The European Commission has approved pembrolizumab plus platinum- and fluoropyrimidine-based chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative gastroesophageal junction adenocarcinoma whose tumors have PD-L1 expression.
The European Commission has approved pembrolizumab (Keytruda) plus platinum- and fluoropyrimidine-based chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative gastroesophageal junction (GEJ) adenocarcinoma whose tumors whose tumors express PD-L1 (combined positive score [CPS] ≥10).1
The regulatory decision was supported by findings from the phase 3 KEYNOTE-590 trial (NCT03189719), which demonstrated that pembrolizumab plus 5-fluororacil (5-FU) and cisplatin significantly improved overall survival (OS) and progression-free survival (PFS) over 5-FU/cisplatin alone in all prespecified populations.
The pembrolizumab combination reduced the risk of death by 27% (HR, 0.73; 95% CI, 0.62-0.86; P <.0001) over 5-FU/cisplatin alone in the overall patient population (n = 749); it also resulted in a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.55-0.76; P <.0001). The median OS in the investigative and control arms was 12.4 months (95% CI, 10.5-14.0) and 9.8 months (95% CI, 8.8-10.8), respectively, and the median PFS was 6.3 months (95% CI, 6.2-6.9) and 5.8 months (95% CI, 5.0-6.0), respectively.
Moreover, in a prespecified analysis of patients whose tumors had a PD-L1 expression with a CPS of 10 or higher (n = 383), pembrolizumab plus 5-FU/cisplatin resulted in a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.49-0.78; P <.0001) and a 49% reduction in the risk of disease progression or death (HR, 0.51; 95% CI, 0.41-0.65; P <.0001) vs chemotherapy alone. In this subset, the median OS in the investigative and control arms was 13.5 months (95% CI, 11.1-15.6) and 9.4 months (95% CI, 8.0-10.7), respectively, and the median PFS was 7.5 months (95% CI, 6.2-8.2) and 5.5 months (95% CI, 4.3-6.0), respectively.
“We have seen few advances over the last 3 decades that have improved historically poor survival outcomes for patients with esophageal cancer,” Professor Antoine Adenis, of the Department of Medical Oncology at Montpellier Cancer Institute, stated in a press release. “The EC’s approval of [pembrolizumab] plus chemotherapy for the treatment of certain patients with esophageal and HER2-negative GEJ cancer provides a new option in the first-line setting that has shown significant improvements in PFS and OS.”
The randomized, double-blind, placebo-controlled trial examined pembrolizumab plus chemotherapy vs placebo plus chemotherapy in the frontline treatment of patients with esophageal cancer.
To be eligible for enrollment, patients needed to have locally advanced unresectable or metastatic esophageal cancer, esophageal squamous cell carcinoma (ESCC), or advanced/metastatic esophagogastric junction (EGJ) Siewert type 1 adenocarcinoma. Patients also needed to be treatment naïve, have an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria.
Participants were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus 5-FU at 800 mg/m2 for days 1 to 5 every 3 weeks for up to 35 cycles plus cisplatin at 80 mg/m2 every 3 weeks for up to 6 cycles (n = 373) or chemotherapy alone (n = 376). Patients were stratified based on region (Asia vs non-Asia), disease (esophageal cancer vs ESCC), and performance status (0 or 1).
The co-primary end points of the trial were OS and PFS per RECIST v1.1 criteria and investigator assessment, and an important secondary end point was objective response rate (ORR) per RECIST v1.1 criteria and investigator assessment.
The median age of study participants across the arms was 63 years, with 43% of patients aged 65 years or older. The majority of patients were male (83.4%), from the Asia region (52.5%), had an ECOG performance status of 1 (59.8%), and had metastatic disease (91.2%). Moreover, 8.8% of patients had unresectable or locally advanced disease, 73.2% had squamous cell carcinoma, and 26.8% had adenocarcinoma. Of those with adenocarcinoma, 14.7% had esophageal cancer and 12.2% had EGJ cancer. Additionally, 51.2% of patients had a PD-L1 CPS of 10 or higher.
Additional findings revealed that the ORR achieved with pembrolizumab/chemotherapy was 45.0% (95% CI, 39.9%-50.2%) vs 29.3% (95% CI, 24.7%-34.1%) with chemotherapy alone (P <.0001). The median duration of response (DOR) in the investigative arm was 8.3 months (range, 1.2+ to 31.0+) vs 6.0 months (range, 1.5+ to 25.0+) in the control arm.
Regarding safety, any-grade toxicities were reported in all patients who received pembrolizumab and chemotherapy vs 99.5% of those who received chemotherapy alone; 98.4% and 97.3% of patients, respectively, experienced events that were related to treatment. Slightly more patients on the investigative arm experienced grade 3 adverse effects (AEs) or higher vs the control arm, at 71.9% and 67.6%, respectively.
Almost 20% (19.5%) of patients who received the pembrolizumab regimen experienced an AE that resulted in treatment discontinuation vs 11.6% of those who received chemotherapy alone; 2.4% and 1.4% of patients, respectively, experienced an effect that resulted in death. Moreover, immune-mediated AEs and infusion reactions were reported in 25.7% and 11.6% of those in the investigative and control arms, respectively; these effects were grade 3 or higher in 7.0% and 2.2% of patients, respectively.
Patients on the trial experienced nausea, decreased appetite, anemia, fatigue, decreased neutrophil count, vomiting, diarrhea, neutropenia, stomatitis, decreased white blood cells, increased blood creatinine, decreased platelet count, and mucosal inflammation.