This is a multicenter, randomized, controlled, open-label, Phase 3 study designed to demonstrate that NVL-655 is superior to alectinib in prolonging PFS in patients with treatment-naïve, ALK-positive, advanced NSCLC

Subjects will be randomized 1:1 to receive either:

• NVL-655 (150mg QD, initial dose)
• Alectinib (600mg BID, initial dose)

The primary endpoint is PFS, which is defined as the time from randomization to BICR-assessed radiographic disease progression per RECIST 1.1 or death due to any cause, whichever occurs first.

1. Age ≥ 18 years.
2. Histologically or cytologically confirmed locally advanced (not amenable for multimodality treatment) or metastatic NSCLC.
3. Documented ALK rearrangement in tissue or blood (circulating tumor DNA [ctDNA])
4. No prior systemic anticancer treatment for NSCLC including but not limited to molecularly targeted agents, angiogenesis inhibitors, immunotherapy, or chemotherapy.
   Adjuvant/neoadjuvant chemotherapy and/or immunotherapy is allowed if completed more than 12 months prior to randomization. Prior ALK tyrosine kinase inhibitor (such as alectinib) as adjuvant or neoadjuvant therapy is not permitted.
5. Must have measurable disease, defined as ≥ 1 radiologically measurable target lesion according to RECIST 1.1 (Appendix 2).
6. Pretreatment tumor tissue (archived, if available, or a fresh biopsy) must be submitted for central analysis during Screening.
7. Life expectancy of at least 12 weeks.
8. ECOG PS score of 0, 1, or 2.
9. Adequate organ function and bone marrow reserve as indicated by the following laboratory values on last assessment prior to randomization:
   a. Bone marrow function: absolute neutrophil count (ANC) ≥ 1500/µL; platelet count > 75,000/µL; hemoglobin ≥ 9 g/dL (without transfusion).
   b. Renal function: estimated creatinine clearance ≥ 45 mL/min.
   c. Hepatic function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total serum bilirubin within the normal range.
10. All clinically relevant toxicities related to prior anticancer therapy (i.e., radiation) must have recovered to Grade ≤ 1 except for AEs that in the investigator’s judgment do not constitute a safety risk for the patient.
11. Women of childbearing potential (WOCBP) must be surgically sterile or be willing to abstain from sexual activity or use a highly effective contraceptive method (Clinical Trials Coordination Group [CTCG] 2024) from the time of signing the informed consent form (ICF) through at least 6 months after the last administration of NVL-655 or at least 5 weeks after the last administration of alectinib (or longer, if required by local or country-specific guidance). Male patients with pregnant or nonpregnant WOCBP partners must use male contraception (condom)and advise their nonpregnant WOCBP partners to consider use of contraception (CTCG 2024), from the time of signing the ICF through at least 4 months after the last administration of NVL-655 or at least 3 months after the last administration of alectinib (or longer, if required by local or country-specific guidance).
12. Provide written informed consent and willing and able to comply with requirements of the study protocol.

1. Patient’s cancer has a known oncogenic driver alteration other than ALK. Investigators should discuss enrollment with the Sponsor regarding co-mutations.
2. Known allergy/hypersensitivity to excipients of NVL-655 or alectinib.
3. Major surgery within 4 weeks prior to randomization. Minor surgical procedures (e.g., port insertion) are permitted, but with sufficient time for wound healing as deemed clinically appropriate.
4. Ongoing or recent radiation therapy within the following time frame prior to randomization:
   a. Radiation therapy (except palliative radiation to relieve bone pain) < 14 days
   b. Palliative radiation to relieve bone pain < 48 hours
   c. Stereotactic or small field brain irradiation < 7 days
   d. Whole brain radiation < 14 days
5. Uncontrolled clinically relevant infection requiring systemic therapy.
6. Has known active tuberculosis, known active Hepatitis B or C, or known active HIV. Active Hepatitis B is defined as a known quantitative Hepatitis B virus (HBV) DNA results greater than the lower limits of detection of the assay. Active Hepatitis C is defined by a known quantitative Hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay.
   Active HIV is defined by a known quantitative HIV RNA results greater than the lower limit of detection of the assay.
   Note: Patients with no prior history of HIV, current symptoms, or clinical reasons to test for HIV are not required to test for HIV to determine eligibility.
7. Patient has a QT corrected for heart rate by Fridericia's formula (QTcF) > 470 msec (repeated demonstration on more than one assessment). Patient has a history of prolonged QT syndrome or Torsades de pointes.
8. Patient has clinically significant cardiovascular disease as follows:
   a. Within 3 months of randomization: cerebral vascular accident/stroke; myocardial infarction; unstable angina; Grade ≥ 3 atrial fibrillation.
   b. History of congestive heart failure (New York Heart Association Classification Class ≥ II); second-degree or third-degree atrioventricular block (unless paced) or any atrioventricular block with PR interval consistently > 220 msec; or ongoing cardiac
   dysrhythmias of National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≥ 2 (excluding atrial fibrillation).
9. Patient has brain metastases associated with progressive neurological symptoms or requiring increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks prior to randomization. Asymptomatic leptomeningeal carcinomatosis is allowed.
10. Symptomatic spinal cord compression.
11. Patients with moderate to severe cognitive impairment or psychiatric disturbances that would compromise the patient’s ability to comply with study requirements in the investigator’s opinion.
12. Evidence of active malignancy (other than current ALK-positive solid malignancy) requiring systemic therapy within 2 years prior to randomization. Exceptions: nonmelanoma skin cancer, in situ melanoma, in situ cervical cancer, papillary thyroid cancer, or localized and presumed cured breast or prostate cancer. Patients on long-term antihormonal therapy for a prior
    malignancy are allowed if the malignancy has not been active within 2 years prior to randomization.
13. Concomitant use (within 14 days prior to randomization) of strong CYP3A4 inducers or strong CYP3A4 inhibitors, herbal supplements, or high-dose vitamins/minerals.
14. Manifestation of malabsorption due to prior gastrointestinal surgery, disease, or other illness that could affect oral absorption, distribution, metabolism, or excretion of the study drug.
15. Patient is actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
16. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or noninfectious pneumonitis.
17. Patient is pregnant or breastfeeding. WOCBP must have a negative pregnancy test prior to randomization (performed no more than 72 hours prior to initiation of study treatment).
18. Any medical condition or laboratory abnormality that in the opinion of the investigator or Sponsor would pose a risk to study patient or confound the ability to interpret study results.