March 2015, Vol. 2, No. 2
PD-L1 Inhibitor Pembrolizumab Produces Good Responses in Advanced Gastric Cancer
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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