Furmonertinib Plus Radiotherapy for EGFR+ NSCLC With Pleural Effusion

Официальное название

A Prospective, Multicenter Study on the Safety and Efficacy of Furmonertinib Combined With Local Chest Radiotherapy in EGFR+ Non-small Cell Lung Adenocarcinoma Patients With Malignant Pleural Effusion

Обзор

This study is designed as a prospective, multi-center investigation to explore the efficacy and safety of furmonertinib combined with upfront thoracic radiotherapy with or without metastatic lesion radiotherapy in subjects with EGFR-mutant NSCLC and malignant pleural effusion (MPE), aiming to provide additional evidence-based medical support for optimizing the management of NSCLC-MPE subjects. In addition, peripheral blood ctDNA next-generation sequencing (NGS) will be performed at two time points-before the first furmonertinib treatment and one month after the completion of thoracic radiotherapy-to identify subpopulations most likely to benefit from this therapeutic approach and to elucidate resistance mechanisms specific to the radiotherapy-plus-furmonertinib combination, ultimately facilitating more personalized care for these subjects.

Подробное описание

This study is designed as a prospective, multi-center investigation that plans to enroll 63 subjects with stage IV non-small cell lung adenocarcinoma harboring EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R mutation) complicated by malignant pleural effusions (MPE). Subjects will receive an initial 10-12 weeks of furmonertinib therapy with or without therapeutic thoracentesis to achieve adequate control of MPE, followed by thoracic radiotherapy targeting residual primary pulmonary lesions, regional lymph node metastases, and pleural metastatic lesions, with or without radiotherapy to osseous, adrenal, hepatic, or brain metastases (total irradiated sites ≤6, involved organs ≤3). For brain metastases, consolidative radiotherapy will be withheld if residual tumor diameter is \<1 cm after furmonertinib treatment and no significant neurological symptoms are present.

1. Radiotherapy techniques: Depending on the availability at each participating center, subjects may receive one of the following modalities:

* Intensity-modulated radiation therapy (IMRT), * Volumetric-modulated arc therapy (VMAT), * Stereotactic body radiation therapy (SBRT), * Stereotactic radiosurgery (SRS), or * Fractionated stereotactic radiosurgery (fSRS). 2. Prescription doses for primary and metastatic lesions: Based on institutional technical capabilities and the dose constraints of organs at risk in the radiotherapy plan, the following stereotactic or hypofractionated regimens are permissible:

* Hypofractionated radiotherapy: DT 3000-4000 cGy/10 fractions, 3-4 Gy/fraction, once daily, 5 days/week; * SBRT: 27-50 Gy/3-5 fractions, 8-10 Gy/fraction, once daily, every other day; * SRS (for brain metastases): 20-24 Gy/fraction; * fSRS (for brain metastases): 27 Gy/3 fractions or 30 Gy/5 fractions.

Oral furmonertinib will be withheld before, during, and for 3 days after the completion of radiotherapy. Furmonertinib maintenance will be resumed 3 days after radiotherapy completion and continued until disease progression or unacceptable toxicity. We hypothesize that this treatment paradigm will effectively control MPE, significantly improve progression-free survival (and potentially overall survival), with manageable treatment-related toxicity.

Additionally, dynamic monitoring of peripheral blood ctDNA via next-generation sequencing (NGS) will be performed at two time points-before the first furmonertinib administration and one month after the completion of thoracic radiotherapy-to identify individuals most likely to benefit from this regimen and to elucidate resistance mechanisms to furmonertinib under the radiotherapy-plus-TKI combination, thereby informing clinical decision-making.

Вмешательства

• Препарат Furmonertinib
  Subjects will receive furmonertinib 80 mg orally once daily. The drug will be suspended before radiotherapy initiation, maintained on hold during the entire radiotherapy course, and withheld for an additional 3 days after radiotherapy ends, after which it will be resumed.
• Лучевая терапия Thoracic Radiotherapy (TRT)
  The radiotherapy target volume encompasses residual primary pulmonary lesions, regional lymph node metastases, and pleural metastases, with the option to additionally irradiate osseous, adrenal, hepatic, or brain metastases (with a maximum of 6 total irradiated sites and no more than 3 involved organs). Consolidative cranial irradiation for brain metastases will be deferred in cases where the residual lesion diameter is \<1 cm following furmonertinib therapy and the patient remains free of clini

Первичные конечные точки

• Progression-Free Survival (PFS) [Срок оценки: From date of first dose to date of first documented disease progression or death from any cause, assessed up to 24 months.]

Вторичные конечные точки (6)

• Overall Response Rate (ORR) [Срок оценки: Evaluations are performed at 1 month post-radiotherapy, and subsequently every 3 months, with a total follow-up period of 18 months.]
• Malignant pleural effusion recurrence rate [Срок оценки: Evaluations are performed at 1 month post-radiotherapy, and subsequently every 3 months, with a total follow-up period of 18 months.]
• Disease Control Rate (DCR) [Срок оценки: Evaluations are performed at 1 month post-radiotherapy, and subsequently every 3 months, with a total follow-up period of 18 months.]
• Overall Survival (OS) [Срок оценки: From date of first dose to date of death from any cause, assessed up to 36 months .]
• Adverse event [Срок оценки: From date of first dose to 30 days after last dose .]
• Peripheral Blood ctDNA Level [Срок оценки: Next-generation sequencing (NGS) was used to detect circulating tumor DNA (ctDNA) in peripheral blood samples collected before the first furmonertinib treatment and 1 month after the completion of thoracic radiotherapy (2 time points in total).]

