Significant OS Benefit Seen With TAS-102 Monotherapy in Refractory mCRC

Takayuki Yoshino, MD

Significantly extended overall survival (OS) and progression-free survival (PFS) was seen with oral nucleoside TAS-102 treatment in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, according to phase III results presented at the European Society for Medical Oncology 16th World Congress on Gastrointestinal Cancer.

“We found that the primary endpoint of overall survival was met with a statistically significant and clinically meaningful improvement,” stated lead author Takayuki Yoshino, MD, a medical oncologist at National Cancer Center Hospital East in Chiba, Japan. “Looking at the secondary endpoint, progression-free survival was also statistically improved, and disease control rate was also improved.”

Treatment with the novel cytotoxic agent reduced the risk of progression by 52% and extended survival by 32% when compared with placebo in patients with refractory mCRC. Based on these promising results, the company developing the drug, Taiho Oncology, plans to submit a New Drug Application to the Food and Drug Administration by the end of this year.

Tanios Bekaii-Saab, MD, Discusses Bevacizumab or Cetuximab for CRC

Bekaii-Saab is an associate professor at The Ohio State University.

In the RECOURSE trial, 800 patients with refractory mCRC were randomized in a 2:1 ratio to receive best supportive care plus TAS-102 (n = 534) or placebo (n = 266). Patients had received at least 2 prior lines of treatment, and were stratified by KRAS status, time since mCRC diagnosis, and geography.

TAS-102 was administered at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle. The primary endpoint of the study was OS, with secondary endpoints focused on PFS, overall response rate (ORR), and disease control rate (DCR).

For patients treated with TAS-102, the median OS was 7.1 months compared with 5.3 months with placebo (HR = 0.68; 95% CI:0.58-0.81;P<.0001). The median PFS in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR = 0.48; 95% CI: 0.41-0.57;P<.0001).

A statistically significant advantage in ORR was not demonstrated for TAS-102 in the study (1.6% vs 0.4%). However, when adding stable disease rates, the DCR was 44% versus 16.3% (P<.0001) for TAS-102 and placebo, respectively.

&ldquo;TAS-102 is well tolerated, with a very mild safety profile. The most frequently observed side effect is hematologic, including anemia and neutropenia,&rdquo; Yoshino said. &ldquo;There were very few increases in grade 3 or higher diarrhea, pyrexia, and vomiting, but these were generally manageable. This agent is very much tolerated for almost all patients.&rdquo;

The most frequently observed grade 3/4 adverse events (AEs) in the TAS-102 arm compared with placebo were diarrhea (3% vs 0.4%), vomiting (2.1% vs 0.4%), nausea (1.9% vs 1.1%), fatigue (3.9% vs 5.7%) and stomatitis (0.4% vs 0%).

The most common grade 3/4 hematologic AEs for TAS-102 and placebo were neutropenia (34.9% vs 0%), leukopenia (12.8% vs 0%), anemia (16.5% vs 2.6%), and thrombocytopenia (5.1% vs 0.4%). Febrile neutropenia was experienced by 3.8% of patients treated with TAS-102 compared with none in the placebo arm.

&ldquo;Febrile neutropenia was 3.8% in this trial. Keep in mind, during the first cycle, being 4 weeks, the majority of neutropenia occurred during the 3rd week to 4th week,&rdquo; Yoshino explained. &ldquo;At this point, we catch the febrile neutropenia, then we use GM-CSF or another supportive care drug. Keep in mind that the first 3 to 4 weeks are very important.&rdquo;

TAS-102 consists of the cytotoxic agent trifluorothymidine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride, which prevents FTD from degrading as a result of thymidine phosphorylase. Following the administration of treatment, FTD is phosphorylated into the DNA by thymidine kinase 1 (TK1), preventing the formation of new cancer cells.

&ldquo;FTD is incorporated into the tumor cell and phosphorylation is done by TK1. Phosphorylation is needed to get inside to the cancer DNA. So, this is a reasonable predictive marker, but not validated yet,&rdquo; Yoshino noted.

The prognostic qualities of TK1 for patients with mCRC treated with TAS-102 were analyzed in data presented at the 2013 European Cancer Congress. This analysis looked specifically at 150 patients who underwent immunohistochemical analysis for TK1 from multiple phase II studies of the drug.

The median OS in TK1-high patients (n = 27) was 10.4 months versus 7.7 months in TK1-low patients (n = 72; HR = 0.51; 95% CI:0.27-0.97). In the placebo arm, TK1-high patients (n = 13) had a median OS of 4.9 months compared with 7.2 months in TK1-low patients (n = 38). When applied to the entire population, the HR for OS in TK1-high patients was 0.14 (P= .0013). In TK1-low patients, the HR was 0.62 (P= .044).

Reference

&ldquo;We also collected samples from this RECOURSE trial so that we can validate whether high TK1 level is associated with response in the near future,&rdquo; Yoshino said.