On 22-September-2015, the US Food and Drug Administration (FDA) approved an oral pill that combines two drugs, trifluridine and tipiracil hydrochloride, (Longsurf®, formerly known as TAS-102, Taiho Pharmaceutical) for patients with advanced colorectal cancer (CRC) who are no longer responding to other therapies (chemotherapy and biologic therapy).1
“The past decade has brought us a new understanding around colorectal cancer, through which we can both better detect and treat this devastating disease,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “But there are many patients who still need additional options, and today’s approval is a testament to the FDA’s commitment to work with companies to develop new drugs in disease areas where unmet needs remain.”
TAS-102 is an oral fixed dose combination comprising of trifluridine (FTD) and tipiracil hydrochloride (TPI). FTD, the active cytotoxic component, is an antineoplastic nucleoside analog, which is incorporated directly into DNA, thereby interfering DNA repair, synthesis and function. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme thymidine phosphorylase.
The mechanism of action of FTD (active ingredient of TAS-102) appears distinct from other fluoropyrimidine agents such as 5-fluorouracil (5-FU), capecitabine. Preclinical evidence indicates that FTD can overcome acquired resistance to 5-FU, and this capacity appears translated into clinical efficacy by extending overall survival in Japanese mCRC patients refractory to 5-FU.2
The efficacy and safety of TAS-102 has been investigated in a phase III international, double-blinded, placebo-controlled, randomized control trial involving 800 patients with advanced colorectal cancer refractory to chemotherapy and biologic therapy (VEGF inhibitor if KRAS mutated, or EGFR inhibitor if KRAS wildtype). Participants received either TAS-102 or placebo on top of best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival.3
The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102. Study participants experienced a median delay of 1.7 months in performance status (PS) deterioration (ECOG PS from 0 or 1 to >2, where 0 indicating no symptoms and high number (up to 5) indicating increasing degree of disability) on treatment of TAS-102 compared with placebo.
The most common side effects of the treatment were neutropenia, leucopenia, thrombocytopenia, physical weakness, fatigue, nausea, decreased appetite, diarrhea, abdominal pain and fever.
FDA recommends evaluating complete blood count prior to and on day 15 of each cycle due to treatment-related severe myelosuppression, and adjusting/ holding dose as clinically indicated.
About colorectal cancer
Colorectal cancer causes significant mortality worldwide. It has been one of the most common killer cancers in Hong Kong for years (based HK Cancer Registry data), only second to lung cancer, and constituted 16.4% (or 4,563 cases) and 14.3% (or 1,903 cases) of all incidence and cancer death in 2012.4
Regulatory status of trifluridine/ tipiracil
To-date (23-September-2015), trifluridine/ tipiracil has been approved for treating unresectable advanced or recurrent colorectal cancer refractory to standard therapy in Japan (in 2014).