Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations or other uncommon single/compound EGFR mutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Patients randomized to chemotherapy alone will be allowed to cross over to zipalertinib monotherapy after documented progressive disease. The primary endpoint in Part B is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023. Clinical trial information: NCT05973773.