SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Adding everolimus to paclitaxel failed to significantly improve outcomes in pretreated patients with gastric or esophagogastric junction adenocarcinoma in a German randomized phase III study.

Median overall survival in the double-blind multicenter study ( RADPAC ) was 6.12 months among 150 patients randomized to receive treatment with paclitaxel plus everolimus as 2nd, 3rd, or 4th line therapy, and 5.03 months among those who received paclitaxel and placebo (hazard ratio, 0.93), Salah-Eddin Al-Batran, MD , reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

Median progression-free survival was 2.20 vs. 2.07 months in the treatment and placebo groups, respectively (hazard ratio, 0.88), said Dr. Al-Batran of Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany.

Study subjects had a mean age of 62 years and had progressed after treatment with a fluoropyrimidine/platinum-containing regimen. All had at least one, and a maximum of three prior lines of therapy (median of two in both groups).

Of note, accrual was slow and was stopped early, largely because of the very-high rate of taxane use for first-line treatment, but also because combination ramucirumab/paclitaxel was approved during the course of the study, Dr. Al-Batran said.

The treatment and placebo groups were well balanced. Treatment included 80 mg/m2 of paclitaxel on days 1, 8 and 15, plus placebo or 10 mg of everolimus daily on days 1-28, repeated every 28 days. Dose adjustment was more common in the treatment group (26% vs. 13%) but cumulative doses were similar in the groups.

Also, more patients in the everolimus group discontinued treatment for toxicity (11% vs. 5%). However, the only toxicity that was significantly increased was grade 3-5 oral mucositis in the treatment group (13% vs. 1% in the placebo group).

Gastric cancer is aggressive and difficult to treat, with median survival of only 9-11 months, Dr. Al-Batran said, adding that at the time the RADPAC study was initiated, no treatments had been approved for patients who failed first-line therapy, although agents like paclitaxel and irinotecan were in use.

He and his colleagues sought to evaluate everolimus, because 50%-60% of gastric cancers are driven by dysregulation in the P13k/Akt/mTOR pathway – a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, and because everolimus – an oral mTOR inhibitor – showed efficacy in preclinical models of gastric cancer.

In the phase III GRANITE-1 trial, it was associated with trends toward improved progression-free survival and overall survival, compared with best supportive care, he noted.

Subgroup analyses in the current trial suggested that patients with prior taxane use derived greater benefit from everolimus. Overall survival in those patients, who comprised about half of the study population, was 6 months vs. 4 months with placebo; the difference did not reach statistical significance, but showed a strong trend in that direction (P = .072). Progression-free survival was, however, significantly greater with everolimus than with placebo (2.66 vs. 1.81 months; HR, 0.50) in those with prior taxane use.

“Interestingly, the very few patients having ECOG performance status of 2 really performed very poorly,” Dr. Al-Batran said, explaining that those patients had better outcomes with paclitaxel monotherapy.

“So, in conclusion, everolimus combined with paclitaxel improved outcomes as compared with paclitaxel alone in the intention to treat population. However, activity was seen in the taxane pretreated subgroup. Biomarker studies could attempt to identify a subgroup with more benefit, as we see some activity, but this activity is not enough,” he concluded.

Dr. Al-Batran reported receiving honoraria, serving as a consultant or advisor, receiving research funding from, and/or being on the speakers’ bureau for Celgene, Hospira, Lilly, Medac, Merck, Roche, Sanofi, Vifor, and Nordic Bioscience.