Is TAS-118 Plus Oxaliplatin a New Standard First-Line Therapy for Advanced Gastric Cancer in Asians?

By Marilynn Larkin

July 30, 2020

NEW YORK (Reuters Health) - TAS-118 (oral S-1 plus leucovorin) plus oxaliplatin was more effective than S-1 plus cisplatin in a phase III trial and could be considered a new first-line treatment for advanced gastric cancer in Asian patients, researchers suggest.

Dr. Narikazu Boku of The National Cancer Centre Hospital in Tokyo randomized 711 patients (about 70% men; 58% under age 65) to TAS-118 plus oxaliplatin or S-1 plus cisplatin. Participants had advanced gastric cancer with negative or unknown HER2 status, Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment.

Patients received either TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for seven days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every two weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day one or eight) every five weeks.

Eleven untreated and 19 ineligible patients were excluded from the primary analysis, leaving the TAS-118 plus oxaliplatin group with 347 patients and the S-1 plus cisplatin group with 334.

As reported in The Lancet Oncology, after a median follow-up of 26 months, median overall survival was 16 months in the TAS-118 plus oxaliplatin group and 15.1 months in the S-1 plus cisplatin group (hazard ratio, 0.83).

The most common grade 3 or higher adverse events in the TAS-118 plus oxaliplatin group versus the S-1 plus cisplatin group were anemia (16% vs. 18%), neutropenia (15% vs. 25%), decreased appetite (15% vs. 13%), diarrhea (9% vs. 4%), and peripheral sensory neuropathy (9% vs.<1%).

Serious adverse events were observed in 44% of the TAS-118 plus oxaliplatin group vs. 46% in the S-1 plus cisplatin group, the most serious of which in both groups was decreased appetite, reported in 10% of patients in the TAS-118 plus oxaliplatin group versus 7% in the S-1 plus cisplatin group.

Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia).

Dr. Emmanuelle Samalin of the Montpellier Cancer Institute, coauthor of a related editorial, told Reuters Health by email, "Compared to the S1 plus cisplatin combination, the overall survival benefit offered by TAS-118 plus oxaliplatin is small, with a median overall survival gain of 0.9 months and a death risk reduction of 17%."

"What is the real added value of leucovorin to S-1 compared to S-1 when the platin salts are different between both treatment arms?" he asked. "Even if oxaliplatin is non-inferior to cisplatin, when combined with S-1, it is not clear."

"TAS-118 plus oxaliplatin deserves to be tested in non-Asian patients, where other standard practices are used," he said. "In Europe and North America, infusional fluorouracil plus leucovorin or capecitabine are considered as alternatives to S-1 in combination with doublet regimens with oxaliplatin or cisplatin."

"Ongoing phase 3 trials will elucidate the role of promising compounds such as anti-CLDN18.2 monoclonal antibodies (zolbetuximab) or immune checkpoint inhibitors in other clinical settings of patients with HER2- negative gastric cancers," he added.

Dr. Rutika Mehta, a medical oncologist in the GI Oncology Program of Moffitt Cancer Center in Tampa, told Reuters Health by email, "This study will be applicable for clinicians in Asia and not outside of Asia."

Like Dr. Samalin, she noted, "It still remains unclear how the addition of leucovorin to S1 significantly improves outcomes in this population."

"In my view, additional studies wouldn't be needed for its approval in Asia," she said. "On the other hand, since S1 itself is not approved for use in the Western World, the implication of the SOLAR study to change the treatment paradigm here is very low."

Dr. Boku did not respond to requests for a comment. The study was funded by Taiho Pharmaceutical and Yakult Honsha. Dr. Boku and many coauthors have received funds from the companies.

SOURCE: and The Lancet Oncology, online July 16, 2020.