Randomized open-label Phase 2 trial evaluating the impact of enhanced versus standard dermatologic management on selected dermatologic adverse events among patients with first-line locally advanced or metastatic EGFR-mutated NSCLC treated with amivantamab + lazertinib

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• 1. History of uncontrolled illness, including but not limited to - Uncontrolled diabetes - Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting background anticancer treatment] or diagnosed or suspected viral infection. For the amivantamab SC Expansion cohort, this includes active localized serious infections. - Active bleeding diathesis - Impaired oxygenation requiring continuous oxygen supplementation - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of background anticancer treatment or doxycycline/minocycline - Psychiatric illness, social situation, or any other circumstances that would limit compliance with study requirements - Any ophthalmologic condition that is clinically unstable - Pre-existing skin condition that would prevent adequate evaluations of dermatologic toxicity, as determined by the investigator
• 2. Medical history of ILD, including drug-induced ILD or radiation pneumonitis
• 3. Known allergy, hypersensitivity, or intolerance to the excipients of amivantamab, lazertinib, or to tetracyclines, doxycycline, minocycline, timolol*, ruxolitinib*, zinc*, corticosteroids* or their excipients or to any component of the enhanced dermatologic management (refer to the IBs or product labels). NOTE: For the amivantamab SC Expansion cohort, participants with known allergies, hypersensitivity, intolerance to excipients or contraindications to propranolol will not be excluded from the study. However, if these participants experience scalp DAEIs during the study, propranolol should not be initiated. Participants should receive treatment with clobetasol 0.05% shampoo only. *Only applicable for participants to be included in the amivantamab SC expansion cohort
• 4. History of clinically significant cardiovascular disease including, but not limited to, the following: - Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of background anticancer treatment(s), or any of the following within 6 months prior to the first dose of background anticancer treatment(s): myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheterassociated clots, are not exclusionary. - Significant genetic predisposition to VTEs such as Factor V Leiden. - Prior history of VTE and is not on appropriate therapeutic anticoagulation as per NCCN or local guidelines. Participants with history of VTE K1 month prior to the first dose of background anticancer treatment and on appropriate therapeutic anticoagulation may be eligible. - Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). - Uncontrolled (persistent) hypertension: systolic blood pressure >160 mmHg; diastolic blood pressure >100 mm Hg. - Congestive heart failure, defined as NYHA class III-IV or hospitalization for congestive heart failure (any NYHA class) within 6 months of treatment initiation at C1D1 (Appendix 10: New York Heart Association (NYHA) Criteria). - Pericarditis/clinically significant pericardial effusion. - Myocarditis. - Baseline LVEF below the institution’s lower limit of normal at screening, as assessed by echocardiogram or MUGA scan.
• 6. Participant has received any prior systemic treatment at any time for locally advanced Stage III or metastatic Stage IV disease (adjuvant or neoadjuvant therapy for Stage or II disease is allowed if administered more than 12 months prior to the development of locally advanced or metastatic disease).
• 7. Participant has an active or past medical history of leptomeningeal disease.