Phase II Study to Evaluate the Efficacy and Safety of HLX43 in Subjects with Advanced Non-Small Cell Lung Cancer (NSCLC)

Trial ID: 2025-523803-31-00
Protocol: HLX43-NSCLC201
Sponsor: Shanghai Henlius Biotech Inc.

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective is to evaluate the clinical efficacy of HLX43, an anti-PD-L1 ADC, in subjects with advanced non-small cell lung cancer. Secondary objectives include:

Assessment of safety and tolerability.
Evaluation of pharmacokinetic characteristics and immunogenicity.
Investigation of potential predictive or resistance biomarkers.

Participants

This clinical trial involves 202 participants diagnosed with advanced non-small cell lung cancer. The study population consists of male and female individuals who are 18 years of age or older. Eligible participants must have histologically or cytologically confirmed locally advanced or metastatic disease that is not suitable for radical treatment. Inclusion requires the presence of at least one measurable lesion according to RECIST 1.1 criteria and an ECOG performance status of 0-1. The cohort includes both patients with and without actionable genomic alterations, provided they have experienced failure of at least one line of prior standard treatment, including platinum-based chemotherapy. Furthermore, participants must demonstrate adequate organ function and a life expectancy exceeding three months. Individuals of childbearing potential are required to utilize highly effective contraception methods during the study period.

Plans and Procedures

This Phase II, open-label, multi-center, global study is designed to evaluate the efficacy and safety of HLX43, an anti-PD-L1 antibody-drug conjugate, in subjects diagnosed with advanced non-small cell lung cancer. The research methodology focuses on determining the objective response rate as the primary endpoint, alongside secondary measures such as overall survival, progression-free survival, and pharmacokinetics. The study procedures begin with a screening visit to confirm eligibility through histological verification, genomic alteration testing, and assessment of PD-L1 expression. Following enrollment, participants receive HLX43 for injection via intravenous administration. The trial includes subsequent follow-up visits for monitoring adverse events, vital signs, laboratory tests, and disease control rate. The study is expected to conclude by April 2029. Participant involvement may be subject to early termination based on protocol-defined conditions or clinical requirements.

Treatment

The investigational treatment consists of HLX43, an antibody-drug conjugate targeting programmed death-ligand 1. This substance is prepared as a powder for solution for infusion. The administered dose is 2.5 mg/ml, delivered via intravenous administration.

Efficacy

The primary efficacy endpoint is the objective response rate (ORR), which will be evaluated by Blinded Independent Central Review (BICR) in accordance with RECIST v1.1. Secondary efficacy assessments include overall survival (OS), progression-free survival (PFS), duration of response (DOR), and disease control rate (DCR), as measured by both the BICR and the investigator.

Further evaluation of efficacy involves the following parameters:

Assessment of quality of life.
Analysis of predictive or drug resistance biomarkers, including PD-L1 expression levels, tumor-related gene mutations, or serum proteomic profiles.
Monitoring of pharmacokinetics parameters for HLX43, including antibody-drug conjugate (ADC), total antibody, and free small molecule toxin levels, as well as blood drug concentration.
Determination of the positive rates for anti-drug antibody (ADA) and neutralizing antibody (NAb).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Have a full understanding of the study content, process, and possible adverse reactions before the study, and sign the informed consent form (ICF); voluntarily participate in the study; be able to complete the study as per protocol requirements
Aged ≥ 18 years at the time of signing the ICF, male or female
Histologically or cytologically confirmed, locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC not suitable for radical treatment (complete surgical resection, concurrent/sequential radio-chemotherapy) according to the Union for International Cancer Control and the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition), and should meet the following criteria: 1) Subjects without actionable genomic alterations (AGAs): • Subjects with non-squamous NSCLC must have documented negative test results for EGFR and ALK alterations. If no prior test results for EGFR and ALK are available, subjects must undergo EGFR and ALK testing at the study site. For subjects with squamous NSCLC, EGFR and/or ALK testing is not required prior to enrollment if their status is unknown; • No other known actionable genomic alterations, such as ROS1, NTRK, BRAF, MET exon 14 skipping, and RET; • Prior standard treatment failure of ≥ 1 line, including at least anti-PD-(L)1 antibody and platinum-based chemotherapy; 2) Subjects with AGAs: • Previous test results confirming the presence of one or more actionable genomic alterations; • Prior standard treatment failure of ≥ 1 line, including at least targeted therapy for driver gene alterations (patients with EGFR mutations must be previously treated with EGFR inhibitors) and platinum-based chemotherapy; Note: Definition of prior treatment failure with platinum-based chemotherapy: 1) Progressive disease following platinum-based chemotherapy in the recurrent or metastatic setting; 2) Progressive disease or recurrence during platinum-based chemotherapy, or within 6 months after the end of platinum-based chemotherapy during neoadjuvant chemotherapy, concurrent chemoradiotherapy, or adjuvant chemotherapy; 3) Intolerance to platinum-based chemotherapy
At least one measurable lesion as per RECIST 1.1 within 4 weeks prior to randomization; Note: Measurable target lesions should not be selected from previous radiotherapy sites or brain lesions. A measurable lesion within the field of local radiotherapy can be selected as the target lesion only when it is the only optional target lesion and the imaging evidence before and after progression should be available
Subjects who agree to provide archived tumor tissue specimens that meets the testing requirements (either from the most recent surgery or biopsy, preferably within 2 years) or agree to undergo a biopsy to collect tumor tissue for PD-L1 expression testing; Note: Formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin blocks or unstained sections, which must meet the quality control criteria for testing) collected from non-radiotherapy sites during the most recent surgery or biopsy at or after the diagnosis of malignant tumor and pathological reports of such specimens shall also be provided
The following conditions must be met prior to randomization: at least 3 weeks (or 5 half-lives of the drug, whichever is shorter) from the previous major surgery, medical device treatment, locoregional radiotherapy (except for palliative radiotherapy for bone lesions), cytotoxic chemotherapy, immunotherapy, or biological product therapy; at least 2 weeks from the previous hormone therapy or small molecular targeted therapy; at least 1 week from the administration of the traditional Chinese medicine for anti-cancer indications or minor surgery; and recovery of treatment-induced AEs to Grade ≤ 1 (CTCAE v5.0, except for peripheral neurotoxicity and alopecia)
ECOG PS score of 0-1 within 1 week prior to randomization
Life expectancy > 3 months
Adequate organ functions as confirmed by laboratory tests within 1 week prior to randomization (no blood transfusions or treatment with granulocyte colony-stimulating factor is allowed within 14 days prior to randomization):
Male and female subjects with child-bearing potential must agree to use at least one highly effective contraception method during the study and within at least 8 months after the last dose of the investigational product; female subjects of childbearing age must be negative for pregnancy test within 7 days prior to enrollment.

