Trifluridine/Tipiracil and Regorafenib in Patients with Metastatic Colorectal Cancer: A Retrospective Study at a Tertiary Oncology Center

BackgroundTrifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist.Materials and MethodsA retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana‐Farber Cancer Institute, was conducted. Using best tumor response assessments, real‐world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan‐Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second‐ or third‐line were performed.ResultsOne hundred twenty‐six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value <.05; rwDCR 64.2% vs. 46.1%; adjusted OR = 2.5; all p value <.05). Similar findings were observed for FTD/TPI versus regorafenib as second‐ or third‐line therapy (rwORR 54.8% vs. 25.9%; adjusted OR = 4.1; all p value <.05; rwDCR 69.0% vs. 37.0%; adjusted OR = 4.9; all p value <.05). A greater proportion of patients treated with FTD/TPI versus regorafenib survived at 3 months (86.2% vs. 73.4%; p value = .016) and 4 months (79.6% vs. 65.8%; p value = .017). Adjusted OS hazard ratio for FTD/TPI versus regorafenib was 0.80, p value = .157.ConclusionPatients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second‐ or third‐line suggests that early use of FTD/TPI may have clinical benefits.Implications for PracticeIn this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real‐world objective response rate (rwORR) and real‐world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow‐up, particularly at months 3 and 4. This study offers insight into patients'' treatment experience in real‐world clinical settings.     

Effectiveness and Safety of Regorafenib vs. Trifluridine/Tipiracil in Unresectable Colorectal Cancer: A Retrospective Cohort Study

IntroductionCompared with the best supportive care, a survival benefit of using regorafenib and trifluridine/tipiracil (TFTD) in patients with colorectal cancer has been shown in previous randomized controlled trials (RCTs). However, there is no RCT or large-scale observational study directly comparing regorafenib and TFTD.Patients and MethodsWe used a nationwide claims database in Japan and compared the effectiveness of regorafenib and TFTD for metastatic colorectal cancer during 2013 to 2018. The patients were divided into 4 groups (regorafenib monotherapy, regorafenib/TFTD: regorafenib followed by TFTD, TFTD monotherapy, and TFTD/regorafenib: TFTD followed by regorafenib). Overall survival (OS) and adverse events were compared between the groups. In a subgroup analysis, we also compared treatment effectiveness between the group in which regorafenib was administered first and the group in which TFTD was administered first.ResultsWe identified 7279 patients (regorafenib: 1501, regorafenib/TFTD: 973, TFTD: 3777, and TFTD/regorafenib: 1028). The corresponding median OS was 6.4, 16.4, 10.2, and 16.9 months, respectively. A log-rank test showed significant intergroup differences (P < .001). In the subgroup analysis, the group in which TFTD was administered first showed significantly longer OS. The incidences of most adverse events were the lowest in the TFTD group. The TFTD group showed longer OS than the regorafenib group, and sequential drug use resulted in the most prolonged OS.ConclusionOur findings indicate that it might be better to prescribe TFTD first. Furthermore, owing to the longer OS than monotherapy, sequential administration of regorafenib and TFTD ought to be considered.     

Optimizing Treatment Sequence for Late-line Metastatic Colorectal Cancer Patients Using Trifluridine/Tipiracil and Regorafenib

Background

Treatment sequencing for patients with refractory metastatic colorectal cancer (mCRC) has been highly debated. The thymidine-based nucleoside trifluridine/tipiracil (TAS-102) and the multikinase inhibitor regorafenib have demonstrated clinical benefits in randomized phase III trials compared with placebo. However, limited data are available on the most optimal therapy sequence involving TAS-102 and regorafenib.

Role of Predictive Value of the Modified Glasgow Prognostic Score for Later-line Chemotherapy in Patients With Metastatic Colorectal Cancer

Background

Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated.

Cost-effectiveness Analysis of Regorafenib and TAS-102 in Refractory Metastatic Colorectal Cancer in the United States

Background

Regorafenib and TAS-102 are standard treatment options in refractory metastatic colorectal cancer based on improvement in overall survival by 6 and 8 weeks, respectively, when compared with best supportive care alone (BSC). Given the small incremental clinical benefit, we evaluated their cost-effectiveness from a United States payer’s perspective.

Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter,Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27)

