal cancer patients, with the most benefit in oesophageal squamous cancer and tumours with high PD-L1 expression (CPS ≥ 10). Adjuvant nivolumab improved disease-free survival (DFS) in resectable oesophageal cancer patients with residual pathologic disease after neoadjuvant chemoradiation. In human epidermal growth factor receptor 2 (HER2)-positive oesophago-gastric adenocarcinoma, a phase II trial showed improved DFS when pertuzumab and trastuzumab were added to perioperative FLOT (5-fluorouracil/leucovorin, oxaliplatin, docetaxel). Another phase II trial showed improved response rates and survival in pretreated metastatic HER2-positive gastric and gastrooesophageal junction cancer patients who received the antibody-drug conjugate trastuzumab deruxtecan compared to physician's choice of chemotherapy. Chemo-immunotherapy combinations will become the new standard of care for some patients with metastatic oesophago-gastric cancers. Adjuvant nivolumab is a new option for oesophageal cancer patients with poor response after neoadjuvant chemoradiation.

The effect of trifluridine/tipiracil for patients with heavily pretreated metastatic gastric cancer: A protocol for systematic review and meta-analysis.

Background:Gastric cancer is a global health problem with high incidence rate and mortality rate. Due to the limitations of traditional chemotherapy drugs, such as patient intolerance, low efficacies and serious adverse effects, trifluridine/tipiracil has been considered to be a promising treatment for patients with heavily pretreated metastatic gastric cancer. However, the relevant systematic review has not been occurring. The presentation of this protocol is to scientifically evaluate the efficacy and safety of trifluridine/tipiracil in patients with highly pretreated metastatic gastric cancer.Methods:The protocol followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. We will systematically search MEDLINE, PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database (CNKI), VIP Chinese Science and Technology Periodical Database (VIP), Wan Fang Database up to November 1, 2020 to identify published articles. Using the Cochrane risk assessment tool to assess the methodological quality of the RCTs, and all included studies will be analyzed according to the criteria in the Cochrane Handbook. Review Manager 5.3 software will be used for literature quality evaluation and data analysis.Results:Objective to evaluate the efficacy and safety of trifluridine/tipiracil in patients with heavily pretreated metastatic gastric cancer by analyzing the eligible data extracted under limited conditions.Conclusion:This study provides clear evidence to evaluate the effectiveness and safety of trifluridine/tipiracil for patients with highly pretreated metastatic gastric cancer, and the findings will also be published in a peer-reviewed journal.Ethics and dissemination:No ethical statement will be required for this study because there is no direct involvement of human. This review will be published in a peer-reviewed journal as a conference report or an article.Registration:OSF registration number: DOI 10.17605/OSF.IO/6MF5U.

Efficacy of Cytotoxic Agents After Progression on Anti-PD-(L)1 Antibody for Pre-treated Metastatic Gastric Cancer.

The efficacy of treatment using the anti-programmed cell death-1 (anti-PD-1) antibody for metastatic gastric cancer (mGC) has been established previously. Exploratory analyses in various types of tumours suggest that prior exposure to immune checkpoint inhibitors can enhance the efficacy of subsequent cytotoxic chemotherapy (CTx). Our aim is to evaluate the efficacy and safety of CTx for mGC after progression on anti-PD-(ligand) 1 [anti-PD-(L)1] antibody. We retrospectively evaluated patients with mGC who underwent CTx. The patients received CTx after progression on anti-PD-(L)1 antibody (cohort A) or as a third-line treatment without prior exposure to anti-PD-(L)1 antibody (cohort B). We evaluated: i) clinical characteristics, ii) efficacies, iii) prognoses, and iv) adverse events (AEs). In cohorts A and B, 16 and 68 patients fulfilled the criteria, respectively. In the univariate analysis, the overall response rate was significantly higher in cohort A compared to cohort B (31% vs. 10%, respectively; Odds Ratio:3.96, 95% Confidence Interval:1.06-14.8, p=0.040). The multivariate analysis showed a similar trend. Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed. CTx after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with mGC.

Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS

BackgroundIn TAGS, an international, double-blind, phase 3 trial, trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS.MethodsPatients were randomized 2:1 to trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2.ResultsOf 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS.ConclusionQoL was maintained in TAGS, and there was a trend towards trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo.Trial registration ClinicalTrials.gov number: NCT02500043

Trifluridine/tipiracil for the treatment of metastatic gastric cancer

ABSTRACTIntroduction: Trifluridine/tipiracil is a novel oral cytotoxic chemotherapy consisting of a thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Trifluridine/tipiracil was approved for the treatment of metastatic colorectal cancer refractory to standard therapies. A phase II trial in Japan demonstrated that this therapy has antitumor activity and is tolerated by patients with advanced gastric cancer (AGC); as a result, the phase III TAGS trial (Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer) was initiated.Area covered: Trifluridine/tipiracil has proved effective for heavily pretreated AGC and has thus been approved for use in the United States in February 2019, Japan in August 2019 and the European Union in September 2019. Detail of the phase III TAGS trial is discussed in this review.Expert opinion: Trifluridine/tipiracil after at least two previous courses of systemic chemotherapy improved rates of survival of gastric cancer; thus it has become one of the treatment options in affected patients. Currently, several clinical trials of trifluridine/tipiracil in combination with other anticancer agents such as ramucirumab (an anti-vascular endothelial growth factor receptor 2 monoclonal antibody) for patients with AGC are ongoing.

Nivolumab in Heavily Pretreated Metastatic Gastric Cancer Patients: Real-Life Data from a Western Population.

PurposeATTRACTION-2 trial assessed the role of Nivolumab as a new standard treatment for Asian patients with pretreated metastatic gastric cancer (mGC). The aim of this analysis was to evaluate the safety and efficacy of Nivolumab in a real-life Western population, considering the lack of evidence to date.Patients and MethodsPatients progressed after ≥2 chemotherapy regimens and able to receive Nivolumab (3 mg/kg q14) were eligible for the analysis.Results16 patients received Nivolumab as third (81.3%) or fourth line (18.7%) from September 2017 to July 2019. The safety was in line with the literature and only one patient discontinued treatment due to persistent hematological toxicity. Overall response rate and disease control rate were 18.7% and 31.2%, respectively. Median duration of response was 5 months. With a median follow-up of 21 months, median OS was 6 months (7, 21 and 22 months in the responders) and median PFS 3 months. PD-L1 and microsatellite status were retrospectively collected in 12 patients. All the major responders were MSI, although no statistically significant difference in OS or PFS was observed according to molecular analysis.ConclusionNivolumab is feasible and effective in Western patients with mGC. Further investigation is urgently needed also in non-Asians.

PCN159 COST-UTILITY ANALYSIS OF TRIFLURIDINE/TIPIRACIL FOR HEAVILY PRETREATED METASTATIC GASTRIC CANCER IN JAPAN

Trifluridine/tipiracil (FTD/TPI) significantly improved overall survival (OS) compared with a placebo in patients with heavily pretreated metastatic gastric cancer (mGC) in the TAGS trial. Based on the ATTRACTION-2 trial, nivolumab has been approved and recommended in patients with heavily pretreated mGC in Japan. Recently, FTD/TPI was approved in same patients in Japan and US. Our objective was to conduct a cost–utility analysis of FTD/TPI against nivolumab for those patients from the healthcare payer’s perspective. A partitioned survival model (PSM), which consisted of three health states—“pre-progression,” “post-progression,” and “death”—was constructed for this analysis. The PSM calculated the proportion of patients in each state; the cost, life-years, and quality-adjusted life-years (QALYs) were then estimated. Efficacy and safety data were derived from the TAGS and ATTRACTION-2 trials. Weibull and exponential distributions were adopted to estimate survival curves for OS and progression-free survival (PFS). Utility scores were obtained from the phase II “INTEGRATE” trial of regorafenib, as no utility data were collected in the TAGS nor ATTRACTION-2 trials. One-way and probabilistic sensitivity analyses were performed. The threshold value was set to JPY7,500,000/QALY. The expected median PFS were 1.99 months and 1.55 months for FTD/TPI and nivolumab, respectively. The median OS were 5.59 months and 5.26 months for FTD/TPI and nivolumab, respectively. The QALYs were 0.4379 and 0.5294 for FTD/TPI and nivolumab, respectively. The expected cost per patient was JPY2,054,625 and JPY5,018,148 for FTD/TPI and nivolumab, respectively. The expected median PFS and OS were equivalent between FTD/TPI and nivolumab, whereas QALY of FTD/TPI was slightly lower than that of nivolumab; however, the effect of cost reduction was very high. The incremental cost-effectiveness ratio of nivolumab against FTD/TPI was JPY32,352,489 (EUR265,184) per QALY gained. FTD/TPI was thought to be cost-effective against nivolumab for patients with heavily pretreated mGC.

Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy

Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy. ClinicalTrials.gov identifier: NCT02500043.

801P - Efficacy and safety of trifluridine/tipiracil (FTD/TPI) in European patients with heavily pretreated metastatic gastric cancer (mGC): An analysis of the TAGS study

801P - Efficacy and safety of trifluridine/tipiracil (FTD/TPI) in European patients with heavily pretreated metastatic gastric cancer (mGC): An analysis of the TAGS study

The results of Japanese subgroup analyses from TAGS: a phase 3 study of FTD/TPI (TAS-102) in heavily pretreated mGC

Abstract Background Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) is an oral cytotoxic agent consisting of a thymidine-based nucleoside analogue and a thymidine phosphorylase inhibitor. TAGS (NCT02500043), a phase III study showed FTD/TPI significantly improved overall survival (OS) compared to placebo (P) in heavily pretreated metastatic gastric cancer (mGC) patients (pts) (Shitara K. et al, Lancet Oncol. 2018). Here we show the results in Japanese subpopulation. Methods This study enrolled pts aged 18 years or older (20 years or older in Japan) with histologically confirmed, non-resectable mGC, Eastern Cooperative Oncology Group Performance Status 0/1, and two or more prior chemotherapy regimens. Pts were randomised 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1-5 and 8-12 of each 28-day cycle) or P. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and safety. Results Between Feb 2016 and Jan 2018, 507 pts were randomised to receive FTD/TPI (n = 337) or P (n = 170). 73 pts were enrolled from 9 sites in Japan, of which 46 pts were randamized in FTD/TPI. Median OS was 6.3 months (m) for FTD/TPI and 5.9 m for P (Hazard Ratio (HR) 0.77, 95% Confidence Interval (CI) 0.46-1.30). Median PFS was 2.0 m for FTD/TPI and 1.7 m for P (HR 0.33, 95% CI 0.19-0.59). Overall response rate and disease control rate for FTD/TPI were 2.6% and 38.5%, respectively. Grade 3 or worse adverse events (AEs) of any cause were reported in 37/46 (80.4%) FTD/TPI-treated pts and 9/27 (33.3%) placebo-treated pts. Grade 3/4 haematological AEs in FTD/TPI-treated pts included neutropenia (52.2%), anaemia (41.3%) and leucopenia (6.5%). Three FTD/TPI-treated pts experienced febrile neutropenia. No new safety signals were observed. Also, we are going to show the details of safety. Conclusions FTD/TPI was effective and well tolerated in Japanese pts with heavily pretreated mGC. The results in Japanese subpopulation were consistent with the overall population.

Novel Agents in Heavily Pretreated Metastatic Gastric Cancer: More Shadows Than Lights.

Metastatic gastric cancer is still a disease with a poor prognosis. Recently, different novel agents (e.g., apatinib, nivolumab, TAS-102) have demonstrated a survival advantage compared with placebo for patients with heavily pretreated metastatic gastric cancer. Although the possible availability of active agents may be a desirable option in a very poor therapeutic scenario, clinical data from the recent studies with these drugs raise yet controversial issues. The purpose of this review is to briefly summarize the results of these novel drugs focusing on the limitations that bring some shadows on their positive therapeutic results.

