Merck Keytruda plus chemotherapy gets European approval for new first-line indications in advanced HER2-negative gastric or GEJ adenocarcinoma in tumours expressing PD-L1 (CPS =1) and advanced biliary tract cancer

Merck, known as MSD outside of the United States and Canada, announced the European Commission (EC) has approved two new indications for Keytruda, Merck’s anti-PD-1 therapy, in gastrointestinal cancers:

Keytruda in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 with a Combined Positive Score (CPS) =1; Keytruda in combination with gemcitabine and cisplatin for the first-line treatment of locally advanced unresectable or metastatic biliary tract carcinoma (BTC) in adults.

These approvals by the EC follow positive recommendations from the Committee for Medicinal Products for Human Use received in October 2023 and November 2023 and were based on overall survival (OS) results from the phase 3 KEYNOTE-859 and KEYNOTE-966 trials, respectively.

In KEYNOTE-859, Keytruda plus chemotherapy significantly improved OS in the overall patient population, reducing the risk of death by 22% (HR=0.78 [95% CI, 0.70-0.87]; p<0.0001) compared to chemotherapy alone at a median follow-up of 12.0 months (range, 0.1 to 45.9 months). In patients whose tumours expressed PD-L1 (CPS =1), Keytruda plus chemotherapy reduced the risk of death by 26% (HR=0.74 [95% CI, 0.65-0.84]; p<0.0001). Median OS was 13.0 months (95% CI, 11.6-14.2) for patients treated with KEYTRUDA plus chemotherapy vs 11.4 months (95% CI, 10.5-12.0) for chemotherapy alone. In the study, approximately 80% of patients had tumours which expressed PD-L1 (CPS =1).

In KEYNOTE-966, Keytruda plus chemotherapy demonstrated a statistically significant improvement in OS, reducing the risk of death by 17% (HR=0.83 [95% CI, 0.72-0.95]; one-sided p=0.0034) compared to chemotherapy alone at the trial’s pre-specified final analysis for OS. Median OS was 12.7 months (95% CI, 11.5-13.6) for Keytruda plus chemotherapy versus 10.9 months (95% CI, 9.9-11.6) for chemotherapy alone.

“Keytruda has shown its potential as an important treatment option in the EU across a number of gastrointestinal cancers, with seven indications based on data from our extensive clinical development program,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “With these two new approvals of Keytruda-based regimens in advanced HER2-negative gastric and gastroesophageal junction cancer and advanced biliary tract cancer, Merck continues to demonstrate progress in providing treatment options to patients in Europe.”

The safety of Keytruda plus chemotherapy has been evaluated in 4,787 patients across tumor types. In KEYNOTE-859, the incidence of Grade 3-5 adverse reactions in patients with gastric cancer was 75% for Keytruda plus chemotherapy and 70% for chemotherapy. In KEYNOTE-966, the incidence of Grade 3-5 adverse reactions in patients with BTC was 85% for Keytruda plus chemotherapy and 84% for chemotherapy alone.

These approvals allow marketing of these Keytruda regimens for these indications in all 27 EU member states, as well as Iceland, Liechtenstein, Norway and Northern Ireland. With these decisions, Keytruda is now approved for 26 indications in the EU, including seven in gastrointestinal cancers.

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-859 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov NCT03675737) evaluating Keytruda in combination with chemotherapy compared to placebo in combination with chemotherapy for the first-line treatment of patients with HER2-negative locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. The primary endpoint is OS, and secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety. The trial enrolled 1,579 patients who were randomized to receive Keytruda (200 mg every three weeks for up to approximately two years) in combination with fluoropyrimidine- and platinum-containing chemotherapy, or placebo in combination with chemotherapy.

KEYNOTE-966 is a randomized, double-blind phase 3 trial (ClinicalTrials.gov NCT04003636) evaluating Keytruda in combination with gemcitabine and cisplatin compared to placebo plus gemcitabine and cisplatin for the first-line treatment of advanced or unresectable BTC. The primary endpoint is OS, and the secondary endpoints include PFS, ORR, DOR and safety. The trial enrolled 1,069 patients who were randomized to receive Keytruda (200 mg every three weeks for up to approximately two years) plus gemcitabine and cisplatin, or placebo plus gemcitabine and cisplatin.

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). More than half of patients with gastric cancer have tumours expressing PD-L1 (CPS =1), and the majority of gastric cancers are HER2-negative, affecting approximately four out of every five patients. 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. The five-year survival rate for patients diagnosed with gastric cancer at an advanced stage is only 6%.

Biliary tract cancer is a group of rare and highly aggressive cancers in the liver, gallbladder and bile ducts. Biliary tract cancer is the second most common type of primary liver cancer after hepatocellular carcinoma, accounting for approximately 15% of all liver cancers. It is estimated there are approximately 211,000 patients diagnosed with BTC and 174,000 patient deaths from the disease each year globally. Biliary tract cancer is most frequently diagnosed in patients between 50 and 70 years old, and approximately 70% of BTC patients are diagnosed at an advanced stage. Patients diagnosed with BTC face a very poor prognosis, with a five-year relative survival rate of 5-15% across all patients.

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.

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