Merck Keytruda plus chemotherapy gets US-FDA approval to treat locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma

Merck, known as MSD outside of the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Keytruda, Merck’s anti-PD-1 therapy, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The approval is based on data from the phase 3 KEYNOTE-859 trial, in which Keytruda plus chemotherapy reduced the risk of death by 22% (HR=0.78 [95% CI, 0.70-0.87]; p<0.0001) compared to chemotherapy alone for these patients. Median overall survival (OS) was 12.9 months (95% CI, 11.9-14.0) for Keytruda plus chemotherapy versus 11.5 months (95% CI, 10.6-12.1) for chemotherapy alone.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda. Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.

“The majority of patients with gastric cancer are diagnosed at an advanced stage, at which point they face a poor prognosis with a five-year survival rate of 6%,” said Dr. Zev A. Wainberg, professor of medicine at University of California, Los Angeles School of Medicine and co-director of the UCLA GI Oncology Programme. “This approval of pembrolizumab plus chemotherapy offers patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer.”

“At Merck, we have a comprehensive development program across a broad range of gastrointestinal cancers with the goal of providing meaningful new options to patients and their healthcare providers,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “This latest approval of a Keytruda-based treatment option is an important milestone for patients with advanced HER2-negative gastric or GEJ adenocarcinoma and reinforces Merck’s commitment to addressing the needs of these patients in the US.”

KEYNOTE-859 is a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov, NCT03675737) that enrolled 1,579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible.

Patients were randomized (1:1) to receive Keytruda (200 mg every three weeks) in combination with fluoropyrimidine- and platinum-containing chemotherapy (n=790), or placebo in combination with chemotherapy (n=789). All patients received investigator’s choice of chemotherapy (5-fluorouracil plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]). All study medications, except oral capecitabine, were administered as an intravenous infusion for every three-week cycle. Platinum agents could be administered for six or more cycles following local guidelines. Treatment with Keytruda continued until RECIST v1.1-defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity or a maximum of 24 months.

The major efficacy outcome measure was OS. Additional secondary efficacy outcome measures included progression-free survival (PFS), objective response rate (ORR) and duration of response as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Ninety-seven percent of patients had metastatic disease (stage IV) and 3% had locally advanced unresectable disease. Seventy-eight percent of patients had tumours that expressed PD-L1 (CPS =1) and 5% (n=74) had tumours that were microsatellite instability-high (MSI-H). Eighty-six per cent of patients received Capox.

A statistically significant improvement in OS, PFS and ORR was demonstrated in patients randomized to receive Keytruda plus chemotherapy compared to chemotherapy alone at the pre-specified interim analysis of OS. In the study, there was a 22% reduction in the risk of death with Keytruda plus chemotherapy (HR=0.78 [95% CI, 0.70-0.87]; p<0.0001) versus chemotherapy alone. The median OS for patients receiving Keytruda plus chemotherapy was 12.9 months (95% CI, 11.9-14.0) versus 11.5 months (95% CI, 10.6-12.1) for those receiving chemotherapy alone.

In an exploratory subgroup analysis in patients whose tumours express PD-L1 (Combined Positive Score [CPS <1]) (n=344) at the time of the pre-specified interim analysis of OS, the median OS was 12.7 months (95% CI, 11.4-15.0) for Keytruda plus chemotherapy and 12.2 months (95% CI, 9.5, 14.0) for chemotherapy alone (HR=0.92 [95% CI, 0.73-1.17]).

The median duration of exposure to Keytruda was 6.2 months (range, 1 day to 33.7 months). Serious adverse reactions occurred in 45% of patients receiving Keytruda. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhoea (3.9%), haemorrhage (3.9%) and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received Keytruda including infection (2.3%) and thromboembolism (1.3%). Permanent discontinuation of Keytruda due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of Keytruda in =1% were infections (1.8%) and diarrhoea (1.0%). Dosage interruptions of Keytruda due to adverse reactions occurred in 65% of patients; adverse reactions or laboratory abnormalities leading to interruption of Keytruda (=2%) were neutropenia (21%), thrombocytopenia (13%), diarrhoea (5.5%), fatigue (4.8%), infection (4.8%), anaemia (4.5%), increased aspartate aminotransferase (AST) (4.3%), increased alanine aminotransferase (ALT) (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome and vomiting (2% each). The most common adverse reactions (all grades =20%) for patients receiving Keytruda were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhoea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%) and weight loss (20%).

Gastric (stomach) cancer tends to develop slowly over many years and rarely causes early symptoms, resulting in most patients presenting with 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). In the US, it was estimated there will be approximately 26,500 patients diagnosed with gastric cancer and 11,000 deaths from the disease in 2023. Overall, more than 70% of patients with gastric cancer are diagnosed with advanced-stage disease, and the majority of gastric cancers are HER2-negative.The five-year survival rate for patients diagnosed with gastric cancer at an advanced stage is 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 program. There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical programme 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 adults with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma whose tumour express PD-L1 (CPS =1) as determined by an FDA-approved test. 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.

At Merck, the company committed to supporting accessibility to our cancer medicines. Merck provides multiple programmes to help appropriate patients who are prescribed Keytruda have access to our anti-PD-1 therapy. The Merck Access Programme provides reimbursement support for patients receiving Keytruda, including information to help with out-of-pocket costs and co-pay assistance for eligible patients.

Merck is committed to helping provide patients and their caregivers support throughout their treatment with Keytruda. The KEY+YOU Patient Support Program provides a range of resources and support.

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