A Single-Arm, Multicenter, Phase II Clinical Trial of Firmonertinib in Combination With Definitive Radiotherapy for Patients With Stage III Unresectable Pulmonary Adenocarcinoma Harboring Positive EGFR Uncommon Driver Mutations
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Hunan Cancer Hospital
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Progression-Free Survival
Overview
Brief Summary
This is a prospective, single-arm, Phase II clinical study aimed at evaluating the efficacy and safety of 160mg fimonertinib in combination with definitive radiotherapy for patients with EGFR uncommon driver mutation-positive, Stage III unresectable lung adenocarcinoma. The primary endpoint is Progression-Free Survival (PFS), assessed by the investigator according to RECIST 1.1 criteria, defined as the time from the first dose to objective disease progression or death (from any cause). Secondary endpoints include PFS by different mutation types, OS, ORR, DCR, as well as adverse events and their severity.
Detailed Description
The standard treatment for patients with unresectable Stage III non-small cell lung cancer (NSCLC) is definitive concurrent chemoradiotherapy followed by consolidative immunotherapy with durvalumab. However, the efficacy of this approach remains limited. For EGFR-mutant patients, the benefit of immunotherapy is modest, highlighting the need for alternative strategies. Although the third-generation EGFR-TKI firmonertinib has become a standard first-line therapy for advanced NSCLC harboring common EGFR mutations (exon 19 deletions and L858R), patients with uncommon EGFR mutations (e.g., G719X, S768I, L861Q, and various exon 20 insertion mutations) represent a heterogeneous and understudied population. For most of these uncommon mutations, no approved targeted therapy currently exists in the setting of Stage III unresectable NSCLC.
Firmonertinib is a novel, brain-penetrant third-generation EGFR-TKI that selectively and irreversibly inhibits both EGFR-sensitizing and T790M resistance mutations. It has demonstrated significant efficacy and a manageable safety profile in patients with EGFR T790M-mutant advanced NSCLC, and has also shown promising results in the first-line treatment of common EGFR mutations. Preclinical and clinical evidence suggests that combining EGFR-TKIs with radiotherapy may yield synergistic effects. Radiotherapy induces DNA damage and alters the tumor microenvironment, potentially enhancing both local and systemic efficacy of targeted agents. This combination strategy could be superior to sequential therapy or radiotherapy alone, particularly in molecularly selected populations. This study aims to explore the potential of this targeted-radiotherapy combination as a novel, chemotherapy-sparing, curative-intent treatment paradigm for patients with Stage III, EGFR uncommon mutation-positive lung adenocarcinoma.
This is an exploratory, Phase II, single-arm study. Enrolled patients will receive the study intervention consisting of oral firmonertinib (160 mg once daily) administered continuously until disease progression, unacceptable toxicity, or other treatment discontinuation criteria are met, concurrently with definitive radiotherapy. Radiotherapy will be delivered using intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to a total dose of 60 Gy in 30 fractions over approximately 6 weeks, with strict adherence to standard organ-at-risk dose constraints and institutional quality-assurance protocols. The primary objective is to evaluate progression-free survival (PFS). Secondary objectives include overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and exploratory analyses within specific mutation subgroups.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Provision of informed consent prior to any study-specific procedures;
- •Age 18-75 years;
- •ECOG performance status of 0 or 1 with no deterioration within the 2 weeks prior to enrollment, and a life expectancy of ≥12 weeks;
- •Histologically or cytologically confirmed non-squamous non-small cell lung cancer;
- •Assessed as having unresectable or inoperable locally advanced non-squamous non-small cell lung cancer suitable for definitive radiotherapy (Stage III according to AJCC 9th edition TNM staging);
- •Presence of EGFR uncommon mutations (excluding 19del, L858R, T790M) confirmed by genetic testing in a tertiary grade A hospital; specific types are detailed in Appendix 11;
