Josep Tabernero, MD, PhD
TAS-102 (trifluridine/tipiracil; Lonsurf) provided a 31% reduction in the risk of death compared with placebo in patients with heavily pretreated metastatic or advanced gastric cancer, according to findings from the phase III TAGS study reported at the 2018 World Gastrointestinal Cancer Congress.
The median overall survival (OS) was 5.7 months with TAS-102 compared with 3.6 months for placebo (HR, 0.69; 95% CI, 0.56-0.85; P
= .0003). Twelve-month OS rates were 21.2% versus 13.0%, for TAS-102 and placebo, respectively, representing a significant improvement in survival for a poor prognosis group. Taiho Oncology, the company developing the drug, plan to submit a supplemental new drug application (nNDA) to the FDA, based on the TAGS data.
“TAS-102 represents an effective treatment option for patients with heavily pretreated metastatic gastric cancer,” said lead investigator Josep Tabernero, MD, PhD, director of the Val de Hebron Institute of Oncology in Barcelona, Spain, and OncLive Giant of Cancer Care in GI Cancer. “Most patients with gastric cancer present with advanced or metastatic disease and, therefore, have a poor prognosis. The 5-year overall survival rate is just 4%.”
The TAGS study investigated the efficacy and safety of TAS-102 plus best supportive care (BSC) compared with placebo plus BSC in patients with metastatic gastric cancer that was refractory to standard treatments. Patients were randomized in a 2:1 ratio to receive TAS-102 at a 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle (n = 337) or placebo (n = 170). Post study systemic therapy was received by a quarter of patients in each group.
Patient characteristics were similar in the treatment arms; the primary cancer site was gastric in 71% of patients in both arms and 44% of patients per arm had received prior gastrectomy. Approximately 37% of patients in each group had received 2 prior treatments, and about 63% had received 3 or more prior treatments, including fluoropyrimidine, platinum, irinotecan, taxanes, ramucirumab, and immunotherapy. Twenty percent and 16% of patients in the TAS-102 and placebo arms had HER2-positive tumors, with 18% and 14% of patients, respectively, receiving prior anti-HER2 therapy.
ECOG performance status was 1 for 64% and 60% of patients and the median age was 64.0 and 62.5 years in the TAS-102 and placebo groups, respectively. Overall, approximately 15% of patients were enrolled in Japan and the rest were from other parts of the world.
The primary endpoint of the TAGS study was OS, and the secondary endpoints focused on progression-free survival (PFS) and quality of life (QoL). Computed tomography scans were performed every 8 weeks and QoL assessments every 4 weeks. Crossover to open-label TAS-102 was allowed.
Median PFS with TAS-102 was 2.0 versus 1.8 months with placebo, representing a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.47-0.70; P
<.0001). The 6-month PFS rates were 21% versus 13%, respectively.
As of data cut-off on March 31, 2018, 19 patients (6%) in the TAS-102 and 3 (2%) in the placebo group remained on treatment. Discontinuation was due to disease progression in 76% and 87% of patients in the TAS-102 and placebo arms, respectively. Ten percent of patients in the TAS-102 arm discontinued due to an adverse event (AE) compared with 7% in the placebo group.
Treatment-related AEs occurred in 81% and 57% of patients in the TAS-102 and placebo groups, respectively. Treatment-related deaths rates were low at 0.3% versus 0.6%, for TAS-102 and placebo, respectively. The most common non-hematologic grade ≥3 AEs for TAS-102 and placebo, respectively, were decreased appetite (9% vs 7%), fatigue (7% vs 6%), general physical deterioration (7% vs 9%), asthenia (5% vs 7%), vomiting (4% vs 2%), abdominal pain (4% vs 9%), nausea (3% vs 3%), and diarrhea (3% vs 2%).
The most common grade 3/4 hematologic laboratory abnormalities in the TAS-102 group versus placebo, respectively, were neutropenia (38% vs 0%), leukopenia (21% vs 0%), lymphocytopenia (19% vs 8%), anemia (19% vs 7%), and thrombocytopenia (6% vs 0%). Two percent of TAS-102–treated patients had febrile neutropenia.
“TAS-102 showed a predictable and manageable safety profile, consistent with that seen previously in patients with metastatic gastric cancer,” Tabernero noted.
TAS-102 is comprised of trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. In a prior phase II study (EPOC1201) conducted in Japan, TAS-102 showed a disease control rate of 65.5% and a median OS of 8.7 months for patients with metastatic gastric cancer following 1 or 2 lines of standard chemotherapy.
In addition to gastric cancer, the TAS-102 has also been investigated as a treatment for colorectal cancer. The agent was approved by the FDA in 2015 as a treatment for patients with colorectal cancer 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.
"We are excited to be able to share these important data with the medical oncology community and to continue to add to the growing body of research supporting the efficacy and safety of Lonsurf," Martin J. Birkhofer, MD, senior vice president and Chief Medical Officer, Taiho Oncology, Inc, said in a statement. "We intend to include these data in an sNDA submission to the U.S. Food and Drug Administration for consideration as a third-line treatment option for appropriate patients with metastatic gastric cancer."
Tabernero et al. Overall Survival Results from a Phase III Trial of Trifluridine/Tipracial vs Placebo in Patients with Metastatic Gastric Cancer Refractory to Standard Therapies (TAGS). Ann Oncol. 2018;29 (suppl 5; abstr LBA-002).