A phase 1 study to determine the safety, tolerability, PK, PD, and preliminary anti-tumor activity of ascending doses of EPI-326 administered to patients with locally advanced or metastatic HNSCC and to patients with any documented EGFR-mutant locally advanced or metastatic NSCLC.

This study will be a first-in-human (FIH), Phase 1, multicenter, open-label study to determine the safety, tolerability, PK, PD, and preliminary anti-tumor activity of ascending doses of EPI-326 as a single agent administered to patients with EGFR-mutant (per clinically validated molecular testing, e.g., next-generation sequencing [NGS]) locally advanced or metastatic NSCLC and locally advanced or metastatic HNSCC. All patients will be treated until documented disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Inclusion Criteria:

1. Participant has a life expectancy > 12 weeks at Day 1.

2. Participant has an ECOG performance status of 0-2.

3. Participant has pathologically confirmed NSCLC or HNSCC.

   o For NSCLC: the tumor harbors any documented EGFR mutation, insertion, or deletion.

4. Participant has locally advanced or metastatic NSCLC or HNSCC.

5. Participant has adequate organ function

Exclusion Criteria:

1. Participant has history of uncontrolled illness.
2. Participant has symptomatic brain metastases.
3. Participant has a diagnosis of any secondary malignancy within 3 years prior to enrollment, except for those patients treated with curative intent and no evidence of active disease.