Anti-PD-1 Antibody in Gastric Cancer

Of the 39 advanced gastric cancer patients treated with the immunotherapy antibody, pembrolizumab (Keytruda, Merck), 22.2% had an objective response. The median time to response was 8 weeks and the median progression-free survival (PFS) was 1.9 months. These updated results were from the gastric cancer cohort of the phase I KEYNOTE-012 clinical trial.

The results were presented at the 2015 Gastrointestinal Cancers Symposium organized by the American Society of Clinical Oncology, held January 15-17 in San Francisco.

Eight patients of the 36 evaluable patients had a partial response (22%). Five patients (13.9%) had stable disease. The median duration of response was 24 weeks, and ranged from eight to more than 33 weeks.

The PFS rate was 24% and the overall survival rate was 69%. The median follow-up was 8.8 months.

Response rates of pembrolizumab is high in patients with many prior chemotherapies, Kei Muro, MD, of the Aichi Cancer Center Hospital in Nagoya, Japan, lead author of the study, told OncoTherapy Network. Muro also said that the responses are quite durable.

Patients were treated with 10 mg/kg every 2 weeks for up to 24 months. A total of 19 Asian and 22 non-Asian patients were enrolled on the study. The median age of patients was 63 years and 72% of those enrolled were men. Patients from Asia had more prior therapies-79% had two or more prior therapies compared to 55% of the patients from the rest of the world. Patients were assessed for PD-L1 expression of their tumors.

“I think that there are not any differences between Asian gastric cancer and non-Asian gastric cancer in biology,” said Muro. “However, in general, the tumor burden in Asian populations is smaller than that in non-Asian populations. Consequently, there are more prior chemotherapy lines in Asian than that in non-Asians, in general.”

The initial findings from the gastric cancer cohort were presented at the annual European Society of Medical Oncology (ESMO) congress meeting in September of 2014.

According to Muro, pembrolizumab had a tolerable toxicity profile. Four patients experienced five high adverse events that were drug related, including Grade 3 decreased appetite, fatigue and peripheral sensory neuropathy, Grade 4 pneumonitis, and Grade 5 hypoxia. There was one death that occurred on the trial in the patient who experienced Grade 5 hypoxia, and was considered to be treatment-related. But, the patient had previously experienced a Grade 3 tracheobronchomalacia not considered to be treatment related and of unknown cause, and the hypoxia may ultimately not have been drug-related Muro told OncoTherapy Network. “It was hypothesized that the patient developed myopathy of the intrinsic muscles in his tracheobronchial tree, leading to alveolar collapse and progressive hypoxia that was ultimately fatal.”

Thirteen patients (33%) are still on therapy.

Pembrolizumab is a humanized monoclonal antibody targeting the programmed death-1 (PD-1) cell surface receptor that works by boosting the ability of the immune system to target tumor cells. The antibody binds to PD-1 on the surface of T-cells, blocking the ability of PD-1 to interact with PD-L1, overexpressed on some tumor cells. The interaction of PD-1 and PD-L1 normally inhibits the ability of T-cell function.

According to the study authors, there was a trend towards an association between higher PD-L1 expression levels and response, PFS and overall survival (P-values between .102 and .162).

Pembrolizumab is currently approved as a second-line treatment of metastatic melanoma, following ipilimumab or vemurafenib treatment.

Based on these gastric cancer results, the phase 2, two-arm KEYNOTE-059 trial in advanced gastric cancer will begin in 2015. Patients enrolled will be treated with either pembrolizumab alone or in combination with cisplatin and 5-fluorouracil.

“This drug and immuno-checkpoint inhibitor drugs such as PD-1 or PD-L1 antibody are very promising for advanced gastric cancer treatment,” said Muro.