NCT04644237已完成2 期
A Phase 2, Multicenter, Randomized Study of Trastuzumab Deruxtecan in Subjects With HER2-mutated Metastatic Non-small Cell Lung Cancer (NSCLC) (DESTINY-LUNG02)
适应症
干预措施
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 152
- 试验地点
- 50
- 主要终点
- Percentage of Participants With Confirmed Objective Response Rate by Blinded Independent Central Review Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer
研究概览
简要总结
This study was designed to evaluate the safety and efficacy of trastuzumab deruxtecan in HER2-mutated metastatic non-small cell lung cancer (NSCLC) participants who had disease recurrence or progression during/after at least one regimen of prior anticancer therapy (second line or later) that must have contained a platinum-based chemotherapy drug.
详细描述
This randomized, two-arm, phase 2, multicenter study will evaluate the safety and efficacy of 5.4 mg/kg and 6.4 mg/kg trastuzumab deruxtecan administered every 3 weeks (Q3W) in participants with HER2-mutated metastatic NSCLC. Each participant is expected to receive approximately 14 months of trastuzumab deruxtecan treatment. The primary endpoint of the study will be confirmed objective response rate (blinded independent central review). Secondary endpoints will include, but not limited to, disease control rate, duration of response, progression-free survival, objective response rate (investigator), overall survival, and safety.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent
- •Men or women ≥18 years, follow local regulatory requirements if the legal age of the consent for study participation is >18 years
- •Pathologically documented metastatic NSCLC with a known activating HER2 mutation. Note: A HER2 mutation documented only from a liquid biopsy samples cannot be used for enrollment.
- •Had previous treatment including platinum therapy in the metastatic/locally advanced setting and not amenable to curative surgery or radiation. Participant must have progressed during or after the last treatment regimen or discontinued because of unacceptable toxicity.
- •Presence of at least 1 measurable lesion confirmed by the blinded Independent Central Review based on RECIST version 1.1
- •Willing and able to provide an archival tumor tissue sample. A fresh biopsy is required if an archival tumor tissue sample cannot be supplied. Resection and core needle biopsy are acceptable. Fine needle aspirates or cell block are not acceptable.
- •Eastern Cooperative Oncology Group performance status 0 to 1
- •Left ventricular ejection fraction ≥ 50% within 28 days before randomization Resection and core needle biopsy are acceptable - Adequate organ function as specified in protocol within 14 days before randomization
- •Adequate treatment washout period before randomization
- •Participants of reproductive/childbearing potential agree to use a highly effective form of contraception (or avoid intercourse) during study period and up to 7 months (females) and 4 months (males) after last study dose
- •Males should not freeze or donate sperm throughout the study period up to at least 4 months after last study dose; females should not donate or retrieve ova for their own use throughout the study period and up to at least 7 months after last study dose
- •Life expectancy 3 months or more
排除标准
- •Known driver mutation in the epidermal growth factor receptor (EGFR), BRAF, or MET exon 14 gene or a known anaplastic lymphoma kinase (ALK), ROS1, RET, or NTRK fusion
- •Medical history of myocardial infarction within 6 months before randomization, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Participants with troponin levels above upper limit of normal at screening (as defined by the manufacturer) and without any myocardial infarction (MI)-related symptoms should have a cardiologic consultation before randomization to rule out MI
- •Corrected QT interval (QTcF) prolongation > 470 msec (females) or >450 msec (males) based on average of the triplicate12-lead electrocardiogram at screening
- •History of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
- •Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
- •Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated
- •History of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product
- •History of severe hypersensitivity reactions to other monoclonal antibodies
- •Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- •Substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the participant's participation in the clinical study or evaluation of the clinical study results
- •Known human immunodeficiency virus (HIV) infection
- •Known active, clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C) such as those with serologic evidence of viral infection within 28 days of Cycle 1, Day 1
- •Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline
- •Pregnant, breastfeeding, or planning to become pregnant
- •Otherwise considered inappropriate for the study by the Investigator
- •Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg. pulmonary emboli within three months of the study randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.)
- •Any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening
- •Prior complete pneumonectomy
- •Had prior treatment with any agent, including an antibody drug conjugate (ADC), containing a chemotherapeutic agent targeting topoisomerase I
研究组 & 干预措施
Trastuzumab deruxtecan 6.4 mg/kg
Experimental
Participants will be randomized to receive trastuzumab deruxtecan 6.4 mg/kg administered by intravenous infusion every 3 weeks (Q3W).
干预措施: Trastuzumab deruxtecan (Drug)
Trastuzumab deruxtecan 5.4 mg/kg
Experimental
Participants will be randomized to receive trastuzumab deruxtecan 5.4 mg/kg administered by intravenous infusion every 3 weeks (Q3W).
