Background: Oncogenic EGFR ex20ins mutations, found in ̃2% of non-small cell lung cancers (NSCLC) and a small percentage of other cancers, are generally not responsive to EGFR-targeted agents that have been approved for treatment of NSCLC with a common EGFR mutation, including L858R and exon 19 deletion. Similar to these more common types of EGFR-mutated NSCLC, CNS metastases are a challenge with EGFR ex20ins NSCLC and are associated with poor outcomes. While two EGFR ex20ins-targeting drugs were recently approved by the FDA (amivantamab and mobocertinib), neither have established CNS activity. BLU-451 is a CNS penetrant, wild type-sparing, covalent small molecule inhibitor of EGFR ex20ins as well as atypical (G719C, G719S, L861Q) and common EGFR mutants. Preclinical data have shown BLU-451 to have potent antitumor activity, including in an intracranial xenograft model, which has led to its clinical development in EGFR-mutant NSCLC. Methods: BLU-451-1101 (NCT05241873) is a phase 1/2, global, open-label study designed to evaluate single-agent BLU-451 in patients with NSCLC harboring EGFR ex20ins that has progressed following prior treatment for incurable recurrent or metastatic disease. Patients with Eastern Cooperative Oncology Group performance status 0–1 and EGFR ex20ins, exon 18 G719X or exon 21 L861Q mutant NSCLC (phases 1 and 2) or other cancers except primary CNS tumors (phase 1 only) are eligible. Patients with known ROS, RAF, ALK, or EGFR C797S mutations will be excluded. Stable, asymptomatic brain metastases are permitted, and active asymptomatic brain metastases are permitted in specific cohorts. Primary endpoints are determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and tolerability (phase 1), in addition to evaluation of antitumor activity at the RP2D by RECIST v1.1 (phase 2). Secondary endpoints are evaluation of pharmacokinetics (PK) and antitumor activity by RECIST v1.1.(phase 1) and PK, safety, tolerability, and CNS antitumor activity (phase 2). Dose escalation will utilize a 3+3 design with up to 6 patients per cohort in phase 1 dose escalation and up to 12 per cohort in phase 1 dose expansion. Phase 2 will enroll patients in 3 cohorts (n = 18 each): patients with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned for approximately 40 centers in North America, the Asia-Pacific region, and/or Europe. Clinical trial information: NCT05241873.