The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to HLX22, an innovative anti-HER2 monoclonal antibody (mAb), for the treatment of patients with gastric cancer. This designation provides significant development incentives, including tax credits for clinical trial costs, application fee waivers, and 7 years of market exclusivity upon approval.
HLX22 represents a potential breakthrough for patients with HER2-positive metastatic gastric (GI) or gastroesophageal junction (GEJ) cancer, a population with limited treatment options and poor prognosis.
Mechanism of Action and Differentiation
HLX22 is specifically designed to target the HER2 extracellular subdomain IV at a different binding site than trastuzumab (Herceptin), enabling simultaneous binding of both agents to HER2 dimers on tumor cell surfaces. This dual-binding mechanism promotes internalization and degradation of HER2 dimers, enhancing antitumor activity and potentially addressing resistance mechanisms that limit existing HER2-targeted therapies.
The novel binding properties of HLX22 allow it to complement trastuzumab's activity rather than compete with it, providing a rationale for combination therapy that could improve outcomes for patients with HER2-positive gastric cancers.
Promising Phase 2 Results
Data from the phase 2 HLX22-GC-201 study (NCT04908813) presented at the 2025 Gastrointestinal Cancers Symposium demonstrated remarkable efficacy for the combination therapy. Among patients with gastric/GEJ cancer who received HLX22 in combination with the trastuzumab biosimilar HLX02 (Hercessi), capecitabine, and oxaliplatin (n = 31), the median progression-free survival (PFS) by independent radiology review committee assessment was not yet reached (95% CI, 23.5 months-not evaluable) compared to 8.3 months (95% CI, 5.7-12.7) in the placebo group (n = 31; HR, 0.2; 95% CI, 0.06-0.45).
The 12-month PFS rates were 73.8% (95% CI, 50.3%-87.4%) in the HLX22 arm versus 34.2% (95% CI, 12.0%-58.1%) in the placebo arm. Even more striking, the 24-month PFS rates were 61.5% (95% CI, 30.4%-82.0%) and 11.4% (95% CI, 0.8%-38.1%), respectively.
The objective response rate was 87.1% (95% CI, 70.2%-96.4%) in the HLX22 arm, with one patient achieving a complete response, compared with 80.6% (95% CI, 62.5%-92.5%) in the placebo arm. The median duration of response was not reached in the HLX22 arm versus 9.7 months in the placebo arm.
Safety Profile
The safety profile of HLX22 appears manageable based on phase 2 data. Any-grade treatment-emergent adverse effects (TEAEs) occurred at rates of 96.8% and 100% in the HLX22 and placebo arms, respectively. Grade 3 or greater TEAEs were reported in 54.8% of patients in the HLX22 arm compared to 48.4% in the placebo arm.
Notably, TEAEs leading to treatment discontinuation were lower in the HLX22 arm (9.7% vs 22.6%), and no patients experienced TEAEs leading to death in the investigational arm, while four patients died due to TEAEs in the control arm.
The most common adverse events included decreased platelet counts, decreased neutrophil counts, anemia, and decreased white blood cell counts, consistent with the known toxicity profiles of the chemotherapy backbone.
Ongoing Phase 3 Trial
Following these promising results, a global phase 3 trial (HLX22-GC-301, NCT06532006) is currently underway. This multicenter, randomized, double-blind, placebo-controlled study is being conducted across multiple countries and regions, including the United States, China, Japan, and Australia.
The trial is evaluating the efficacy and safety of HLX22 when given in combination with trastuzumab and chemotherapy as a first-line treatment for patients with HER2-positive metastatic GI or GEJ cancer. The first patient has already been dosed in the study.
The phase 3 trial is divided into multiple arms comparing different dosing regimens:
- Group A: HLX22 given at 25 mg/kg plus trastuzumab-strf, capecitabine, and oxaliplatin
- Group B: HLX22 at 15 mg/kg plus trastuzumab-strf, capecitabine, and oxaliplatin
- Group C: Placebo plus trastuzumab-strf, capecitabine, and oxaliplatin
Primary endpoints include progression-free survival and objective response rate, assessed by an independent review committee using RECIST v1.1 criteria. Secondary endpoints will evaluate additional efficacy measures, safety data, quality of life, immunogenicity, and pharmacokinetics.
Clinical Implications
Gastric cancer remains a significant global health burden, with approximately one million new cases diagnosed worldwide each year. HER2 overexpression occurs in approximately 20% of gastric cancers and is associated with poor prognosis.
Current standard first-line treatment for HER2-positive metastatic gastric cancer includes trastuzumab plus chemotherapy, but resistance often develops, and treatment options after progression are limited.
The orphan drug designation for HLX22 recognizes the significant unmet need in this patient population and may accelerate the development timeline, potentially bringing this promising therapy to patients sooner.
Dr. Jason Zhu, Chief Medical Officer of Henlius Biotech, the company developing HLX22, stated, "The orphan drug designation from the FDA represents an important milestone in our development program for HLX22. The promising data from our phase 2 study suggests that HLX22, when combined with trastuzumab and chemotherapy, could significantly improve outcomes for patients with HER2-positive gastric cancer."
As the phase 3 trial progresses, oncologists and patients alike will be watching closely to see if HLX22 can fulfill its promise as a potential new standard of care for HER2-positive gastric cancer.
