The FDA on Wednesday granted accelerated approval to Merck & Co.'s Keytruda (pembrolizumab) in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy to treat patients with locally advanced, unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma in the first-line setting. The decision comes about a week after an FDA advisory panel recommended the agency rescind an earlier accelerated approval that was bestowed on the PD-1-blocking antibody for use as monotherapy in later-line gastric cancer because it had failed to show significant benefit in confirmatory trials.
"This is the first time an anti-PD-1 therapy has been approved in combination with anti-HER2 therapy and chemotherapy as a first-line treatment for these patients," said Merck chief medical officer Roy Baynes of the latest FDA decision, adding that Keytruda has shown "meaningful improvement" in objective response rate (ORR) over standard treatment among HER2-positive gastric and GEJ cancer patients.
The new approval was based on data from the ongoing Phase III KEYNOTE-811 trial, which was designed to enroll 692 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Participants were randomised to receive either Keytruda or placebo, both on top of trastuzumab followed by investigator's choice of combination chemotherapy. Major outcome measures included ORR and duration of response (DoR).
An interim analysis was based on data from the first 264 randomised patients, with Merck noting that 87% of these had tumours that expressed PD‑L1 with a combined positive score (CPS) ≥1. According to the results, Keytruda together with trastuzumab plus chemotherapy demonstrated a statistically significant ORR of 74%, compared to 52% for trastuzumab and chemotherapy alone. Complete and partial response rates among Keytruda-treated patients were 11% and 63%, respectively, compared with 3.1% and 49% for the comparator group. In addition, the median DoR was 10.6 months for patients treated with Keytruda and 9.5 months for those in the placebo arm.
Keytruda's first FDA nod in gastric cancer came in 2017, when it was cleared as a third-line treatment for patients with recurrent, locally advanced or metastatic gastric or GEJ cancer whose tumours express PD-L1 with CPS ≥1. However, the agency ran a three-day review last week of accelerated approvals for checkpoint inhibitors where confirmatory trials have failed to demonstrate a significant benefit, with an advisory panel voting 6 to 2 against maintaining that particular indication for Merck's drug.
Members of the advisory committee did vote in favour of letting Keytruda keep two other accelerated approvals in bladder cancer and hepatocellular carcinoma. For more analysis, see ViewPoints: FDA acts on accelerated approval angst.
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