Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy.Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100 mg) was injected subcutaneously once daily. The primary endpoint was the 2-month response rate determined upon CHOI criteria.Thirty two patients with metastatic colorectal cancer were enrolled. Five patients demonstrated response (Choi criteria) and 22 patients had stable disease as the best 2-month overall response. Median progression-free and overall survival were 5.4 (95% CI, 3.6–6.6) and 14.5 months (95% CI, 9–20.6) respectively. Twenty patients experienced grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia in 8 (25%) patients, digestive side effects in 7 (21.9%) patients and hypertension in 6 (18.75%) patients. No treatment-related deaths or serious adverse events were reported.5-FU plus bevacizumab and anakinra has promising activity and a manageable safety profile, suggesting that this combination might become a potential treatment option for patients with refractory mCRC.

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“…The median overall survival improved from 5.3 months (95% CI, 4.6–6) to 7.1 months (95% CI, 6.5–7.8) (hazard ratio 0.68; p < 0.001). 20 …”

Section: Discussionmentioning

confidence: 99%

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

et al. 2018

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“…26,27 Faz 2 klinik çalışmalarında, metastatik kolorektal kanserli 169 Japon hastaya trifluridin+tipira-sil (TAS-102) kombinasyonu (1. ila 5. günlerde ve 8 ila 12. günlerde sabah-akşam 35 mg/m 2 ve her dört haftada) plasebo ile karşılaştırılmalı olarak verilmiş ve ilacı alan hastalarda ortalama genel sağ kalım 9 ay, plasebo alan hastalarda 6.6 ay olarak belirlenmiştir. 26 Trifluridin+tipirasil (TAS-102), standart kemoterapiye dirençli metastatik kolorektal kanserli rastgele seçilen 800 hastaya yapılan plasebo kontrollü, çift kör, çok uluslu, faz 3 RECOURSE klinik çalışmalarıyla değerlendirilmiştir.…”

Section: Terapöti̇k Etki̇nli̇k Ve Kli̇ni̇k çAlişmalarunclassified

“…Ortalama genel sağkalım, plasebo ile 5.3 ay iken TAS-102 alan hastalar arasında 7.1 ay olarak belirlenmiştir. 27 …”

Section: Terapöti̇k Etki̇nli̇k Ve Kli̇ni̇k çAlişmalarunclassified

“…Trifluridin+tipirasil ile ilişkili en yaygın 3. veya 4. dereceden nonhematolojik toksisite, yorgunluk (%7) ve iştah azalması (%4) gözlenmiştir. 27 Klinik olarak anlamlı en sık görülen yan etki (derece 3 veya 4) nötropeni olmuştur ve TAS-102 ile tedavi edilen hastaların %38'de görülmüştür. TAS-102 alan 533 hastanın %4'de febril nötropeni meydana gelerek bu, septik şoka bağlı ölümle sonuçlanmıştır.…”

Section: Yan Etki̇leri̇unclassified

“…TAS-102 ile tedavi edilen hastaların %1'den azında ise floropirimidinlerin kullanımı ile ilişkili olan 3. veya 4. derece stomatit, el ayak sendromu ve koroner spazm ile karşılaşılmıştır. 27 …”

Section: Yan Etki̇leri̇unclassified

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New Drug Combination in Colorectal Cancer Treatment: Trifluridine and Tipiracil

Avci¹,

Tunçbìlek²

2017

Turkiye Klinikleri J Med Sci

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Ö ÖZ ZE ET T Kanser önemli bir insan sağlığı problemi olup, hem gelişmekte olan hem de sanayileşmiş ülkelerdeki morbidite ve mortalitenin önde gelen nedenlerinden biridir. Kanser, dünyadaki ölümlerin önde gelen ikinci nedenidir ve global olarak, 6 ölümden yaklaşık 1 tanesi kansere bağlıdır. Kolorektal kanser dünyada üçüncü en yaygın kanser ve yılda 700.000 ölümle kanserle ilgili ölümlerde dördüncü ölüm sebebi haline gelmiştir. Cinsiyete göre ise kadınlarda ikinci sı-rada (%9.2), erkeklerde üçüncü sırada (%10) görülmektedir. 1990 yılından 2012 yılına kadar her yıl 200.000 yeni vakayla kolorektal kanser görülme sıklığı artmıştır. Kolorektal kanser vakalarının çoğu Batı ülkelerinde (%55) tespit edilmektedir. Kolorektal kanserin erken evrede tespit edilmesi tedavi için önemlidir. Tarama programları ile kolorektal kansere bağlı morbidite ve mortalitenin azaltılabildiği gözlenmiştir. Tedavide gerekli durumlarda cerrahi müdahale yapı-lırken; 5-florourasil (5-FU), irinotekan, kapesitabin, oksaliplatin gibi kemoterapötikler ile setuksimab, bevasizumab, panitumumab gibi monoklonal antikorlar da kullanılmaktadır. "Trifluridin+tipirasil" kombinasyonu 15 ve 20 mg dozlarında tablet formülasyonunda, yeni bir antineoplastik ajandır. Trifluridin, timidin nükleozit analoğu ve tipirasil, timidin fosforilaz (TP) inhibitörüdür. Metastatik kolorektal kanser hastalarının tedavisi için Amerika Birleşik Devletleri, Avrupa ve Japonya'daki ulusal sağlık otoriteleri tarafından onaylanmış yeni bir oral floropirimidin tedavisidir. Bu çalışma ile metastatik kolorektal kansere karşı kullanılmak üzere yeni bir ilaç kombinasyonu olan "trifluridin+tipirasil"in yapısı, sentezi ve biyolojik etkilerinin incelenmesi amaçlanmıştır.A An na ah ht ta ar r K Ke el li im me el le er r: : Kolorektal kanser; trifluridin; tipirasil A AB BS ST TR RA AC CT T Cancer is a major human health problem and one of the principal reasons of morbidity and mortality in both developing and industrialized countries. Cancer is the second leading cause of death worldwide and globally nearly 1 in 6 deaths is due to cancer. Colorectal cancer is third most common cancer and the fourth most common cause of cancer-related death, with 700.000 deaths per year. By gender, colorectal cancer is the second most common cancer in women (9.2%) and the third in men (10%). The incidence of colorectal cancer has risen by 200.000 new cases per year from 1990 to 2012. Most cases of colorectal cancer are detected in Western countries (55%). Early detection of colorectal cancer is important for treatment. It has been observed that morbidity and mortality due to colorectal cancer can be reduced by screening programs. Surgical intervention, chemotherapeutics such as 5-fluorouracil (5-FU), irinotecan, capecitabine, oxaliplatin and monoclonal antibodies like cetuximab, bevacizumab, panitumumab are used for treatment. The combination of "Trifluridine/tipiracil" 15 and 20 mg tablets, is a new antineoplastic agent. "Trifluridine/tipiracil" is comprised of an antineoplastic thymidine-based nucleoside ana...

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Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer

Jin

Qin

et al. 2018

JAMA

274

235

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IMPORTANCE Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.OBJECTIVE To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS FRESCO (Fruquintinib Efficacy and Safety in 3+ LineColorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017.INTERVENTIONS Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURESThe primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded Ն8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTSOf the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% ( 27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.CONCLUSIONS AND RELEVANCE Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China.

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Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Abstract: In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).

Cited by 1,154 publications

References 18 publications

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

New Drug Combination in Colorectal Cancer Treatment: Trifluridine and Tipiracil

Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer

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