NCT07314216

Firmonertinib Combined With Definitive Radiotherapy in Stage III Unresectable EGFR Uncommon Mutant Pulmonary Adenocarcinoma

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

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 15 (estimated)
• Sponsor: Hunan Cancer Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

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.

Conditions

• NSCLC (Non-small Cell Lung Carcinoma)
• Stage III
• EGFR Uncommon Mutations

Interventions

Type	Name	Description
DRUG	Firmonertinib	Oral administration
RADIATION	Definitive Thoracic Radiotherapy	Conformal radiotherapy delivered to the primary tumor and involved regional lymph nodes.

Timeline

• Start date: 2026-01-01
• Primary completion: 2030-12-31
• Completion: 2030-12-31
• First posted: 2026-01-02
• Last updated: 2026-01-06

Locations

1 site across 1 country: China