New Agent Active in Refractory Metastatic Colorectal Cancer

Medscape Medical News > Oncology
New Agent Active in Refractory Metastatic Colorectal Cancer
Roxanne Nelson, RN
May 14, 2015

A novel agent, TAS-102 (Taiho Oncology), modestly improved survival in patients with metastatic colorectal cancer, but more important, it was active in patients who were heavily pretreated and refractory to standard therapies.
Findings from the phase 3 RECOURSE trial, initially presented last year at the World Congress on Gastrointestinal Cancer, were published in the May 14 issue of the New England Journal of Medicine.

In RECOURSE, patients treated with TAS-102 experienced what the researchers describe as a "clinically relevant" prolongation of overall survival in essentially all treatment subgroups, compared with placebo.
Median overall survival was significantly better in the TAS-102 group than in the placebo group (7.1 vs 5.3 months), and the hazard ratio (HR) for death in the TAS-102 group was 0.68 (P < .001). But more important, the compound showed activity in a population in which about half the patients had just finished treatment with a fluoropyrimidine, such as 5-fluorouracil (5-FU) or capecitabine (Xeloda), but had failed to benefit. "These patients experienced a survival benefit when they were given TAS-102, and this confirms what was seen in the laboratory — that TAS-102 is acting in an independent and different manner than the fluoropyrimidines," said lead author Robert J. Mayer, MD, faculty vice president for academic affairs, medical oncologist, and colorectal cancer researcher at the Dana-Farber Cancer Institute in Boston. "In this heavily pretreated group, there was an effect on outcomes," he told Medscape Medical News. The effect was "not only in survival, but in delaying disease progression and in delaying the time for symptoms to develop and for ECOG performance status to change." "This is a modest prolongation of survival, but it is showing that the drug is acting in a different manner. It will undoubtedly lead to opportunities in the very near future to compare TAS-102 with a fluoropyrimidine at an earlier stage in the course of treatment," Dr. Mayer explained. The "benefit in survival is very convincing, and occurs across subgroups," said Anthony J. Olszanski, RPh, MD, director of early clinical drug development at the Fox Chase Cancer Center in Philadelphia. "The survival curves separated early, and the hazard ratio is quite favorable, revealing that treatment with TAS-102 led to a 32% risk reduction in death, compared with placebo, in this population of heavily pretreated individuals," he told Medscape Medical News. "This trial established that heavily pretreated patients refractory to 5-FU benefit from TAS-102, as depicted by a robust but modest improvement in overall survival. This benefit came at the price of manageable toxicity." Induces Response in Refractory Patients
TAS-102 is an orally administered combination of trifluridine, which is a thymidine-based nucleic acid analogue, and tipiracil hydrochloride, which is a thymidine phosphorylase inhibitor. When it was initially studied in Japan, it showed promise in patients with colorectal cancer. This led to small early clinical trials in the United States, which showed that TAS-102 is active in the treatment of refractory disease.

Dr. Mayer and colleagues subsequently conducted their phase 3 trial to evaluate the efficacy and safety of TAS-102 in patients from 13 countries, including Australia, Japan, the United States, and some European countries.
All 800 patients had metastatic colorectal cancer that was refractory to all standard therapies, including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab. In addition, patients with wild-type KRAS tumors were refractory to cetuximab or panitumumab.
Study participants were randomly assigned in a 2:1 ratio to receive TAS-102 or placebo. The primary end point was overall survival.

More patients in the TAS-102 group than in the placebo group were still alive at 6 months (58% vs 44%) and at 12 months (27% vs 18%). And fewer patients in the TAS-102 group experienced disease progression or death (88% vs 94%).
Median progression-free survival was longer in the TAS-102 group than in the placebo group (2.0 vs 1.7 months; HR, 0.48; P < .001). Of the study participants, 760 were evaluated for tumor response (502 in the TAS-102 group and 258 in the placebo group). A partial response was achieved by eight patients in the TAS-102 group, and a complete response was achieved by one patient in the placebo group. This translated to objective response rates of 1.6% in the TAS-102 group and 0.4% in the placebo group (P = .29). When assessed at least 6 weeks after randomization, more patients in the TAS-102 group than in the placebo group achieved disease control, defined as a complete or partial response or stable disease (44% vs 16%; P < .001). Overall, adverse events of grade 3 or higher occurred more frequently in the TAS-102 group than in the placebo group (69% vs 52%). The most common clinically significant events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%. In addition, 4% of patients in the TAS-102 group developed febrile neutropenia, and one death was related to TAS-102. Also more common in the TAS-102 group than in the placebo group were nausea of grade 3 or higher (2% vs 1%), vomiting (2% vs <1%), and diarrhea (3% vs <1%). Use at Earlier Stage?
The next step will be to study TAS-102 in combination with other agents, and at an earlier stage in the course of the disease, Dr. Mayer explained.
Dr. Olszanski said he agrees that this is a feasible direction for the compound. "In this study, TAS-102 led to stabilization of disease in a heavily pretreated population. In an earlier setting, it could plausibly lead to increased responses," he noted.
"It clearly works through a different mechanism than 5-FU, and further studies at an earlier disease stage will be necessary before it will supplant 5-FU use," Dr. Olszanski added. "This study, as well as others, suggests that TAS-102 works even in patients resistant to 5-FU. TAS-102 works through a mechanism of action not previously exploited in the treatment of colorectal cancer and, as such, will likely become a welcome addition to the current armamentarium of treatment choices for patients."
The study was funded by Taiho Oncology–Taiho Pharmaceutical. Dr. Mayer has disclosed no relevant financial relationships. Several of his coauthors report relationships with industry, including the manufacturer, as detailed in the publication.
N Engl J Med. 2015;372:1909-1918. Abstract