Inspection Delays Prompt FDA Deferral on Tislelizumab in Second-line ESCC

The COVID-19 pandemic continues to cause headaches for pharmaceutical manufacturers, as BeiGene and Novartis announced Thursday that the FDA has deferred action on the biologics license application for tislelizumab because regulators can’t travel to China to inspect the facilities where it will be made.

The announcement comes 2 days after the scheduled action date, which was July 12, 2022. BeiGene and Novartis seek approval to use the anti–PD-1 monoclonal antibody to treat patients after their first relapse with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

In a joint statement, the companies said, “The FDA has been unable to conduct required inspections in China due to COVID-19 related travel restrictions. As a result, the FDA is deferring action on the application until the inspections are complete.”

The companies noted that the FDA letter cited travel restrictions only, with no other reason given for the deferral. No new action date has been set. “We are working with our partner, Novartis, to facilitate the required inspections and bring tislelizumab to patients with second-line esophageal cancer in the US following regulatory approval,” said John V. Oyler, cofounder, chairman, and CEO of BeiGene.

BeiGene has big plans for tislelizumab, the first drug from its immuno-oncology biologics program; studies are under way to use it both alone and in combination with other drugs for an array of solid tumor and hematologic cancers.

This week’s deferral comes after FDA accepted the application in September 2021 for tislelizumab in ESCC, based on results from the phase 3 RATIONALE 302 trial. This study of 512 patients in Europe, the United States, and Asia found that tislelizumab demonstrated a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.57-0.85, P = .0001). Investigators also reported an extended median overall survival of 2.3 months compared with chemotherapy in the patients with ESCC who had prior systemic therapy.1

Tislelizumab works by limiting binding to Fc-gamma (Fcγ) receptors on macrophages, which helps the body’s immune cells find and fight tumors. Preclinical studies showed that binding to Fcγ receptors on macrophages undercuts the cancer-fighting abilities of PD-1 antibodies.

This is not the first approval put on hold because of the COVID-19 pandemic. FDA missed the November 16, 2020, target date for the chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel) from Bristol Myers Squibb (BMS) due to inspection delays. When regulators arrived to inspect in December, they cited major problems. Although BMS later claimed the company resolved outstanding issues quickly, FDA did not approve liso-cel until February 5, 2021.

The delay meant those who held contingent value rights stemming from BMS’ acquisition of Celgene—and were expecting payments worth $6.4 billion—lost their investments. BMS is being sued by investors over the missed deadline.

Reference

1. Shen L, Kato K, Kim SB, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase 3 study. J Clin Oncol. Published April 20, 2022. doi: 10.1200/JCO.21.01926