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

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).

Study Overview

• Status: Terminated
• Conditions: NSCLC
• Intervention / Treatment: Drug: Poziotinib

Detailed Description

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 epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (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.

• Study Type: Interventional
• Enrollment (Actual): 648
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Saint Luc University Hospital
  • Leuven, Belgium
    • University Hospitals Leuven
  • Mons, Belgium
    • Ambroise Pare University Hospital Center
  • Roeselare, Belgium
    • General Hospital Delta
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer - Vancouver
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Regional Cancer Program
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• France
  • Toulouse, France
    • Hopital Larrey, CHU Toulouse, Unité d'Oncologie des Voies Respiratoires
  • Villejuif, France
    • Gustave Roussy Oncology Institute, Department of Medical Oncology
• Israel
  • Beersheba, Israel
    • Soroka Medical Center
  • Haifa, Israel
    • Rambam Healthcare Campus
  • Jerusalem, Israel
    • Hadassah Medical Center
  • Petah Tikva, Israel
    • Rabin Medical Center
• Italy
  • Milan, Italy
    • National Cancer Institute, IRCCS, Department of Medical Oncology
  • Ravenna, Italy
    • Santa Maria delle Croci Hospital
  • Rome, Italy
    • National Cancer Institute Regina Elena, IRCCS, Operative Unit of Medical Oncology A 1
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus Medical Center
• Spain
  • Barcelona, Spain
    • University Hospital Germans Trias i Pujol, Department of Medical Oncology
  • Madrid, Spain
    • University Hospital 12 de Octubre
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • California
    • Arcadia, California, United States, 91007
      • Oncology Physician's Network Inc./OPN Healthcare
    • Duarte, California, United States, 91010
      • City of Hope
    • La Jolla, California, United States, 92093
      • UCSD -Moores Cancer Center
    • Long Beach, California, United States, 90813
      • Pacific Shores Medical Group
    • Los Angeles, California, United States, 90017
      • Los Angeles Hematology Oncology Medical Group
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • UC Davis Comprehensive Cancer Center
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Comprehensive Cancer Center at Mt Zion
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology
    • Torrance, California, United States, 90502
      • The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
    • Vallejo, California, United States, 94589
      • Kaiser Permanente Medical Center
  • Colorado
    • Boulder, Colorado, United States, 80303
      • Rocky Mountain Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University, Yale Cancer Center Smilow Cancer Hospital at Yale
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Orlando, Florida, United States, 32804
      • Florida Hospital
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
    • Winter Haven, Florida, United States, 33881
      • The Bond & Steele Clinic, P.A. dba Bond Clinic, P.A.
  • Georgia
    • Athens, Georgia, United States, 30607
      • University Cancer & Blood Center, LLC
    • Newnan, Georgia, United States, 30265
      • CTCA - Southeastern Regional Medical Center
  • Illinois
    • Zion, Illinois, United States, 60099
      • CTCA - Midwestern Regional Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology Hematology, P.A.
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic Hematology/Oncology
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • Port Jefferson Station, New York, United States, 11776
      • North Shore Hematology Oncology Associates P.C. DBA NY Cancer and Blood Specialists
    • The Bronx, New York, United States, 10461
      • Montefiore Einstein Medical Center for Cancer Care
    • The Bronx, New York, United States, 10469
      • North Shore Hematology Oncology Associates DBA New York Cancer and Blood Specialists
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists and Research Institute, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19124
      • CTCA - Eastern Regional Medical Center
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Baptist Cancer Center
  • Texas
    • Austin, Texas, United States, 78745
      • Texas Oncology- Austin
    • Houston, Texas, United States, 77030
      • Md Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists, PC
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Poziotinib 16 mg; Participants previously treated for epidermal growth factor receptor (EGFR) exon 20 insertion mutation-positive non-small cell lung cancer (NSCLC) received poziotinib, 16 milligrams (mg), orally, once daily (QD) in each 28-day cycle until disease progression, death, intolerable adverse events (AEs), or for up to a maximum of 35 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 2: Poziotinib 16 mg; Participants previously treated for human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutation-positive NSCLC received poziotinib, 16 mg, orally, QD in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 32 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 3: Poziotinib 16 mg; Treatment naïve participants with EGFR exon 20 insertion mutation-positive NSCLC received poziotinib, 16 mg, orally, QD in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 24 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 4: Poziotinib 8 mg; Treatment naïve participants with HER2 exon 20 insertion mutation-positive NSCLC received poziotinib, 8 mg, orally, twice daily (BID) in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 27 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 4: Poziotinib 16 mg; Treatment naïve participants with HER2 exon 20 insertion mutation-positive NSCLC received poziotinib, 16 mg, orally, QD in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 27 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 5: Poziotinib 6 mg; Participants who met the criteria for enrollment in Cohort 1 to Cohort 4, but the enrollment in the respective cohort had been closed were enrolled in this cohort and received poziotinib, 6 mg, orally, BID in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 23 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 5: Poziotinib 8mg; Participants