Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation

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).

The Screening period (Day -30 to Day -1) lasts up to approximately 30 days prior to Cycle 1, Day 1. Participant must meet all Inclusion/Exclusion Criteria to participate in the study. Eligible participants will provide written Informed Consent prior to undergoing any study procedures.

Each treatment cycle is 28 calendar days in duration. There will be seven participant cohorts and eligible participants will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status:

* Cohort 1: Previously treated participant with EGFR exon 20 insertion mutation positive NSCLC (complete)
* Cohort 2: Previously treated participant with HER2 exon 20 insertion mutation positive NSCLC (complete)
* Cohort 3: Treatment naïve participant with EGFR exon 20 insertion mutation positive NSCLC (complete)
* Cohort 4: Treatment naïve participant with HER2 exon 20 insertion mutation positive NSCLC (fully enrolled)
* Cohort 5: Participants who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed (closed to enrollment)
* Cohort 6: Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib (closed to enrollment)
* Cohort 7: Participants with EGFR or HER2 activating mutations (closed to enrollment)

Toxicity will be assessed based on the grade of the adverse events using CTCAE version 4.03.

On Day 1 of each 28-day cycle, the participant's absolute neutrophil count (ANC) must be ≥1.5×10\^9/L and platelet count must be ≥100×10\^9/L before administering poziotinib. All participants will be treated until disease progression (except for first progression in Cohort 5), death, intolerable adverse events (AEs), or other protocol-specified reasons for participant withdrawal.

Eligibility Criteria:
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