Study of Furmonertinib in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) With Activating, Including Uncommon, Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 2 (HER2) Mutations

Study Overview
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Brief Summary
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This is a Phase 1b, open-label, multi-center, dose-escalation and dose expansion study designed to evaluate the safety, pharmacokinetics (PK), and preliminary antitumor activity of furmonertinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with activating, including uncommon, Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 2 (HER2) mutations. Patients will be enrolled into one of 2 stages: Stage 1 (Dose Escalation and Backfill Cohorts) and Stage 2 (Dose Expansion).

Official Title
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A Phase 1b Dose Escalation and Dose Expansion Study Evaluating the Safety, Pharmacokinetics, and Antitumor Activity of Furmonertinib in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) With Activating Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 2 (HER2) Mutations

Conditions
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Non-Small Cell Lung Cancer (NSCLC), Metastatic Non-Small Cell Lung Cancer, Advanced Non-Small Cell Lung Cancer, HER2 Exon 20 Mutations, EGFR Exon 20 Mutations, EGFR Uncommon Mutations, Including G719X and S768I

Intervention / Treatment
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* Drug: Furmonertinib
* Drug: Furmonertinib
* Drug: Furmonertinib
* Drug: Furmonertinib
* Drug: Furmonertinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically or cytologically documented, locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. Disease that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable; or for whom a clinical trial of an investigational agent is a recognized standard of care. Documented radiologic disease progression during or after the last systemic anti-cancer therapy before the first dose of furmonertinib. For patients with Epidermal Growth Factor Receptor (EGFR) mutations sensitive to osimertinib, the patient must have received osimertinib prior to study enrollment in regions where osimertinib is approved, including the US. Stage 1 dose escalation and backfill cohorts and Stage 2 Cohorts 1, 2, 3 and 4: -Patients with CNS metastases (including leptomeningeal disease) may be eligible if meeting additional protocol specified criteria. Stage 1 Dose Escalation and Backfill Cohorts Inclusion Criteria: - Documented validated results from local testing of tumor tissue or blood confirming the presence of an activating, including uncommon, EGFR mutation or HER2 exon 20 insertion mutation performed at a CLIA-or equivalently certified laboratory. Stage 2 Cohort 1 Previously Treated, Locally Advanced or Metastatic NSCLC Patients with EGFR Exon 20 Insertion Mutations Inclusion Criteria Documented validated results from local testing of either tumor tissue or blood confirming the presence of EGFR Exon 20 insertion mutations, performed at a CLIA- or equivalently certified laboratory. The patient must have experienced disease progression or have intolerance to treatment with platinum-based chemotherapy. Stage 2 Cohort 2 Previously treated, Locally Advanced or Metastatic NSCLC Patients with HER2 Exon 20 Insertion Mutations Inclusion Criteria Documented validated results from local testing of either tumor tissue or blood confirming the presence of HER2 Exon 20 insertion mutations, performed at a CLIA- or equivalently certified laboratory. The patient must have experienced disease progression or have intolerance to treatment with platinum-based chemotherapy. In regions in which fam-trastuzumab deruxtecan-nxki is approved and available for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 exon 20 mutations, the patient must have received or be considered not appropriate to receive fam-trastuzumab deruxtecan-nxki. Stage 2 Cohort 3 Previously Treated, Locally Advanced or Metastatic NSCLC Patients with EGFR Activating Mutations Mutations, who are not eligible for Cohorts 1 and 4 Inclusion Criteria Documented validated results from local testing of either tumor tissue or blood confirming the presence of an EGFR activating mutation, performed at a CLIA- or equivalently certified laboratory. The patient must have experienced disease progression or have intolerance to treatment with the standard of care EGFR TKI. Patients with CNS metastases may be eligible if meeting additional protocol specified criteria. Stage 2 Cohort 4 Untreated or Previously Treated EGFR TKI-Naïve, Locally Advanced or Metastatic NSCLC Patients with EGFR Uncommon Mutations excluding EGFR Exon 20 insertions Inclusion Criteria Previously untreated in the locally advanced or metastatic setting or have progressed after at least 1 available standard therapy, or for whom standard therapy has proven to be ineffective, intolerable, or considered inappropriate Documented validated results from local testing of either tumor tissue or blood confirming the presence of an EGFR Uncommon mutation, performed at a CLIA- or equivalently certified laboratory a. Representative mutations include, but are not limited to, G719X, S768I, E709X, G779F, L747X, V774M, E709_T710delinsD, R776C/H, G724S, E736K, I740_K745dup, N771G, K757M/R, V769L/M, T854X, T751_I759delinsN