BackgroundNo treatment option was available for patients with RAS-mutated (RASmt) metastatic colorectal cancer (mCRC) who progress after standard combined chemotherapies at the time of the study. After promising results in phase II, the aim of the present NEXIRI-2/PRODIGE 27 trial was to assess the 2-month non-progression rate for sorafenib (NEX) plus irinotecan (IRI), that is, NEXIRI, treatment.MethodsPatients with RASmt mCRC after failure of oxaliplatin, IRI, fluoropyrimidines, and bevacizumab were randomized between NEXIRI (IRI 120-180 mg/m² intravenous, D1 = D15 plus oral NEX 400 mg twice a day) versus IRI (180 mg/m²) versus NEX. Primary endpoint was the 2-month non-progression rate. Secondary endpoints included progression-free and overall survival (PFS and OS), safety, and germline cyclin D1 (CCND1) rs9344 polymorphisms analyses.ResultsA total of 173 patients were included, 59 in NEXIRI, 57 in IRI, and 57 in NEX arms. The 2-month non-progression rate was 52.6% (95% confidence interval [CI]: 39%–66%), 21.4% (10%–33%), and 19.3% (9%–30%) for NEXIRI, IRI, and NEX. Median PFS was 3.6 (95% CI: 2–4.2), 1.7 (1.7–1.8), and 2 (1.8–2.3) months and the median OS was 7.2 (5.8–9.4), 6.3 (4.8–8), and 5.6 (3.9–7.7) months for NEXIRI, IRI, and NEX, respectively. For NEXIRI rs9344CCND1 A/A genotype patients, OS was 19.6 months (95% CI: 4.8–not reached). Main grade 3 toxicities included neutropenia, febrile neutropenia, diarrhea, hand-foot syndrome, and hypertension.ConclusionsIn patients with RASmt mCRC who progressed after standard combined chemotherapies, the results of 2-month non-progression rate and median PFS in the NEXIRI arm were in favor of an increase of the time before progression.     

S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized,Open-label,Multicenter, Phase III Superiority Trial

BackgroundThe efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries).Patients and MethodsPatients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m² of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m² of oxaliplatin on day 1 and 80 mg/m² of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS).ResultsA total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%–62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05).ConclusionAs postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.     

Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia

Objective: Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. Methods: A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. Results: With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. Conclusion: Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.     

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study

Lessons Learned

• Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity.
• This combination might represent a treatment option for refractory metastatic colorectal cancer.

     

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study)

Lessons Learned

• A biweekly TAS‐102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS‐102 plus BEV combination.
• Biweekly TAS‐102 plus BEV combination could reduce unnecessary dose reduction of TAS‐102, maintain higher doses, and possibly be effective even in cases without chemotherapy‐induced neutropenia (CIN).
• The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS‐102 plus BEV.

BackgroundTAS‐102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS‐102 (70 mg/m²/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS‐102 plus BEV combination.MethodsPatients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS‐102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression‐free survival rate at 16 weeks (16‐w PFS rate).ResultsFrom October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS‐102 (70 mg/m²/day). Of the 44 eligible patients, the 16‐w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression‐free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%).ConclusionBiweekly TAS‐102 plus BEV showed promising antitumor activity with safety.     

A Phase I/II Study of XELIRI Plus Bevacizumab as Second‐Line Chemotherapy for Japanese Patients With Metastatic Colorectal Cancer (BIX Study)

Background.

Capecitabine is used mainly with oxaliplatin to treat metastatic colorectal cancer (mCRC). Results from capecitabine plus irinotecan (XELIRI) with or without bevacizumab (BV) have been reported in Europe but not in Japan. Consequently, the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC were assessed in a single-arm phase II study.

Methods.

Eligible patients had had prior chemotherapy containing BV for mCRC and wild-type or heterozygous UGT1A1. Therapy in each 21-day treatment cycle consisted of capecitabine (800 mg/m² twice daily on days 1–15), irinotecan (200 mg/m² on day 1), and BV (7.5 mg/kg on day 1). The primary endpoint was dose-limiting toxicity in phase I and progression-free survival (PFS) in phase II.

Results.

A total of 34 patients (6 in phase I, 28 in phase II) were enrolled from May 2010 to June 2011. Baseline characteristics included a median age of 60 years (range: 22–74 years) for 24 men and 10 women. No dose-limiting toxicities appeared in phase I. Median PFS was 240 days (95% confidence interval: 179–311 days). Overall response rate was 18.1%, and the disease-control rate was 90.9%. The incidence of adverse events frequently associated with irinotecan and capecitabine were neutropenia (any grade, 55.9%; grade 3 or 4, 11.8%), diarrhea (any grade, 50%; grade 3 or 4, 5.9%), and hand-foot syndrome (any grade, 61.8%; grade 3 or 4, 5.9%).

Conclusion.

Our results suggest that XELIRI plus BV is well tolerated and effective as a second-line treatment for mCRC in Japanese patients. This regimen could be especially appropriate for patients resistant to oxaliplatin-based regimens.     

Aflibercept in Combination With FOLFIRI as First-line Chemotherapy in Patients With Metastatic Colorectal Cancer (mCRC): A Phase II Study (FFCD 1302)

BackgroundFOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line.Patients and MethodsPatients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H₀: 55% and H₁= 75%. Data were analyzed in intention to treat.ResultsForty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification.ConclusionAlthough the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.     

Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT)

BackgroundConcomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer.Patients and MethodsOut of the per‐protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment‐by‐PPI‐use interaction was examined after adjusting for stratification factors.ResultsOf the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression‐free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment‐by‐PPI‐use interaction was significant for overall survival and progression‐free survival.ConclusionThe significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression‐free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs.Implications for PracticeThis study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug‐drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.