September 2015, Vol. 2, No. 5

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Pembrolizumab Has Encouraging Preliminary Activity in Advanced PD-L1–Positive Gastric Cancer


An analysis of the KEYNOTE-012 phase 1 trial suggests that pembrolizumab has durable efficacy in heavily pretreated patients with programmed death-1 (PD-1) ligand 1 (PD-L1)-positive gastric cancer. Pembrolizumab had a manageable safety profile with no new or unexpected events observed (Abstract 4001).

“PD-L1 expression on both tumor and immune cells may be important to enrich the patient population for benefit. Data support the further evaluation of pembrolizumab for advanced gastric cancer,” said lead author Yung-Jue Bang, MD, PhD, Seoul National University College of Medicine, Korea.

Based on these positive phase 1 findings, pembrolizumab is being studied further in advanced gastric cancer in KEYNOTE-059, a phase 2 study of monotherapy or in combination with chemotherapy, and in KEYNOTE-061, a phase 3 study of pembrolizumab versus paclitaxel as second-line therapy.

The anti–PD-1 antibody pembrolizumab is approved in several countries for the treatment of advanced melanoma, and the monoclonal antibody has shown clinical activity in multiple tumor types.

KEYNOTE-012 included a cohort of patients with recurrent or metastatic gastric adenocarcinoma (stomach or gastroesophageal junction) with PD-L1–positive tumors and no active brain metastasis. Patients were treated with pembrolizumab 10 mg/kg every 2 weeks until complete response (CR), partial response (PR), stable disease, or confirmed progressive disease. Response assessment was performed every 8 weeks per RECIST.

Among 39 patients with PD-L1–positive gastric cancer, median age was 63, 72% were male, 19 (48.7%) were Asian, and 19 (48.7%) were white; 1 (2.6%) was “other.”

About 51% had prior gastrectomy, and two-thirds had at least 2 prior therapies for advanced disease.

Two-thirds of patients had an adverse event; the most common adverse events of any grade (occurring in ≥10%) were fatigue 7 (17.9%), decreased appetite 5 (12.8%), hypothyroidism 5 (12.8%), pruritus 5 (12.8%), and arthralgia 4 (10.3%).

Five patients (12.8%) experienced a grade 3/4 adverse event; these were evenly distributed among fatigue, hypothyroidism, pemphigoid, peripheral sensory neuropathy, and pneumonitis.

There was 1 treatment-related death (hypoxia).

Immune-related grade 1/2 adverse events were reported in 7 patients (17.9%); grades 3/4 immune-related adverse events were reported in 1 patient (2.6%).

The overall response rate was 22.2% by central review and 33.3% by investigator review. There were no CRs; PR was 22.2% and 33.3%, respectively, for central review and investigator review. Looking at a waterfall plot, 53.1% of patients experienced a decrease in target lesions on pembrolizumab.

Some patients had durable responses. Median time to response was 8 weeks (range, 7-16 weeks); 4 of 8 responses were ongoing at the time of data cutoff. Median response duration was 40 weeks (range, 20-48 weeks).

Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) showed the following: median PFS of 1.9 months, 6-month PFS rate of 26%; median OS of 11.4 months, and 6-month OS of 66%.

PD-L1 expression was assessed using the Dako Assay, and both PD-L1–positive tumor cells and immune cells were detected; the scoring method used accounted for both cell types. An immunohistochemistry score of >1% was considered PD-L1 positive, a relatively low cutoff point, Bang said.

Preliminary evidence suggested that there was a relationship between PD-L1 expression and efficacy in this preselected population.

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Enthusiasm Mounts as Immunotherapy Continues to Play a Positive Role in Many Disease States

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