Pembrolizumab in Combination With Platinum-, Fluoropyrimidine-Based Chemotherapy Receives FDA Approval for GEJ

Pembrolizumab (Keytruda; Merck) with trastuzumab, a fluoropyrimidine- and platinum-containing chemotherapy, was approved by the FDA for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2-positive (HER2+) gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS greater than or equal to 1). The decision is based on clinically meaningful results from the KEYNOTE-811 trial (NCT03615326).¹

Vial of pembrolizumab | Image Credit: © Soni's - stock.adobe.com

Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide and the fourth leading cause of cancer-related deaths. HER2 is a common mutation characterized by the overexpression or amplification of epidermal growth factor receptors. It is highly prevalent in various cancers, including breast, prostate, and lung cancers. An estimated 7.3% to 20.2% of patients with advanced GEJ adenocarcinoma have HER2 overexpression.²

Pembrolizumab is a humanized monoclonal antibody that increases the body's immune system's ability to fight tumor cells by blocking PD-1's function with its ligands, PD-L1 and PD-L2, to activate T lymphocytes. It has received approval for a number of malignancies, including melanoma, urothelial carcinoma, non-small cell lung cancer, and head and neck cancers, in conjunction with other agents. In 2021, pembrolizumab was approved for treatment of metastatic or locally advanced esophageal or GEJ based on data from KEYNOTE-590 (NCT03189719).^3-5

In the KEYNOTE-811 trial, pembrolizumab with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy showed significant promise as a combination treatment for patients with GEJ. The multicenter, randomized, double-blind, placebo-controlled trial enrolled 698 patients with HER2+ advanced gastric or GEJ adenocarcinoma not previously treated with systemic therapy for metastatic disease. Of the population, 85% had tumors expressing PD-L1 with a CPS greater than or equal to 1 using the PD-L1 IHC 22C3 pharmDx kit.⁶

The patients were randomly assigned to receive either pembrolizumab 200 mg or placebo, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin. To measure the efficacy and safety of the combination, investigators evaluated progression-free survival (PFS) and overall survival (OS).⁶

Patients who received the pembrolizumab combination achieved statistically significant improvements in OS (12.4 months; 95% CI: 10.5, 14.0) compared with patients who received the placebo plus chemotherapy treatment (9.8 months; 95% CI: 8.8, 10.8). The median PFS was about 6.3 months (95% CI: 6.2, 6.9) and 5.8 months (95% CI: 5.0, 6.0), respectively (HR 0.65; 95% CI: 0.55, 0.76; P < .0001).⁶

The safety profile was favorable, with adverse events reported in greater than or equal to 20% of patients, of which the most common were nausea, constipation, diarrhea, vomiting, stomatitis, fatigue/asthenia, decreased appetite, and weight loss.⁶

For esophageal cancer, 200 mg of pembrolizumab every 3 weeks or 400 mg every 6 weeks is the suggested dosage.⁶

REFERENCES

1. Pembrolizumab/​placebo plus trastuzumab plus chemotherapy in human epidermal growth factor receptor 2 positive (HER2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-811/​KEYNOTE-811). Updated March 17, 2025. Accessed March 19, 2025. https://clinicaltrials.gov/study/NCT03615326

2. Li W, Zhang X, Du Y, et al. HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives. Biomark Res. September 30, 2022. Doi:10.1186/s40364-022-00416-x

3. Pembrolizumab plus standard of care receives priority review for resectable locally advanced head and neck cancer. Pharmacy Times. Updated February 26, 2025. Accessed March 19, 2025. https://www.pharmacytimes.com/view/pembrolizumab-plus-standard-of-care-receives-priority-review-for-resectable-locally-advanced-head-and-neck-cancer

4. FDA approves pembrolizumab for esophageal or GEJ carcinoma. FDA. March 22, 2021. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-esophageal-or-gej-carcinoma

5. First-line esophageal carcinoma study with pembrolizumab plus chemo vs. chemo (MK-3475-590/​KEYNOTE-590). Updated October 15, 2024. Accessed March 19, 2025. https://clinicaltrials.gov/study/NCT03189719

6. FDA approves pembrolizumab for HER2 positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1). FDA. March 19, 2025. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-her2-positive-gastric-or-gastroesophageal-junction-adenocarcinoma