The US Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda®, Merck & Co/MSD) in combination with trastuzumab (Herceptin®; Genentech/Roche) and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1).[1][2][3]
In May 2023 pembrolizumab received accelerated approval for this indication on May 5, 2021, based on an earlier interim analysis.
Efficacy and Safety
Efficacy was evaluated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 698 patients with HER2-positive advanced gastric or GEJ adenocarcinoma not previously treated with systemic therapy for metastatic disease.
Among the 698 participating patients, 594 (85%) had tumors expressing PD-L1 with a CPS ≥1 using the PD-L1 IHC 22C3 pharmDx kit. Patients were randomized (1:1) to pembrolizumab 200 mg or placebo, in combination with trastuzumab, and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.
The major efficacy outcome measures assessed in patients were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Additional outcome measures included overall response rate (ORR) and duration of response (DOR). A statistically significant improvement in OS and PFS was demonstrated in patients randomized to pembrolizumab in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy.
In patients with tumors that were PDL1 CPS≥1, median PFS was 10.9 months (95% CI: 8.5, 12.5) in the pembrolizumab arm and 7.3 months (95% CI: 6.8, 8.4) in the placebo arm (Hazard ratio [HR] 0.72 [95% CI: 0.60, 0.87]). Median OS was 20.1 months (95% CI: 17.9, 22.9) and 15.7 months (95% CI: 13.5, 18.5) in the respective arms (HR 0.79 [95% CI: 0.66, 0.95]. ORR was 73% (95% CI: 68, 78) and 58% (95% CI: 53, 64), and median DOR was 11.3 months (95% CI: 9.9, 13.7) and 9.6 months (95% CI: 7.1, 11.2).
Overall, when compared with placebo, pembrolizumab significantly improves progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. [1]
The adverse reaction profile observed in patients receiving pembrolizumab was consistent with the known pembrolizumab safety profile.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks in combination with trastuzumab and chemotherapy.
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Clinical Trias
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) – ClinicalTrials.gov ID NCT03615326
Highlights of Prescribing Information
Pembrolizumab (Keytruda®, Merck & Co/MSD)[Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche)[Prescribing Information]
Cisplatin (Platinol®; Bristol-Myers Squibb)[Prescribing Information]
Capecitabine (Xeloda®; Genentech/Roche)[Prescribing Information]
Oxaliplatin (Eloxatin®; Sanofi) [Prescribing Information]
Reference
[1] Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yanez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin SK, Van Cutsem E, Tabernero J, Li K, Shih CS, Bhagia P, Rha SY; KEYNOTE-811 Investigators. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023 Dec 9;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0. Epub 2023 Oct 20. PMID: 37871604.
[2] Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yañez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin S, Van Cutsem E, Tabernero J, Luo S, Mahave M, Tang Y, Lowery M, Monteiro MMF, Xu L, Shih CS, Sharan KP, Bhagia P, Rha SY. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med. 2024 Oct 10;391(14):1360-1362. doi: 10.1056/NEJMc2408121. Epub 2024 Sep 14. PMID: 39282917; PMCID: PMC11620791.
[3] Qureshi Z, Jamil A, Fatima E, Altaf F, Siddique R, Shah S. Pembrolizumab in combination with trastuzumab for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer. Ann Med Surg (Lond). 2024 Jun 21;86(8):4647-4656. doi: 10.1097/MS9.0000000000002305. PMID: 39118760; PMCID: PMC11305801.
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DOI
 has approved pembrolizumab (Keytruda®, Merck & Co/MSD) in combination with trastuzumab (Herceptin®; Genentech/Roche) and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1)){kind=link}