干预措施: Trastuzumab deruxtecan (Drug)
结局指标
主要结局
Percentage of Participants With Confirmed Objective Response Rate by Blinded Independent Central Review Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer
时间窗: 9 months after the last participant is randomized to data cut off, up to approximately 21 months
Confirmed objective response rate (ORR), defined as the proportion of participants with complete response (CR) or partial response (PR), was assessed by blinded independent central review (BICR) based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
次要结局
- Percentage of Participants With Confirmed Objective Response Rate by Investigator Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung CancerTumors(9 months after the last participant is randomized or later to data cut off, up to approximately 35 months)
- Duration of Response Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer(9 months after the last participant is randomized or later to data cut off, up to approximately 35 months)
- Disease Control Rate Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer(9 months after the last participant is randomized or later to data cut off, up to approximately 35 months)
- Progression-free Survival Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer(9 months after the last participant is randomized or later to data cut off, up to approximately 35 months)
- Overall Survival Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer Tumors(9 months after the last participant is randomized or later to data cut off, up to approximately 35 months)
- The Percentage of Participants Reporting Treatment-emergent Adverse Events Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer Tumors(9 months after the last participant is randomized or later to data cut off, up to approximately 35 months)
- Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) for Trastuzumab Deruxtecan, Total Anti-HER2 Antibody, and Active Metabolite MAAA-1181a(Cycle 1 Day 1; Cycle 2 Day 1, and Cycle 3 Day 1: pre- and post-dose; Cycle 1 Day 8: 7 days post-dose; Cycle 1 Day 15: 14 days post-dose; Cycle 4 Day 1 and Cycle 6 Day 1: pre-dose (each cycle is 21 days))
- Pharmacokinetic Parameter Minimum Observed Concentration (Ctrough) for Trastuzumab Deruxtecan, Total Anti-HER2 Antibody, and Active Metabolite MAAA-1181a(Cycle 1 Day 1; Cycle 2 Day 1, and Cycle 3 Day 1: pre- and post-dose; Cycle 1 Day 8: 7 days post-dose; Cycle 1 Day 15: 14 days post-dose; Cycle 4 Day 1 and Cycle 6 Day 1: pre-dose (each cycle is 21 days))
- Pharmacokinetic Parameter Area Under the Serum Concentration-Time Curve (AUC) for Trastuzumab Deruxtecan, Total Anti-HER2 Antibody, and Active Metabolite MAAA-1181a(Cycle 1 Day 1; Cycle 2 Day 1, and Cycle 3 Day 1: pre- and post-dose; Cycle 1 Day 8: 7 days post-dose; Cycle 1 Day 15: 14 days post-dose; Cycle 4 Day 1 and Cycle 6 Day 1: pre-dose (each cycle is 21 days))
- Number of Participants With Anti-Drug Antibodies (ADA) Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Metastatic Non-small Cell Lung Cancer Tumors(Pre-dose on Day 1 of Cycles 1, 2 and 4, and then every 4 cycles (each cycle is 21 days), up to Cycle 28 and End of Treatment.)
- Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and EORTC Quality of Life Questionnaire for Lung Cancer Trials (QLQ-LC13) Scores(At baseline and at end of treatment 40-day follow-up visit)
- Time to Deterioration in European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) Scores(At baseline and at end of treatment 40-day follow-up visit)
研究者
研究点 (50)
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相关资讯
Trastuzumab Deruxtecan's Expanding Role in HER2-Expressing Solid Tumors- Trastuzumab deruxtecan (T-DXd) received FDA approval for HER2-positive solid tumors, marking a significant expansion beyond breast, lung, gastric, and colorectal cancers.
- Clinical trials like DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 demonstrated T-DXd's efficacy across various tumor types, especially those with high HER2 expression.
- T-DXd treatment requires careful monitoring due to potential adverse events like interstitial lung disease (ILD), necessitating proactive management strategies.
- The DEBBRAH trial showed promising antitumor activity of T-DXd in HER2+ and HER2-low advanced breast cancer patients with leptomeningeal disease (LMD), warranting further investigation.last yearTrastuzumab Deruxtecan Shows Promise in HER2-Mutated NSCLC- Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with previously treated HER2-mutated non-small cell lung cancer (NSCLC).
- The DESTINY-Lung01 trial showed a 55% objective response rate in HER2-mutated NSCLC patients treated with T-DXd at 6.4 mg/kg.
- A lower dose of T-DXd (5.4 mg/kg) was approved by the FDA in 2022 for HER2-mutant NSCLC due to comparable efficacy and reduced toxicity.
- Ongoing research explores the potential of T-DXd as a frontline therapy for HER2-overexpressing or mutated NSCLC.last yearEnhertu Shows Promise in Frontline HER2-Mutated NSCLC Treatment• Fam-trastuzumab deruxtecan-nxki (Enhertu) is under investigation as a first-line treatment for HER2-mutated and -overexpressing non-small cell lung cancer (NSCLC).
• The DESTINY-Lung01 trial revealed a 55% objective response rate and a median progression-free survival of 8.2 months in HER2-mutated NSCLC patients.
• Combining ADCs with other agents like immunotherapy or chemoimmunotherapy is being explored, with ongoing trials monitoring overlapping toxicities like cytopenia and ILD.
• Antibody-drug conjugates (ADCs) are demonstrating increasing efficacy in NSCLC, potentially shifting treatment paradigms in both second-line and first-line settings.last year