Safety and activity of CLN-081 (TAS6417) in NSCLC with EGFR Exon 20 insertion mutations (Ins20).
Authors: Zofia Piotrowska, Helena Alexandra Yu, James Chih-Hsin Yang, Marianna Koczywas, Egbert F. Smit, Daniel Shao-Weng Tan, Victor Ho-Fun Lee, Ross A. Soo, John M. Wrangle, Alexander I. Spira, Vamsidhar Velcheti, Mark A. Socinski, Asher Page, David Witter, Leigh Zawel, Jon M. Wigginton, Myles Steven Clancy, Danny Nguyen
Journal: Journal of Clinical Oncology (2021)

9077 Background: NSCLC with EGFR ins20 represents a significant area of unmet need, with no approved targeted therapies. While several agents targeting EGFR ins20 are in development, wild-type (WT) EGFR-related adverse events (AEs) have been common and challenging to manage. CLN-081 is a novel oral EGFR TKI with broad activity against clinically relevant EGFR mutations, including ins20, and has attenuated activity against WT EGFR relative to EGFR ins20 in vitro, suggesting that CLN-081 may have a more favorable clinical therapeutic window. We present interim results of a multicenter, Phase (Ph) 1/2a trial evaluating CLN-081 in advanced, EGFR ins20 NSCLC (NCT04036682). Methods: Patients (pts) with EGFR ins20 previously treated with platinum-based therapy (tx) were eligible to enroll. Ph 1 dose escalation in this adaptive trial began with an accelerated titration (AT) design, and converted to a rolling six design based upon pre-specified safety criteria or at clinically active doses. Cohort expansion in Ph 1 occurred at any dose where responses were seen. Transition from Ph 1 to 2a was based on a Simon-Two Stage design. Prior tx with EGFR ins20-specific inhibitors was allowed in AT cohorts only. CLN-081 was dosed twice daily (BID) in 21-day cycles. Results: As of 10 November 2020, 37 pts [median age 64 years (44-82); median 2 (1-9) prior lines of tx] received CLN-081 at doses of 30 mg (n = 8), 45 mg (1), 65 mg (12), 100 mg (13), and 150 mg (3) BID. The most common all-grade (gr) treatment-related AEs (TRAEs) were rash (49%), diarrhea (24%), paronychia (16%), nausea (14%), stomatitis (14%), and dry skin (11%). Gr 3 TRAEs included anemia (5%), diarrhea (3%), and increased alkaline phosphatase (ALP) (3%). There was 1 DLT, gr 3 diarrhea at 150 mg BID. No gr ≥ 3 rash or gr 4/5 TRAEs were reported. Four pts (11%) required dose reductions for rash (2), diarrhea (1), and increased ALP (1). Two pts (5%) discontinued tx due to TRAEs of gr 2 hypersensitivity reaction (1) and gr 2 pneumonitis (1); the latter also experienced pneumonitis while receiving prior osimertinib. Among the 25 response evaluable pts (RECIST 1.1), 10 (40 %) had a partial response (PR) (6 confirmed, 2 pending confirmation, 2 unconfirmed), 14 (56%) had stable disease (SD), and 1 (4%) had progressive disease as best response. Of the 4 pts that received prior EGFR ins20 inhibitors, 2 had PR and 2 SD. Of pts with SD or PR as best response, 20/24 (83 %) experienced tumor regression [median regression: -18 % (-100 to +3)]. Enrollment is ongoing and updated data will be presented. Conclusions: CLN-081 has an acceptable safety profile, including diarrhea in &lt; 25% of pts treated to date. CLN-081 has demonstrated encouraging preliminary anti-tumor activity across the full dose range tested, in multiple distinct EGFR ins20 variants, and in heavily pre-treated pts that are either naïve or refractory to other EGFR ins20 inhibitors. Since the time of the data cut, a Ph 2a expansion has been initiated at 100 mg BID. Clinical trial information: NCT04036682.