A Randomized Phase 2/3 Study of BMS-986504 in Combination with Pembrolizumab and Chemotherapy Versus Placebo Plus Pembrolizumab and Chemotherapy in First-line Metastatic Non-small Cell Lung Cancer Participants with Homozygous MTAP Deletion

This randomized Phase 2/3 clinical trial evaluates the efficacy and safety of BMS-986504 in combination with pembrolizumab and chemotherapy versus placebo plus pembrolizumab and chemotherapy in patients with first-line metastatic non-small cell lung cancer harboring homozygous MTAP deletion. The primary objective in Phase 2 is to evaluate progression-free survival (PFS) with the investigational combination compared to the control regimen. This endpoint is clinically relevant as it assesses the ability of the novel therapeutic combination to delay disease progression in this genetically defined patient population. Phase 3 has dual primary objectives: first, to compare PFS between treatment arms, and second, to compare overall survival (OS) of BMS-986504 plus pembrolizumab and chemotherapy versus placebo plus pembrolizumab and chemotherapy. These objectives are critical for determining whether the addition of BMS-986504 provides a survival benefit in this molecularly selected cohort. The secondary objectives include:

• Phase 2: To evaluate objective response (OR), disease control (DC), time to objective response (TTOR), and duration of response (DOR) of BMS-986504 plus pembrolizumab and chemotherapy versus placebo plus pembrolizumab and chemotherapy

• Phase 3: To evaluate OR, DC, DOR, PFS, and second progression-free survival (PFS2) of BMS-986504 plus pembrolizumab and chemotherapy versus placebo plus pembrolizumab and chemotherapy

• Phase 2: To assess the safety and tolerability of BMS-986504 plus pembrolizumab plus chemotherapy versus placebo plus pembrolizumab plus chemotherapy

These secondary endpoints provide comprehensive assessment of tumor response dynamics, treatment efficacy beyond initial progression, and the safety profile of the combination regimen in this targeted patient population.

This clinical trial enrolled a total of **389 participants** diagnosed with **metastatic non-small cell lung cancer**. The study population included both **male and female** adults aged **18 years and older**. Participants were required to have **Stage IV or recurrent disease** with no prior systemic anti-cancer therapy for metastatic disease. All participants had histologically confirmed **NSCLC** with homozygous **methylthioadenosine phosphorylase (MTAP) deletion** or **MTAP loss**. The trial population was selected based on specific clinical characteristics, including an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0-1, indicating good functional status, and the presence of at least one measurable lesion according to **RECIST v1.1** criteria. The study did not include vulnerable populations.

This is a randomized, phase 2/3 clinical trial evaluating the efficacy and safety of **BMS-986504** in combination with **pembrolizumab** and **chemotherapy** compared to **placebo** plus pembrolizumab and chemotherapy in participants with **metastatic non-small cell lung cancer** with homozygous **MTAP deletion**. The trial is designed to investigate the therapeutic potential of BMS-986504, administered as a **film-coated tablet** via **oral use**, in combination with pembrolizumab given via **intravenous use** and standard chemotherapy regimens. The chemotherapy options include **carboplatin**, **cisplatin**, **pemetrexed**, **paclitaxel**, and **paclitaxel albumin-bound**, all administered via intravenous use. The control arm receives a matching placebo instead of BMS-986504, along with pembrolizumab and chemotherapy.

The study follows a two-phase design. In phase 2, the main objective is to evaluate **progression free survival** of BMS-986504 plus pembrolizumab and chemotherapy versus placebo plus pembrolizumab and chemotherapy. Phase 3 has dual primary objectives: to compare progression free survival and to compare **overall survival** between the two treatment arms. Secondary endpoints include **objective response**, **disease control**, **time to objective response**, **duration of response**, and **PFS2** as assessed by RECIST v1.1 criteria. Safety endpoints encompass treatment-related and all-cause **adverse events**, **serious adverse events** including fatal events, adverse events leading to dose interruption, dose reduction, or study treatment discontinuation, and laboratory abnormalities.

Participants eligible for enrollment must be aged 18 years or older at the time of informed consent. They must have metastatic or recurrent non-small cell lung cancer with no prior systemic anti-cancer therapy for metastatic disease. A histologically confirmed diagnosis of non-small cell lung cancer with homozygous methylthioadenosine phosphorylase deletion or MTAP loss is required. Participants must have an **Eastern Cooperative Oncology Group performance status** of 0 to 1 and at least one measurable lesion according to RECIST v1.1 criteria.

