Antitumor Activity and Safety of BEBT-109, a Novel EGFR Inhibitor, in Previously Treated NSCLC

Study Overview
=================
Brief Summary
-----------------
This clinical study was a first-in-human, phase 1B, single-center, single-arm, open-label, dose escalation and expansion trial that aimed to determine the safety, tolerability and efficacy of BEBT-109 in patients with locally advanced or metastatic NSCLC harboring EGFR exon20ins mutations who had received at least one line of previous treatment.

Official Title
-----------------
Antitumor Activity and Safety of BEBT-109, a Novel EGFR Inhibitor, in Previously Treated NSCLC With EGFR Exon 20 Insertion Mutations: a Phase 1B, Dose Escalation and Expansion Trial

Conditions
-----------------
NSCLC

Intervention / Treatment
-----------------
* Drug: BEBT-109


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sign written informed consent before implementing any trial-related procedures; Age ≥18 years and no limit on the gender. Histologically or cytologically confirmed locally advanced or metastatic NSCLC with EGFR exon20ins mutation according to assessments made in local laboratories. Previous treatment and type of mutation: Disease progression in doses extension cases may have been treated with an EGFR-TKI (e.g., gefitinib, erlotinib, eclitinib, afatinib, or dapatinib) and prior written test reports confirming EGFR T790M mutation. Disease progression after prior chemotherapy regimen and/or EGFR-TKI treatment in dose-extension cases, and prior written test reports confirming EGFR 20 exon insertion mutations. Disease progression following prior chemotherapy regimen and/or EGFR-TKI treatment in dose-extension cases, and prior written test reports confirming other rare mutations in EGFR (EGFR G719A, L861Q, or S768I point mutations). Patients who are intolerant to chemotherapy or EGFR-TKI and have no other effective treatment can also be admitted to the dose expansion group after judgment by the investigator. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with brain metastasis were only enrolled if the metastases were stable. Subjects had at least 1 measurable lesion that met the RECIST 1.1 criteria. If female subjects are of childbearing potential, adequate contraception (e.g., condoms, etc.) should be used, no breastfeeding should be used, and a negative pregnancy test before administration should be given. Exclusion Criteria: Combined with any other malignancy (except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix). Genetic testing confirmed the presence of C-MET amplification, HER-2 amplification and KRAS mutations, and other genetic mutations that clearly confirm resistance to EGFR-TKI. From the last treatment of EGFR-TKI (such as erlotinib, gefitinib, eclitinib, afatinib or osimertinib, etc.) to the first administration of this clinical trial, the interval is less than 14 days or 5 half-lives (whichever is longer is the exclusion criterion), and the specific drugs involved are decided by the investigator based on comprehensive consideration. In the 4 weeks prior to the first administration of the study treatment, participants had used other anticancer drugs (including immune cell therapy) in the previous treatment regimen. Those who have not withdrawn from other clinical trials within 4 weeks prior to the first administration of the study treatment. Previous homogeneous drug restriction: Patients with EGFR mutation previously treated with osimertinib or other third-generation EGFR inhibitor drugs (eg, ivelitinib, emetinib, and eflotinib) ; EGFR exon20 insertion mutants have used drugs that target EGFR 20 exon insertion mutants (e.g. Poziotinib tarloxotinib TAK788 JNJ-61186372 CLN-081, etc.) Other EGFR rare mutations (EGFR G719A, L861Q, or S768I point mutations) have been treated with afatinib.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEBT-109 120mg<br>BEBT-109 orally at an initial dose of 120 mg once daily. | Drug: BEBT-109<br>* BEBT-109 is based on the 3+3 model, with a dose ascent starting from 120mg qd<br>|
| Experimental: BEBT-109 180mg<br>BEBT-109 orally at an initial dose of 180 mg once daily. | Drug: BEBT-109<br>* BEBT-109 is based on the 3+3 model, with a dose ascent starting from 120mg qd<br>|
| Experimental: BEBT-109 240mg<br>BEBT-109 orally at an initial dose of 240mg (120mg bid) once daily. | Drug: BEBT-109<br>* BEBT-109 is based on the 3+3 model, with a dose ascent starting from 120mg qd<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Defined as one of adverse events defined by NCI CTCAE V5.0 from the first day to the 28th day of the treatment period. | 2 years | 
| MTD | If only 1 of 3 participants in a dose group has DLT, 3 additional subjects in this group will be tested at the same dose level; If no participants developed DLT, the next dose study was conducted; If 2 of the first 3 participants developed DLT or 2 of 6 participants developed DLT, the previous dose of the dose was the maximum tolerated dose (MTD). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Defined as the proportion of subjects in complete remission (CR) and partial remission (PR) to the total subjects | 2 years | 
| DCR | Defined as the proportion of subjects with complete remission (CR), partial remission (PR) and stable disease (SD) to the total subjects | 2 years |