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Inclusion Criteria:

* Signed informed consent must be obtained prior to participation in the study.
* Dose escalation and dose expansion group 1:

Patients with histologically or cytologically confirmed diagnosis of advanced (metastatic or unresectable) NFE2L2/KEAP1/CUL3 mutant NSCLC. Local data confirming the NFE2L2/KEAP1/CUL3 mutation status in tissue must be available for enrollment.

* Dose expansion group 2:

Patients with histologically or cytologically confirmed diagnosis of advanced (metastatic or unresectable) NSCLC irrespective of NFE2L2/KEAP1/CUL3 mutation status.

* All patients:

Patients must have progressed after 1 platinum-based chemotherapy regimen and PD-(L)1 antibody therapy either sequentially or concurrent with chemotherapy, where indicated, for Stage IV NSCLC.

Patients treated with neo-adjuvant / adjuvant platinum-based therapy that progressed within 6 months of treatment are permitted to participate.

Prior therapy with VEGF/VEGFR targeting agents is permitted. Prior treatment with approved targeted drugs (e.g., EGFRi, ALKi, METi) is mandatory in patients with NSCLC whose tumor bears actionable mutations.

* Presence of at least one measurable lesion according to RECIST v1.1.
* Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening and during study treatment. A recent biopsy collected after the last systemic treatment and within 3 months before study entry may be submitted at screening.

Exclusion Criteria:

* Having out of range laboratory values defined as:

Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) \< 60 mL/min Total bilirubin \> 1.5 x ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN ALT \> 3 x ULN AST \> 3 x ULN ANC \< 1.0 x 109/L Platelet count \< 75 x 109/L Hemoglobin \< 9 g/dL

* Impaired cardiac function or clinically significant cardiac disease, including any of the following:

Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade ≥2), uncontrolled hypertension or clinically significant arrhythmia.

QTcF \> 470 msec on screening ECG or congenital long QT syndrome. Acute myocardial infarction or unstable angina pectoris \< 3 months prior to study entry.

* Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids within 2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
* Known active COVID-19 infection.
* Unable or unwilling to swallow capsules as per dosing schedule. Other protocol-defined inclusion/exclusion criteria may apply.

• Boston, Massachusetts, United States
• Boston, Massachusetts, United States
• St Louis, Missouri, United States
• New York, New York, United States
• New York, New York, United States
• New York, New York, United States
• Houston, Texas, United States
• Frankfurt am Main, Hesse, Germany
• Cologne, North Rhine-Westphalia, Germany
• Essen, Germany
• Chuo Ku, Tokyo, Japan
• Seoul, South Korea
• Madrid, Spain
• Geneva, Switzerland
• Sankt Gallen, Switzerland