Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved clinical outcomes for patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC); however, patients will inevitably progress due to acquired resistance mutations. Lazertinib is a potent, brain-penetrant, 3rd-generation EGFR TKI with efficacy against activating EGFR and resistance T790M mutations. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating EGFR and MET mutations. Synergistic inhibition of the EGFR by targeting the receptor’s extracellular domain with amivantamab and the kinase domain with lazertinib, may lead to more potent inhibition of the EGFR pathway and potentially delay resistance. In the ongoing CHRYSALIS phase 1 study (NCT02609776), preliminary antitumor activity has been demonstrated with the combination of lazertinib and amivantamab in patients with treatment-naïve and osimertinib-relapsed EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). Methods: CHRYSALIS-2 is an ongoing phase 1/1b open-label study of lazertinib as monotherapy and in combination with amivantamab in patients with advanced EGFRm NSCLC (NCT04077463; https://clinicaltrials.gov/ct2/show/NCT04077463). Phase 1 of the study has confirmed the safety and tolerability of lazertinib monotherapy in Japanese patients. The objective of phase 1b is to characterize the preliminary efficacy of lazertinib in combination with amivantamab in subpopulations of patients with EGFRm NSCLC (Phase 1b Expansion Cohorts) at the recommended combination dose of 1050 mg (1400 mg, ≥80 kg) IV amivantamab dosed weekly in cycle 1 (28-day cycle), every other week thereafter, and 240 mg oral lazertinib QD. Global enrollment in Phase 1b Expansion Cohorts is currently ongoing. Expansion Cohort A is enrolling patients who have progressed on 1st or 2nd-line osimertinib followed by platinum chemotherapy; Expansion Cohort B is enrolling patients with EGFR exon 20 insertion (Exon20ins) mutation who have progressed on prior therapy; and Expansion Cohort C is enrolling patients with uncommon non-Exon20ins EGFR mutations (i.e., S768I, L861Q, G719X) who are treatment-naïve or received 1st or 2nd-generation EGFR TKI as last therapy. The primary endpoints of the study are frequency of dose-limiting toxicity for phase 1 and 1b combination cohorts, and overall response rate for phase 1b expansion cohorts. Key secondary endpoints include safety (adverse events), pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, and overall survival. Safety assessments will include monitoring AEs, clinical laboratory tests, ophthalmologic examination, ECG, and ECHO/MUGA. Blood samples will be collected to access PK. Tumor response will be assessed every 6 weeks by the investigator using RECIST, v1.1. Clinical trial information: NCT04077463