First Global Phase III Trial to Outperform PD-1 Plus Chemotherapy: China Biopharma’s 'Defu Combination' Shows Significant Positive Results in First-Line Squamous NSCLC

A “Pinnacle Showdown” Between Chinese Innovative Drugs Is Drawing Global Attention. On May 22 (local time), the abstracts selected for presentation at the annual American Society of Clinical Oncology (ASCO) meeting were released. Among them, Phase III clinical trial data for Sino Biopharm’s “Defu Combination” (bemosuribart plus anlotinib capsules) as first-line treatment for locally advanced or metastatic squamous non-small cell lung cancer (sq-NSCLC) were disclosed for the first time. With a median progression-free survival (PFS) of 10.12 months, the regimen head-to-head outperformed BeiGene’s tislelizumab (PFS: 7.79 months). This marks the first Phase III clinical study worldwide to report positive results comparing immune checkpoint (PD-1) inhibitor combined with chemotherapy versus other regimens as first-line therapy for squamous non-small cell lung cancer.

Xie Qirun, Chairman of the Board of Sino BiopharmIt was stated that anti-angiogenic therapy combined with immune checkpoint inhibitors has become the standard of care for various advanced malignancies. For squamous non-small cell lung cancer (sqNSCLC), the “Defu Combination”—a regimen consisting of benmelstobart combined with chemotherapy, followed by sequential combination with anlotinib—significantly improves progression-free survival (PFS), reducing the risk of disease progression or death by 36%. With a manageable safety profile, this regimen holds promise as a new and superior clinical treatment option for patients with sqNSCLC worldwide.

TQB2450-III-12 is a multicenter, randomized, double-blind, parallel-controlled Phase III clinical study comparing bemisobemab combined with chemotherapy followed by sequential combination with anlotinib versus tislelizumab combined with chemotherapy as first-line treatment for locally advanced or metastatic squamous non-small cell lung cancer. This study was selected for an ASCO Rapid Oral Abstract presentation, with Professor Shi Yuankai of the Cancer Hospital, Chinese Academy of Medical Sciences, serving as both the corresponding author and the first author.

In this clinical study, 565 patients with locally advanced or metastatic squamous non-small cell lung cancer (sq-NSCLC) who had not previously received systemic therapy were randomized in a 1:1 ratio to the experimental group or the control group. The experimental group received four cycles of bemisulimab combined with chemotherapy, followed by maintenance therapy with bemisulimab plus anlotinib. The control group received four cycles of tislelizumab combined with chemotherapy, followed by maintenance therapy with tislelizumab plus placebo.

Studies have shown that, as of March 1, 2024, the regimen of bemisobemab combined with chemotherapy followed by sequential combination with anlotinib significantly prolonged median progression-free survival (PFS) compared to tislelizumab combined with chemotherapy (10.12 months vs. 7.79 months; HR=0.64, P=0.0038), representing a 36% reduction in the risk of disease progression or death in the experimental group. Subgroup analysis indicated that nearly all subgroups benefited from the treatment with bemisobemab plus chemotherapy followed by sequential combination with anlotinib. Notably, in the population with PD-L1 expression of 1–49%, the HR was 0.47 (95% CI: 0.30–0.73). The objective response rates (ORR) were 71.9% and 65.1% in the experimental and control groups, respectively. The median duration of response (DoR) was significantly longer in the experimental group than in the control group (9.69 months vs. 8.34 months; HR=0.58, P=0.0091). Overall survival (OS) data are not yet mature.

Regarding safety, the incidence rates of treatment-emergent adverse events (TEAEs) of Grade ≥3 related to bemisotamab/tislelizumab or anlotinib/placebo were 61.57% in the experimental group and 51.06% in the control group. There was no significant difference in the incidence rates of TEAEs leading to death between the two groups (5.69% in the experimental group vs. 5.63% in the control group).

According to the 2022 global cancer statistics, lung cancer ranks first among all malignant tumors in both incidence and mortality rates worldwide and in China, with non-small cell lung cancer (NSCLC) accounting for 80%-85% of all lung cancer cases [1]. Squamous non-small cell lung cancer (sq-NSCLC) is one of the major subtypes of NSCLC, representing approximately 30% of all NSCLC cases.

