IZABRIGHT-Lung01: A Randomized, Open-label, Phase 2/3 Study of Izalontamab Brengitecan (BMS-986507) versus Platinum-based Chemotherapy in Patients with EGFR-mutated Non-small Cell Lung Cancer and Disease Progression on EGFR Tyrosine Kinase Inhibitor Therapy

This Phase 2/3 randomized, open-label study evaluates izalontamab brengitecan (iza-bren, BMS-986507) compared to platinum-based chemotherapy in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who experienced disease progression following treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs). The primary objective in Phase 2 is to determine the recommended Phase 3 dose (RP3D) for izalontamab brengitecan to advance to the Phase 3 stage of the study. The primary objective in Phase 3 is to compare the progression-free survival of izalontamab brengitecan at RP3D versus platinum-based chemotherapy in participants with advanced EGFR-mutated NSCLC and disease progression after any third-generation TKIs. This comparison addresses a critical unmet need in patients who have exhausted targeted therapy options with third-generation EGFR TKIs, where effective treatment alternatives remain limited. The secondary objective is to compare the overall survival of izalontamab brengitecan at RP3D versus platinum-based chemotherapy in the same patient population, providing additional evidence regarding the long-term clinical benefit of this novel antibody-drug conjugate approach in this treatment-refractory setting.

This clinical trial enrolled a total of **403 participants** diagnosed with **EGFR-mutated non-small cell lung cancer**. The study population included both **male** and **female** adults and elderly individuals. Participants were required to have **non-squamous NSCLC** not amenable to curative treatment, with documented evidence of specific **EGFR mutations** (exon 19 deletion or L858R mutation). Eligible individuals had experienced **progressive disease** following treatment with a **3rd-generation EGFR-TKI** (such as osimertinib, furmonertinib, or lazertinib) as their most recent therapy in an adjuvant, locally advanced, or **metastatic** setting. Additionally, participants needed to be suitable candidates for **platinum-based doublet chemotherapy** consisting of either **cisplatin** or **carboplatin** in combination with **pemetrexed**. The trial excluded vulnerable populations.

This is a randomized, open-label, Phase 2/3 clinical trial evaluating **izalontamab brengitecan** (BMS-986507) compared to **platinum-based chemotherapy** in participants with **EGFR-mutated non-small cell lung cancer** who have experienced disease progression following treatment with **EGFR tyrosine kinase inhibitor** therapy. The trial employs a two-stage design, with Phase 2 focused on determining the recommended Phase 3 dose based on safety, tolerability, efficacy, and pharmacokinetic/pharmacodynamic data, while Phase 3 aims to compare progression-free survival between izalontamab brengitecan at the recommended Phase 3 dose and platinum-based chemotherapy. The study utilizes **Blinded Independent Central Review** for assessment of disease progression according to **RECIST v1.1** criteria. The trial is expected to commence recruitment in January 2026 and continue until May 2031.

Eligible participants must have non-squamous non-small cell lung cancer not amenable to curative treatment, with documented evidence of **EGFR mutation** (exon 19 deletion or L858R mutation). Participants must have experienced progressive disease on a third-generation EGFR tyrosine kinase inhibitor-based regimen as their most recent line of therapy in an adjuvant, locally advanced, or metastatic treatment setting. Additionally, participants must be eligible to receive a platinum-based doublet chemotherapy regimen consisting of either **cisplatin** or **carboplatin** in combination with **pemetrexed**.

The investigational medicinal product, izalontamab brengitecan, is administered as a **powder for solution for infusion** via **intravenous use**. The comparator arm consists of platinum-based chemotherapy utilizing carboplatin (maximum daily dose 750 mg, maximum total dose 3000 mg) or cisplatin (maximum daily dose 75 mg/m², maximum total dose 300 mg/m²) as **concentrate for solution for infusion** via intravenous use, combined with pemetrexed (maximum daily dose 500 mg/m²) also administered intravenously. **Pegfilgrastim** (maximum daily dose 6 mg) is available as an auxiliary medicinal product, administered as a **solution for injection** via **subcutaneous use**. The maximum treatment period for platinum agents is 84 days, while pemetrexed and izalontamab brengitecan may be administered for extended periods as clinically indicated.

The primary endpoints differ by study phase. In Phase 2, the primary endpoint is determination of the recommended Phase 3 dose based on the totality of safety, tolerability, efficacy, and pharmacokinetic/pharmacodynamic data. In Phase 3, the primary endpoint is **progression-free survival** assessed by RECIST v1.1 per Blinded Independent Central Review. Secondary endpoints for Phase 2 include **overall survival** and progression-free survival rates by RECIST v1.1 per Blinded Independent Central Review, while Phase 3 secondary endpoints focus on overall survival. The length of participant involvement will vary depending on individual treatment response and tolerability, with participants continuing treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified criteria for discontinuation are met. Early termination from the study may occur due to adverse events, disease progression, participant withdrawal, investigator decision, or protocol violations.

The experimental medication **BL-B01D1** contains the active substance **izalontamab brengitecan** (sponsor product code BMS986507), which is of biological/biotechnological origin. The product is supplied as a **powder for solution for infusion** and is administered via **intravenous use**. The maximum daily dose amount is not specified with a fixed value in the protocol. The product will be over-labeled and repackaged for use in this clinical trial.

**Carboplatin** is used as a **comparator** treatment in this study. The product is supplied as a **concentrate for solution for infusion** of chemical origin and is administered via **intravenous use**. The maximum daily dose amount is **750 mg**, with a maximum total dose amount of **3000 mg**. The maximum treatment period is **84 days**. The product will be over-labeled and repackaged for use in this clinical trial.

**Cisplatin** serves as a comparator treatment and is supplied as a concentrate for solution for infusion of chemical origin. The product is administered via intravenous use. The maximum daily dose amount is **75 mg/m²**, with a maximum total dose amount of **300 mg/m²**. The maximum treatment period is 84 days. The product will be over-labeled and repackaged for use in this clinical trial.

**Pemetrexed** is used as a comparator treatment in this study. The product is supplied as a concentrate for solution for infusion of chemical origin and is administered via intravenous use. The maximum daily dose amount is **500 mg/m²**. The product will be over-labeled and repackaged for use in this clinical trial.

**Pegfilgrastim** is used as an **auxiliary medication** in this study. The product is supplied as a **solution for injection** of chemical origin and is administered via **subcutaneous use**. The maximum daily dose amount is **6 mg**. The product will be over-labeled and repackaged for use in this clinical trial.

Efficacy will be assessed using distinct primary endpoints for each phase of the study. In Phase 2, the recommended Phase 3 dose will be determined based on the totality of safety, tolerability, efficacy, and pharmacokinetic/pharmacodynamic data. In Phase 3, the primary efficacy endpoint is progression-free survival assessed according to RECIST version 1.1 criteria per Blinded Independent Central Review. Secondary efficacy endpoints include Overall Survival by RECIST version 1.1 per Blinded Independent Central Review and Progression-Free Survival rates by RECIST version 1.1 per Blinded Independent Central Review in Phase 2. In Phase 3, overall survival will be evaluated as a secondary endpoint.