[Edaily Reporter Kim Jinsoo ] TiumBio Co., Ltd.(321550)Tium Bio appears to be one step closer to becoming “first-in-class” as it accelerates clinical trials of “Tosfosetip,” which works by blocking TGF-β. Although there have been ongoing efforts worldwide to develop anticancer drugs targeting TGF-β, no successful cases have emerged to date; however, Tosfosetip is raising expectations for its development because it also incorporates a vascular endothelial growth factor (VEGF) inhibition mechanism.

According to the results of a Tosfosetip clinical trial in patients with recurrent or metastatic head and neck cancer released by TiumBio Co., Ltd. last month, Tosfosetip showed potential for improvement over existing standard treatments in first-line therapy.

Specifically, in a Phase 2 clinical trial involving a total of 12 patients treated with the combination of Tosfosetip and Keytruda, the response rate was 75%, with one patient achieving complete remission and eight achieving partial remission. The median progression-free survival (mPFS) was recorded at 10.9 months. As patient survival is ongoing, median overall survival (mOS) data are not yet available. Furthermore, the drug’s competitiveness was enhanced by the fact that partial remission was observed in 4 out of 6 patients with PD-L1 CPS 1–19, a group in which the efficacy of immunotherapy is generally considered to be relatively limited.

Will It Survive the ‘Clinical Graveyard’ of TGF-β?

Although there have been numerous research and development efforts for drugs that block TGF-β, there have been no successful cases to date. Consequently, concerns have been raised regarding the development of Tosfosetip; however, TiumBio Co., Ltd. is confident in its success based on the characteristics of the clinical trial participants and the drug’s mechanism of action.

First, “vintrafusp alfa”—which garnered significant attention when Merck (MSD) licensed the technology to GSK—failed in a clinical trial for stage 4 non-small cell lung cancer patients, followed by consecutive failures in studies for first- and second-line treatments of bile duct cancer. Consequently, GSK returned the rights to Merck.

Subsequently, several TGF-β inhibitor anticancer drugs—including “presolimumab,” which Sanofi was developing; Novartis’ “NIS793”; BMS’ “AVID200”; and Eli Lilly’s “galunisertib”—failed to demonstrate efficacy after clinical trials or had to halt or postpone R&D due to issues such as side effects.

One of the reasons cited for the difficulty in developing TGF-β-targeted anticancer drugs is the “dual nature” of TGF-β inhibition. In normal tissues and early-stage tumors, TGF-β plays a powerful tumor-suppressing role. It inhibits cancer cell proliferation by inducing cell cycle arrest, differentiation, and apoptosis, while maintaining genomic stability. However, in advanced cancers, TGF-β plays a role in promoting tumor development. It enables cancer cells to acquire an invasive and metastatic phenotype, thereby accelerating tumor growth and progression.

Therefore, the patient population targeted in clinical trials of TGF-β-blocking agents is a critical consideration. Tosfosetip is currently undergoing clinical trials in patients with recurrent or metastatic head and neck cancer.

A representative from TiumBio Co., Ltd. explained, “Since patients with recurrent or metastatic head and neck cancer are already at an advanced stage of the disease, we expect that blocking TGF-β will often yield positive results. Furthermore, because patients who have failed previous treatments are participating in the study, many of them have advanced-stage cancer.”

"Enhanced Efficacy and Ensured Safety Through a Dual Mechanism"

Unlike previously developed TGF-β-blocking anticancer drugs, Tosfosetip distinguishes itself by simultaneously targeting vascular endothelial growth factor (VEGF). This effectively compensates for the limited efficacy of TGF-β-only mechanisms.

VEGF is a key regulator of tumor angiogenesis. Furthermore, VEGF does not merely promote blood vessel formation; it also plays a role in suppressing T-cell proliferation. Since both TGF-β and VEGF are associated with abnormal angiogenesis and immunosuppression, targeting both simultaneously helps improve efficacy.

Furthermore, because it is a dual-mechanism approach, the TGF-β dosage can be reduced compared to TGF-β monotherapy. This helps mitigate the side effects associated with TGF-β blockade. In fact, cases of skin tumors—including squamous cell carcinoma (SCC), keratoacanthoma (KA), and basal cell carcinoma (BCC)—were observed in patients treated with Sanofi’s presolimumab.

In contrast, tosfosetip demonstrated a favorable safety and tolerability profile. Specifically, the incidence of Grade 3 or higher treatment-related adverse events (TRAEs) during combination therapy with tosfosetip and Keytruda was 48.3%, which was manageable and comparable to that of other competitive compounds. No Grade 5 or higher adverse events, such as cardiovascular events or death, were reported.

Furthermore, unlike existing TGF-β-targeted drugs developed for intravenous administration, Tosfosertib is being developed as an oral formulation. Consequently, it appears to have a short half-life and rapid elimination; the toxicity burden has also been reduced through an intermittent dosing regimen of two weeks on, followed by one week off.

A representative from TiumBio Co., Ltd. stated, “We have recently been presenting our clinical data on the global stage, and so far, the drug has attracted industry attention for its lower incidence of side effects compared to existing TGF-β blockers. Tosfosetip effectively combines TGF-β blockade with VEGF inhibition—a dual mechanism that enhances efficacy while reducing side effects.”