Since March 2021, the U.S. Food and Drug Administration has issued four approvals for PD-L1 Inhibitors for patients with Esophageal Cancer.  Check out ECAN’s Deep Dive into Immunotherapy for Patients with Esophageal Cancer with the lead investigators on the studies that led to these approvals below.

Immunotherapy for Previously Untreated Esophageal Cancer Patients

Both Keytruda (pembrolizumab) and Opdivo (nivolumab) have been approved as first-line therapies in combination with chemotherapy for patients with advanced or metastatic Esophageal Cancer. This means that, for the first time, Esophageal Cancer patients do not have to experience disease progression on other treatments before getting the chance to receive immunotherapy.

First-Line Keytruda (Pembrolizumab) plus Chemo in Locally Advanced, Unresectable or Metastatic Esophageal Cancer

The FDA approved Keytruda (pembrolizumab), another PD-LI inhibitor, in combination with chemotherapy in patients with previously untreated advanced esophageal squamous cell carcinoma, esophageal adenocarcinoma, or esophagogastric junction adenocarcinoma.  The application was based upon the Keynote-590 study which found that overall survival was improved for all patients who received Keytruda with chemotherapy rather than chemotherapy alone.

Benefits were greatest in patients with high expression of programmed death ligand-1 (PD-L1), the check-point target of Keytruda.  Patients with a PD-L1 combined positive score of 10 or more experienced the greatest benefit from the addition of Keytruda to their chemotherapy, however, the FDA did not place any constraints on the use of Keytruda for these patients based upon their PD-L1 expression.

First-Line Opdivo (Nivolumab) plus Chemo for Advanced, Metastatic Esophageal Cancer

Opdivo (nivolumab) has been approved as first-line therapy for patients with metastatic or advanced Esophageal Adenocarcinoma, Gastroesophageal Junction Cancer, and Gastric Cancer in combination with fluoropyrimidine- (5 FU) and platinum-containing chemotherapy.  The FDA did not constrain use of Opdivo based on any minimum level of PD-L1 expression.

The application was based on the results of the Checkmate-649 study which included patients with previously untreated, non-HER2-positive advanced or metastatic gastroesophageal junction cancer or esophageal adenocarcinoma.

Researchers assigned patients to nivolumab plus chemotherapy (FOLFOX), nivolumab plus ipilimumab (Yervoy) an anti-CTLA-4 monoclonal antibody, or chemotherapy alone. The nivolumab-chemotherapy regimen significantly improved overall survival and progression-free survival among patients whose tumors expressed programmed death ligand-1 (PD-L1 – the checkpoint target of Opdivo) with a combined positive score of 5 or higher. Researchers also reported a significant overall survival benefit with the combination in the overall study population.

Opdivo for Patients who Have Undergone Esophagectomy after Chemoradiation

The FDA has approved Opdivo for Esophageal Cancer patients who have undergone Chemoradiation and Esophagectomy but have not achieved a pathologic complete response.   Esophageal Cancer patients who undergo esophagectomy but fail to achieve a pathologic complete response are at substantial risk for recurrence of their disease.

The Checkmate-577 study provided Opdivo (nivolumab) to Esophageal Cancer patients who had undergone chemoradiation and esophagectomy but did not achieve a pathologic complete response.  When compared to patients who did not receive Opdivo, progression-free survival was doubled and the risk of recurrence or death was reduced by 31% in the group that received Opdivo.

The National Cancer Institute defines pathologic complete response as a “lack of all signs of cancer in tissue samples removed during surgery or biopsy after treatment with radiation or chemotherapy. To find out if there is a pathologic complete response, a pathologist checks the tissue samples under a microscope to see if there are still cancer cells left after the anticancer treatment.” The number of Esophageal Cancer patients who achieve a pathologic complete response after esophagectomy is relatively low.