Neoadjuvant Umbrella Trial for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations. (NUMER)

Neoadjuvant Umbrella Trial Directed by Next Generation Sequencing for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations (Without EGFR Sensitizing Mutations)

This umbrella trial directed by next generation sequencing (NGS) includes patients with treatment-naive unresectable stage III non-small-cell lung cancer (NSCLC). The aim of the umbrella study is to evaluate the efficacy of induction NGS-directed targeted therapies followed by surgery for stage III NSCLC patients whose tumor harbors a rare mutation.

Study Overview

• Status: Recruiting
• Conditions: Mutation; Lung Cancer Stage III
• Intervention / Treatment: Drug: Sunvozertinib; Drug: Crizotinib; Drug: Pralsetinib; Drug: Larotrectinib; Drug: Savolitinib; Drug: Pyrotinib; Drug: Dabrafenib+Trametinib; Drug: Glecirasib; Drug: Ensartinib

Detailed Description

Stage III non-small-cell lung cancer (NSCLC) patients account for about one-third of newly diagnosed NSCLC, with a large population and strong heterogeneity, posing significant challenges for clinical treatment. Concurrent chemoradiotherapy plus immune checkpoint inhibitors is the recommended therapeutic approach for patients with unresectable stage III non-small cell lung cancer (NSCLC), although surgery offers the chance of cure. However, existing evidence suggests that patients with driver mutation positive NSCLC have limited benefits from immunotherapy. There is still controversy over the definition of 'unresectable', and some stage IIIA and specific stage IIIB-N2 patients may also benefit from comprehensive surgical treatment. Emerging data supports the use of targeted therapies in NSCLC patients with a rare mutation. The aim of this umbrella study is to explore the efficacy of induction next generation sequencing (NGS)-directed targeted therapies followed by surgery for unresectable stage III NSCLC patients whose tumor harbors a rare mutation (Without EGFR Sensitizing Mutations).

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Si-Yu Wang, MD; Phone Number: +86 20 87343439; Email: wangsy@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun yat-sen University Cancer Center
      • Contact: Si-Yu Wang, Doctor; Phone Number: +86 20 87343439; Email: wsysums@163.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects must have treatment-naive unresectable stage III NSCLC according to the AJCC 8th edition staging;
• Squamous or non-squamous NSCLC histology;
• Subjects should have a rare mutation based on NGS, including mutations of EGFR exon20ins, ROS1 fusion, RET fusion, NTRK fusion, MET 14 exon, HER2, BRAF V600E, KRAS G12C, and ALK fusion.
• Subjects should be without EGFR exon 19 deletions or exon 21 L858R activating mutation;
• Male and female, aged 18-75 years;
• Blood and specimens before and after treatment must be provided;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
• Adequate hematological function: Absolute neutrophil count (ANC) ≥2.0 x 109/L, and Platelet count ≥100 x 109/L, and Hemoglobin ≥9 g/dL (may be transfused to maintain or exceed this level);
• Adequate liver function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN), Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 x ULN;
• Adequate renal function: Serum creatinine ≤ 1.25 x ULN, or ≥ 60 ml/min;
• Female subjects should not be pregnant or breast-feeding;
• Written informed consent provided. Being willing and able to comply with the visits, treatment plan, laboratory examinations and other study procedures scheduled in the study.

Exclusion Criteria:

