First Approval for Immunotherapy for Esophageal Cancer - Medscape

Esophageal cancer has now joined the list of tumor types that can be treated with immunotherapy, after approval of the immune checkpoint inhibitor pembrolizumab (Keytruda, Merck & Co) for this indication.

This latest indication joins a growing list that also includes melanoma, lung cancer, head and neck cancer, liver, kidney and urothelial cancers, among others.

Specifically, pembrolizumab has now been approved by the US Food and Drug Administration (FDA) for use as monotherapy for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

"Historically, patients with advanced esophageal cancer have had limited treatment options, particularly after their disease has progressed," said Jonathan Cheng, MD, vice president for oncology clinical research at Merck Research Laboratories.

With this approval, pembrolizumab offers "an important new monotherapy option for physicians and patients in the United States," he commented in a company press release.

The approval was made on the basis of results from the company-sponsored KEYNOTE-181 (NCT02564263), which was presented earlier this year at the Gastrointestinal Cancers Symposium and reported at the time by Medscape Medical News.

KEYNOTE-181 was a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease.

Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory, and PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit.

Patients were randomly assigned to receive either pembrolizumab 200 mg every three weeks or investigator's choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m² on days 1, 8, and 15 of every four-week cycle, docetaxel 75 mg/m² every three weeks, or irinotecan 180 mg/m² every two weeks.

Treatment was continued until unacceptable toxicity or disease progression. Assessment of tumor status was performed every 9 weeks.

Results were presented in January by principal investigator Takashi Kojima, MD, professor in the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan.

The primary endpoint was overall survival.

Although it was directionally favorable, the difference in overall survival was not statistically significant in the intention-to-treat (ITT) group (7.1 months vs 7.1 months; hazard ratio [HR], 0.89; P = .0560), he reported.

There was a clear benefit, however, in the subgroup of patients who had tumors with a PD-L1 combined positive score (CPS) ≥10, regardless of histology.

In this subgroup, treatment with pembrolizumab yielded a 12-month overall survival of 43%, vs 20% for those treated with either paclitaxel, docetaxel, or irinotecan.

At a median follow-up of 7.1 months for pembrolizumab and 6.9 months for chemotherapy, the overall survival rate for patients with a PD-L1 CPS ≥10 (n = 222) who received pembrolizumab was 9.3 months vs 6.7 months in the chemotherapy arm (HR, 0.69; P = .0074).

"The overall response rate was also higher with pembrolizumab than with chemotherapy," Kojima added, "and the safety profile was better with pembrolizumab vs chemotherapy."

"These data suggest that pembrolizumab should be considered a new standard of care in patients with a PD-L1 CPS of 10 or greater in the second-line setting," he concluded.

"Patients with advanced esophageal cancer after first-line chemotherapy have a poor prognosis and limited treatment options," explained Kojima. "Taxanes and irinotecan have been used after first-line therapy, but no overall survival benefit has been seen in a phase 3 study with chemotherapy."

The product label for pembrolizumab notes that immune-mediated adverse reactions, which may be severe or fatal, can occur. These can include the following: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Depending on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate.

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