The European Commission has approved pembrolizumab for use in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-positive gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 with a combined positive score of at least 1.
The European Commission has approved pembrolizumab (Keytruda) for use in combination with trastuzumab (Herceptin), fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) of at least 1.1
The approval and earlier endorsement of the regimen from the European Medicines Agency’s Committee for Medicinal Products for Human Use was based on findings from the phase 3 KEYNOTE-811 trial (NCT03615326), in which the addition of pembrolizumab to trastuzumab and chemotherapy led to significant improvements in progression-free survival (PFS) and overall response rate (ORR) vs trastuzumab and chemotherapy alone in the PD-L1–positive population.1,2 A trend toward improved overall survival (OS) with pembrolizumab vs placebo was seen in the intention-to-treat population, but the results fell short of statistical significance, according to the prespecified analysis plan. OS will continue to be evaluated.1
Data from the trial will be presented at the 2023 ESMO Congress.
“Patients in the European Union [EU] diagnosed with HER2-positive advanced gastric cancer face an aggressive disease associated with a poor prognosis, underscoring the need for additional first-line treatment options for these patients,” Scot Ebbinghaus, MD, vice president, global clinical development, Merck Research Laboratories, stated in a news release. “With today’s approval of [pembrolizumab], we’re proud that patients whose tumors express PD-L1 with a CPS [of at least] 1 and healthcare providers in the EU will have an option that includes immunotherapy for this difficult-to-treat disease.”
The randomized, double-blind KEYNOTE-811 trial evaluated the addition of pembrolizumab or placebo to trastuzumab and chemotherapy as first-line treatment in patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.
Approximately 732 patients were randomly assigned to receive 200 mg of pembrolizumab or matched placebo every 3 weeks plus trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, including 5-fluorouracil plus cisplatin or capecitabine (Xeloda) plus oxaliplatin.
The co-primary end points of the study were PFS per RECIST v1.1 criteria evaluated by blinded independent central review and OS. Secondary end points included ORR, duration of response (DOR), and safety.
In May 2021, the FDA granted an accelerated approval to pembrolizumab, trastuzumab, and platinum-containing chemotherapy as frontline therapy in patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma irrespective of PD-L1 expression. In addition to the dosing schedule of 200 mg every 3 weeks, patients may receive 400 mg of pembrolizumab every 6 weeks per the FDA label.3
Findings from the prespecified interim analysis, upon which the approval was based, showed that the investigational regimen led to an ORR of 74% (95% CI, 66%-82%) vs 52% (95% CI, 43%-61%) with the control regimen (1-sided P < .0001). Median DOR was 10.6 months (range, 1.1+ to 16.5+) and 9.5 months (range, 1.4+ to 15.4+), respectively.
Continued approval for the regimen may depend on confirmation of clinical benefit in a phase 3 trial. In the meantime, Merck is working with the FDA to update the label to patients with PD-L1–positive tumors.