On May 3, 2023 Taiho Oncology, Inc. and Servier reported the publication of results from the pivotal Phase 3 SUNLIGHT* clinical trial of trifluridine/tipiracil (LONSURF), alone or in combination with bevacizumab, in refractory metastatic colorectal cancer (mCRC) in the May 4, 2023, issue of the New England Journal of Medicine (NEJM) (Press release, Taiho, MAY 3, 2023, View Source [SID1234630947]).
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Results of this multinational trial, led by Professor Josep Tabernero, MD, PhD, Head of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, showed that treatment with the investigational combination of trifluridine/tipiracil and bevacizumab resulted in statistically significant and clinically meaningful improvements in overall survival and progression-free survival for patients with refractory mCRC following disease progression or intolerance on two prior chemotherapy regimens compared to trifluridine/tipiracil alone. In addition, the median time to worsening of ECOG (Eastern Cooperative Oncology Group) performance-status score was significantly delayed in patients receiving the investigational combination of trifluridine/tipiracil and bevacizumab. The safety profile of the investigational combination was consistent with that of each agent.
"Individuals living with metastatic colorectal cancer and who have progressed following fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-Epidermal Growth Factor Receptor (EGFR) antibodies – if RAS wild-type – have limited treatment options. There is a growing need for new approaches that improve survival in this population," said Marwan Fakih, MD, Professor, Medical Oncology and Therapeutics Research, City of Hope, and lead U.S. investigator for the SUNLIGHT trial. "The publication of the SUNLIGHT results in the New England Journal of Medicine speaks to the quality of the science and potential impact of this investigational combination on the treatment of metastatic colorectal cancer."
Added Professor Tabernero: "Trifluridine/tipiracil plus bevacizumab may represent a meaningful new treatment option in patients with mCRC who have progressed after two lines of therapy."
Based on results of the SUNLIGHT trial, Servier and Taiho Oncology submitted respectively a type II variation for approval to the European Medicines Agency (EMA) and a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration (FDA) for trifluridine/tipiracil in combination with bevacizumab for the treatment of adult patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. Taiho Oncology announced on April 18, 2023, that the FDA accepted the sNDA for Priority Review and set an anticipated Prescription Drug User Fee Act (PDUFA) action date of August 13, 2023.
Please click here for the Original Article, "Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer."
Please click here for a NEJM "Quick Take" video summarizing the article findings.
About Colorectal Cancer
Colorectal cancer is the third most common cancer worldwide1 with nearly 1.4 million people diagnosed with colorectal cancer (CRC) each year equating to 10% of the global cancer cases.1 CRC is the second most common cause of cancer mortality, accounting for 881,000 deaths globally in 2018.2 The worldwide incidence of colorectal cancer is expected to exceed 3 million cases annually by 2040,3 and the number of deaths is predicted to increase by more than 70% to 1.6 million per year.3
About the SUNLIGHT Trial
SUNLIGHT is a multinational, randomized, active-controlled, open-label, two-arm Phase 3 clinical trial to investigate the efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone, in patients with refractory mCRC following two chemotherapy regimens. A total of 492 patients were randomly allocated (in a 1:1 ratio) to receive trifluridine/tipiracil in combination with bevacizumab or trifluridine/tipiracil monotherapy. The primary objective was to assess trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone, in terms of OS (primary endpoint). Key secondary endpoints were PFS, overall response rate (ORR), disease control rate (DCR) and quality of life (QoL), as well as the safety and tolerability of trifluridine/tipiracil used in combination with bevacizumab in comparison with trifluridine/tipiracil monotherapy.
The SUNLIGHT trial was conducted by Servier and Taiho Oncology, Inc. For more information on SUNLIGHT, please visit: View Source
About LONSURF
LONSURF is an oral nucleoside antitumor agent discovered and developed by Taiho Pharmaceutical Co., Ltd. LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase (TP) inhibitor, tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.
Indications and Use in the United States
LONSURF is indicated for the treatment of adult patients with:
Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy; and
Metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy
IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS
Indications and Use
LONSURF is indicated for the treatment of adult patients with:
Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy
metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Severe Myelosuppression:
LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (38%), anemia (18%), thrombocytopenia (5%), and febrile neutropenia (3%). Two patients (0.2%) died due to neutropenic infection. A total of 12% of LONSURF-treated patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, absolute neutrophil count less than 500/mm3, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose as clinically indicated.
Embryo-Fetal Toxicity:
LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the final dose.
USE IN SPECIFIC POPULATIONS
Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breast-fed infant or the effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants, advise women not to breastfeed during treatment with LONSURF and for 1 day following the final dose.
Male Contraception: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.
Geriatric Use: Patients 65 years of age or over who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs 32%), Grade 3 anemia (22% vs 16%), and Grade 3 or 4 thrombocytopenia (7% vs 4%).
Hepatic Impairment: Do not initiate LONSURF in patients with baseline moderate or severe (total bilirubin greater than 1.5 times ULN and any AST) hepatic impairment. Patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST) were not studied. No adjustment to the starting dose of LONSURF is recommended for patients with mild hepatic impairment.
Renal Impairment: No adjustment to the starting dosage of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min). Reduce the starting dose of LONSURF for patients with severe renal impairment (CLcr of 15 to 29 mL/min) to a recommended dosage of 20 mg/m2.
ADVERSE REACTIONS
Most Common Adverse Drug Reactions in Patients Treated With LONSURF (≥5%): The most common adverse drug reactions in LONSURF-treated patients vs placebo-treated patients with mCRC, respectively, were asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), infections (27% vs 16%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%). In metastatic gastric cancer or gastroesophageal junction (GEJ), the most common adverse drug reactions, respectively were, nausea (37% vs 32%), decreased appetite (34% vs 31%), vomiting (25% vs 20%), infections (23% vs 16%) and diarrhea (23% vs 14%).
Pulmonary emboli occurred more frequently in LONSURF-treated patients compared to placebo: in mCRC (2% vs 0%) and in metastatic gastric cancer and GEJ (3% vs 2%).
Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.
Laboratory Test Abnormalities in Patients Treated With LONSURF: The most common laboratory test abnormalities in LONSURF-treated patients vs placebo-treated patients with mCRC, respectively, were anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%). In metastatic gastric cancer or GEJ, the test abnormalities, respectively, were neutropenia (66% vs 4%), anemia (63% vs 38%), and thrombocytopenia (34% vs 9%).