Критерии участия

Критерии включения

• Age ≥ 18 years.
• Histologically or cytologically confirmed advanced lung adenocarcinoma.
• Unlimited number of metastatic lesions, but with involvement of no more than 3 organs.
• Previously untreated, clinical stage IV disease per AJCC/UICC 9th edition.
• Presence of pleural effusion as indicated by chest CT or ultrasound; cytological confirmation of malignant cells in the pleural effusion is preferred. If malignant cells are not detected in the pleural effusion, chest CT with contrast or whole-body PET/CT must demonstrate unequivocal pleural nodular metastases.
• After 8-10 weeks of furmonertinib therapy with or without therapeutic thoracentesis, the overall radiographic response is assessed as effective (CR + PR + SD), and malignant pleural effusion is adequately controlled (defined as no pleural effusion or only minimal pleural effusion on ultrasound or chest CT: maximum depth < 3 cm, estimated volume < 500 mL). Concurrent minimal pericardial effusion is permissible (defined as maximum diastolic width < 1 cm on echocardiography, estimated volume < 100 mL).
• No prior thoracic radiotherapy.
• Positive for EGFR-sensitive mutations (exon 19 deletion or exon 21 L858R).
• No prior systemic anticancer therapy.
• ECOG performance status 0-2, with a life expectancy of ≥ 12 weeks.
• At least one measurable lesion per RECIST 1.1.
• Adequate bone marrow function to tolerate anticancer treatment: WBC ≥ 3 × 10⁹/L, Hb ≥ 80 g/L, PLT ≥ 75 × 10⁹/L, and absolute neutrophil count (NEUT) ≥ 1.5 × 10⁹/L.
• Essentially normal hepatic and renal function:

• Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 50 mL/min;
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN is acceptable in patients with liver metastases);
• Total bilirubin (TBIL) ≤ 1.5 × ULN;
• Albumin ≥ 30 g/L and prealbumin ≥ 150 g/L.
• Asymptomatic brain metastases.
• Written informed consent obtained from all subjects.

Критерии исключения

• Pre-existing interstitial lung disease (ILD) or infectious fever prior to treatment.
• Radiographic progression (PD) after 8-10 weeks of TKI therapy, or development of grade ≥ 2 ILD.
• Concurrent autoimmune disease requiring long-term oral corticosteroid therapy.
• Severe anemia.
• Known hypersensitivity to furmonertinib.
• Significant respiratory symptoms (e.g., chest tightness, cough) that preclude tolerance to radiotherapy.
• Active hepatitis B or C virus infection with concomitant grade > 2 hepatic impairment. Patients may be considered eligible if liver function recovers to grade 1 after active hepatoprotective therapy and antiviral treatment.
• Poorly controlled or continuously progressive pleural effusion after 8-10 weeks of furmonertinib therapy.
• Symptomatic brain metastases.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Li Q, Hu C, Su S, Ma Z, Geng Y, Hu Y, Jin H, Li H, Lu B. Impact of thoracic tumor radiotherapy on survival in non-small-cell lung cancer with malignant pleural effusion treated with targeted therapy: Propensity score matching study. Cancer Med. 2023 Jul;12(14):14949-14959. doi: 10.1002/cam4.6130. Epub 2023 Jun 8. PMID 37288833
• Li W, Wu P, Liang Z, Li L, Chen Y, Zhang W, Zhang H, Fang C. Efficacy and safety of tyrosine kinase inhibitors with thoracic radiotherapy for patients with oncogene-mutated non-small cell lung cancer: a meta-analysis. Radiat Oncol. 2024 Nov 6;19(1):154. doi: 10.1186/s13014-024-02538-y. PMID 39506792
• Hibino M, Hiranuma O, Takemura Y, Katayama Y, Chihara Y, Harada T, Fujita K, Kita T, Tamiya N, Tsuda T, Shiotsu S, Tamura Y, Aoyama T, Nakamura Y, Terashima M, Morimoto Y, Nagata K, Yoshimura K, Uchino J, Takayama K. Osimertinib and Bevacizumab Cotreatment for Untreated EGFR-Mutated NSCLC With Malignant Pleural or Pericardial Effusion (SPIRAL II): A Single-Arm, Open-Label, Phase 2 Clinical Trial. PMID 36438852
• Nokihara H, Ogino H, Mitsuhashi A, Kondo K, Ogawa E, Ozaki R, Yabuki Y, Yoneda H, Otsuka K, Nishioka Y. Efficacy of osimertinib in epidermal growth factor receptor-mutated non-small-cell lung cancer patients with pleural effusion. BMC Cancer. 2022 Jun 1;22(1):597. doi: 10.1186/s12885-022-09701-2. PMID 35650550
• Kiritani A, Amino Y, Uchibori K, Akita T, Harutani Y, Ogusu S, Tsugitomi R, Manabe R, Ariyasu R, Kitazono S, Yanagitani N, Nishio M. Efficacy of osimertinib in patients with EGFR-mutation positive non-small cell lung cancer with malignant pleural effusion. Thorac Cancer. 2024 Feb;15(5):402-409. doi: 10.1111/1759-7714.15210. Epub 2024 Jan 16. PMID 38226415
• Li Q, Hu C, Su S, Ma Z, Geng Y, Hu Y, Li H, Lu B. Failure pattern and radiotherapy exploration in malignant pleural effusion non-small cell lung cancer treated with targeted therapy. Front Oncol. 2023 May 19;13:974735. doi: 10.3389/fonc.2023.974735. eCollection 2023. PMID 37274290

Идентификаторы

NCT: NCT07482605 · 2025 312 号 B

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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