Background: EGFR ins20-mutant NSCLC has historically been challenging to treat. While new agents targeting EGFR ins20 have recently been approved, adverse events (AEs), particularly wild type (WT) EGFR-related AEs are common. CLN-081 is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations, including ins20, and increased selectivity for ins20 versus WT EGFR. CLN-081 has been granted FDA Breakthrough Therapy Designation for the treatment of pts with EGFR ins20 NSCLC. We present updated results of the initial multicenter Ph1/2a study of CLN-081 in pts with advanced, EGFR ins20-mutant NSCLC, including 39 pts treated in an expanded cohort at the dose of 100 mg twice daily (BID). Methods: Ph1 dose escalation utilized an accelerated titration (AT) and rolling six design. Individual cohorts were expanded in Phase 1 and 2a based on prespecified protocol criteria. Pts were required to have received prior platinum-based chemotherapy. Stable, treated brain metastasis (mets) were allowed. CLN-081 is dosed in 21-day cycles. Results: As of 13 December 2021, 73 pts [median age: 65 (36-82), median lines of prior therapy: 2 (1-9), 28 (39%) with a history of brain mets] received CLN-081 at 30 mg (8), 45 mg (1), 65 mg (14), 100 mg (39), and 150 mg (11), all BID. Treatment-related AEs in ≥ 15% of pts were rash (74%), diarrhea (27%), paronychia (25%), fatigue (19%), anemia (18%), dry skin (18%), nausea (16%). Treatment-related Gr ≥ 3 AEs in ≥ 4 % of pts included anemia (10%), increased ALT (4%), and increased AST (4%). Gr 3 rash and Gr 3 diarrhea were observed in 1 and 2 pts, respectively, at 150 mg BID, while no pts treated at ≤ 100 mg BID experienced Gr 3 rash or diarrhea. Treatment-related dose reductions and discontinuations across all dose levels occurred in 10 pts (14%) and 5 pts (7%) respectively. Among 70 response-evaluable pts across all dose levels, 25 (36%) had a confirmed partial response (PR), 34 (49%) had stable disease (SD), and 3 (4%) had progressive disease as a best response. Seven pts (10%) had a PR that remained unconfirmed; 1 (1%) pt was pending a confirmatory scan. Of 36 response-evaluable pts at 100 mg BID, 14 (39%) had a confirmed PR, 17 (47%) had SD, and 1 (3%) had PD. Three pts had a PR that remained unconfirmed (8%); 1 (3%) pt was pending a confirmatory scan. Notably, among Ph1 pts treated at 100 mg BID (N = 13) in whom longer follow-up is available, the mDOR and mPFS (estimated by Kaplan-Meier) was > 15 months and 12 months, respectively. Disease control (SD ≥ 6 months or any PR) was observed in 12/13 pts (92%). Updated data with additional follow-up will be presented. Conclusions: In pts with heavily-pretreated advanced EGFR ins20 NSCLC, CLN-081 has a manageable safety profile, with anti-tumor activity across the range of doses tested. Further, CLN-081 has demonstrated a favorable clinical profile at the dose of 100 mg BID, with an encouraging objective response rate, response durability, and no Gr 3 rash or diarrhea. Clinical trial information: NCT04036682.