FDA Approves First Line KEYTRUDA® in Combination with Chemotherapy for Esophageal or Gastroesophageal Carcinoma

SUMMARY: The FDA on March 22, 2021, approved KEYTRUDA® (Pembrolizumab) in combination with Platinum and Fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GastroEsophageal Junction (tumors with epicenter 1 to 5 cm above the GastroEsophageal Junction) carcinoma, who are not candidates for surgical resection or definitive chemoradiation. The American Cancer Society estimates that in the US about 19,260 new esophageal cancer cases will be diagnosed in 2021 and about 15,530 people will die of the disease. Esophageal cancer is more common among men than among women. Majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine. The prognosis for advanced esophageal cancer is poor, with median survival of less than 12 months.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

KEYNOTE-590 is a global, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, in which first line KEYTRUDA® plus chemotherapy was compared with placebo plus chemotherapy, in patients with locally advanced/unresectable or metastatic adenocarcinoma or esophageal Squamous Cell Carcinoma (ESCC) or Siewert type 1 EsophagoGastric Junction adenocarcinoma (EGJ), who were not candidates for surgical resection or definitive chemoradiation. In this study, 749 eligible patients, regardless of PD-L1 expression were randomized 1:1 to KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles (2 years) along with chemotherapy consisting of Cisplatin 80mg/m2 IV given on day 1, plus 5FU 800 mg/m2 IV given on days 1-5, every 3 weeks for 6 cycles, or placebo plus chemotherapy. Treatment was continued until disease progression or unacceptable toxicity, and crossover was not permitted. Approximately 50% of all patients had tumors with a PD-L1 Combined Positive Score (CPS) 10 or more, and half the population was Asian. The dual Primary endpoints of the study were Overall Survival (OS) and Progression Free Survival (PFS). The researchers evaluated outcomes in the overall treatment population, in patients with a PD-L1 CPS 10 or more, and according to histology (Esophageal Squamous Cell Carcinoma versus adenocarcinoma). The Secondary end point was Objective Response Rate (ORR) in all patients. The median follow up was 10.8 months.

There was a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA® with chemotherapy. The median OS among all patients was 12.4 versus 9.8 months (HR=0.73; P<0.0001) and the median PFS among all patients was 6.3 versus 5.8 months, respectively (HR=0.65; P<0.0001). The confirmed ORR in all patients was 45% versus 29.3% (P < 0.0001), with a median Duration of Response of 8.3 versus 6.0 months, respectively. In patients with a PD-L1 CPS 10 or higher, the median OS with the KEYTRUDA® plus chemotherapy was 13.5 months versus 9.4 months with chemotherapy alone (HR=0.62; P<0.0001) and the median PFS was 7.5 months versus 5.5 months, respectively (HR=0.51; P<0.0001). The most common adverse reactions reported in 20% or more of patients who received the KEYTRUDA® combination were nausea, vomiting, constipation, diarrhea stomatitis, fatigue/asthenia, decreased appetite, and weight loss.

It was concluded that treatment with KEYTRUDA® plus chemotherapy combination resulted in superior Overall Survival, Progression Free Survival, and Objective Response Rate, with a manageable safety profile, when compared to chemotherapy alone, in patients with advanced untreated esophageal and EsophagoGastric Junction cancer. These data demonstrate that first line KEYTRUDA® plus chemotherapy is a new standard of care in this patient population.

Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Kato K, Sun J, Shah MA, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.