A Phase 2 Study of Poziotinib in Patients with Non-Small Cell Lung Cancer (NSCLC), Locally Advanced or Metastatic, with EGFR or HER2 Exon 20 Insertion Mutation (ZENITH20)

This is a Phase 2, open-label, multi-center study to evaluate the efficacy and the
safety/tolerability of poziotinib in seven participant cohorts for up to 603 previously
treated and treatment-naïve NSCLC participant. Cohorts 3 and 4 were added with Amendment 1
and three additional cohorts were added with Amendment 2 (Cohorts 5, 6 and 7).

Key Inclusion Criteria:

- Participant must be willing and capable of giving written Informed Consent, adhering
to dosing and visit schedules, and meeting all study requirements

- Participant has histologically or cytologically confirmed locally advanced or
metastatic non-small cell lung cancer (NSCLC) that is not amenable to treatment with
curative intent

- Prior treatment status:

- Cohorts 1 and 2: Participant has had at least one prior systemic treatment for
locally advanced or metastatic NSCLC

- Cohorts 3 and 4: Participant is treatment-naïve for locally advanced or
metastatic NSCLC and eligible to receive first-line treatment with poziotinib as
determined by the Investigator. Adjuvant/neo-adjuvant therapies (chemotherapy,
radiotherapy, or investigational agents) are permissible as long as they end at
least 15 days prior to study entry.

- Cohort 5: Participants who meet the criteria for enrollment in Cohorts 1 to 4,
but the enrollment in the respective cohort has been closed

- Cohort 6: Participant with EGFR mutation-positive NSCLC who progressed while on
treatment with first-line osimertinib

- Cohort 7: Participant has had at least one prior systemic treatment for locally
advanced or metastatic NSCLC

- Specific mutations:

- Cohort 1 and 3: Documented EGFR exon 20 insertion mutation

- Cohort 2 and 4: Documented HER2 exon 20 insertion mutation

- Cohort 5: Documented EGFR or HER2 exon 20 insertion mutations

- Cohort 6: Documented acquired EGFR mutation (tested after osimertinib
progression)

- Cohort 7: Documented EGFR or HER2 activating mutations

- Participant has adequate organ function at Baseline

Key Exclusion Criteria:

- Participant has had previous treatment with poziotinib or any other EGFR or HER2 exon
20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study
participation. The currently approved TKIs (ie, erlotinib, gefitinib, afatinib,
osimertinib) are not considered to be exon 20 insertion-selective and are permissible
(Cohorts 1 and 2).

- Participant is concurrently receiving chemotherapy, biologics, immunotherapy for
cancer treatment; systemic anti-cancer treatment or investigational treatment should
not be used within 2 weeks or 5 half lives, whichever is longer; local radiation
therapy for bone pain may be allowed

- Participant has had other malignancies within the past 3 years, except for stable
non-melanoma skin cancer, fully-treated and stable, early-stage prostate cancer, or
carcinoma in situ of the cervix or breast without need of treatment

- Participant is pregnant or breast-feeding