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Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1-3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6-19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase 111 KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 (https://clinicaltrials.gov, NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
A pre-existing immune response to tumour antigens is associated with clinical activity of immune checkpoint blockade23. Enabling such a response through use of tumour-targeting antibodies for facilitation of cross-priming or chemotherapeutic agents for inducing immunogenic cell death or reducing immune suppressive populations is a logical next step in the development of combinatorial anticancer therapies. 1n preclinical models and patient-derived samples, trastuzumab increases HER2 internalization and cross-presentation by dendritic cells6, which in turn stimulates HER2-specific T cell responses7-9. Trastuzumab has also been shown to upregulate expression of PD-1 and its ligand programmed death ligand 1 (PD-L1), induce expression of tumour-infiltrating lymphocytes, and modulate expression of major histocompatibility complex class II10-14. Following treatment with oxaliplatin, dying cancer cells can stimulate dendritic cells, which enhances antigen processing and presentation and facilitates priming of CD8+ tumour-specific T cells15-17. Coadministration of immune checkpoint inhibitors and trastuzumab has been shown to enhance HER2-specific T cell responses, promote immune cell trafficking and induce expansion of peripheral memory T cells78,14,18,19. The possible mechanistic interaction of these modalities has been demonstrated in a HER2-positive transgenic mouse model in which dual inhibition of PD-1 and HER2 resulted in tumour eradication14.
Clinical efficacy and manageable safety for the combination of pembrolizumab, trastuzumab, and chemotherapy in patients with HER2-positive advanced oesophageal, gastro-oesophageal or gastric adenocarcinoma have been demonstrated in two single-arm, phase 11 studies20,21. To further study the combination, we...