Pembrolizumab shows promise for some with advanced gastric cancer

Last Updated: 2018-06-18

By Will Boggs MD

NEW YORK (Reuters Health) - While pembrolizumab does not improve overall survival compared with paclitaxel as second-line therapy for advanced gastric cancer, certain patients do appear to achieve a survival benefit, according to results from the KEYNOTE-061 trial.

"Pembrolizumab did show a trend but not statistically significant improvement of overall survival," Dr. Kohei Shitara from the National Cancer Center Hospital East, in Kashiwa, Japan, told Reuters Health by email.

"However, efficacy of pembrolizumab is greater in patients in ECOG performance status (PS) 0, higher PD-L1 CPS (combined positive score) (CPS10), or high microsatellite instability (MSI-H) tumors, which suggested stratification by these clinicopathological factors is important to decide optimal treatment for gastric cancer," he told Reuters Health by email.

Pembrolizumab is a monoclonal antibody that binds to PD-1, preventing the interaction of PD-1 with PD-L1 and PD-L2. It is approved for treatment of recurrent locally advanced or metastatic gastric or gastroesophageal-junction adenocarcinoma that expresses PD-L1 (CPS1 or higher) and progressed on or after two or more previous lines of therapy.

Dr. Shitara and colleagues from 148 medical centers in 30 countries compared pembrolizumab with paclitaxel as second-line therapy in a randomized, open-label, phase 3 trial of 592 patients with previously treated, advanced gastric or gastroesophageal-junction cancer; 395 patients had a PD-L1 CPS of 1 or higher.

Median overall survival was 9.1 months for pembrolizumab and 8.3 months for paclitaxel, a nonsignificant difference, the team reports in The Lancet, online June 4.

Among patients with ECOG PS0, median overall survival was significantly higher with pembrolizumab (12.3 months) than with paclitaxel (9.3 months), whereas median overall survival in patients with ECOG PS1 did not differ significantly between pembrolizumab (5.4 months) and paclitaxel (7.5 months).

In post hoc analysis, the pembrolizumab treatment effect was greater for patients with PD-L1 CPS 10 or higher and for patients with MSI-H.

Among patients with a PD-L1 CPS of 1 or higher, confirmed response rates were similar in the pembrolizumab and paclitaxel groups, but the median response duration was higher with pembrolizumab (18.0 months) than with paclitaxel (5.2 months).

More patients treated with paclitaxel (232/276, 84%) than with pembrolizumab (155/294, 53%) experienced adverse events attributed to study treatment, and grade 3-5 severity events were more common in the paclitaxel group (35%) than in the pembrolizumab group (14%).

"A currently ongoing phase 3 study in first-line (KEYNOTE 062) will give us further insight for optimal positioning of pembrolizumab in gastric cancer," Dr. Shitara said. "Ongoing biomarker analysis, as well as multivariate analysis, will give us further information."

Dr. Elizabeth C. Smyth from Royal Marsden Hospital, in London, who coauthored a linked editorial, told Reuters Health by email, "The most interesting aspect of these results is that the survival curves cross. In the beginning, patients treated with chemotherapy have better outcomes; then after a period of time those treated with pembrolizumab have the advantage. This reflects the different mechanisms of action of chemotherapy and immunotherapy."

"With chemotherapy," she added, "we can see relatively quick tumor shrinkage, but unfortunately this does doesn't last for long. With immunotherapy, the tumor shrinkage effect may not occur so quickly, but if this does happen it is more long lasting."

"The proportion of patients with gastroesophageal cancer who benefit from anti-PD-1 therapy is modest," Dr. Smyth said. "Even in a PD-L1 selected population approximately one in six patients will respond to pembrolizumab. Combination therapy either with chemotherapy or other targeted drugs will be required to extend the benefits of immune checkpoint blockade to more gastroesophageal-cancer patients."

"We should also focus on translational research in these datasets to identify biomarkers associated with de novo and acquired resistance so we can design smarter combinations in future," she added.

Dr. Benjamin A. Weinberg from Lombardi Comprehensive Cancer Center at Georgetown University, in Washington, D.C., who recently reviewed immuno-oncology biomarkers for gastric cancers, told Reuters Health by email, "As the authors note, the standard second-line regimen is now paclitaxel plus ramucirumab (not paclitaxel by itself), so the control arm is already obsolete (thus, pembrolizumab is even less likely to be superior to paclitaxel plus ramucirumab if it can't beat paclitaxel by itself)."

"For now, pembrolizumab is still relegated to the third-line setting as indicated on the FDA label," he said. "Trials combining pembrolizumab with chemotherapy are ongoing and may ultimately change the standard of care. Other trials are actively looking at immunotherapy combinations (e.g., anti-PD1 plus anti-LAG3 antibodies)."

Merck Sharp and Dohme, a subsidiary of Merck and Co., funded the study, employed three of the authors and had various relationships with several others, including Dr. Shitara.

SOURCE: https://bit.ly/2JWULwT and https://bit.ly/2JMfpUz

Lancet 2018.