Immunotherapy for Gastric and Esophageal Cancer – Current Status and Future Outlook 2019

Each year, 1.6 million new cases of esophagogastric (esophageal-gastric) cancer are diagnosed worldwide, and 1.25 million people die from these cancers annually. Gastric and esophageal cancers are the second most common causeof cancer-related death worldwide. Expected 5-year survival in regionally advanced but operable gastric-esophageal cancer is approximately 30%. In stage 4 disease, expected survival remains poor despite systemic treatment and rarely exceeds 1 year. This unfavorable disease course creates an urgent need for new treatments for metastatic gastric-esophageal cancers.

Developing Better Treatments Requires Understanding Cancer’s Biogenetic Features, Such as Genetics, the Microenvironment, Growth Signaling Pathways and Other Such Biogenetic Characteristics of Cancer

We have seen excellent examples in melanoma, kidney, lung and breast cancer. However, little progress has yet been made in upper gastrointestinal cancers (liver, biliary tract, pancreas, stomach and esophagus). Compared with many other cancers, gastric-esophageal cancers are highly genetically heterogeneous (complex), limiting individualized treatment. Indeed, dividing conventional gastric cancer (gastric adenocarcinoma) into 4 genetic subtypes—chromosomal instability, high microsatellite instability, EBV-positive and genomically stable—shows how complex their biology is.

Until the last 10 years, treatment options for gastric-esophageal cancers remained limited. Fluoropyrimidine and platinum -based chemotherapies long formed the backbone of systemic treatment. Trastuzumab, approved in 2010, significantly improved outcomes for patients with HER2 -positive gastric cancer.

In recent years, promising results have also been obtained with immunotherapy for gastric and esophageal cancer. For example, MSI-H and EBV-positive gastric cancer subgroups have been found to be immunogenic and to benefit substantially from immunotherapy. MSI-H means that DNA repair mechanisms are defective. Because this group is immunogenic, treatment with pembrolizumab (Keytruda) alone produced a 53% response rate. When EBV positivity accompanies MSI-H, response rates reach 70%. Indeed, pembrolizumab received approval in 2017 for MSI-H or PD-L1-positive gastric-esophageal cancers. Nivolumab (Opdivo) was approved for gastric cancer in Japan in 2017 regardless of PD-L1 status. Other immune checkpoint-modulating immunotherapies —avelumab, ipilimumab and tremelimumab—showed minimal efficacy in cancers of this region.

Can We Predict the Benefit of Immunotherapy in Gastric Cancer Using PD-L1 Levels?

Unfortunately, as in other solid (organ) cancers, in gastric cancer tumor PD-L1 expression has not been proportional to immunotherapy benefit. However, studies of the anti-PD-1 agent pembrolizumab found a response rate of 22.7%, particularly when given as 3rd-line treatment for PD-L1-positive gastric cancer. This benefit was not shown in strongly PD-L1-positive cancer. Unlike pembrolizumab, nivolumab showed lower efficacy independent of PD-L1 positivity (response rate 11%). The ongoing phase III Keynote 62 and CheckMate 649 studies are investigating first-line combination treatment efficacy in PD-L1-positive patients.

Anti-PD-1-Based COMBINATION Treatments for Gastric-Esophageal Cancers

Because very few patients respond to anti-PD-1 immunotherapies alone—pembrolizumab and nivolumab—combination treatments have been investigated. Studies combining nivolumab and ipilimumab (Yervoy) (CM 032, CM649) found an overall response rate of 24% in all patients versus 44% in the PD-L1-positive group. Alongside this marked increase, grade 3-4 (severe) immunotherapy side effects occurred in 47%. Therefore, combined ipilimumab + nivolumab treatment does not appear usable in clinical practice.

When anti-PD-1 treatment was combined with anti-Her2 treatment as 1st-line therapy in HER2-positive metastatic gastric-esophageal cancer, the response rate was 87%, disease control rate 100% and median progression-free survival 11.4 months; overall survival had not yet been reached. Results of the ongoing Keynote 811 trial in this patient group may change clinical practice.

In conclusion, apart from conventional chemotherapy and Anti-Her2 treatments that currently strengthen our options for gastric-esophageal cancer, there have been few practice-changing developments. However, tumors can be assessed for MSI-H and PD-L1 expression. If both are positive, immunotherapy may be used because its benefit would exceed chemotherapy’s and its side effects would be fewer. We will await results of ongoing combination immunotherapy studies to see whether they produce practice-changing findings.

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