Key Exclusion Criteria: Treatment with chemotherapy, targeted therapy, biologic therapy or an investigational agent as anti-cancer therapy within 3 or 3 elimination weeks or five half-lives prior to initiation of furmonertinib, whichever is shorter, or endocrine therapy within 2 weeks prior to initiation of furmonertinib. Radiation therapy as cancer therapy within 4 weeks prior to initiation of furmonertinib. Palliative radiation to bone metastases within 2 weeks prior to initiation of furmonertinib. AE from prior anticancer therapy that have not resolved to Grade ≤ 1 except for alopecia or Grade ≤ 2 peripheral neuropathy. Stage 2 Cohort 4 Untreated or Previously Treated EGFR TKI-Naïve, Locally Advanced or Metastatic NSCLC Patients with EGFR Uncommon Mutations Exclusion Criteria Prior treatment with any EGFR TKIs Progression during neoadjuvant or adjuvant therapy (e.g., chemotherapy, radiotherapy, immunotherapy or investigational agents) or within 12 months of completion of above therapies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 Dose Escalation and Backfill<br>Experimental: Previously treated patients with advanced or metastatic NSCLC with activating EGFR or HER2 mutations | Drug: Furmonertinib<br>* Furmonertinib tablet<br>* Other names: AST2818;|
| Experimental: Stage 2 Expansion Cohort 1<br>Previously Treated NSCLC Patients with EGFR Exon 20 Insertion Mutations | Drug: Furmonertinib<br>* Furmonertinib tablet<br>* Other names: AST2818;|
| Experimental: Stage 2 Expansion Cohort 2<br>Previously treated NSCLC Patients with HER2 Exon 20 Insertion Mutations | Drug: Furmonertinib<br>* Furmonertinib tablet<br>* Other names: AST2818;|
| Experimental: Stage 2 Expansion Cohort 3<br>Previously treated NSCLC Patients with EGFR Activating Mutations, who are not eligible for Cohorts 1 and 4 | Drug: Furmonertinib<br>* Furmonertinib tablet<br>* Other names: AST2818;|
| Experimental: Stage 2 Expansion Cohort 4<br>Untreated or Previously treated EGFR TKI Naïve NSCLC Patients with EGFR Uncommon Mutations, excluding EGFR exon 20 insertion mutations | Drug: Furmonertinib<br>* Furmonertinib tablet<br>* Other names: AST2818;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Number of incidence and severity of adverse events (AEs) as a measure of safety and tolerability of Furmonertinib |  | Up to 36 months after first dose | 
| Stage 2: Overall Response Rate (ORR) |  | Up to 36 months after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 2, all cohorts: Depth of Response |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Overall survival |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Central Nervous System ORR |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Central Nervous System DOR |  | Up to 36 months after first dose | 
| Stage 2, Cohort 4 only: Overall Response Rate |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Number of incidence and severity of AEs as a measure of safety and tolerability of Furmonertinib |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Plasma concentrations of furmonertinib and its major metabolite (AST5902) |  | Up to 36 months after first dose | 
| Stage 1: Overall Response Rate |  | Up to 36 months after first dose | 
| Stage 1: Duration of Response (DOR) |  | Up to 36 months after first dose | 
| Stage 1: Disease Control Rate |  | Up to 36 months after first dose | 
| Stage 1: Progression Free Survival |  | Up to 36 months after first dose | 
| Stage 1: Depth of Response |  | Up to 36 months after first dose | 
| Stage 1: Overall survival |  | Up to 36 months after first dose | 
| Stage 1: Central Nervous System ORR |  | Up to 36 months after first dose | 
| Stage 1: Central Nervous System DOR |  | Up to 36 months after first dose | 
| Stage 1: Plasma concentrations of furmonertinib and its major metabolite (AST5902) |  | Up to 36 months after first dose | 
| Stage 1, Cohort 1, Backfill only: Plasma concentrations of furmonertinib and its major metabolite (AST5902) |  | Up to 36 months after first dose | 
| Stage 1, Cohort 1, Backfill only: Plasma concentrations of midazolam and its metabolite (1-OH-midazolam) |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Duration of Response |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Disease Control Rate |  | Up to 36 months after first dose | 
| Stage 2, all cohorts: Progression Free Survival |  | Up to 36 months after first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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S768I, E709X, R776C/H, G724S, E736K, I740_K745dup, N771G, K757M/R, G719A, G719S, R776C, R776H, K757M, K757R, V769L, V769M, osimertinib, afatinib, E709_T710del insD, G779F, L747X, Non-small cell lung cancer (NSCLC), Metastatic Non-Small Cell Lung Cancer, Advanced Non-Small Cell Lung Cancer, EGFR, HER2, Exon 20 Insertion Mutations, HER2 kinase domain mutations, Epidermal Growth Factor Receptor (EGFR) kinase domain mutations, Exon 20, Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations, HER2 Exon 20 Insertion Mutations, Tyrosine Kinase Inhibitor (TKI), Human Epidermal Growth Factor Receptor 2 (HER2), Epidermal Growth Factor Receptor (EGFR), EGFR uncommon mutations, EGFR atypical mutations, EGFR rare mutations, V774M, G719X, V769L/M, T854X, T751_I759delinsN