December 17, 2020 - The FDA has granted priority review to a new supplemental biologics license application for pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy as a first-line treatment in patients with locally advanced unresectable or metastatic esophageal and gastroesophageal junction cancer.
The FDA has granted priority review to a new supplemental biologics license application for pembrolizumab (Keytruda) in combination with platinum- and fluoropyrimidine-based chemotherapy as a first-line treatment in patients with locally advanced unresectable or metastatic esophageal and gastroesophageal junction (GEJ) cancer.1
The application is based on data from the phase 3 KEYNOTE-590 trial (NCT03189719), which showed that the frontline regimen significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemotherapy alone in this patient population.
Results presented during the 2020 ESMO Virtual Congress showed that the median OS with the chemoimmunotherapy regimen was 12.4 months vs 9.8 months with chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; P <.0001).2 The OS rate at 12 months in the investigative arm was 51% vs 39% in the control arm; these rates were 28% vs 16%, respectively, at 24 months.
Additionally, the median PFS months per investigator assessment and RECIST v1.1 criteria was 6.3 months and 5.8 months with pembrolizumab/chemotherapy and chemotherapy alone, respectively (HR, 0.65; 95% CI, 0.55-0.76; P <.0001). The 12-month PFS rates were 25% vs 12% in the investigative and control arms, respectively; the rates at 18 months were 16% vs 6%, respectively.
Under Prescription Drug User Fee Act, the FDA must make a decision by April 13, 2021.
“Patients with newly diagnosed esophageal and GEJ cancer face an aggressive disease with a poor prognosis, despite the currently available treatment options,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “We look forward to working with the FDA to bring a new option to patients in the first-line setting.”
In the randomized, double-blind, placebo-controlled phase 3 trial, investigators evaluated pembrolizumab in combination with chemotherapy compared with placebo plus chemotherapy in the first-line treatment of patients with advanced esophageal cancer.
To be eligible for participation, patients had to be treatment naïve, an ECOG performance status of 0-1, and measurable disease in accordance with RECIST v1.1 criteria. Patients also needed to have locally advanced resectable or metastatic esophageal cancer, ESCC, or advanced/metastatic esophagogastric junction Siewert type 1 adenocarcinoma.
Study participants were stratified based on several factors, including region (Asia vs non-Asia), disease (ESCC vs esophageal), and performance status (0 vs 1). Patients were randomized 1:1 to receive either intravenous (IV) pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles in combination with chemotherapy comprised of IV 5-fluorouracil at 800 mg/m2 on days 1-5 every 3 weeks for up to 35 cycles and IV cisplatin at 80 mg/m2 every 3 weeks for up to 6 cycles (n = 370) or just the chemotherapy agents plus placebo (n = 370).
The primary objectives of KEYNOTE-590 were OS and PFS per RECIST v1.1 criteria and investigator assessment. With regard to OS, the following patient subsets were evaluated: those with ESCC and a PD-L1 combined positive score (CPS) or 10 or higher, those with ESCC, those just with a PD-L1 CPS of 10 or higher, and the entire study population. PFS was evaluated in the following subgroups: those with ESCC, those with a PD-L1 CPS of 10 or higher, and all study participants. The secondary objective of the trial was ORR per RECIST v1.1 criteria and investigator assessment. Investigators evaluated patients for tumor response at week 9 of treatment and every 9 weeks thereafter.
Regarding safety, treatment-associated toxicities were experienced by 98.4% of patients who received pembrolizumab/chemotherapy vs 97.3% of those who received placebo/chemotherapy. Grade 3 or higher effects were reported in more patients who received the chemoimmunotherapy vs those who just received chemotherapy, at 71.9% vs 67.6%, respectively.
Toxicities determined to be related to treatment and led to discontinuation were reported in 19.5% of those given pembrolizumab/chemotherapy compared with 11.6% of those who received chemotherapy alone. Additionally, slightly more patients in the investigational arm experienced treatment-related adverse effects that resulted in death compared with those in the control arm, at 2.4% vs 1.4%, respectively.
Almost 26% of patients who received the chemoimmunotherapy regimen experienced immune-mediated toxicities vs 11.6% of those who received chemotherapy alone; these effects were grade 3 or higher in 7.0% vs 2.2% of patients, respectively.
Pembrolizumab was approved by the FDA in July 2019 for use as a single agent in the second-line treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors have a PD-L1 CPS of 10 or higher.
The decision was based on data from the phase 2 KEYNOTE-180 and the phase 3 KEYNOTE-181 trials. In KEYNOTE-180, the agent was found to induce an ORR of 14% with a median duration of response that had not been reached in third-line patients with ESCC and tumors with a PD-L1 CPS of 10 or higher.3 In KEYNOTE-181, pembrolizumab monotherapy resulted in a median OS of 10.3 months vs 6.7 months with chemotherapy (HR, 0.64), an ORR of 22% vs 7%, respectively, and a median DOR of 9.3 months vs 7.7 months, respectively, in second-line patients with ESCC and a CPS of 10 or higher.4,5
The agent was also approved in this indication in China and Japan.