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

Inclusion criteria:

• Participant has pathologically confirmed, definitively diagnosed, locally advanced (not able to be treated with surgery or radiotherapy) or metastatic NSCLC and hasnot 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 localsite Investigator/radiology assessment.

• Participant has an ECOG Performance Status of 0 or 1.

• Participant should not have received any prior anticancer therapy for metastaticdisease.

• Participants can have received previous anticancer therapy (except a selectiveRET inhibitor) in the neoadjuvant or adjuvant setting but must have experiencedan interval of at least ≥ 6 months from completion of therapy to recurrence.

• Participants that received previous immune checkpoint inhibitors in theadjuvant or consolidation following chemoradiation are not allowed to receivepembrolizumab if randomized in Arm B

• Participant is an appropriate candidate for and agrees to receive 1 of theInvestigator 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 heterosexualintercourse) or use a condom and agree to refrain from donating sperm.

Exclusion criteria:

• Participant's tumor has any additional known primary driver alterations other thanRET, such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF. Investigatorsshould 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 beforerandomization or more than 30 Gy of radiotherapy to the lung in the 6 months beforerandomization.

• Participant with a history of pneumonitis within the last 12 months.

• Participant has CNS metastases or a primary CNS tumor that is associated withprogressive neurological symptoms or requires increasing doses of corticosteroids tocontrol the CNS disease. If a participant requires corticosteroids for management ofCNS 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 diagnosedor required therapy within the past 3 years prior to randomization.