TAS-102 FOR GASTRIC CANCER

 A combination treatment already used to treat colorectal cancer significantly extends overall survival when added to best supportive care in patients with advanced/metastatic gastric cancer, who typically have a very poor prognosis.

The combination of the oral thymidine analog trifluridine and the thymidine phosphorylase inhibitor tipiracil, or TAS-102 (Lonsurf, Taiho Oncology) was tested in more than 500 patients with metastatic gastric or gastroesophageal junction cancer in whom at least two previous treatment regimens had failed.

TAS-102 increased overall survival by 31% over placebo and doubled the likelihood of surviving for 12 months.

Progression-free survival (PFS) was also significantly increased, albeit by less than a month, and the adverse events experienced by patients did not typically lead to treatment discontinuation, the researchers commented..

These new results, from the TAGS phase 3 trial, were presented here at the 2018 World Congress on Gastrointestinal Cancer (WCGC).

Lead author Josep Tabernero, MD, PhD, from Vall d'Hebron University Hospital, Barcelona, Spain, and President Elect of the European Society for Medical Oncology (ESMO), said that the combination treatment "showed a statistically significant and clinically meaningful improvement in overall survival."

With "no new safety signals" seen in the patients, he said that TAS-102 "represents a new effective treatment option for those patients with advanced refractory gastric cancer."

Session co-chair David Cunningham, MD, consultant medical oncologist, Royal Marsden NHS Foundation Trust, Surrey, United Kingdom, who was not involved in the study, told Medscape Medical News that the results were "really important."

He said that the study "was able to show a significant impact on survival in this group of patients where we have an unmet need."

We have nothing else we can offer those patients. Dr David Cunningham

"We have nothing else we can offer those patients, and this study shows that we can extend life expectancy and improve disease control rates up to a very significant level," he added.

Cunningham concluded: "I think that it's quite likely that this drug will become part of the standard of care within that setting, and it looks like a very interesting drug to move forward into earlier phases of the treatment of gastric cancer."

Study Details 

Tabernero explained that most patients with gastric cancer, which is the fifth most common form of the disease worldwide, present with advanced/metastatic disease and, as a result, have a poor prognosis, with a 5-year overall survival rate of 4%.

Because there is a lack of approved third-line treatments for gastric cancer and TAS-102 is already approved for metastatic colorectal cancer, a phase 2 study of the drug in metastatic gastric cancer was conducted in Japan. It achieved a disease control rate of 65.5% and a median overall survival of 8.7 months.

Following on from that, the phase 3 TAGS study  examined the safety and efficacy of TAS-102 in patients with metastatic gastric cancer and gastroesophageal junction cancer in whom at least two prior regimens had failed and who had an Eastern Cooperative Oncology Group performance status of 0 or 1.

The team recruited 507 patients from 110 sites in 18 countries, randomly assigning them in a 2:1 fashion to TAS-102, 35 ng/m² twice a day on days 1 to 5 and 8 to 12 of each 28-day cycle, or placebo, plus best supportive care.

The median age was 64.0 years in the TAS-102 group and 62.5 years in the placebo group; 75% and 69%, respectively, were male. In both groups, the primary tumor site was gastric in 71% of cases, while 54% and 58% of patients in both groups, respectively, had three or more metastatic sites.

More than 60% of patients in both groups had received at least three prior treatment regimens. The most commonly used agents included fluoropyrimidine, platinum, taxane, and irinotecan.

Overall survival, which was the primary endpoint, was significantly longer with TAS-102 and placebo, at a median survival of 5.7 months vs 3.6 months and a hazard ratio of 0.69 (P = .0003).

At 12 months, 21% of TAS-102–treated patients were still alive, compared with 13% of patients in the placebo group.

PFS was also significantly longer with TAS-102, at 2.0 months, than with placebo, at 1.8 months; the hazard ratio was 0.57 (P < .0001).

As expected, patients receiving TAS-102 experienced more grade 3 or greater adverse events than those in the placebo group, at 80% vs 58%. However, the number of events leading to discontinuation was similar in the two groups, at 13% and 17%, respectively.

Treatment-related adverse events were seen in 81% of TAS-102 recipients compared with 57% of the placebo group.

There were relatively few differences in the rates of nonhematologic adverse events occurring in more 10% of patients between TAS-102 and placebo.

TAS-102 patients, however, were far more likely to experience grade 3/4 hematologic adverse events, which included neutropenia (38%), leukopenia (21%), lymphocytopenia (19%), anemia (19%), and thrombocytopenia (6%).

In the discussion following his presentation, Tabernero said that although the current data focus solely on survival and safety, there are ongoing analyses of other clinical variables, as well as potential predictive biomarkers.

He added: "There is also ongoing research on whether TAS-201 can be combined with other agents, with platinum agents, with irinotecan, so perhaps in the near future there will be a redefinition of the primary setting for treating patients with TAS-102."

"Nevertheless, the refractory setting is a clear unmet need, so I think for the time being this is an option for patients who didn't have treatments in this setting," he concluded.

The study was sponsored by Taiho Oncology and Taiho Pharmaceutical. Tabernero declares consulting for Bayer, Boehringer Ingelheim, Genentech/Roche, Lilly, Merck Serono, Merrimack, MSD, Novartis, Roche, Sanofi, Symphorien, and Taiho. Cunningham has disclosed no relevant financial relationships.

2018 World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-002. Presented June 21, 2018.

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