A Study to Learn More About How Well Sevabertinib Works and How Safe it is Compared With Standard Treatment, in Participants Who Have Advanced Non-small Cell Lung Cancer (NSCLC) With Mutations of the Human Epidermal Growth Factor Receptor 2 (HER2)

Inclusion Criteria:

• Participant must be ≥18 years of age or over the legal age of consent in countrieswhere that is greater than 18 years at the time of signing the informed consent.

• Documented histologically or cytologically confirmed locally advanced non-squamousNSCLC, not suitable for definitive therapy or metastatic non-squamous NSCLC atscreening (small cell or mixed histologies are excluded) (Stage III-IV NSCLC).

• Documented activating HER2 mutation in the tyrosine kinase domain (TKD) assessed bytissue molecular test in a CLIA-certified (US sites) or an equally accredited (outside of the US) local laboratory. However, participants may be included at thediscretion of the investigator if the laboratory performing the assay is not CLIA orsimilar certified but the laboratory is locally accredited.

• No prior systemic therapy for locally advanced or metastatic disease. No priortreatment with a HER2 ex20ins-targeted therapy (e.g. poziotinib, trastuzumabderuxtecan). Participants who received adjuvant or neoadjuvant therapy are eligibleif the adjuvant/neoadjuvant therapy was completed at least 12 months prior to thestart of screening.

• Eligible to receive treatment with the selected platinum-based doublet-chemotherapy (i.e. cisplatin/pemetrexed or carboplatin/pemetrexed) and pembrolizumab inaccordance with the SmPC/Product Information.

Exclusion Criteria:

• Known history of prior malignancy except if the participant has undergonepotentially curative therapy with no evidence of that disease recurrence for fiveyears since initiation of that therapy. Exception: the following cancer types areacceptable within five years if curatively treated or under surveillance:

• a. in situ cancers of cervix, breast, or skin,

• b. superficial bladder cancer (Ta, Tis and T1),

• c. limited-stage prostate cancer,

• d. basal or squamous cancers of the skin.

• Tumors with targetable alterations with approved available therapy, with theexception of HER2 mutation in the TKD.

• Inability to discontinue treatment with chronic systemic corticosteroids.Participants who require intermittent use of bronchodilators, inhaled steroids, orlocal steroid injections would not be excluded from the study. Replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is acceptable, provided that the dose is stable for >4 weeks prior toplanned start of study intervention.

• Pre-existing peripheral neuropathy that is Grade ≥2 by CTCAE (v5.0).

• History of severe hypersensitivity reaction to treatment with a monoclonal antibody.

• Prior radiotherapy outside of the brain within 21 days before of planned start ofstudy intervention. Participants must have recovered from all radiation-relatedtoxicities and not require corticosteroids.