Cost-effectiveness of trifluridine/tipiracil (TAS102) for heavily pretreated metastatic gastric cancer.

Trifluridine/tipiracil (TAS102), a novel oral cytotoxic chemotherapy, significantly improved overall survival compared with placebo in heavily pretreated advanced gastric cancer. This study aimed to evaluate the cost-effectiveness of TAS102 in the third-line or later treatment for this population from the US payer perspective. A Markov model was developed to simulate advanced gastric cancer, including three health states: progression-free survival (PFS), progressive disease (PD) and death. Model inputs were derived from a randomised, double-blind, placebo-controlled, phase 3 trial (TAGS trial, NCT02500043). Utilities were extracted from public resources. Costs were calculated from an American payer perspective. Sensitivity analyses were conducted to explore the impact of uncertainty. From the US payer perspective, treatment with TAS102 for patients with heavily pretreated advanced gastric cancer was estimated to increase costs by $59,180 compared with the placebo, with a gain of 0.06 quality-adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $986,333 per QALY. The costs for progression-free survival of TAS102 group had the greatest impact on the ICERs, as well as the cost of TAS102. Trifluridine/tipiracil (TAS102) is not a cost-effective choice for patients with heavily pretreated metastatic gastric cancer from an American payer perspective.

Trifluridine With Tipiracil Lifts Survival in Refractory Gastric Cancer

gastric cancer: gastric cancerBARCELONA—A chemotherapy combination consisting of trifluridine with tipiracil showed a “clinically meaningful and statistically significant” improvement in overall survival and progression-free survival (PFS) compared with placebo in patients with heavily pretreated metastatic gastric cancer (mGC) refractory to standard therapies in the randomized phase III TAGS study reported at the ESMO World Congress on Gastrointestinal Cancer 2018 (Abstract LBA-002). “The TAGS study has shown in a randomized phase III setting that trifluridine-tipiracil is an available option for treating patients with gastric or gastroesophageal cancer in the metastatic refractory setting,” said lead author Josep Tabernero, MD, PhD, Chair of Medical Oncology at Vall d'Hebron University Hospital in Barcelona, Spain. Research Details Study results show that patients lived a median of 5.7 months when treated with the new combination compared with 3.6 months in the control group receiving best supportive care—a 2.1 months extension of life and a 31-percent reduction in the risk of death (HR=0.69). The researchers found that the safety profile was “predictable and manageable” with “no new safety signals” and concluded that the combination represented an effective treatment option for patients with heavily pretreated mGC. The TAGS study randomized 507 patients with mGC (including gastroesophageal junction cancer) who had at least two prior regimens, including fluoropyrimidine, platinum, taxane, irinotecan, or a HER2 inhibitor. The 170 patients in the control group were given a placebo plus best supportive care, while the experimental arm of 337 patients (randomized 2-to-1) were treated with a combination of the novel oral thymidine analog trifluridine together with the thymidine phosphorylase inhibitor tipiracil and best supportive care. “The study met the primary endpoint of increasing overall survival. Patients also benefit in long-term survival—in 1 year, for example,” said Tabernero. The study also observed an advantage in PFS that was statistically significant. “There were no differences in safety profile between the two arms in the number of patients who had to discontinue treatment because of treatment-emergent adverse events,” he noted. The safety profile in gastric cancer was found to coincide with documented toxicities in patients with metastatic colorectal cancer treated with trifluridine plus tipiracil. Discussion Points Tabernero told Oncology Times the data were clinically promising, “especially for this highly unmet need population” and that he hoped trifluridine with tipiracil would be approved by regulatory authorities for gastric cancer as it had already been “in more than 50 countries” for metastatic colorectal cancer. Commenting on the study findings David Cunningham, MD, FRCP, Consultant Medical Oncologist and Director of Clinical Research at the Royal Marsden Hospital in London, said the significant survival advantage among patients treated with the new combination was interesting and that it was another option. “When patients have gone through the standard treatment options—usually including 5-FU, a platinum drug, and a taxane—and they have progressed, we can think about offering them the possibility of trifluridine and tipiracil,” he explained. However, for clinical practice, Cunningham recommended that patients be assessed before receiving such treatment, especially as some were not likely to be fit for further therapy after failing three lines of treatment. “We need to be clear about this. This won't be for everybody. But for those patients who are still fit, have good organ function, and wish to explore the possibility of further treatment these drugs represent a genuine alternative,” he said. Cunningham concluded that trifluridine with tipiracil had emerged as an option for patients who had failed standard chemotherapy. “Other options include the checkpoint antibodies like nivolumab. But this represents a regimen that can help some patients.” Peter M. Goodwin and Sarah Maxwell are contributing writers. Learn About More Conferences Start looking ahead to 2019 hematology/oncology conferences by visiting the Oncology Times online conference listing at http://bit.ly/1B38kF4. Here you will find dates, locations, and links for more information.

