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SAN FRANCISCO -- Anti-PD 1 therapy continued its successful run in oncology, as patients with heavily pretreated gastric cancer lived longer when treated with nivolumab (Opdivo), results of a randomized trial showed.

Treatment with nivolumab led to a median overall survival of 5.32 months compared with 4.14 months for placebo, a statistically significant difference associated with a 37% reduction in the hazard ratio. More than twice as many patients in the nivolumab group remained alive for at least 12 months.

Progression-free survival (PFS) differed significantly in favor of nivolumab, although the absolute benefit was only about a week, as reported here at the .

"These results indicate that nivolumab could be a new treatment option for patients with heavily pretreated advanced gastric cancer and also provide a strong rationale to explore nivolumab in earlier lines of treatment for gastric cancer," said , of Asan Medical Center and the University of Ulsan in Seoul, Republic of Korea.

Invited discussant , of the University of Southern California in Los Angeles, found the results impressive, considering the difficult patient population.

"You see a significant benefit in a highly refractory gastric cancer population," said Lenz. "Don't get stuck on the median, because the median did not give the full benefit. You see a continuous separation of the [survival] curves, and as you know, the hazard ratio is the combined difference of both [survival] curves over the whole course of survival, the cumulative effect."

Future studies should focus on identifying the subgroup or subgroups of patients whose response to nivolumab drove the overall results, he added.

In contrast to the results with the anti-PD-1 agent, another randomized trial showed from the addition of everolimus (Afinitor) to paclitaxel as second-line therapy for advanced gastric cancer.

Recent clinical trials established conventional chemotherapy as standard of care for first- and second-line treatment of advanced gastric or gastroesophageal juncture (GEJ) cancer. No consensus has evolved for treatment in third-line and beyond, providing a rationale to evaluate new and novel therapies, said Kang.

Advanced gastric cancers are characterized by a high mutational burden and amplification of immune checkpoint inhibitory proteins, including PD-1 ligand, suggesting that advanced gastric cancer might be responsive to PD-1 inhibition, he continued. Phase I/II trials of nivolumab suggested efficacy in gastric cancer, but the observations had not been confirmed in a randomized, controlled trial.

Kang reported data from the phase III, randomized, placebo-controlled trial of patients with gastric/GEJ cancer that had progressed on at least two prior regimens. Investigators in Japan, Korea, and Taiwan enrolled and randomized 493 patients 2:1 to a standard dose of nivolumab or to placebo. Treatment continued until disease progression, death, or unacceptable toxicity.

The primary endpoint was overall survival. The results showed a statistically significant 37% reduction in the survival hazard with nivolumab (95% CI 0.50-0.78, P<0.0001). The 12-month overall survival was 26.6% with nivolumab and 10.9% with placebo. Subgroup analysis demonstrated a consistent survival benefit across all prespecified patient groups.

Median PFS was 1.61 months with nivolumab and 1.45 months with placebo, representing a 40% reduction in the hazard for disease progression or death (95% CI 0.49-0.75, P<0.0001). The proportion of patients who were alive without progression at 12 months was 7.6% in the nivolumab arm and 1.5% in the placebo group.

The overall response rate was 30% (all partial responses) with nivolumab versus 0% with placebo. Additionally, 29.1% of patients had stable disease with nivolumab compared with 25.2% of the placebo group. The median of duration of response with nivolumab was 9.53 months.

Adverse events were more frequent with nivolumab, but no new or unexpected side effects were observed, said Kang.

The rationale for the everolimus-paclitaxel trial came from observations that the PI3K/Akt/mTOR pathway is dysregulated in half or more of gastric cancers. Preclinical studies of the mTOR inhibitor everolimus had suggested activity in models of gastric cancer. A previous phase II trial showed improved PFS and a trend toward improved overall survival with everolimus versus best supportive care, said , of University Cancer Center Frankfurt in Germany.

Investigators at multiple sites in Germany enrolled patients with advanced gastric/GEJ cancer that had progressed on or proven refractory to fluoropyrimidine/platinum chemotherapy. Eligible patients could have received as many as three prior lines of therapy.

Patients were randomized to paclitaxel 80 mg/m2 plus either placebo or everolimus 10 mg/day. The primary endpoint was overall survival.

The trial ended prematurely after 4 years (in September 2015) because of slow accrual, with 150 patients in each arm. Al-Batran blamed the apparent lack of interest in the study on several factors: a high rate of first-line taxane therapy in Germany, approval of ramucirumab and paclitaxel, and the failure of the earlier randomized trial to demonstrate improvement in overall survival.

The results showed a median overall survival of 6.12 months with everolimus and 5.03 months with paclitaxel plus placebo (P=0.544). Median PFS was about 2 months in both treatment arms.