Spotlight on Clinical Trials: A Phase II Study of Pembrolizumab in Refractory Advanced Esophageal Cancer

 April 13, 2017

Peter Enzinger, MD

Peter Enzinger, MD

In a trial involving 3 DF/HCC member institutions (Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, and Massachusetts General Hospital), Peter Enzinger, MD (DFCI), will evaluate pembrolizumab in patients with refractory, advanced esophageal cancer. 

Pembrolizumab is an antibody that binds to and inhibits the programmed cell death 1 (PD-1) receptor on the surface of T cells. In cancer, PD-1 ligands can be upregulated, which in turn can prevent active T-cell immune surveillance of tumors. Pembrolizumab, along with other so-called checkpoint inhibitors, stops the effects of upregulation and allows the immune system to become more active against cancer cells again. 

Pembrolizumab is currently approved for use in advanced non-small-cell lung cancer, advanced melanoma, recurrent/metastatic head and neck squamous cell carcinoma, and classical Hodgkin’s lymphoma. 

Esophageal Adenocarcinoma Similar to Gastric Adenocarcinoma

“Pembrolizumab has also been shown to be effective in gastric cancer, extending to the gastroesophageal junction,” Dr. Enzinger said. In experiments co-led by DF/HCC member Adam Bass, MD (DFCI), The Cancer Genome Atlas (TCGA), which conducts deep genomic analyses of tumors, found that esophageal adenocarcinomas are virtually identical to gastric adenocarcinomas (Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017 Jan 12;541(7636):169-175.). “Our hypothesis was that pembrolizumab would work well in esophageal adenocarcinoma just as it has in gastric adenocarcinoma,” Dr. Enzinger said. “The goal of the study, therefore, is to treat patients with esophageal adenocarcinoma to see if they respond to this agent.” 

The researchers will also assess the immune environment. “We are carefully looking at all tumors at baseline and also after several weeks of treatment to see how the immune environment changes with pembrolizumab to see which factors are upregulated, and which are downregulated,” he said. The researchers will also elucidate any possible mechanisms of resistance and synergy.

Potential for Prolonging Survival
“It's an exciting study,” Enzinger said. “These agents are likely going to be approved by the FDA within the next year or two. I strongly feel that every patient with esophageal adenocarcinoma or squamous cell carcinoma should at least receive treatment with one of these agents because I do think that in a select group of patients it significantly prolongs survival,” he added.

“Pembrolizumab is generally well tolerated,” Enzinger said. Occasionally fatigue or rash can develop, and about one out of a hundred patients can develop significant autoimmune reactions, such as pneumonitis, thyroiditis, pancreatitis, and nephritis. 

Study Design

Patients will receive 200 mg pembrolizumab every 3 weeks as an IV infusion. The primary outcome is major response rate (CR + PR) as measured by immune-related response evaluation criteria in solid tumors (irRECIST). Secondary outcomes include overall and progression-free survival, as well as durability of response, safety, and tolerability. 

Dr. Enzinger noted that the trial has been open for a few weeks, and patients are currently being screened and their biopsies evaluated. The trial will enroll about 50 patients in the US, including patients with squamous cell carcinomas. “Generally there are very few trials for squamous cell carcinoma of the esophagus, and so we are including those patients as well,” he added.

Phase II Trial
A Phase II Study of Pembrolizumab in Refractory Advanced Esophageal Cancer
Principal Investigator: Peter C. Enzinger, MD (DFCI)
NIH Trial Number: NCT02971956
DF/HCC Protocol Number: 16-293

The trial is starting to recruit patients. Find more information at ClinicalTrials.gov.

— By Emma Hitt Nichols, PhD