Anti–PD-1 Treatment With Pembrolizumab in Gastric/Gastroesophageal Junction Cancers: Who Is Likely to Respond?

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Immune checkpoint inhibitors have emerged as one of the most promising new areas of drug development in oncology. Broad activity has been observed for these agents across a spectrum of hematologic malignancies and solid tumors. As reviewed in this issue of The ASCO Post, Muro and colleagues now report on one of the first series of patients with gastric and gastroesophageal junction cancers treated with the anti–PD-1 (programmed cell death protein 1) agent pembrolizumab (Keytruda) in an international, multicenter expansion cohort trial.1

Patient tumors were screened for immunohistochemical expression of the PD-1 ligand (PD-L1) in either tumor tissue or stroma; eligibility required at least 1% tissue staining, and 40% of patients screened had positive staining. By central review in 36 evaluable patients, 20% had RECIST (Response Evaluation Criteria in Solid Tumors) responses, with a median duration of response of 10 months, and half of the responses were more durable.

In addition to PD-L1 expression and MSI status, other potential immunotherapy biomarkers, such as degree of immune cell infiltration and interferon gamma gene-expression signatures, remain to be studied and validated.
— David H. Ilson, MD, PhD

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Genomic profiling of nearly two-thirds of the cancers revealed a microsatellite-instability high (MSI-H) status in 17%, and two of the four patients with MSI-H tumors responded. Response also correlated with an increased expression of an interferon gamma gene expression panel and an increase in mononuclear cell infiltrate score. The strong signal of activity reported in this study, and results from other early trials of anti–PD-1 and anti–PD-L1 therapies, provide justification for ongoing trials of these agents in esophagogastric cancers.

Conventional chemotherapy in the treatment of advanced esophagogastric cancer has limited benefit, with survival in first-line chemotherapy not even reaching 1 year. Modest progress has been made with the HER2-targeted agent trastuzumab (Herceptin) improving outcomes in the first-line treatment of HER2-positive disease. The vascular endothelial growth factor (VEGF)-targeted drug ramucirumab (Cyramza) improves response and survival in second-line therapy.

Clear Molecular Subsets

HER2 remains the only clear biomarker for targeted therapy in these diseases. Now, data are emerging from genomic profiling studies in esophagogastric cancers indicating there are clear molecular subsets of these cancers. Data from the Cancer Genome Atlas project have identified four molecular subsets: MSI-H tumors, genomically unstable tumors with amplification of receptor-associated tyrosine kinase pathways and p53 mutation, tumors associated with Epstein-Barr virus (EBV) infection, and genomically stable cancers with relatively low rates of gene mutation or amplification.2

A recent alternative classification from Asia also identified four subsets, with a classification based on MSI status, the presence or absence of p53 mutation, and a subgroup classified as epithelial-to-mesenchymal transition.3 A pooled analysis of these classifications indicates potential prognostic effects of molecular subtypes, with superior survival seen in MSI-H cancers and inferior survival seen in the epithelial-to-mesenchymal subtype.3 Genomic profiling has also identified the MSI-H– and EBV-associated subtypes as having higher expression of the ligands PD-L1 and PD-L2.2

Molecular classification of cancers needs to be incorporated into the design of future trials of novel agents and novel treatment approaches in both advanced disease and in the adjuvant setting. Hopefully, classification can also be studied retrospectively in completed trials to gain insight into the impact of genomic signatures on response to therapy and outcomes.

Who Is Likely to Respond?

Although no clear biomarker has emerged to identify which patients are more likely to respond to immune checkpoint inhibitors, response to these agents appears more likely in cancers that have a higher mutational burden and that may have a greater potential for neoantigen exposure to the immune system, as exemplified by melanoma and non–small cell lung cancer (NSCLC). In NSCLC, a greater degree of response has been observed in tumors with a higher mutational burden. Although a greater degree of expression of the ligand PD-L1 also appears to correlate with response to therapy, not all trials select patients for increased PD-L1 expression. Responses to immune checkpoint inhibitors have been observed in tumors with both low and high PD-L1 expression.

A strong putative biomarker has emerged in MSI-H status, which results either from germline mutation of DNA mismatch–repair genes, as seen in patients with Lynch syndrome, or in tumors with promoter hypermethylation leading to potential gene silencing of DNA mismatch–repair pathways. MSI-H status results in a higher tumor mutational burden, and patients with MSI-H colorectal and noncolorectal cancers have shown striking responses to anti–PD-1 therapy in recent trials of pembrolizumab.4 Whether or not the same is observed in MSI esophagogastric cancers remains to be established. In addition to PD-L1 expression and MSI status, other potential immunotherapy biomarkers, such as degree of immune cell infiltration and interferon gamma gene-expression signatures, remain to be studied and validated.

Active Areas of Investigation

Activation of costimulatory pathways, the combination of anti–PD-1 and PD-L1 agents with anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) agents, and overcoming other potential immunosuppressive pathways, as with such agents as IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitors, are active areas of further investigation. Efforts at applying immune checkpoint inhibitor therapy in the earlier treatment of advanced disease and moving these drugs into the adjuvant and neoadjuvant settings in esophagogastric cancers are also moving forward. The potential for radiation or other local ablative therapies to release tumor antigens may potentially further augment an immune response, as observed in the abscopal effect. This makes the application of immune checkpoint inhibitors to the chemoradiotherapy-based treatment of esophagogastric cancer a particular area of research interest. ■

Disclosure: Dr. Ilson reported no potential conflicts of interest.


1. Muro K, Chung HC, Shankaran V, et al: Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial. Lancet Oncol. May 3, 2016 (early release online).

2. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202-209, 2014.

3. Cristescu R, Lee J, Nebozhyn M, et al: Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21:449-456, 2015.

4. Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509-2520, 2015.

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