Eligible participants will be stratified at randomization by Asian race (regardless of geographic location), smoking status (whether a current or former smoker), and the presence or absence of treated and stable brain metastases at baseline and randomized in a 1:1 ratio to receive either BAY 2927088 (20 mg BID) or SoC (pembrolizumab in combination with platinum-based chemotherapy [cisplatin or carboplatin, along with pemetrexed], administered in 21-day cycles per the approved labels).

BAY 2927088 20mg BID vs SoC

To evaluate the effect of BAY 2927088 compared with the standard of care (SoC) in progression free survival (PFS)

• Documented activating HER2 mutation
• No prior systemic therapy for locally advanced or metastatic disease. No prior treatment with a HER2 ex20ins-targeted therapy (eg poziotinib, trastuzumab deruxtecan). Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the start of screening
• ECOG PS of 0 or 1

• Inability to discontinue treatment with chronic systemic corticosteroids. Participants who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Replacement therapy (eg, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is acceptable, provided that the dose is stable for >4 weeks prior to planned start of study intervention.
• Participants with active brain metastases (ie, new brain metastases or progressive brain metastases that have not been subjected to CNS-directed therapy since documented progression) and leptomeningeal disease (ie, positive cerebrospinal fluid cytology or unequivocal radiologic or clinical evidence of leptomeningeal involvement) are excluded.
  Participants with treated brain metastases that are asymptomatic at screening are eligible if all of the following criteria are met:
  o There is no evidence of progression (new or enlarging brain metastases) for at least 6 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
  o Participants must be off or receiving low-dose of corticosteroids (≤10 mg prednisone or equivalent) for 7 days prior to the first dose of study intervention.