PD-L1 Inhibitor Pembrolizumab Produces Good Responses in Advanced Gastric Cancer

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Add gastric cancer to the list of cancers that respond to immunotherapy. In patients with advanced gastric cancer who express programmed cell death (PD)-1 ligand 1 (PD-L1), the humanized monoclonal antibody pembrolizumab demonstrated robust antitumor activity and an acceptable safety profile, according to updated results presented at the 2015 Gastrointestinal Cancers Symposium.

In the phase 1b KEYNOTE-012 trial in patients with previously treated advanced gastric cancer, 22.2% achieved an objective response with pembrolizumab, said Kei Muro, MD, of the Aichi Cancer Center Hospital, Nagoya, Japan, and lead investigator of the KEYNOTE-012 trial.

“Overall, these findings support the importance of the PD-L1 pathway in gastric cancer and the further development of pembrolizumab as a treatment option for patients with advanced gastric cancer,� said Muro.

“PD-1 is a negative costimulatory receptor expressed on the surface of the activated T cell and plays an important role in suppressing immune surveillance,� he said. “Binding of PD-1 to its ligands, PD-L1 and PD-L2, inhibits effector T-cell function, which dampens the immune response and leads to neoplastic growth.� The expression of PD-L1 in tumors correlates with poor prognosis.

Pembrolizumab is a selective, humanized monoclonal antibody designed to block the interaction between PD-1 and its ligands, thereby reactivating the immune system to eradicate the host tumor.

The administration of 10-mg/kg pembrolizumab monotherapy every 2 weeks was evaluated in KEYNOTE-012 in patients with recurrent or metastatic stomach or gastroesophageal cancer with PD-L1 expression. Of the 162 evaluable patients, 65 (40%) had PD-L1 expression. Of these 65 patients, 39 were enrolled in the trial and received pembrolizumab intravenously.

Overall, 51.3% of the patients had a previous gastrectomy; 66.7% had received ?2 previous therapies for advanced disease.

After a median follow-up of 8.8 months, “pembroliz­umab demonstrated strong evidence of anticancer activity,� said Muro. The response rate was 22.2% by central review (33.3% by investigator review); all were partial responses. Stable disease was recorded in 13.9% of patients by central review (12.8% by investigator).

“Overall, 53.1% experienced a decrease from baseline in the size of their target lesions,� Muro said.

The median time to response was 8 weeks, and the median duration of response was 24 weeks. “Response to pembrolizumab was durable, with 6 of the 8 responders maintaining response,� said Muro.

The 6-month rate of progression-free survival (PFS) was 24%, and the median PFS was 1.9 months. The overall survival (OS) rate at 6 months was 69%, and the median OS had not been reached at the time of the analysis.

“There was a trend toward an association between higher levels of PD-L1 expression and response, PFS, and OS,� Muro said. “Further analysis of these preliminary data is ongoing to help determine the relationship between PD-L1 expression and antitumor activity in gastric cancer.�

The safety profile of pembrolizumab was acceptable. Most adverse events were grade 1 or 2. The most common adverse events were fatigue (17.9%), decreased appetite (12.8%), hypothyroidism (12.8%), and arthralgia (10.3%). Four patients had severe adverse events (peripheral sensory neuropathy, fatigue, decreased appetite, and pneumonitis); 1 patient died from treatment-associated hypoxia.

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