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The Japan Pharmaceuticals and Medical Devices Agency has approved the PD-1 inhibitor pembrolizumab for frontline use in combination with 5-fluorouracil plus cisplatin chemotherapy in patients with radically unresectable, advanced, or recurrent esophageal carcinoma.
The Japan Pharmaceuticals and Medical Devices Agency (PMDA) has approved the PD-1 inhibitor pembrolizumab (Keytruda) for frontline use in combination with 5-fluorouracil (5-FU) plus cisplatin chemotherapy in patients with radically unresectable, advanced, or recurrent esophageal carcinoma, according to a news release from Merck, the manufacturer of pembrolizumab.1
The approval represents the first PD-1/PD-L1 inhibitor–based regimen approved in Japan for the first-line treatment of this patient population. Additionally, the approval marks the 16th indication for pembrolizumab in Japan, and the second indication for the agent in esophageal cancer.
“The burden of esophageal cancer is high in Japan, where cases are increasing,” said P. Kyle Tattle, representative director and president of MSD KK Japan.1 “It is encouraging that now appropriate patients with esophageal cancer have an immunotherapy regimen option with [pembrolizumab] earlier in the treatment course that can potentially extend their lives. We remain committed to addressing the most challenging cancers affecting Japanese patients and working with the government to provide access to patients in Japan.”
The regulatory decision is based on findings from the phase 3 KEYNOTE-590 trial (NCT03189719), in which the combination of pembrolizumab and chemotherapy improved overall survival (OS) compared with placebo and chemotherapy in patients with previously untreated, advanced esophageal squamous cell carcinoma whose PD-L1 combined positive score (CPS) was at least 10.2
The pembrolizumab-based combination also improved OS and progression-free survival (PFS) in patients with esophageal squamous cell carcinoma and a PD-L1 CPS of at least 10, as well as in all randomized patients irrespective of histology.
In KEYNOTE-590, patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer were randomized 1:1 to receive 200 mg of intravenous pembrolizumab or placebo plus 5-FU and cisplatin once every 3 weeks for up to 35 cycles.
Patients were stratified by geographical region, histology, and performance status.
At a median follow-up of 22.6 months, the median OS was 13.9 months with pembrolizumab/chemotherapy vs 8.8 months with placebo/chemotherapy in patients with esophageal squamous cell carcinoma and a PD-L1 CPS of at least 10 (HR, 0.57; 95% CI, 0.43-0.75; P < .0001). In patients with esophageal squamous cell carcinoma irrespective of PD-L1 status, the median OS was 12.6 months vs 9.8 months, respectively (HR, 0.72; 95% CI, 0.60-0.88; P = .0006). In patients with a PD-L1 CPS of at least 10 irrespective of histology, the median OS was 13.5 months vs 9.4 months, respectively (HR, 0.62; 95% CI, 0.49-0.78; P < .0001). Finally, in all randomized patients, the median OS was 12.4 months vs 9.8 months, respectively (HR, 0.73; 95% CI, 0.62-0.86; P < .0001).
The median PFS was 6.3 months with pembrolizumab/chemotherapy vs 5.8 months with placebo/chemotherapy in patients with esophageal squamous cell carcinoma (HR, 0.65; 95% CI, 0.54-0.78; P < .0001), 7.5 months vs 5.5 months, respectively, in patients with a PD-L1 CPS of at least 10 (HR, 0.51; 95% CI, 0.41-0.65; P < .0001), and 6.3 months vs 5.8 months, respectively, in all randomized patients (HR, 0.65; 95% CI, 0.55-0.76; P < .0001).
“In Japan, patients living with advanced esophageal cancer face a poor prognosis with current chemotherapy regimens,” said Scot Ebbinghaus, MD, vice president and therapeutic area head for Late Stage Oncology Clinical Development at Merck Research Laboratories. “This approval offers a new treatment option with [pembrolizumab], which has been shown to improve [OS] and [PFS] when combined with chemotherapy compared to standard of care chemotherapy as a first-line treatment for patients with radically unresectable, advanced or recurrent esophageal carcinoma.”
Regarding safety, grade 3 or higher treatment-related adverse effects (AEs) occurred in 72% of patients treated with pembrolizumab plus chemotherapy vs 68% of patients treated with placebo plus chemotherapy.
The most common all-grade AEs included nausea (63%), decreased appetite (39.2%), anemia (38.6%), fatigue (36.5%), decreased neutrophil count (36.5%), vomiting (29.7%), diarrhea (26.2%), neutropenia (25.9%), stomatitis (25.9%), and decreased white blood cell count (24.1%).
In 2020, pembrolizumab was approved in Japan for the second-line treatment of patients with PD-L1–positive radically unresectable, advanced, or recurrent esophageal squamous cell carcinoma.1