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Shah Shares Immunotherapy, STAT3 Inhibitor Data in GI Cancers

Brandon Scalea
Published: Wednesday, Aug 08, 2018

Manish A. Shah, MD
Manish A. Shah, MD
Two clinical trials presented at the 2018 ASCO Annual Meeting addressed unmet needs for select with patients with gastrointestinal (GI) cancers; however, a number of challenges remain, explained Manish A. Shah, MD.

The KEYNOTE-180 trial tested pembrolizumab (Keytruda) in patients with metastatic squamous cell carcinoma or adenocarcinoma of the esophagus who received at least 2 prior lines of therapy. In the open-label phase II study, patients received pembrolizumab at 200 mg every 3 weeks for up to 2 years or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR).

Data suggested modest efficacy with an ORR of 10% for the overall patient population.1 Patients were divided into subgroups based on PD-L1 expression, with PD-L1–high tumors demonstrating a slightly better response (14%).

Shah noted that those patients who responded to immunotherapy showed significant durability. He added that a phase III trial, KEYNOTE-181, is evaluating pembrolizumab against standard therapy for patients with advanced esophageal/esophagogastric junction carcinoma who progressed after frontline treatment (NCT02564263).

The BRIGHTER study, also presented at the 2018 ASCO Annual Meeting, tested the stem cell inhibitor napabucasin (BBI-608) in patients with gastric and gastroesophageal junction adenocarcinoma. By targeting STAT3, napabucasin is intended to block cancer stem cell self-renewal.

Patients on napabucasin received the oral inhibitor at 480 mg twice daily; paclitaxel was administered in the standard dose of 80 mg/mg2 on days 1, 8, and 15 in a 4-week cycle. However, trial investigators did not report an improvement in survival for patients on napabucasin compared with paclitaxel.2 Subset analyses will determine whether patients who have high expression of STAT3 benefited from the agent, Shah said.

In an interview with OncLive, Shah, director of Gastrointestinal Oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, shared insight on the challenges that remain in the treatment of esophageal and gastric cancers.

OncLive: Please provide some background to the KEYNOTE-180 trial.

Shah: Esophageal cancer is a deadly disease. Unfortunately, most patients with metastatic disease die within 1 year. There are very few targeted therapies in esophageal cancer and most patients don't get treatment after the second line of therapy. The active cytotoxic drugs have modest activity, but we are really in search for more. It's certainly an unmet need.

Pembrolizumab is a PD-1 inhibitor as we all know, and we examined that in esophageal cancer—both squamous cell and adenocarcinoma—in the third-line setting. We looked at patients who were both PD-L1 positive and PD-L1 negative, and we looked at the efficacy. We saw there was modest efficacy at about 10% ORR. It was 14% in the PD-L1–positive population and 6% in the PD-L1–negative population. Squamous cell cancers seemed to respond more than adenocarcinomas, but even that was modest.




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