Is Immunotherapy Effective in Stage 4 Stomach and Esophageal Cancer?

Stomach cancer was described even in ancient Egyptian papyri around 3000 BC. Statistical analyses from the 1760s called it the most common and deadliest cancer, but both incidence and mortality have fallen rapidly over the last 20 years. This particularly relates to eliminating Helicobacter infection and other environmental risk factors implicated in its development, and of course the invention of refrigeration.

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For locally advanced, recurrent or metastatic (stage 4) stomach cancer, treatment aims at palliation: relieving pain, nausea, bleeding or obstruction-related complaints and prolonging survival. This can be achieved with regional treatments or systemic approaches such as chemotherapy, smart drugs or immunotherapy .

Studies have begun reporting the gastric cancer effectiveness of a new-generation immunotherapy already effective in cancers such as lung cancer, malignant melanoma and kidney cancer, an immune checkpoint inhibitor called pembrolizumab (Keytruda).

Pembrolizumab (Keytruda)

This immune-regulating PD-1 inhibitor works by removing immune cells’ blindness to tumor cells. A total of 259 gastric and gastroesophageal junction cancer patients were enrolled in KEYNOTE 59, which led to pembrolizumab’s September 2017 FDA (United States Food and Drug Administration) approval. An important biomarker of immunotherapy effectiveness, PD-L1, when strongly positive, was associated with greater benefit. Although patients had received more than two prior lines, median duration of benefit with pembrolizumab was 8.4 months. The benefit rate was %16, while only 2 patients (%0.8) discontinued because of drug-related side effects. Generally well tolerated, pembrolizumab received FDA approval through this trial.

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The most important type of efficacy study compares a drug with an established standard regimen for the disease. Until now, no study in stomach cancer had directly compared immunotherapy with chemotherapy , but a study published in June 2018 in the respected oncology journal Lancet Oncologyand presented at the 2018 World Congress on Gastrointestinal Cancer attracted attention.

It compared second-line paclitaxel chemotherapy with pembrolizumab. Patients with PD-L1 > %1 were enrolled, totaling 592. Overall survival and time to worsening did not differ statistically between groups. However, subgroup analysis, though not statistically significant, showed 1-year survival %13 higher with pembrolizumab, with a greater difference in gastroesophageal junction tumors. In patients with good performance status, pembrolizumab contributed an additional 3 months of survival.

Treatment-related side effects were %30 more frequent with chemotherapy.

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This study suggests a subgroup benefits more from pembrolizumab in stomach cancer, but I believe further analyses are needed to identify those patients.

For nivolumab (Opdivo), another widely used immunotherapy, a study involving 493 gastric or gastroesophageal junction cancer cases, with 493 patients enrolled, included those receiving two or more prior chemotherapy lines. The benefit rate was %11, with an additional 1.2 months of survival. The additional 12-month survival contribution was %16. I believe treating all patients regardless of PD-L1 explains the less-than-desired result. A study of nivolumab combined with ipilimumab (Yervoy) was presented at the ASCO 2017 Congress, but detailed results remain unpublished. Based on these studies, nivolumab has entered use for stomach cancer in Japan.

In light of these studies, I believe pembrolziumab has established itself as an effective, safe option in gastric and gastroesophageal junction tumors, while studies of unanswered questions continue. We will keep sharing every announced scientific finding.

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