The estimated recruitment start date is October 30, 2025, and the estimated end date of the trial is August 12, 2031, indicating an overall trial duration of approximately six years. The maximum daily dose of BMS-986504 is specified up to 9999 mg, with maximum total dose amounts also set at 9999 mg. For chemotherapy agents, maximum daily doses are defined as follows: cisplatin at 75 mg/m², pemetrexed at 500 mg/m², paclitaxel albumin-bound at 100 mg/m², pembrolizumab at 200 mg, and paclitaxel at 200 mg/m². The maximum treatment period for all investigational products is set at 9999 days.

Participant involvement includes a screening visit to assess eligibility criteria, followed by randomization to either the experimental or control arm. Treatment visits occur at regular intervals for administration of study medications and monitoring of disease response and safety parameters. Follow-up visits are conducted to assess progression free survival, overall survival, and long-term safety outcomes. The end-of-study visit marks the completion of participant involvement in the trial. Early termination from the study may occur due to disease progression, unacceptable toxicity, participant withdrawal of consent, or other protocol-defined criteria.

The experimental medication **MRTX1719**, also known by the sponsor product code **BMS-986504**, is administered as a **film-coated tablet** for **oral use**. The active substance is 2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]-2-methylpyrazol-3-yl]-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile, which is of chemical origin. The maximum daily dose is specified as 9999 mg, with a maximum total dose of 9999 mg and a maximum treatment period of 9999 days. This investigational product is manufactured by Bristol-Myers Squibb International Corporation.

**Placebo** matching MRTX1719 is utilized as a comparator treatment in this clinical trial. The placebo is administered to maintain blinding in the study design. Specific pharmaceutical form and route of administration details are not provided for the matching placebo formulation.

**Pembrolizumab** is administered as a **solution for infusion** via **intravenous use**. The active substance is pembrolizumab, a protein of biological origin. The maximum daily dose is 200 mg, with a maximum total dose of 9999 mg and a maximum treatment period of 9999 days. The product will be over-labeled and repackaged for use in the clinical trial.

**Carboplatin** is provided as a **concentrate for solution for infusion** administered via **intravenous use**. The active substance is carboplatin of chemical origin. The dosage is expressed in mg/ml, with a maximum daily dose of 9999 mg/ml and a maximum total dose of 9999 mg/ml. The maximum treatment period is 9999 days. The product will be over-labeled and repackaged for trial purposes.

**Cisplatin** is supplied as a **concentrate for solution for infusion** for **intravenous use**. The active substance is cisplatin of chemical origin. The dosage is calculated based on body surface area, with a maximum daily dose of 75 mg/m², a maximum total dose of 9999 mg/m², and a maximum treatment period of 9999 days. The product will be over-labeled and repackaged for the study.

**Pemetrexed** is administered as a **concentrate for solution for infusion** via **intravenous use**. The active substance is pemetrexed of chemical origin. The dosage is calculated based on body surface area, with a maximum daily dose of 500 mg/m², a maximum total dose of 9999 mg/m², and a maximum treatment period of 9999 days. The product will be over-labeled and repackaged for clinical trial use.

**Paclitaxel** is provided as a **concentrate for solution for infusion** for **intravenous use**. The active substance is paclitaxel of chemical origin. The dosage is calculated based on body surface area, with a maximum daily dose of 200 mg/m², a maximum total dose of 9999 mg/m², and a maximum treatment period of 9999 days. The product will be over-labeled and repackaged for the trial.

**Paclitaxel albumin-bound** is supplied as a **powder for dispersion for infusion** administered via **intravenous use**. The active substance is paclitaxel albumin-bound, classified as a specified substance group. The dosage is calculated based on body surface area, with a maximum daily dose of 100 mg/m², a maximum total dose of 9999 mg/m², and a maximum treatment period of 9999 days. The product will be over-labeled and repackaged for use in the clinical trial.

Efficacy will be assessed using distinct parameters across the two phases of this clinical trial. In Phase 2, the primary efficacy endpoint is progression-free survival as determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary efficacy endpoints in Phase 2 include objective response, disease control, time to objective response, and duration of response, all evaluated according to RECIST v1.1. In Phase 3, the trial incorporates dual primary objectives: the first is to compare progression-free survival between treatment arms using RECIST v1.1, and the second is to compare overall survival between the treatment groups. Secondary efficacy endpoints in Phase 3 comprise objective response, disease control, time to objective response, duration of response, progression-free survival, and PFS2, all assessed by RECIST v1.1 criteria.