New Drug for Colorectal Cancer Shows Promise in Phase II Trial

A new oral treatment is showing promise in relapsed, refractory colorectal cancer. Patients given the antitumor agent TAS-102 showed improved survival and reduced risk of death compared to those given a placebo. Patients in the TAS-102 arm had a median overall survival of 9 months compared to 6.6 months in the placebo group (hazard ratio for death 0.56, P = .0011). The TAS-102 group was also 44% less likely to die during trial period compared to those on the placebo. The results are published in the Lancet Oncology.

Micrograph of colonic adenocarcinoma. Source: Nephron, Wikimedia Commons

TAS-102 is a new oral nucleoside antitumor agent-a combination of a trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI). According to Taiho Pharmaceutical, the company that manufactures TAS-102, FTD is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. TPI functions to prevent FTD from being degraded in the oral form of the drug.

“Preclinical studies have shown that TAS-102 exerts an antitumor effect against fluoropyrimidine-sensitive as well as insensitive cancer cells,” said Takayuki Yoshino, of the department of gastroenterology and gastrointestinal oncology at the National Cancer Center Hospital East, Japan, and lead author of the phase II study. “TAS-102 possesses a mechanism of action different from that of other antitumor agents, including fluoropyrimidine, irinotecan, and oxaliplatin. TAS-102 is expected to be effective against tumors refractory to the various antitumor agents currently available.”

A phase III trial to test TAS-102 in a large colorectal cancer population is already underway, scheduled to be completed by the end of 2014. The international RECOURSE phase III clinical trial began in June of this year. The trial is randomizing approximately 800 advanced, recurrent colorectal cancer patients to either a twice-daily dose of TAS-102 or placebo. All patients have colorectal cancer that is refractory to chemotherapies including irinotecan, fluoropyrimidines, and oxaliplatin, or EGFR antibodies if the patient has KRAS-positive colorectal cancer. The trial will compare TAS-102 to best supportive care for these patients.

Taiho Pharmaceutical is currently planning further clinical development of TAS-102 in other solid tumors, including combination therapy trials. “We are now conducting a phase II trial to evaluate the efficacy and safety in patients with pretreated metastatic or unresectable advanced gastric cancer as the investigator-initiated trial,” said Yoshino. The phase II trial is being conducted in Japan.

Phase II Results

The phase II trial enrolled 169 patients in Japan who had metastatic colorectal cancer and were intolerable to standard chemotherapy. Many of the patients were heavily pretreated, having also received bevacizumab and cetuximab in previous lines of treatment, in addition to chemotherapy. Patients were randomized two to one to either TAS-201, given orally at 35 mg/m² twice daily in a 28-day cycle, or placebo-57 patients in the placebo arm, 112 in the experimental arm. TAS-102 is given for 5 days followed by a rest period of 2 days for 2 weeks followed by a 2-week rest period. All patients in the study received best supportive care. Approximately 60% of participating patients had liver metastases and almost 80% had lung metastases.

Patients were followed up for a median of 11.3 months. Half of the patients in the TAS-102 arm had grade 3 or 4 neutropenia, 28% had leucopenia, and 17% had anemia. Serious adverse events occurred in 19% of TAS-102 arm patients and 9% in the placebo-arm patients. The authors stated that TAS-102 is relatively safe and well tolerated. All patients who experienced blood-related adverse reactions were able to resume treatment after their blood disorder was addressed.

Refractory colorectal cancer is an unmet need. While patients initially respond to chemotherapy and/or EGFR antibodies for KRAS-negative colorectal cancer, few options for advanced, refractory colorectal cancer exist.

“Our results show that TAS-102 has a promising efficacy and an easily manageable safety profile for a group of patients who have virtually no other treatment options available to them,” said Yoshino.

In an accompanying editorial, Alberto Sobrero, MD of the Ospedale San Martino in Genoa, Italy called the results “impressive,” emphasizing the low toxicity (no treatment-related deaths and only 5 patients who discontinued treatment). Sobrero cautions that results of the phase III trial will ultimately show the promise of TAS-102. Reading too much into phase II results can result in disappointment, as recently occurred with perifosine, an AKT inhibitor that initially showed promise in a phase II trial but did not live up to efficacy expectations in a follow-up phase III trial.

Sobrero also cautions that analysis of each refractory patient is necessary as re-induction with a previously used therapy can have positive outcomes. “If patients were not truly refractory in Yoshino and coworkers’ trial, the long time from progression to death and the large percentage of patients receiving fifth-line treatment could be explained,” said Sobrero. The editorial author also points out the efficacy results could be due to a nonspecific effect of fluoropyrimidine rechallenge rather than a specific drug effect.

Sobrero emphasized that the model of small phase II trials compared to best supportive care for new agents may be the best approach to achieve robust overall survival results and movement of the agent into a phase III trial. If this model works for TAS-102, it will provide a model for the development of colorectal cancer agents going forward.