Merck Keytruda plus trastuzumab and chemotherapy gets European nod to treat HER2-positive advanced gastric or GEJ adenocarcinoma expressing PD-L1

Merck, known as MSD outside of the United States and Canada, today announced that the European Commission (EC) has approved Keytruda, Merck’s anti-PD-1 therapy, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumours express PD-L1 (Combined Positive Score [CPS] =1).

This approval by the EC follows the positive recommendation from the Committee for Medicinal Products for Human Use received in July 2023 and was based on results from the phase 3 KEYNOTE-811 trial. In the study, Keytruda plus trastuzumab and chemotherapy significantly improved progression-free survival (PFS), and objective response rate (ORR), compared to trastuzumab and chemotherapy alone in this patient population. In the study, more than 80% of patients had tumours that were PD-L1 positive.

There was a trend toward improvement in overall survival (OS), the trial’s other primary endpoint, in the ITT population for patients who received the Keytruda combination versus placebo in combination with trastuzumab and chemotherapy; however, these results did not meet statistical significance per the pre-specified statistical analysis plan. OS analysis for this trial is ongoing.

Results from KEYNOTE-811 will be presented at the upcoming 2023 European Society for Medical Oncology (ESMO) Annual Meeting.

“Patients in the 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,” said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. “With today’s approval of Keytruda, we’re proud that patients whose tumours express PD-L1 with a combined positive score =1 and healthcare providers in the EU will have an option that includes immunotherapy for this difficult-to-treat disease.”

This approval allows marketing of this Keytruda regimen in all 27 European Union (EU) member states plus Iceland, Lichtenstein, Norway and Northern Ireland.

In May 2021, Keytruda was approved in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma in the US This indication was approved by the FDA under accelerated approval based on ORR data from KEYNOTE-811, and continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Merck is working with the FDA to update this indication to patients whose tumours are PD-L1 positive.

Merck has an extensive clinical development program evaluating Keytruda in gastrointestinal cancers and is continuing to study Keytruda for multiple uses in gastric, hepatobiliary, esophageal and colorectal cancers.

KEYNOTE-811 is a randomized, double-blind phase 3 trial (ClinicalTrials.gov, NCT03615326) evaluating Keytruda in combination with trastuzumab and chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. The dual primary endpoints are PFS per RECIST v1.1 as assessed by blinded independent central review and OS. Secondary endpoints include ORR, duration of response and safety. The trial enrolled an estimated 732 patients who were randomized to receive Keytruda (200 mg every three weeks) in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy (investigator’s choice of 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin), or placebo in combination with trastuzumab and chemotherapy.

Gastric (stomach) cancer tends to develop slowly over many years and rarely causes early symptoms, resulting in most patients presenting with advanced stage disease. Overall, more than 70% of patients with gastric cancer develop advanced-stage disease. Most gastric cancers are adenocarcinomas (about 90% to 95%), which develop from cells in the innermost lining of the stomach (known as the mucosa). Gastric cancer is the fifth most diagnosed cancer and the fourth leading cause of cancer death worldwide, with approximately 1.1 million patients diagnosed and 768,000 patient deaths from the disease globally in 2020.In Europe, it is estimated that there were approximately 136,000 patients diagnosed with gastric cancer and 97,000 patient deaths from the disease in 2020. The five-year survival rate for patients diagnosed with gastric cancer at an advanced stage is only 6%.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumour cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumour cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research programme. There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical program seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.

Keytruda, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumour response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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