Phase III Randomized Open-Label Study of Pralsetinib vs. Standard Care in RET Fusion-Positive Metastatic Non-Small Cell Lung Cancer

The primary objective of this study is to assess whether **pralsetinib** improves progression-free survival (PFS) compared to the investigator's choice of platinum-containing anticancer treatment regimens in patients with RET fusion-positive metastatic non-small cell lung cancer (NSCLC). This objective is clinically relevant as it aims to determine the potential of pralsetinib to delay disease progression, which is a critical factor in the management of metastatic NSCLC.

Secondary objectives include: - Evaluating the efficacy of pralsetinib compared with the investigator’s choice of standard of care (SOC) platinum-containing anticancer treatment regimens, with the corresponding endpoint being the objective response rate (ORR). - Evaluating overall survival (OS). - Assessing the safety and tolerability profile of pralsetinib as compared to the investigator’s choice of SOC platinum-containing anticancer treatment regimens. - Comparing additional measures of anticancer activity, including duration of response, disease control rate, and clinical benefit rate.

The clinical trial involves a total of **93 participants** diagnosed with **RET fusion-positive, metastatic Non-Small Cell Lung Cancer** (NSCLC). The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of advanced unresectable or metastatic NSCLC, documented RET fusion, and measurable disease as per RECIST 1.1 guidelines. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating that participants are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a negative HIV test at screening or be stable on antiretroviral therapy if HIV positive. The trial includes a vulnerable population, ensuring careful consideration of ethical standards in the study design.

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy of **pralsetinib** compared to standard of care for first-line treatment in patients with **RET fusion-positive, metastatic non-small cell lung cancer** (NSCLC). The primary objective is to assess whether pralsetinib improves progression-free survival (PFS) compared to investigator's choice of platinum-containing anticancer treatment regimens. The trial is expected to run from October 22, 2020, to May 31, 2025, with an estimated duration of participant involvement of up to 104 weeks, depending on the treatment arm and individual response.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as confirmed advanced unresectable or metastatic NSCLC, documented RET fusion, measurable disease, and an ECOG performance status of 0-1. Following randomization, participants will receive either pralsetinib or a standard chemotherapy regimen, with treatment cycles and dosing determined by the specific protocol for each arm. Regular follow-up visits will be conducted to monitor treatment response, adverse events, and overall health status, using criteria such as RECIST v1.1 for disease progression and the National Cancer Institute Common Toxicity Criteria for adverse events.

The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it in their best interest. Secondary endpoints include objective response rate, overall survival, and incidence of adverse events, among others. The trial aims to provide comprehensive data on the safety and efficacy of pralsetinib as a first-line treatment option for this patient population.

The clinical trial involves the administration of several **chemotherapy** agents, each with specific pharmaceutical forms, dosages, and administration routes. **Carboplatin** is provided as a solution for infusion, with a maximum daily dose of 750 mg and a total dose limit of 4.5 mg. It is administered via intravenous (IV) injection or infusion over a maximum treatment period of 18 weeks. **Gemcitabine** is supplied as a powder for solution for infusion, with a maximum daily dose of 1250 mg/m² and a total dose limit of 15000 mg/m², administered through IV infusion for up to 18 weeks.

**Pemetrexed** is available as a powder for concentrate for solution for infusion, with a maximum daily dose of 500 mg/m² and a total dose limit of 17000 mg/m², administered via IV infusion over a period of up to 104 weeks. **Sindaxel** (paclitaxel) is provided as a concentrate for solution for infusion, with a maximum daily dose of 200 mg/m² and a total dose limit of 1200 mg/m², administered through IV infusion for a maximum of 18 weeks.

**Keytruda** (pembrolizumab) is a concentrate for solution for infusion, with a maximum daily dose of 200 mg and a total dose limit of 6.8 g, administered via IV infusion over a period of up to 104 weeks. **Cisplatin** is supplied as a concentrate for solution for infusion, with a maximum daily dose of 75 mg/m² and a total dose limit of 450 mg/m², administered through IV infusion for up to 18 weeks.

**Abraxane** (paclitaxel albumin-bound) is provided as a powder for dispersion for infusion, with a maximum daily dose of 100 mg/m² and a total dose limit of 1800 mg/m², administered via IV infusion for a maximum of 18 weeks. The experimental medication, **Pralsetinib**, is administered in the form of hard capsules, with a maximum daily dose of 400 mg and a total dose limit of 680 g, taken orally over a period of up to 56 weeks.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to compare the efficacy of **Pralsetinib** against standard-of-care platinum-containing regimens in patients with RET fusion-positive metastatic non-small cell lung cancer.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **progression-free survival (PFS)**, defined as the time from randomization to the first occurrence of documented progressive disease or death from any cause, as assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints include the objective response rate (ORR), overall survival (OS), incidence and severity of adverse events, changes from baseline in ECOG performance status, targeted vital signs, and clinical laboratory test results. Additionally, the duration of response (DOR), disease control rate (DCR), and clinical benefit rate (CBR) will be evaluated.

These efficacy parameters will be measured and collected at specified intervals throughout the trial. The ORR is defined as the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least four weeks apart. The DOR is the time from the first documented objective response to disease progression or death. The DCR is the proportion of participants with a best response of CR, PR, or stable disease (SD), while the CBR includes participants with SD for a minimum of six months, CR, or PR. The severity of adverse events will be determined according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. These assessments will be conducted using validated scales and laboratory tests, ensuring a comprehensive evaluation of the treatment's efficacy.