This is a Phase 3, randomized, open-label, 2-arm, multicenter, international study assessing the efficacy and safety of T-DXd compared with SoC (platinum-based chemotherapy with pemetrexed in combination with pembrolizumab) in participants with NSCLC harboring HER2 mutations in exon 19 or 20

Participants will be randomized in a 1:1 ratio to one of the following interventions: T-DXd (Arm 1) or platinum (cisplatin or carboplatin; up to 4 cycles) with pemetrexed plus pembrolizumab (Arm 2). Randomization will be stratified by smoking history and presence of brain metastasis at baseline.

The primary endpoint of this study is PFS by BICR according to RECIST 1.1 in the FAS (ITT population). The key secondary efficacy endpoint is OS in the FAS

1 Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP. 2 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative (see Appendix D). 3 Provision of signed and dated written ICF prior to any mandatory study‑specific procedures, sampling, or analyses. Note: Participants without a qualifying HER2-mutation status result will be required to sign a pre-screening ICF to permit blood sample collection for HER2 exon 19 or 20 mutation testing. Main study informed consent and assessment of the main study eligibility is only to be completed following confirmation of a study-qualifying HER2 mutation. 4 Male and female participants must be ≥ 18 years of age at the time of signing the ICF. Other age restrictions may apply as per local regulations. 5 Histologically documented non-squamous locally advanced and unresectable NSCLC not amenable to treatment with curative intent (surgery or chemoradiotherapy) or recurrent or de novo-metastatic NSCLC (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology). Participants with mixed histology are eligible if adenocarcinoma is the predominant histology. 6 Participants must be treatment-naïve for palliative intent systemic therapy in locally advanced or metastatic disease and medically fit to receive first-line treatment. Prior treatment for early-stage disease is permitted. Systemic treatment (neo-adjuvant, adjuvant, or chemoradiotherapy) with platinum-based regimens for early-stage disease is permitted if the last dose of platinum chemotherapy was given at least 6 months before the date of first study intervention. 7 Documented qualifying HER2 exon 19 or 20 mutation (Appendix O lists qualifying activating HER2 exon 19 or 20 mutations) may be determined by any one of the following approaches: a) From an archival tumor tissue sample (Appendix O details the study requirements for qualifying requirements for laboratories). b) From a local plasma ctDNA test (Appendix O lists the acceptable assays for meeting this criterion). c) Participants without a known qualifying HER2-mutation status result will be required to sign a pre-screening ICF to permit blood sample collection for HER2 exon 19 or 20 mutation testing. The main ICF and other study procedures may not be started until the qualifying central laboratory test result is obtained. 8 A FFPE tumor sample must be available for central testing. If there is no written confirmation of the availability of an archived tumor sample (preferred) or alternatively from a recently obtained biopsy (see Section 8.6.1.1) the participant is not eligible for the study. 9 A WHO/ECOG performance score of 0 or 1, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing. 10 At least one measurable lesion by RECIST 1.1. Note: A previously irradiated lesion can be considered a target lesion if the lesion is well defined, measurable per RECIST, and has clearly progressed. Adequate organ and bone marrow function within 14 days before randomization/enrollment 12 Left ventricular ejection fraction ≥ 50% within 28 days before randomization/enrollment. 13 Minimum life expectancy of at least 12 weeks

1 Mixed small-cell lung cancer, squamous histology NSCLC, and sarcomatoid histology variant NSCLC.

2 Tumors that harbor targetable alterations to EGFR (or other targetable mutations including but not limited to ALK, if routinely tested as a targetable alteration with approved available therapy).

3 Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled hypertension, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the participant to give written informed consent.

4 Any spinal cord compression, leptomeningeal disease, or clinically active CNS metastases. Note: Clinically active CNS metastases are defined as untreated AND symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control ssociated symptoms. Participants with CNS metastases must have previously completed local therapy. - Participants with previously treated CNS metastases are allowed if asymptomatic or neurologically stable and have recovered from the acute toxic effects of prior therapy. - Participants with CNS metastases treated by radiation must be: - ≥ 7 days since stereotactic radiosurgery or gamma knife prior to enrollment. o ≥ 14 days since whole brain radiation therapy prior to enrollment.

5 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis and autoimmune myocarditis). The following are exceptions to this criterion: - Participants with vitiligo or alopecia. - Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. - Any chronic skin condition that does not require systemic therapy. - Participants without active disease in the last 5 years may be included but only after consultation with the AstraZeneca Study Physician. - Participants with coeliac disease controlled by diet alone.

6 A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy.

7 Has a concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator.

8 Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.

9 Participants with a medical history of myocardial infarction within 6 months before randomization/enrollment or symptomatic congestive heart failure (NYHA Class II to IV). Note: Participants with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.

10 QTcF prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.

11 History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

12 Lung criteria: - Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc). - Any autoimmune, connective tissue or inflammatory disorders (ie, rheumatoid arthritis, Sjogren’s, sarcoidosis, etc) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the study.- Prior complete pneumonectomy. Note: Prior lobar or segmental resection is permitted.

13 Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis testing in line with local practice).

14 Active primary immunodeficiency, known HIV infection, or active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Note: Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Participants should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board/ethics committee. Participants with past or resolved HBV infection who are anti-HBc positive (+) are eligible only if they are HBsAg negative (-).

15 Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.

16 Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Participants may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, for example: - Chemotherapy-induced neuropathy – Fatigue - Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies which may include: o Hypothyroidism/hyperthyroidism o Type 1 diabetes o Hyperglycemiao Adrenal insufficiency o Adrenalitis o Skin hypopigmentation (vitiligo).

17 Medical contraindication to platinum-based doublet chemotherapy or pembrolizumab.

18 Is unable or unwilling to take folic acid or vitamin B12 supplementation.

19 Previous randomization in the present study.

20 Randomization into a prior T-DXd study regardless of treatment assignment.

21 Concurrent enrollment in another therapeutic clinical study. Note: Enrollment in observational studies will be allowed.

22 Known allergy or hypersensitivity to study intervention or any of the study drug excipients or other mAbs.

23 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

24 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.

25 Pregnant (confirmed with positive pregnancy test) or breastfeeding female participants or participants who are planning to become pregnant.

26 Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the participant’s participation in the clinical study or evaluation of the clinical study results. 5.3 Lifestyle Considerations The following restrictions apply while the participant is receiving study intervention and for the specified times before and after:
1 Participants must follow the contraception requirements outlined in Appendix H.
2 Participants should not donate blood or blood components while participating in this study and through 40 (+ 7 as a window) days after the last dose of T-DXd for participant who receive T-DXd alone. Participants receiving SoC should follow the relevant product label/regulations with regard to the donation of blood or blood components, during and after the last dose.
3 Preservation of sperm should be considered prior to enrollment in this study.
4 Preservation of ova may be considered prior to enrollment in this study. Restrictions relating to concomitant therapies are described in Appendix J 1. 5.3.1 Meals and Dietary Restrictions In general, there are no dietary restrictions for the study assessments or treatment with T-DXd. 5.3.2 Tobacco Use of tobacco products, e-cigarettes and vaping is strongly discouraged but not prohibited. Any prior or current use of these products should be recorded in the eCRF."