A Study of Pralsetinib Versus Standard of Care for First-Line Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This is an international, randomized, open-label, Phase 3 study designed to evaluate whether the potent and selective RET inhibitor, pralsetinib, improves outcomes when compared to a platinum chemotherapy-based regimen chosen by the Investigator from a list of standard of care treatments, as measured primarily by progression free survival (PFS), for participants with RET fusion-positive metastatic NSCLC who have not previously received systemic anticancer therapy for metastatic disease. Participants who have centrally confirmed progressive disease on the control arm have the option to crossover to pralsetinib.

Official Title
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A Phase III, Randomized, Open-Label Study of Pralsetinib Versus Standard of Care for First-Line Treatment of RET Fusion-Positive, Metastatic Non-Small Cell Lung Cancer

Conditions
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RET-fusion Non Small Cell Lung Cancer, Lung Neoplasm, Carcinoma, Non-Small-Cell Lung, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms by Site, Neoplasms, Lung Diseases, Respiratory Tract Disease, Carcinoma, Bronchogenic, Bronchial Diseases, Head and Neck Neoplasms, Adenocarcinoma, Carcinoma, Neoplasms by Histologic Type, Neoplasms, Germ Cell and Embryonal, Neoplasms, Nerve Tissue

Intervention / Treatment
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* Drug: Pralsetinib
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed
* Drug: Pembrolizumab
* Drug: Gemcitabine
* Drug: Paclitaxel
* Drug: Nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participant has pathologically confirmed, definitively diagnosed, locally advanced (not able to be treated with surgery or radiotherapy) or metastatic NSCLC and has not been treated with systemic anticancer therapy for metastatic disease. Participant must have a documented RET-fusion Participant has measurable disease based on RECIST 1.1 as determined by the local site Investigator/radiology assessment. Participant has an ECOG Performance Status of 0 or 1. Participant should not have received any prior anticancer therapy for metastatic disease. Participants can have received previous anticancer therapy (except a selective RET inhibitor) in the neoadjuvant or adjuvant setting but must have experienced an interval of at least ≥ 6 months from completion of therapy to recurrence. Participants that received previous immune checkpoint inhibitors in the adjuvant or consolidation following chemoradiation are not allowed to receive pembrolizumab if randomized in Arm B Participant is an appropriate candidate for and agrees to receive 1 of the Investigator choice platinum-based chemotherapy regimens if randomized to Arm B. For women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception. For men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom and agree to refrain from donating sperm. Exclusion criteria: Participant's tumor has any additional known primary driver alterations other than RET, such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF. Investigators should discuss enrollment with Sponsor designee regarding co-mutations. Participant previously received treatment with a selective RET inhibitor. Participant received radiotherapy or radiosurgery to any site within 14 days before randomization or more than 30 Gy of radiotherapy to the lung in the 6 months before randomization. Participant with a history of pneumonitis within the last 12 months. Participant has CNS metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a participant requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks before Cycle 1 Day 1. Participant has had a history of another primary malignancy that has been diagnosed or required therapy within the past 3 years prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pralsetinib<br>Participants randomized to the Experimental Arm will receive Pralsetinib | Drug: Pralsetinib<br>* Administered orally<br>* Other names: BLU-667;|
| Active Comparator: Platinum-based chemotherapy with or without pembrolizumab<br>Participants randomized to the Active Comparator Arm will receive 1 of 6 platinum-based chemotherapy treatment regimens (with or without pembrolizumab) at the study center as chosen by the treating Investigator (based on histology) Nonsquamous histology Carboplatin or cisplatin / pemetrexed (with vitamin supplementation); with optional pemetrexed (with vitamin supplementation) maintenance. Pembrolizumab / carboplatin or cisplatin / pemetrexed (with vitamin supplementation); followed by pembrolizumab and optional pemetrexed (with vitamin supplementation) maintenance. Squamous histology Carboplatin or cisplatin / gemcitabine Carboplatin with paclitaxel/nab-paclitaxel and pembrolizumab | Drug: Carboplatin<br>* Administered IV<br>Drug: Cisplatin<br>* Administered IV<br>Drug: Pemetrexed<br>* Administered IV<br>Drug: Pembrolizumab<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>Drug: Paclitaxel<br>* Administered IV<br>Drug: Nab-Paclitaxel<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Defined as the time from randomisation date to the first documented progressive disease (PD), as assessed by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 central imaging review or death due to any cause, whichever occurs first. | Estimated at up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as assessed by BICR according to RECIST 1.1 central imaging review. | Estimated at up to 32 months | 
| Overall Survival (OS) | Defined as the time from randomisation date to death due to any cause. | Estimated at approximately 32 months | 
| Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | The intensity of Adverse Events (AEs) will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0). | Baseline, at every 21 day cycle visit until progressive disease or death (estimated 32 months) | 
| Changes in Eastern Cooperative Oncology Group Performance Status (ECOG PS) | Further characterising safety and tolerability. | Baseline, at every 21 day cycle visit until progressive disease or death (estimated 32 months) | 
| Duration of Response (DOR) | Defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as assessed by BICR according to RECIST v1.1. | Estimated at up to 32 months | 
| Clinical Benefit Rate (CBR) | Defined as the proportion of participants who experience a best response of Stable Disease (SD) with a minimum duration of 6 months, a CR, or a PR, as assessed by BICR according to RECIST v1.1. | Estimated at up to 32 months | 
| Disease Control Rate (DCR) | Defined as the proportion of participants who experience a best response of CR, or PR, or SD, as assessed by BICR according to RECIST v1.1. | Estimated at up to 32 months | 
| European Organization for Research and Treatment of Cancer Quality of Life (EORTC-QLQ)-C30 Questionnaires | 0-100 points (lower score represents worse quality of life) | From baseline until progressive disease or death (estimated 32 months) | 
| European Organization for Research and Treatment of Cancer Quality of Life (EORTC-QLQ)-LC13 Scores | The item scale ranges from 1-4 (1 = Not at all; 4 = Very Much) where the EORTC-QLQ-LC13 scoring algorithm is applied to convert to a 0-100 point scale where 100 is best quality of life (QOL), for comparability. | From baseline until progressive disease or death (estimated 32 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RET Altered, Advanced Non-Small Cell Lung Cancer, RET Lung, RET Mutation, RET Alteration, RET Positive, RET Inhibitor, RET Rearrangement, RET NSCLC, RET-Rearranged NSCLC, RET Fusion, RET Fusion Lung Cancer, M918T, TRIM33-RET, Lung Cancer Mutation, BLU 667, Pralsetinib, RET Tyrosine Kinase, RET Gene Mutation, RET Kinase, Advanced Lung Cancer, Metastatic Lung Cancer, KIF5B-RET, CCDC6-RET