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Exclusion Criteria

Histologically or cytologically confirmed tumor containing components of small cell lung cancer, neuroendocrine carcinoma, or sarcomatoid carcinoma
Patients with active systemic infectious diseases requiring intravenous antibiotics within 2 weeks prior to randomization
Patients who have used potent CYP2D6 or CYP3A inhibitors or inducers within 2 weeks prior to randomization
Patients who have received systemic corticosteroids (prednisone > 10 mg/d or equivalent dose of similar drug) or other immunosuppressants within 2 weeks prior to randomization; Except: patients treated with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids; short-term prophylactic use of corticosteroids for contrast agents, etc
Patients with known active or suspected autoimmune diseases. Patients with autoimmune-related hypothyroidism and receiving thyroid hormone replacement therapy and those with type 1 diabetes mellitus controlled with insulin therapy are eligible to be enrolled
Patients who have received live vaccine or live attenuated vaccine within 4 weeks prior to randomization
Patients who are known to have anaphylaxis to macromolecular protein preparations/monoclonal antibodies or are allergic to any component in the formulation of the investigational product
Patients with active tuberculosis
Patients with a history of immunodeficiency, including human immunodeficiency virus (HIV)-positive or other acquired or congenital immunodeficiencies, or history of organ transplantation
Patients with active HBV or HCV infection or HBV/HCV co-infection; Note: Patients who test positive for HBsAg or HBcAb during screening must further undergo HBV-DNA testing. If the test result suggests < 500 IU/mL, < 2500 copies/mL, or < ULN, the patient can be enrolled. Patients with HBV-DNA detected must agree to receive treatment with anti-HBV nucleos(t)ide analogues during the study. Patients who test positive for HCV antibody must further undergo HCV-RNA testing. If the test result suggests < ULN, the patient can be enrolled. Patients with HBV/HCV co-infection must be excluded
Pregnant or lactating women (For Japanese subjects, pregnancy includes situations where the investigator believes that the subject may be pregnant, and lactating women can be enrolled in the study if breastfeeding is stopped, but breastfeeding cannot be resumed after receiving the study treatment)
Prior treatment with any medication targeting topoisomerase I, including chemotherapy or ADCs
Patients who are not suitable for participating in this clinical study due to any clinical or laboratory abnormalities or other reasons as assessed by the investigator
Radical radiation therapy within 3 months prior to randomization
History of any second malignancy within 2 years prior to randomization, except for early-stage malignancies (carcinoma in situ or stage I tumors) that have received radical treatment, such as non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma
History of adverse events leading to permanent discontinuation of immunotherapy, or occurrence of ≥ Grade 2 immune-related pneumonitis or myocarditis during prior immunotherapy
Presence of uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage
Presence of spinal cord compression or clinically active metastases to central nervous system (referring to untreated or symptomatic metastases, or metastases requiring corticosteroids or anticonvulsants to control associated symptoms), carcinomatous meningitis. Subjects who have previously received treatment for brain metastases (such as whole brain radiotherapy or stereotactic brain radiotherapy) may be eligible, provided that they are clinically stable for at least 4 weeks with no imaging evidence of brain metastasis progression
Subjects with current or prior history of clinically significant pulmonary impairment due to pulmonary comorbidities, including but not limited to: any underlying lung disease (e.g., pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, interstitial pneumonia, pneumoconiosis, drug-related pneumonitis, and pleural effusion, within 3 months prior to randomization), any autoimmune, connective tissue, or inflammatory disease that may involve the lungs (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis), prior pneumonectomy that may interfere with the detection and management of suspected drug-related pulmonary toxicity, or history of radiation pneumonitis within 6 months prior to randomization
Patients with any poorly-controlled cardiovascular and cerebrovascular clinical symptoms or diseases, including but not limited to: (1) NYHA Class II or greater heart failure or left ventricular ejection fraction (LVEF) < 50%; (2) unstable angina pectoris; (3) myocardial infarction or cerebrovascular accident within 6 months (except lacunar infarction, slight cerebral ischemia, or transient ischemic attack); (4) poorly controlled arrhythmia (including QTc intervals ≥ 470 ms) (QTc intervals are calculated by Fridericia's formula); (5) poorly-controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg after active treatment)
Imaging examination during the screening period shows the following evidence: a. Imaging evidence of tumor invasion of large blood vessels, tumor invasion of vital organs, or risk of esophagobronchial fistula or esophagopleural fistula; b. Imaging evidence of tumor encasement of large blood vessels with vascular stenosis, or cavitation or necrosis in a lung lesion, with a risk of hemorrhage if participating in the study as judged by the investigator.