WHAT HAPPENED

Tevimbra (tislelizumab) is a new drug indicated for the treatment of unresectable or metastatic esophageal squamous cell carcinoma (ESCC) in adults following prior systemic chemotherapy that did not include a PD-(L)1 blocker.

Tevimbra, developed by China’s BeiGene, is approved by the U.S. Food and Drug Administration (FDA) in mid-March 2024 [1].

The European Medicines Agency (EMA) granted Tevimbra a similar marketing authorization a little earlier, in mid-September 2023 [2].

 

WHY IT MATTERS

Esophageal cancer (EC) is the eighth most common cancer worldwide and the sixth cause of cancer-related death [1]. Esophageal squamous cell carcinoma (ESCC) is the most common subtype of EC, accounting for 85% of cases [2] [3]. In 2040, the number of new cases of EC is projected to be 957,000, which is 60% higher than the number of new cases in 2020, suggesting the need for additional therapies [1]. At the time of diagnosis, over two-thirds of patients have advanced or metastatic EC. The expected five-year survival rate for EC with distant metastases does not exceed 6% [4].

 

WHAT IT FOUND OUT

The RATIONALE 302 (NCT03430843) phase 3 (randomized, open-label, with active comparison group, multicenter, international) clinical trial enrolled adult patients (n=512) with unresectable, locally advanced, or metastatic esophageal squamous cell carcinoma (ESCC) that progressed on or after first-line treatment.

Administration of tislelizumab resulted in improved outcomes compared to the use of chemotherapy (paclitaxel, docetaxel, or irinotecan) [1]:

  • Median overall survival (OS): 8.6 months — versus 6.3 months. Risk of death was reduced by a relative 30%: hazard ratio (HR) 0.70 (95% CI [hereafter]: 0.57–0.85; p=0.0001).
  • Probability of being alive at 12 months: 37.4% — vs. 23.7%.
  • Overall response rate (ORR): 20% including 2% complete response (CR) and 18% partial response (PR) — vs. 9.8% including 0.4% CR and 9.4% PR.
  • Median duration of response (DoR): 7.1 months — vs. 4.0 months.

In patients with PD-L1 tumor area positivity (TAP) score ≥ 10%, median OS was 10.3 months — vs. 6.8 months: HR 0.54 (0.36–0.79; p=0.0006).

Treatment-related adverse events (TRAEs) that were severe occurred in 19% of patients in the tislelizumab group — vs. 56% in the chemotherapy group.

 

HOW IT WORKS

Tislelizumab (BGB-A317) is a humanized monoclonal IgG4 antibody that binds PD-1 on T cells, thereby preventing it from interacting with its ligands, PD-L1 and PD-L2. As a result, the antitumor immune response, T cell proliferation, and cytokine production are unblocked. Some tumors are characterized by upregulation of PD-1 ligands, which contributes to the suppression of active T-cell immune surveillance of tumors [1].

Tislelizumab is designed to minimally bind Fc-gamma receptor 1 (FcγRI) on macrophages in order to limit antibody-dependent cellular phagocytosis (ADCP) of T cells by macrophages as a potential mechanism of resistance to anti-PD-1 therapies [2] [3] [4].

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Tislelizumab has a higher affinity for PD-1 than Keytruda (pembrolizumab) and Opdivo (nivolumab), the PD-1 blockers from Merck & Co. and Bristol-Myers Squibb, and this may be partially explained by different binding mechanisms to PD-1 [5] [6] [7]. 

 

WHAT’S NEXT

Tevimbra is preparing to expand the list of indications to include the first-line treatment of unresectable, recurrent, locally advanced, or metastatic esophageal squamous cell carcinoma (ESCC) and locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. By July and December 2024, the FDA is expected to issue their respective verdicts [1] [2].

The EMA is about to grant marketing authorization to Tizveni (tislelizumab) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in three indications: as first-line therapy for non-squamous or squamous NSCLC in combination with chemotherapy and as second-line monotherapy after failure of platinum-based chemotherapy [3].

 

BACKGROUND

Tislelizumab made its debut in its native China in late December 2019: Baizean is indicated for the treatment of relapsed or refractory classical Hodgkin’s lymphoma after failure of at least two lines of chemotherapy [1] [2]. Subsequently, tislelizumab decently expanded the list of indications, acting as a kind of local analog of Keytruda, which now covers 35 indications (17 tumor types and 2 tumor-agnostic indications) and is not going to stop there [3] [4]. As of the end of 2023, tislelizumab was approved for 12 indications, with three more expected to be added in 2024 [5].

 

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THE FLIPSIDE

The craze of tislelizumab, which is entirely invented in China, is to free this communist country from the servitude of expensive Western PD-(L)1 blockers [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]. Sooner or later, this is sure to happen, especially since the efficacy of tislelizumab is not inferior to American drugs [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29].

China is literally forcing foreign and local pharmaceutical manufacturers to drastically reduce the price of drugs in order for them to be available and covered by health insurance in such a lucrative market. And, remarkably, the government is encouraging the rapid growth of biotechnology to develop original drugs rather than generics. There is no doubt about the seriousness, and most importantly, the justification of intentions: Fifteen PD-(L)1 blockers alone have appeared over the past six years, with the cheapest one costing 16 times less than Keytruda [30].

It might seem that the arrival of tislelizumab in the highly profitable Western markets would provide BeiGene with impressive earnings. But this is not the case, as nine PD-(L)1 blockers are already available in the U.S. The Chinese pharma company would be wise to either stick to a price-cutting strategy or choose indications for which drugs in this class have not yet been approved. Thus, Coherus BioSciences and Shanghai Junshi Biosciences have priced PD-1 blocker Loqtorzi (toripalimab) 20% lower than Keytruda [31] and targeted it for nasopharyngeal carcinoma, for which no immunotherapy has been offered before [32].

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Julia Mardi

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