Chia Tai keeps the TGF-β faith

Despite the failure of Merck KGaA/GSK’s anti-PD-L1 x TGF-β project bintrafusp alfa several years ago, interest remains in this mechanism, and China’s Chia Tai will soon become the latest group to take an asset into phase 3.

The company’s anti-PD-1/TGF-β fusion protein TQB2868 will begin a Chinese pivotal trial in October in first-line pancreatic cancer, according to a new listing on clinicaltrials.gov. OncologyPipeline shows plenty of other players still pursuing this approach, although most are based in China. Furthermore, various projects appear to have been quietly abandoned since the last time ApexOnco carried out this analysis.

One of these is Chia Tai’s own anti-PD-L1 x TGF-β fusion protein TQB2858, which was in several phase 2 trials that have either been terminated or have unknown status. Perhaps the company decided that hitting PD-1 was a better bet than PD-L1, the target of bintrafusp alfa.

Meanwhile, PM8001, an anti-PD-L1 x TGF-β bispecific antibody that BioNTech gained via last year’s purchase of Biotheus, no longer appears in that company’s pipeline; and neither does PM8003, an anti-PD-L1 x TGF-β x VEGF trispecific.

But another PD-L1 x TGF-β x VEGF project, Zhejiang Doer’s fusion protein DR30206, is still active, with a Chinese phase 1/2 trial in GI cancers set to complete next year.

Pancreatic cancer

Chia Tai is focused on first-line pancreatic cancer, a tumour that still has a high unmet need. Chemo is the mainstay of therapy, producing ORRs of 23-43%, median PFS of 5.5-7.1 months, and median OS of 8.5-11.7 months.

Checkpoint inhibitors haven’t shown a benefit here, a fact Chia Tai blames on dense fibrotic stroma and extensive immunosuppressive cells, which can hinder the efficacy of immunotherapy. The group hopes that TQB2868 could get around this problem by neutralising TGF-β in the tumour microenvironment.

The phase 3 trial, known as TQB2868-ALTN-III-01, will compare TQB2868 plus the China-approved multikinase drug anlotinib and chemo, versus anlotinib plus chemo alone, with a primary endpoint of overall survival.

The triplet showed promising results in a single-arm Chinese phase 2 trial presented at ASCO this year. Among 37 evaluable patients, the overall response rate was 70%. 55% of patients had grade 3 or higher adverse events, with the most common being neutropenia (33%) and leukopenia (20%).

On the face of it these data look better than the 47% ORR recently reported with Revolution Medicines’ pan-RAS inhibitor daraxonrasib in first-line pancreatic cancer in phase 1 (this rose to a 55% ORR with a chemo combo).

Still, there are plenty of caveats about the Chia Tai results, not least questions about whether Chinese data are applicable to global populations, and the inclusion of anlotinib, which isn’t approved in the US.

Bintrafusp fail

There is also caution about the PD-(L)1 x TGF-β-targeting approach in general since the failure of bintrafusp alfa, an anti-PD-L1/TGF-β trap. In 2019 GSK paid Merck KgaA €300m up front to develop the project jointly, but it failed to show a benefit over Keytruda in the pivotal Intr@pid Lung 037 first-line NSCLC study, and the companies ended their deal in 2021.

Since then, other TGF-β projects have hit the skids. Chia Tai will be hoping to buck the trend with TQB2868.

Clinical-stage PD-(L)1 x TGF-β projects

Note: *also hits VEGF; **targets the GARP-TGF-β complex as well as mature TGF-β; ^anti-PD-L1/SIRPα/TGF-β trap fusion protein. Source: OncologyPipeline.