Hengrui's PD-L1 ADC HLX43 Shows Best-in-Class Potential with Strong Clinical Data; BD Talks with J&J and Roche Underway

【03 Overview of EGFR Wild-Type NSCLC Competitors】

HLX43 has demonstrated remarkable efficacy in NSCLC patients with wild-type EGFR genes, rekindling hope in this long-standing challenging field.Lung cancer patients with wild-type EGFR (i.e., not carrying sensitive EGFR mutations) account for the majority of NSCLC cases (almost covering all squamous cell carcinoma and about half of lung adenocarcinoma).. Such patients cannot benefit from EGFR-targeted drugs, and standard treatments are often limited to chemotherapy and immunotherapy, but effective options are lacking after the failure of multiple lines of treatment. Fortunately, in recent years, a group of innovative therapies have gradually shown efficacy in this field, including ADCs, bispecific antibody-ADC fusion drugs, and cytokine fusion proteins, among others. We compare HLX43 with several representative therapies under research as follows:

BL-B01D1 (EGFR×HER3 Bispecific Antibody ADC) by Baili Tianheng:BL-B01D1: A First-in-Class EGFR/HER3 Bispecific Antibody-Drug Conjugate

Innovent Biologics IBI363 (PD-1/IL-2 Bispecific Fusion Protein):IBI363 is not a traditional ADC but an innovative immunotherapy that fuses a PD-1 antibody with a modified IL-2 cytokine. It aims to simultaneously block the PD-1 pathway and activate T-cell proliferation, thereby reinvigorating the immune response in "cold tumors." In the Phase Ib data presented at the 2025 ASCO meeting, IBI363 demonstrated certain efficacy and survival benefits in 58 patients with EGFR wild-type advanced lung adenocarcinoma who were resistant to immunotherapy. In the high-dose group (3 mg/kg Q3W), the confirmed ORR was 24.0%, the disease control rate was 76.0%, the median progression-free survival (PFS) reached 5.6 months, and the 12-month overall survival rate was 71.6%. Although the ORR was slightly lower than that of ADC drugs, IBI363 showed potential for prolonging survival, with some patients remaining stable after one year of treatment. Notably, IBI363 was more effective in adenocarcinoma patients with a smoking history, achieving an ORR of 33.3% and a median PFS of 5.3 months. The drug's independence from PD-L1 expression and its efficacy in both squamous cell carcinoma and adenocarcinoma align with the broad-spectrum characteristics of HLX43. Innovent plans to initiate a Phase III registrational study, and IBI363 has received multiple FDA Fast Track and Orphan Drug designations, positioning it as a potential representative of a new form of immunotherapy.

AbbVie ABBV-400 (c-Met-targeted ADC):ABBV-400 is a next-generation c-Met-targeted ADC developed by AbbVie, also known as Telisotuzumab adizutecan. The c-Met protein is often highly expressed in EGFR wild-type NSCLC (especially lung adenocarcinoma), making it one of the important therapeutic targets following EGFR. In the Phase I expansion cohort data presented at the 2024 ESMO Congress, ABBV-400 demonstrated strong activity in non-squamous, EGFR wild-type NSCLC: among 48 treated patients (at doses of 2.4 or 3.0 mg/kg Q3W), the confirmed ORR was 43.8%, and the clinical benefit rate (CBR, equivalent to DCR) reached 85.4%. The main Grade 3 or higher adverse reactions were anemia (25%) and neutropenia (15%), with overall good tolerability. Notably, most of the enrolled patients had high c-Met expression and were all EGFR wild-type, which differs from HLX43's focus on the broad PD-L1 population. However, the ORRs of both drugs are already at the same level, and ABBV-400’s performance demonstrates the general feasibility of ADCs in EGFR wild-type lung cancer. ABBV-400 has now entered Phase II trials and received Breakthrough Therapy designation from the FDA, indicating its potential for accelerated approval to provide an effective new treatment option for c-Met-positive patient populations.

Conclusion: As seen from the above comparison, whether it is BL-B01D1 targeting dual receptors, IBI363 for immune activation, or c-Met ADC ABBV-400, all have shown certain efficacy in EGFR wild-type NSCLC.Among them, ADCs (HLX43, BL-B01D1, ABBV-400) generally achieved an ORR range of 30-45%, while the fusion protein IBI363 had a relatively lower ORR but provided a long-tail effect of immunotherapy. Particularly notable is HLX43, which achieved an ORR of nearly 47% and a DCR exceeding 93% in the EGFR wild-type non-squamous NSCLC population, significantly outperforming other therapies. Additionally, HLX43 demonstrated effectiveness in PD-L1 negative patients and coverage for those who failed multiple prior lines of treatment, reflecting its mechanistic advantages. It can be said that HLX43 represents the prototype of immune checkpoint ADC dominance in this field, and its emergence has substantially raised the "ceiling" for later-line therapies. Looking ahead, these novel therapies each have unique characteristics and are expected to flourish in the large and unmet market of EGFR wild-type NSCLC, providing personalized options for patients with different molecular profiles.

With the impressive data showcased at WCLC, HLX43 is being highly anticipated by the industry. Some analyses suggest it has the potential to become a "best-in-class" PD-L1 ADC. Summarizing HLX43's unique advantages: it combines precise delivery of potent toxins with immune activation, achieving the dual mechanism of "IO+ADC" in a single drug, which is rare among existing lung cancer treatments. For the large population of EGFR wild-type NSCLC patients, HLX43 has already demonstrated breakthrough efficacy in early clinical trials, significantly raising the effective rate of later-line treatment to unprecedented levels. Additionally, its efficacy is not limited by PD-L1 expression, and at higher doses, its effectiveness is further enhanced while remaining safe and controllable. These factors indicate that HLX43 has the potential to overcome the limitations of current therapies and redefine the treatment paradigm.

In terms of development strategy, HLX43 is pursuing a "broad-spectrum" approach by advancing multiple indications in parallel. To date, Shanghai Henlius Biotech, Inc. has launched global clinical trials for HLX43 targeting various solid tumors, including lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, nasopharyngeal cancer, head and neck cancer, thymic cancer, and cervical cancer. This extensive layout benefits from the characteristic of PD-L1 as a universally highly expressed antigen in tumors, also implying that HLX43 has the potential to become a "**foundational blockbuster**" product covering multiple tumor types. If subsequent trials continue to demonstrate its efficacy and safety across different cancer types, HLX43 could grow into a mega-blockbuster drug with annual sales reaching billions of dollars. In terms of internationalization, HLX43 has already received regulatory approvals from authorities in China, the United States, Japan, and Australia to enter multinational clinical stages, while also attracting significant interest from multinational pharmaceutical companies. It can be anticipated that once key Phase II/III trials succeed, HLX43 may become another benchmark case of a Chinese biopharmaceutical company going global.