• Not unresectable stage III disease according to the investigator;
• Subjects with known EGFR sensitive mutations;
• Previous treatment with systemic antitumor therapy for NSCLC;
• Eye inflammation or eye infection not fully treated or conditions predisposing the subject to this.
• History of another malignancy in the last 5 years with the exception of the following: other malignancies cured by surgery alone and having a continuous disease-free interval of 5 years are permitted. Cured basal cell carcinoma of the skin and cured in situ carcinoma of the uterine cervix are permitted.
• Evidence of clinically active interstitial lung disease;
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
• Inability to comply with protocol or study procedures;
• Any unstable systemic disease (including active infection, active tuberculosis uncontrolled hypertension, unstable angina, congestive heart failure, myocardial infarction within the previous year, serious cardiac arrhythmia requiring medication, hepatic, renal, or metabolic disease);
• A serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient's ability to complete the study and may confuse the study results;
• Women who are pregnant or nursing.
• Ingredients mixed with small cell lung cancer patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment 1-Sunvozertinib; Patients with EGFR exon20ins mutation receive Sunvozertinib 300 mg orally once a day, 28 days as one cycle for 3 cycle.	Drug: Sunvozertinib; 300 mg orally once a day, 28 days as one cycle.; Other Names: DZD9008
Experimental: Treatment 2-Crizotinib; Patients with ROS1 fusion mutation receive Crizotinib 250mg orally once a day, 28 days as one cycle for 3 cycle.	Drug: Crizotinib; 300 mg orally once a day, 28 days as one cycle.; Other Names: Xalkori
Experimental: Treatment 3-Pralsetinib; Patients with RET fusion mutation receive Pralsetinib 400mg orally once a day, 28 days as one cycle for 3 cycle.	Drug: Pralsetinib; 400 mg orally once a day, 28 days as one cycle.; Other Names: GAVRETO
Experimental: Treatment 4-Larotrectinib; Patients with NTRK fusion mutation receive Larotrectinib 100 mg orally twice daily, 28 days as one cycle for 3 cycle.	Drug: Larotrectinib; 100 mg orally twice daily, 28 days as one cycle.; Other Names: VITRAKVI
Experimental: Treatment 5-Savolitinib; Patients with MET 14 exon mutation receive Savolitinib 600 mg or 400 mg (weight <50 kg) orally once a day, 28 days as one cycle for 3 cycle.	Drug: Savolitinib; 600 mg or 400 mg (weight <50 kg) orally once a day, 28 days as one cycle.; Other Names: ORPATHYS
Experimental: Treatment 6-Pyrotinib; Patients with HER2 mutation receive Pyrotinib 400 mg orally once a day, 28 days as one cycle for 3 cycle.	Drug: Pyrotinib; 400 mg orally once a day, 28 days as one cycle.; Other Names: SHR1258
Experimental: Treatment 7-Dabrafenib+Trametinib; Patients with BRAF V600E mutation receive Dabrafenib plus Trametinib, 28 days as one cycle for 3 cycle.	Drug: Dabrafenib+Trametinib; Dabrafenib 150 mg orally twice daily, 28 days as one cycle. Trametinib 150 mg orally twice daily, 28 days as one cycle.
Experimental: Treatment 8-Glecirasib; Patients with KRAS G12C mutation receive Glecirasib 800 mg daily orally, 28 days as one cycle for 3 cycle.	Drug: Glecirasib; 800 mg daily orally, 28 days as one cycle.; Other Names: JAB-21822
Experimental: Treatment 9-Ensartinib; Patients with ALK fusion mutation receive Ensartinib 225 mg daily orally, 28 days as one cycle for 3 cycle.	Drug: Ensartinib; 225 mg daily orally, 28 days as one cycle.; Other Names: X-396

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Resectability rate	Baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Adverse Events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.	Baseline to 24 months
Two-year disease-free survival	Disease-free survival was assessed from randomization to disease recurrence or death as a result of any cause.	2 years after the last patient is randomized
Two-year overall survival	Overall survival was assessed from randomization to death as a result of any cause.	2 years after the last patient is randomized
Number of participants with perioperative complications		Baseline to 12 months

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Si-Yu Wang, MD, Sun yat-sen University Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: August 19, 2024
• First Submitted That Met QC Criteria: August 19, 2024
• First Posted (Actual): August 21, 2024

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 19, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: neoadjuvant; umbrella trial; rare mutations; stage III NSCLC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperidines; Aminopyridines; Crizotinib; larotrectinib; pyrotinib; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; ensartinib; pralsetinib
• Other Study ID Numbers: GASTO-10117

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No