Merck's M7824 Suffers Triple Clinical Setbacks and GSK Exits Collaboration; Domestic PD-(L)1/TGFβ Pipeline Heats Up – Who Will Break Through First?

On September 30, Merck KGaA and GSK jointly announced the termination of the collaboration agreement regarding bintrafusp alfa (PD-L1/TGFβ bifunctional fusion protein M7824), effective September 30, 2021.

Prior to this year, M7824 was a shining star in the field of oncology immunotherapy, backed by Phase 2 lung cancer clinical data demonstrating an objective response rate (ORR) that doubled that of conventional PD-1 inhibitors. When GSK signed a collaboration agreement with Merck Group valued at a total of £3.7 billion, it placed high hopes on the compound, regarding it as a 「game-changing」 blockbuster therapy.

However, this year, M7824 has suffered three consecutive clinical trial failures. The first failure stemmed from a Phase III head-to-head trial against Keytruda; the subsequent two failed trials were both Phase II clinical trials targeting biliary tract cancer (BTC), including one evaluating second-line therapy and one evaluating first-line therapy.

According to Merck’s official press release, the decision to discontinue the collaboration with GSK was primarily based on the Phase III clinical trial INTR@PIDLung037 failing to replicate the encouraging data observed in earlier studies. Based on the data during the agreement period, GSK has not made any milestone payments, nor does it have any remaining future milestone obligations.

However, despite the cooling momentum in overseas development, domestic R&D for similar drugs remains highly active. Yesterday and today, Luye Pharma and Transcenta Group successively submitted regulatory applications for the PD-L1/TGF-β bifunctional antibodies LY01019 and TST005, officially entering the competition in this therapeutic track. The number of comparable domestic products has now reached 12.

According to the Insight database, Hengrui’s SHR-1701 is currently the most advanced product, with the first indication to advance to Phase III being its combination with bevacizumab for the treatment of colorectal cancer.

Source: Insight Database (https://db.dxy.cn)

However, according to the draft guidelines for public comment released by the CDE in July, 《Guiding Principles for Clinical Development of Antitumor Drugs Oriented to Clinical Value》, the crowded development of follow-on candidates may face challenges in demonstrating ultimate clinical benefit. Driven by this policy, several domestic PD-1 monotherapies and combination therapies have successively initiated large-scale Phase III head-to-head clinical trials against Keytruda. Will bispecific antibodies and dual-function fusion proteins subsequently face the same challenges? And which candidate will emerge as the frontrunner?