Professor Shi Yuankai of the Cancer Hospital, Chinese Academy of Medical Sciences, the report’s author and principal investigator of this clinical trial, stated,The regimen of bemisibemab combined with chemotherapy, followed by sequential combination with anlotinib, has broken through the bottlenecks of traditional standard-of-care therapies, yielding encouraging results from this successful practice. As a representative multi-target anti-angiogenic small-molecule tyrosine kinase inhibitor, anlotinib has accumulated substantial evidence-based medical data and demonstrated robust antitumor activity across multiple indications, including later-line treatment for non-small cell lung cancer (NSCLC). However, in patients with squamous NSCLC who have a high proportion of central lesions, first-line anti-angiogenic therapy may carry an elevated risk of hemorrhage. To address this challenge, this study adopted an innovative clinical trial design, administering bemisibemab plus chemotherapy followed by sequential bemisibemab combined with anlotinib. The study results demonstrated favorable safety profiles for this treatment regimen, validating the scientific rationale and feasibility of the therapeutic model characterized by “chemotherapy combined with immunotherapy for rapid tumor shrinkage, followed by targeted therapy combined with immunotherapy for sequential efficacy enhancement.” By employing a scientifically designed phased combination dosing strategy, this approach effectively controlled safety risks while improving clinical benefits, which holds significant importance for patients with squamous NSCLC.

“As the first randomized, double-blind, placebo-controlled Phase III clinical trial worldwide to demonstrate positive results with a PD-1 monoclonal antibody in combination with chemotherapy, this regimen has the potential to transform current treatment paradigms and provide an innovative first-line therapy for patients with advanced squamous non-small cell lung cancer who have limited clinical treatment options,” stated Shi Yuankai.

Beigene’s tislelizumab is currently the domestically produced PD-1 inhibitor with the highest sales revenue in the Chinese market, and it has been approved for marketing in multiple overseas countries, making it one of the representative products of China’s innovative drugs.

XieQirunIt is believed that the “Defu Combination” has achieved a head-to-head victory over tislelizumab, one of the representative high-quality domestic innovative drugs in recent years, drawing global attention at the ASCO Annual Meeting. This once again demonstrates that Sino Biopharm not only possesses strong innovation capabilities but also has a comprehensive system for efficiently translating innovative achievements into clinical value. As a representative of domestically developed innovative drugs, the portfolio of innovative products exemplified by the “Defu Combination” will showcase robust competitiveness on the global stage.

The American Society of Clinical Oncology (ASCO) Annual Meeting is the world’s largest, most academically prestigious, and authoritative clinical oncology conference. Regarded as an industry bellwether, it attracts significant attention from the global pharmaceutical sector and investors. At this year’s ASCO Annual Meeting, more than 70 original studies by Chinese researchers were selected for oral presentations, including numerous “First-in-Class” and “Best-in-Class” candidates. Notably, Sino Biopharm had 12 clinical studies accepted for oral presentation at the conference, setting a new record for Chinese pharmaceutical companies. Among these, four studies featured the “Defu Combination” of bemisotamab (brand name: Andewei) plus anlotinib capsules (brand name: Fukewei).

According to a previous announcement by Sino Biopharm, based on the results of the TQB2450-III-12 clinical study, the company has submitted a marketing application for new indications of the “Defu Combination,” which was accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration on April 22. Currently, Anlotinib has eight approved indications, with five additional indications in the New Drug Application (NDA) stage. Among these, the “Defu Combination” has already received approval for three indications (extensive-stage small cell lung cancer, endometrial cancer, and renal cell carcinoma), while three other indications are currently in the NDA stage.

Xie QirunSino Biopharm stated that it will leverage its innovation and commercialization capabilities to accelerate the market launch of these products, benefiting more patients, while also contributing to the high-quality development of pharmaceutical innovation in China, truly embodying the mission of “Health Technology, Warming More Lives.”