Only patients with PD-L1–positive tumors may receive treatment with pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastroesophageal junction adenocarcinoma following the FDA’s amendment.
The FDA has adjusted the indication for frontline pembrolizumab (Keytruda) in combination with trastuzumab (Herceptin) and fluoropyrimidine- and platinum-based chemotherapy in patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a news release from the agency.1
As part of the revised indication, only patients with a PD-L1 combined positive score (CPS) of at least 1 as detected via an FDA-approved test are eligible to receive treatment with the aforementioned regimen, which maintained its accelerated approval status. Additionally, the FDA granted approval to the Agilent PD-L1 IHC 22C3 pharmDx as a companion diagnostic for detecting PD-L1 expression in certain patients with gastric or GEJ adenocarcinoma.
The FDA originally granted accelerated approval to pembrolizumab plus trastuzumab and chemotherapy as a treatment for those with advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in May 2021.2 Supporting data for the approval came from the phase 3 KEYNOTE-811 trial (NCT03615326).
According to data published at the time of the trial’s interim analysis, pembrolizumab plus chemotherapy elicited an objective response rate (ORR) of 74% (95% CI, 66%-82%) compared with 52% (95% CI, 43%-61%) among patients who received placebo plus chemotherapy (P <.0001).1 Investigators also reported a median duration of response (DOR) of 10.6 months (range, 1.1+ to 16.5+) vs 9.5 months (range, 1.4+ to 15.4+) in each respective arm.
Subgroup analysis findings from a prespecified interim analysis among patients with a PD-L1 CPS of less than 1 (n = 104) highlighted an HR of 1.41 (95% CI, 0.90-2.20) with respect to overall survival (OS) and 1.03 (95% CI, 0.65-1.64) with respect to progression-free survival (PFS). The pembrolizumab-based regimen produced a safety profile that was comparable with prior reports of single-agent pembrolizumab and trastuzumab plus chemotherapy alone.
“We are pleased to bring a new first-line combination regimen with [pembrolizumab] that has shown meaningful improvement in ORR over standard treatment to patients with HER2-positive gastric and GEJ cancer,” Roy Baynes, executive vice president and chief medical officer at Eikon Therapeutics, said in a news release at the time of the original accelerated approval.2
In the KEYNOTE-811 trial, patients who received no prior systemic treatment were randomly assigned 1:1 to receive 200 mg of pembrolizumab intravenously every 2 weeks or matched placebo plus trastuzumab and either fluorouracil in combination with cisplatin or capecitabine plus oxaliplatin.
The trial’s primary end points were PFS as assessed by blinded independent central review per RECIST v1.1 criteria and OS. Secondary end points included ORR, DOR, adverse effects (AEs), and treatment discontinuation associated with AEs.
Patients 18 years and older with histologically or cytologically confirmed locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma and HER2-positive disease as detected by central review were able to enroll on the trial. Additional eligibility criteria included having measurable disease per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy higher than 6 months.
Those who have undergone major surgery, open biopsy, or a significant traumatic injury within 28 days prior to randomization or receipt of radiotherapy within 14 days of study entry were unable to enroll. Patients were also unsuitable for enrollment if they had known active central nervous system metastases and/or carcinomatous meningitis.