This is a Phase 1/2, open-label, multicenter, first-in-human trial to evaluate the safety and tolerability, PK, PD, and preliminary efficacy of CLN-081 in patients with locally-advanced or metastatic NSCLC harboring EGFR ex20ins mutations who have previously received platinumbased systemic chemotherapy. Module A of this study is an open-label, randomized, 2-treatment arm crossover food effect PK assessment module.

Module B, Part 2: Cohort Extension at Candidate Phase 2 Doses:
CLN-081 100 mg BID (with or without food) and 2) 150 mg (fed)

Module C – Antitumor activity of CLN-081 after prior EGFR ex20ins therapy:
CLN-081 after poziotinib and/or mobocertinib among a limited number of patients treated in the Phase 1/2a portion of the trial.

To assess the safety and tolerability of orally administered CLN-081 monotherapy.

To define the maximum tolerated dose (MTD) of orally administered CLN-081 monotherapy

Prior treatment in the recurrent/metastatic disease setting including:
a. A platinum-based chemotherapy regiment (or other chemotherapy regimen if platinum-based chemotherapy is contra-indicated)
b. Any other approved standard therapy that is available to the patient, unless this therapy is contraindicated, intolerable to the patient, or is declined by the patient. In the case of a patient declining such therapy, documentation that the patient has been informed and declined should be documented in the medical record.
c. Prior therapy with an agent approved by the local regulatory authorities for the treatment of EGFR ex20ins mutant NSCLC (Module C only)

1. Prior treatment with an EGFR ex20ins -targeting drug (eg, including, but not limited to poziotinib, mobocertinib, amivantamab, DZD9008, BDTX-189). Note: enrolment of patients treated previously with EGFR ex20ins-targeting drugs allowed selectively during accelerated titration dose escalation and Module C only.

2. Conditions that compromise esophageal or gastrointestinal (GI) function, including esophageal, gastric, pancreatic, hepatobiliary, or small bowel carcinomas, or history of gastric resection.

3. Recurrent diarrhea, nausea, or vomiting.

4. Unable to refrain from or anticipates the use of:
   a. Any drug, including prescription and non-prescription medications, including drugs that change gastrointestinal motility (eg, loperamide) or gastric pH (eg, antacids, H2 antagonists, proton pump inhibitors), herbal remedies, or vitamin supplements within 14 days prior to the first dosing on Day 1 to follow-up.
   b. Any drugs known to be inhibitors or inducers of CYP3A enzymes and/or P-glycoprotein (P-gp), including St. John’s Wort and grape fruit juice, within 28 days prior to the first dosing and throughout the PK assessment