Esophageal Cancer: Pembrolizumab VS Chemotherapy treatment?

Esophageal cancer is cancer that occurs in the esophagus. The esophagus plays an important role in digesting food it helps in moving the food you swallow down to your stomach.

Esophageal cancer is the seventh most common cancer and the sixth most common cause of cancer-related death worldwide, In 2018, there were 572,000 new cases and 509,000 deaths. In some regions, higher rates of esophageal cancer may be attributed to smoking and alcohol use or poor nutritional habits and obesity.

Experts defined the symptoms of esophageal cancer include difficulty swallowing, weight loss without putting an effort, chest pain, pressure or burning, worsening indigestion, coughing, and hoarseness.

Types of esophageal cancer include adenocarcinoma, which is the most common form of esophageal cancer in the United States. It occurs most often in the lower portion of the esophagus.

Squamous cell carcinoma is a type of esophageal cancer that occurs most often in the upper and middle portions of the esophagus. Squamous cell carcinoma is the most prevalent esophageal cancer worldwide. There are other rarer forms of esophageal cancer such as small cell carcinoma, sarcoma, lymphoma, melanoma, and choriocarcinoma.

Study Design

The study conducted a phase 3, randomized, to compare the effects of different treatments such as Pembrolizumab and Chemotherapy to patients that are diagnosed with esophageal cancer. The study aims to give treatment options to patients with unresectable, locally advanced, or metastatic esophageal cancer since treatments are limited.

Pembrolizumab and Chemotherapy were the only two treatments performed in the research to treat esophageal cancer.

Pembrolizumab is a humanized antibody used in cancer immunotherapy. This includes treating melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, and stomach cancer. It is given by slow injection into a vein.

The study was designed by academic investigators and employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ. The Protocol was approved by the appropriate institutional review board or ethics committee at each participating institution.

All authors attest that the trial was conducted in accordance with the Protocol and all its amendments and Good Clinical Practice standards.

Subjects of the Study

Researchers randomly assigned 628 patients between December 8, 2015, and June 16, 2017, a total of 628 patients from 154 sites in 32 countries. Patients were equally divided into 2 treatments 314 patients are in pembrolizumab and also 314 patients to chemotherapy to treat their esophageal cancer.

In this randomized, phase III study, patients were randomly assigned 1:1 to pembrolizumab 200 mg every 3 weeks or investigator’s choice of standard-of-care chemotherapy with paclitaxel 80-100 mg/m2. Researchers provided treatment details in the Trial Protocol.

Central radiology assessed the tumor response during week 9 and every 9 weeks thereafter. Progressive disease was verified by central imaging review.

Adverse events (AEs) were assessed throughout the study and at 30 days (90 days for serious AEs and events of interest to pembrolizumab after treatment discontinuation and were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events.

Statistical Analysis

The statistical structure is composed of specified interim analysis and a final analysis. Researchers found the comparison of different treatments. 346 deaths had occurred in different groups. In the pembrolizumab group there were 165 [83.3%] patients that died while in the chemotherapy group, there were 181 [89.2%] patients that did not successfully survive.

For esophageal cancer treatment, the 12-month survival rate was higher with pembrolizumab treatment having 32.4% compared to chemotherapy having 24.2%.

On the second analysis, researchers found that the death was higher in the chemotherapy group with several 182 patients compared to the pembrolizumab group with 166 death. A hazard ratio of 0.77 was notable in the patients in the chemotherapy group.

Researchers conducted an additional follow-up with the different groups. They found out that out of 553 patients that died in the trial (270 [86.0%] in the pembrolizumab group and 283 [90.1%] in the chemotherapy group.

Survival outcomes were similar with pembrolizumab versus chemotherapy across prespecified subgroups of patients with squamous cell carcinoma and in all patients.

The researchers observed in the 12-month progression-free survival (PFS) rate that the pembrolizumab group has a higher percentage of 20.8% compared to the chemotherapy group with a rate of 6.7%.

Researchers elucidated that grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy.

Limitations of the study

At the Protocol-specified time for final analysis, death events for two patients were not included in the data analysis in the data cut-off date October 15, 2018, because of a data reporting inconsistency.

Treatment-related adverse events led to discontinuation in approximately 6% of patients in each group and death for five patients in each group.

In addition to the limitation of this study, according to the researchers, the open-label nature of the study design may have affected the compliance. Researchers emphasized that although overall survival was superior with pembrolizumab compared with chemotherapy the study was not sufficiently powered to evaluate statistically significant differences between patients squamous cell carcinoma or adenocarcinoma.

Study Results

This study showed that the survival rate for patients with esophageal cancer treated with pembrolizumab is higher than with chemotherapy. Researchers observed during their final analysis that a consistent reduction in death was seen in pembrolizumab treatment compared to chemotherapy.

Researchers noted that Asian patients seemed to have an enhanced benefit with pembrolizumab versus chemotherapy.

Patients experienced durable responses in pembrolizumab (having 53.5%) versus chemotherapy (having 38.1%). For the tumor response, the researchers observed that antitumor activity was more favorable with pembrolizumab versus chemotherapy in patients.

Patients in the chemotherapy group experienced significantly more adverse effects such as fatigue, diarrhea, and hematologic toxicities.

Moreover, esophageal cancer patients in the chemotherapy group experienced significantly more prone to an adverse event.

Conclusion

The international, randomized phase III research study enrolled patients worldwide and showed that pembrolizumab provided a clinically meaningful overall survival benefit versus chemotherapy in a global population of patients with metastatic esophageal squamous cell carcinoma and with tumors that progressed after one prior therapy.

Overall, fewer adverse effects were observed with pembrolizumab versus chemotherapy despite longer drug exposure.

Researchers proved through rainfall plot analysis that patients in the chemotherapy group experienced significantly more adverse events related to fatigue, diarrhea, and hematologic toxicities.

In conclusion, pembrolizumab provided a clinically meaningful survival benefit versus chemotherapy for patients with metastatic esophageal squamous cell carcinoma and also in patients with metastatic esophageal squamous cell carcinoma.