Hengrui gets first OK for a PD-L1/TGF-beta drug for cancer

Jiangsu Hengrui Pharma has chalked up a first-in-class approval for retlirafusp alfa, a bifunctional drug that targets PD-L1 and TGF-beta, as a treatment for advanced gastric cancer.

The green light – in Hengrui's home market of China – is for use of the bispecific fusion protein in combination with fluorouracil and platinum chemotherapy as a frontline treatment for locally advanced unresectable, recurrent, or metastatic gastric and gastroesophageal junction adenocarcinoma with PD-L1 expression (CPS) of 1 or more.

According to Hengrui, it is the first approval of any drug in the PD-1 and TGF-beta inhibitor category worldwide and will "help reshape the landscape of precision immunotherapy for gastric cancer."

The approval means Hengrui has succeeded in a category where much larger pharma companies have failed, notably Merck KGaA and GSK, which abandoned work on their bintrafusp alfa candidate a few years ago after a string of disappointing trial results in lung and biliary tract cancers.

GSK had paid Merck €300 million upfront for rights to the drug in 2019 in a deal that had a top-line value of $4.2 billion, but was scrapped two years later.

Hengrui, meanwhile, has also had some disappointing results with retlirafusp alfa (formerly SHR-1701) in clinical trials, including in cervical and colorectal cancers.

The drug is a fusion protein that combines a PD-L1-targeting antibody with the extracellular domain of the TGF-beta type 2 receptor. The rationale for its activity is that targeting PD-L1 takes the brakes off the immune system in fighting the cancer, while blocking the tumour-driving activity of TGF-beta and "improving the immunosuppressive microenvironment," according to Hengrui.

The phase 3 RELIGHT trial reported at the 2024 ESMO congress revealed a significant 34% improvement in overall survival compared to placebo when added to standard CAPOX chemotherapy, coming in at 15.8 months and 11.2 months, respectively, in a HER2-negative advanced gastric/GEJ cancer population of 737 Chinese patients.

Last year, additional data from the study in patients with a CPS score of 1 or more showed that retlirafusp alfa performed even better in this group, with a 43% improvement in OS to 16.7 months versus placebo and a 54% improvement among patients whose cancer had also spread to the liver.

Nearly one million new cases of gastric cancer are diagnosed each year globally, with over 655,000 deaths, making it the fifth leading cause of cancer-related death.

China alone is estimated to account for up to 44% of all cases, driven by relatively high rates of Helicobacter pylori infection – a bacterium known to raise stomach cancer risk – as well as dietary salt intake, smoking, and obesity. However, the incidence of and mortality rate from gastric cancer have been falling in recent years.