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

Prior treatment

• 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 serious infection requiring systemic antibiotic therapy within 7 days prior to initiation of study treatment, or any active infection that, in the opinion of the investigator, could impact patient's safety

Other illness

• Participants with a medical condition that requires immunosuppression
• Participant has a history of another primary malignancy that has been diagnosed or required therapy within the past 3 years before randomization. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site.

Lab values

• 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 inform the Medical Monitor about the enrollment of participants with tumors having co-mutations

• Participant has pathologically or cytologically confirmed, definitively diagnosed, advanced unresectable NSCLC (i.e., Stage IIIB not eligible for definitive chemoradiotherapy) or metastatic NSCLC (i.e., Stage IV), per the Union Internationale Contre le Cancer/American Joint Committee on Cancer staging system (Amin et al. 2017) of either squamous or non-squamous histology based on the major histologic component that has not been treated with systemic anticancer therapy for metastatic disease
• Participant has documented RET fusion that must meet 1 of the following 2 criteria: a. Documented RET fusion using either tissue or plasma as performed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent accredited diagnostic laboratory. b. Documented RET fusion by a positive result from tumor tissue testing performed centrally by Foundation Medicine (FMI) clinical trial assay or an alternate, approved central laboratory for that region
• Participant has measurable disease based on RECIST 1.1 as determined by the local site Investigator/radiology assessment. Lesions located in a previously irradiated area are considered measurable if progression has been demonstrated after irradiation
• Participants has an ECOG PS of 0-1
• Participants who have a negative HIV test at screening. If HIV positive, participant should be stable on anti-retroviral therapy with a CD4 count ≥ 200/µL, and have an undetectable viral load.
• Participant cannot have received any prior anticancer therapy for metastatic disease a. Participant 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 b. Participant that received previous immune checkpoint inhibitors in the adjuvant or consolidation setting following chemoradiation are not allowed to receive pembrolizumab if randomized in Arm B