Efficacy of cytotoxic agents after progression of anti-PD-(L)1 antibody for pretreated metastatic gastric cancer.

152 Background: The efficacy of anti-PD-1 antibody for metastatic gastric cancer (mGC) was revealed. In non-small cell lung cancer (NSCLC), it was reported that overall response rate (ORR) in patients (pts) treated with chemotherapy (CTx) after immunotherapy exposure was higher than historical data from the pre-anti-PD-(L)1 era. The purpose of this retrospective study was to evaluate whether CTx improved efficacy outcomes after exposure anti-PD(L)1 antibody in mGC. Methods: We investigated retrospectively clinical characteristics at baseline of mGC pts who received CTx after progression of anti-PD-(L)1 antibody between April 2014 and August 2017. Anti-PD-(L)1 antibody was adapted as third- or later-line therapy. Pts fulfilled following criteria: histologically proven adenocarcinoma; ECOG PS 0-2; adequate organ functions; and received CTx including fluoropyrimidines (FU), platinum, and taxane or irinotecan. We evaluated efficacy outcomes, including ORR, disease control rate (DCR), time to treatment failure (TTF), and overall survival (OS). Results: Out of 40 treated with anti-PD-(L)1 antibody, 15 pts were included. Patient characteristics were as follows: median age (range), 67 (46-83) years; male/female, 13/2; ECOG PS (0/1/2), 5/8/2; HER2 positive, 8; histology (differentiated/undifferentiated), 10/5; metastatic lesions (peritoneum/liver/lung), 4/8/3; number of metastatic sites (1/≥2), 2/13; number of prior CTx regimens (3/4/5), 2/9/4; median period (range) from first line CTx, 30.7 (12.7-68.1) months; and CTx regimens (FU+oxaliplatin/taxane/irinotecan), 10/3/2. ORR, DCR, median TTF, and OS were 33% (95% CI, 15.2-58.3), 87% (95% CI, 62.1-96.3), 3.5 (95% CI, 1.6-4.4) months, and 7.6 (95% CI, 4.4-8.5) months, respectively. There were no predictive and prognostic factors associated with ORR, TTF, and OS on univariate analysis. At the beginning of CTx, 4 pts had immune-related adverse events (irAEs), but these were manageable and no new irAEs appeared during CTx. Conclusions: Our data support further evaluation of the use of CTx after progression of anti-PD-L 1 antibody, even in heavily pretreated mGC pts. Updated results will be presented.

INTEGRATE phase II trial: regorafenib vs. placebo in pretreated metastatic gastric cancer patients—is there anything new?

Gastric cancer ranks among the most frequent cancers and the third leading cause of cancer mortality in both sexes worldwide (1,2). Unfortunately in western Countries the majority of gastric tumours are diagnosed in an advanced stage, when outcome remains disappointing. In this setting chemotherapy still represents the standard of care with the notable exception of trastuzumab use in HER-2 over-expressing tumours (3-7). Recent progresses in the molecular characterization of gastric adenocarcinomas opened new insight for new treatment possibilities to be hopefully explored in the near future (8).