- •No prior systemic anti-tumor therapy or radiotherapy for locally advanced non-small cell lung cancer before the first dose of the study drug, including chemotherapy, biologic therapy, targeted therapy, immunotherapy, or investigational drug therapy;
- •At least one accurately measurable lesion according to RECIST 1.1, which has not been previously irradiated and was not biopsied during the screening period. If a subject has only one measurable lesion, biopsy of that lesion is permitted, provided the baseline imaging is performed at least 14 days after the biopsy;
- •Female subjects must use highly effective contraception (see restrictions) for at least 2 weeks prior to the first dose, have a negative pregnancy test, must not be breastfeeding at the time of treatment initiation, OR must meet at least one of the following criteria at screening to demonstrate the absence of childbearing potential;
- •Postmenopausal, defined as age over 50 years and amenorrhea for at least 12 months after cessation of all exogenous hormonal treatments;
Exclusion Criteria
- •Pathological type is pulmonary squamous cell carcinoma or small cell lung cancer;
- •Known history of hypersensitivity to the active or inactive excipients of firmonertinib, or to drugs with a similar chemical structure or class to the investigational drug;
- •Confirmed presence of EGFR exon 19 deletion or exon 21 L858R mutation;
- •Presence of metastatic disease, or assessed as unsuitable for definitive radiotherapy; or unable to undergo definitive radiotherapy due to extensive tumor volume resulting in normal tissue radiation doses exceeding dose constraints;
- •NSCLC involving the superior sulcus, large cell neuroendocrine carcinoma (LCNEC), or sarcomatoid tumor;
- •Prior to the first dose of the study drug, patients who have received any of the following treatments;
- •Any prior EGFR-TKI therapy;
- •Patients who have received intrapleural infusion therapy; these patients may be enrolled only after pleural effusion has been stable for 28 days or more;
- •Major surgery within 28 days prior to the first dose of study drug (In China, major surgery is defined according to the Level 3 and Level 4 surgeries specified in the "Administrative Measures for the Clinical Application of Medical Technologies" implemented on May 1, 2009; see Appendix 5 for details);
- •Treatment with strong CYP3A4 inhibitors or inducers within 7 days prior to the first dose, or patients who require continued use of these drugs during the study period (see Appendix 6 for drug list);
Arms & Interventions
Firmonertinib combined with definitive radiotherapy
Patients in this arm will receive a combined regimen of Firmonertinib targeted therapy and definitive radiotherapy. The treatment consists of three phases:
- Induction Phase: Oral Firmonertinib monotherapy for 12 weeks;
- Combined Radiotherapy Phase: Firmonertinib concurrently with definitive thoracic radiotherapy for 6 weeks;
- Consolidation Phase: Firmonertinib monotherapy continued until disease progression or unacceptable toxicity.
Intervention: Firmonertinib (Drug)
Firmonertinib combined with definitive radiotherapy
Patients in this arm will receive a combined regimen of Firmonertinib targeted therapy and definitive radiotherapy. The treatment consists of three phases:
- Induction Phase: Oral Firmonertinib monotherapy for 12 weeks;
- Combined Radiotherapy Phase: Firmonertinib concurrently with definitive thoracic radiotherapy for 6 weeks;
- Consolidation Phase: Firmonertinib monotherapy continued until disease progression or unacceptable toxicity.
Intervention: Definitive Thoracic Radiotherapy (Radiation)
Outcomes
Primary Outcomes
Progression-Free Survival
Time Frame: From enrollment until 30 months after the completion of treatment
the time from the first dose of study treatment (or treatment initiation in single-arm trials) to disease progression or death from any cause, whichever occurs first.
Secondary Outcomes
- Objective response rate(From enrollment until 30 months after the completion of treatment)
- Disease control rate(From enrollment until 30 months after the completion of treatment)
- Progression-Free Survival by Mutation Type(From enrollment until 30 months after the completion of treatment)
- Overall Survival(From enrollment until 60 months after the completion of treatment)
- AE(From enrollment until 30 months after the completion of treatment, every 12 weeks)