Immunotherapies have been tested in melanoma, breast, prostate, kidney, and lung cancers, and are now being studied in advanced gastric cancers.
Pembrolizumab is an anti-PD-1 antibody tested in the treatment of several types of advanced cancer. The FDA has approved the use of pembrolizumab for the treatment of metastatic melanoma and advanced nonsmall cell lung cancer, and it has provided the drug with breakthrough status for relapsed or refractory classical Hodgkin lymphoma.
Pembrolizumab was studied in the treatment of PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction in the phase Ib Keynote-012 study. Findings from the study were presented at the 2015 ASCO Annual Meeting.
The study was completed across 13 cancer research centers in the United States, Israel, Japan, South Korea, and Taiwan, to compare the results of patients from the Asian Pacificwhere gastric cancers are more common—to patients from the rest of the world.
Archival tumor samples from 162 patients were screened for PD-L1 expression using a prototype immunohistochemistry assay with the 22C3 antibody. Sixty-five patients (40%) were found to be eligible, of which 39 patients enrolled in the study and 36 of 39 were evaluable for assessment.
At baseline, there were 19 Asian patients and 20 patients from elsewhere in the world. Of these, the primary tumor site for the 19 patients from Asia was the stomach compared with 9 of the patients from the rest of the world. The gastroesophageal junction was the primary site for the remaining patients (n = 11). At least 2 prior therapies for advanced disease were received by 67% of all patients.
Patients were given pembrolizumab intravenously at 10 mg/kg every 2 weeks for up to 24 months with responses tested every 8 weeks. As of the 12-month mark, 42% of the patients were still alive.
Objective response rate (ORR) was 22% (95% CI, 10%-39%) according to central review and 33% (95% CI, 19%-50%) by investigator review. Partial response (PR) was experienced by 8 patients and 5 patients had stable disease (SD). No complete responses were observed.
Thirty-three patients (85%) discontinued treatment on pembrolizumab, 32 due to progressive disease and 1 due to an unrelated adverse event (AE). According to the investigator review, 26 patients (67%) had at least 1 treatment-related AE, including mostly grade 1/2 fatigue (13%), decreased appetite (13%), pruritus (13%), hypothyroidism (10%), and arthralgia (10%). Five patients (13%) experienced grade 3/4 AEs including 2 cases of grade 3 fatigue, grade 3 pemphigoid, grade 3 peripheral sensory neuropathy, grade 3 hypothyroidism, and 1 grade 4 pneumonitis. Four patients (10%) temporarily stopped treatment due to immune-mediated toxic effects and 2 of these patients were unable to continue, 1 due to progressive disease. One treatment-related death was noted in the abstract for the 2015 ASCO Annual Meeting but not in the final report.
Pembrolizumab is also being tested in additional clinical trials for gastric cancer treatment, including one phase III trial of pembrolizumab versus paclitaxel for treatment of progressive disease after previous platinum and fluoropyrimidine-based chemotherapy treatment.
Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that has already received FDA approval for the treatment of advanced renal cell carcinoma, nonsmall cell lung cancer, Hodgkin lymphoma, and unresectable or metastatic melanoma. The therapy has also received a breakthrough therapy designation for recurrent or metastatic squamous cell carcinoma of the head and neck.
In the phase I/II CheckMate-032 study patients with advanced or metastatic gastric or gastroesophageal junction cancer were treated with nivolumab or nivolumab plus ipilimumab. A majority of the patients (83%) had already received 2 or more prior treatments for gastric cancers. Patients were enrolled into the study regardless of their PD-L1 expression but responses were tested for both PD-L1-positive and -negative tumors.
According to findings to be presented at the 2016 Gastrointestinal Cancers Symposium, single-agent nivolumab was well tolerated by pretreated patients. ORR was 12% with 1 complete response and 6 partial responses out of 58 patients, and 12 patients (21%) had stable disease.
The median duration of response among responders was 7.1 months (95% CI, 3.0-13.2). The median overall survival duration was 6.8 months (95% CI, 3.3-12.4), with a 1-year survival rate of 38% (95% CI, 23.2-52.7). Patients with PD-L1-positive (39%) and -negative (61%) tumors had ORRs of 18% and 12%, respectively.
At the time of the analysis, 10 patients were still on active treatment and 49 had discontinued, 40 due to progressive disease, 4 from unrelated AEs, and 2 from treatment-related AEs.
Overall, treatment-related AEs occurred in 66% of patients, mostly low-grade, yet 14% experienced grade 3/4 AEs including pneumonitis, fatigue, diarrhea, vomiting, hypothyroidism, and increased aspartate, alanine aminotransferase, and alkaline phosphatase levels. No treatment-related deaths occurred.
Findings are yet to be released for the patients that were treated with both nivolumab and ipilimumab. The nivolumab/ipilimumab combination is FDA-approved for advanced metastatic melanoma.
Further clinical trials for the treatment of gastric cancer are ongoing. While these are just the first steps in immunotherapy research for gastric cancer, further research could result in increased survival rates for patients with advanced gastric cancers.