The CR1STAL-Adaptive study is a randomized, open-label, phase II multicenter interventional trial designed to evaluate the safety and efficacy of Ivonescimab (PD-1/VEGF bispecific antibody) combined with docetaxel versus standard treatment in patients with advanced NSCLC who have achieved long-term benefit from first-line immune checkpoint inhibitors (ICIs), but are ctDNA-MRD positive. Building upon insights from previous CR1STAL study (NCT05198154), the CR1STAL-Adaptive study supports the development of precision-guided, adaptive treatment strategies to delay progression and improve outcomes in NSCLC patients with a long-term response to immunotherapy. It represents a step forward in integrating dynamic molecular monitoring with individualized intervention strategies in the era of immunotherapy.
Sign written informed consent prior to any study-related procedures, be willing and able to complete the visits, treatment regimen, and laboratory tests specified in the schedule, and comply with other requirements of the study;
Aged ≥18 and ≤75 years old;
ECOG PS score 0-1;
Expected survival time ≥ 12 weeks;
Concurrent participation in another interventional clinical study or receipt of another investigational drug, unless participating in an observational clinical study；
Systemic therapy with proprietary Chinese medicines with anti-tumor indications or immunomodulatory drugs (including thiopeptides, interferons, interleukins, except those used locally for the control of hydrothorax or ascites) within 2 weeks prior to the first dose；
No measurable lesions as defined by RECIST 1.1 due to prior radical treatment (e.g., surgery or radiotherapy)
Subjects who have received systemic antiangiogenic therapy;
Parallel
Ivonescimab
DrugFor ctDNA-positive patients, escalation treatment will be administrated Ivonescimab: Intravenous infusion (IV), 20 mg/kg, Day 1, every 3 weeks (Q3W); All enrolled participants will continue treatment until one of the following occurs, whichever comes first: * The investigator determines that there is no longer clinical benefit (based on imaging assessments and clinical status) * Unacceptable toxicity * Completion of 24 months of treatment * Other discontinuation criteria specified in the protocol are met.
Docetaxel
DrugFor ctDNA-positive patients, escalation treatment will be administrated Docetaxel: IV, 75 mg/m², Day 1, Q3W (The investigator may adjust the chemotherapy dose and schedule based on the patient's tolerance during treatment.) All enrolled participants will continue treatment until one of the following occurs, whichever comes first: * The investigator determines that there is no longer clinical benefit (based on imaging assessments and clinical status) * Unacceptable toxicity * Completion of 24 months of treatment * Other discontinuation criteria specified in the protocol are met.
Standard Treatment group
Other interventionFor ctDNA-positive patients, continuing the original immunotherapy maintenance or immunotherapy combined with chemotherapy
Progression-Free Survival (PFS) in ctDNA-Positive Population
The duration from randomization to disease progression or death (whichever occurs first), as assessed by the investigator based on RECIST v1.1 criteria.
Overall Survival (OS)
Defined as the duration from randomization to death due to any cause.
Adverse Event
The incidence of adverse events (AEs) will be evaluated according to CTCAE version 5.0. A detailed description of AEs, as well as laboratory data and vital signs, will be provided. The number of patients who experience at least one adverse event will be calculated.
18-Month PFS Rate
This is defined as the proportion of patients who have not experienced disease progression or death from randomization until 18 months, as assessed by the investigator according to RECIST v1.1 criteria.
ctDNA Clearance Rate
The clearance rate of ctDNA at C3D1 after escalated treatment.
The correlation between biomarkers and efficacy prediction
Including but not limited to PD-L1 expression levels in tumor tissue samples, genetic signatures, immune cell infiltration (T cells, B cells, macrophages, etc.), peripheral blood markers (methylation modifications, RNA levels and modifications, protein modifications), blood immune cell composition (TCR, BCR, etc.), blood metabolites (carbohydrates, lipids, amino acids, etc.), and gut microbiota composition.
Exploration of Multiparametric Imaging Biomarkers Predictive of Efficacy
Including but not limited to imaging data from CT, MRI, and PET-CT.
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Second Xiangya Hospital of Central South University
Lead sponsor
Nanjing Shihejiyin Technology, Inc.
Collaborator
Akeso
Collaborator