who met the criteria for enrollment in Cohort 1 to Cohort 4, but the enrollment in the respective cohort had been closed were enrolled in this cohort and received poziotinib, 8 mg, orally, BID in each 28-day cycle until disease progression (except first progression), death, intolerable AEs, or for up to a maximum of 25 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 5: Poziotinib 10 mg; Participants who met the criteria for enrollment in Cohort 1 to Cohort 4, but the enrollment in the respective cohort had been closed were enrolled in this cohort and received poziotinib, 10 mg, orally, QD in each 28-day cycle until disease progression (except first progression), death, intolerable AEs, or for up to a maximum of 15 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 5: Poziotinib 12 mg; Participants who met the criteria for enrollment in Cohort 1 to Cohort 4, but the enrollment in the respective cohort had been closed were enrolled in this cohort and received poziotinib, 12 mg, orally, QD in each 28-day cycle until disease progression (except first progression), death, intolerable AEs, or for up to a maximum of 26 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 5: Poziotinib 16 mg; Participants who met the criteria for enrollment in Cohort 1 to Cohort 4, but the enrollment in the respective cohort had been closed were enrolled in this cohort and received poziotinib, 16 mg, orally, QD in each 28-day cycle until disease progression (except first progression), death, intolerable AEs, or for up to a maximum of 18 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 6: Poziotinib 8 mg; Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib received poziotinib, 8 mg, orally, BID in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 29 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 6: Poziotinib 16 mg; Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib received poziotinib, 16 mg, orally, QD in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 7 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 7: Poziotinib 8 mg; Participants with EGFR or HER2 activating mutations received poziotinib, 8 mg, orally, BID in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 20 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Experimental: Cohort 7: Poziotinib 16 mg; Participants with EGFR or HER2 activating mutations received poziotinib, 16 mg, orally, QD in each 28-day cycle until disease progression, death, intolerable AEs, or for up to a maximum of 4 months, whichever occurs first.	Drug: Poziotinib; The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR was defined as the percentage of participants whose best overall response (BOR) was confirmed to be complete response (CR) or partial response (PR) from the first dose of poziotinib until the last tumor assessment on study. ORR was assessed by the Independent Radiologic Review Committee according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all non-nodal target lesions. Any pathological lymph nodes must have become normal (i.e., decrease in the short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD. Additionally, progression of target lesions must not have been present.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as AEs that occur from the first dose of study treatment until 35 (±5) days after the last dose of study treatment.	Up to 5 years
Disease Control Rate (DCR)	DCR was defined as percentage of participants with best response of CR, PR, or stable disease (SD) from the first dose of poziotinib to the last tumor assessment on study. CR was defined as the disappearance of all non-nodal target lesion. Any pathological lymph nodes must have become normal (i.e., decrease in the short axis to <10 millimeters (mm). PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD. Additionally, progression of target lesions must not have been present. SD was defined as neither sufficient shrinkage of target lesions to qualify for PR nor sufficient increase to qualify for progressive disease (PD).	Up to 3 years
Duration of Response (DoR)	DoR was evaluated only for participants who had CR or PR and was defined as the time from the date that response evaluation criteria were first met for CR or PR (whichever status was recorded first) until the first subsequent date that PD or death was documented. CR was defined as the disappearance of all non-nodal target lesion. Any pathological lymph nodes must have become normal (i.e., decrease in the short axis to <10 millimeters (mm). PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD. Additionally, progression of target lesions must not have been present. Disease progression was defined as greater than or equal to (≥) 20% increase in the SOD of target lesions taking as reference the nadir SOD (or the baseline, if the baseline is the nadir value). In addition to the relative increase of 20% in SOD, the SOD must also have demonstrated an absolute increase of ≥ 5 mm.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) - Exploratory	PFS was defined as the time (in months) from the treatment start date to the first date of documented PD or death. Disease progression was defined as ≥20% increase in the SOD of target lesions taking as reference the nadir SOD (or the baseline if the baseline is the nadir value). In addition to the relative increase of 20% in SOD, the SOD must also have demonstrated an absolute increase of ≥ 5 mm.	Up to 3 years

Collaborators and Investigators

• Sponsor: Spectrum Pharmaceuticals, Inc
• Investigators: Study Director: Lyndah Dreiling, MD, Spectrum Pharmaceuticals, Inc

Publications and helpful links

General Publications

• Le X, Cornelissen R, Garassino M, Clarke JM, Tchekmedyian N, Goldman JW, Leu SY, Bhat G, Lebel F, Heymach JV, Socinski MA. Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial. J Clin Oncol. 2022 Mar 1;40(7):710-718. doi: 10.1200/JCO.21.01323. Epub 2021 Nov 29.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2017
• Primary Completion (Actual): April 3, 2023
• Study Completion (Actual): April 3, 2023

Study Registration Dates

• First Submitted: October 10, 2017
• First Submitted That Met QC Criteria: October 20, 2017
• First Posted (Actual): October 24, 2017

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: HER2; EGFR; Exon 20 insertion mutation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; HM781-36B
• Other Study ID Numbers: SPI-POZ-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No