Phase 3, Randomized, Open-Label Study of Nogapendekin Alfa Inbakicept in Combination With Standard of Care Versus Standard of Care as First-Line Treatment for Patients With Advanced or Metastatic Non-Small Cell Lung Cancer
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 入组人数
- 494
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
This is a randomized, open-label, phase 3 study evaluating nogapendekin alfa inbakicept (NAI) plus chemoimmunotherapy containing pembrolizumab and platinum-based chemotherapy versus chemoimmunotherapy alone as first-line treatment in patients with stage IV squamous or nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations. Primary endpoint is progression-free survival by RECIST v1.1 based on blinded independent central review.
详细描述
This is a phase 3, randomized, open-label, parallel-group clinical trial evaluating nogapendekin alfa inbakicept (NAI; an IL-15 receptor agonist) in combination with standard first-line chemoimmunotherapy versus standard chemoimmunotherapy alone in participants with stage IV squamous or nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations that have approved targeted therapies. Approximately 494 participants will be randomized 1:1 to receive either NAI plus pembrolizumab and platinum-based chemotherapy (experimental arm) or pembrolizumab and platinum-based chemotherapy alone (control arm), with the possibility of increasing the sample size up to 960 participants based on an interim progression-free survival (PFS) analysis.
In the experimental arm, participants receive induction therapy for up to 4 cycles (21-day cycles) with pembrolizumab 200 mg IV plus cisplatin 75 mg/m² IV or carboplatin AUC 5-6 IV, and a histology-specific third agent (nab-paclitaxel 100 mg/m² IV on Days 1, 8, and 15 for squamous NSCLC, or pemetrexed 500 mg/m² IV on Day 1 for nonsquamous NSCLC), in combination with NAI 1.2 mg subcutaneously (SC) on Day 1 of each cycle (participants ≥100 kg receive NAI 15 μg/kg SC). In the maintenance phase (cycles ≥5), participants in the experimental arm continue pembrolizumab 200 mg IV every 3 weeks with NAI 1.2 mg SC every 3 weeks, with pemetrexed 500 mg/m² IV continued in nonsquamous NSCLC. In the control arm, participants receive the same pembrolizumab plus platinum backbone, with squamous participants receiving either nab-paclitaxel, paclitaxel, or docetaxel per regional product labeling, and nonsquamous participants receiving pemetrexed, followed by maintenance pembrolizumab with or without pemetrexed according to histology. All study treatment is administered for up to 35 cycles (approximately 2 years), or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.
Tumor assessments (CT or MRI) are performed at screening, at week 6 and week 12 following Cycle 1 Day 1, and every 9 weeks (±7 days) thereafter, and tumor response is evaluated per RECIST v1.1 and immune RECIST (iRECIST). The primary endpoint is PFS per RECIST v1.1 as assessed by blinded independent central review (BICR). Key secondary endpoints include overall survival (OS) and objective response rate (ORR) per RECIST v1.1 by BICR. Other secondary endpoints include PFS, ORR, duration of response (DOR), and disease control rate (DCR) by iRECIST (BICR) and by Investigator assessment, change in absolute lymphocyte count (ALC) over time, duration of immune competence (ALC ≥1,000 cells/µL), disease-specific survival (DSS), and safety (treatment-emergent adverse events, serious adverse events, laboratory parameters, vital signs, and ECGs). The study also includes exploratory analyses of whole slide images and blood/tissue-based molecular profiling to explore correlations with clinical outcomes.
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
- None
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
- •Age ≥18 years.
- •Pathologically confirmed stage IV NSCLC (squamous or nonsquamous).
- •No prior systemic chemotherapy for advanced/metastatic NSCLC.
- •Tumor lacks an actionable genomic alteration with approved first-line targeted therapy (EGFR, ALK etc.; AGA status from local or central testing; ctDNA acceptable if tissue unavailable).
- •PD L1 result available before randomization: TPS ≥1%, <1%, or unknown.
- •ECOG performance status 0-
- •At least one measurable lesion per RECIST v1.
- •Able to attend visits and follow-up.
- •Contraception requirements for women of childbearing potential and nonsterile males, with 7 month post-last-dose window.
排除标准
- •Body weight <40 kg.
- •Serious uncontrolled concomitant disease.
- •Certain prior malignancies (exceptions: adequately treated or nonmetastatic, as per protocol).
- •Active autoimmune disease requiring systemic treatment (exceptions: autoimmune thyroiditis, etc.).
- •Prior organ transplant requiring immunosuppression.
- •Prior pneumonitis/interstitial lung disease requiring active systemic treatment.
- •Prior systemic chemotherapy or immunotherapy within 3 years.
- •Requirement for other anticancer therapy while on study (palliative RT allowed).
- •Known CNS metastases, carcinomatous meningitis, and/or spinal cord compression (with specified exceptions for treated or asymptomatic brain mets).
- •HIV infection or active/uncontrolled HBV/HCV not meeting the protocol's controlled criteria.
- •Active infection requiring IV therapy.
- •Inadequate organ function:
- •ANC <1,500/mm³; platelets <100,000/mm³; Hgb <9 g/dL.
- •Total bilirubin >1.5×ULN (with defined Gilbert's exception).
- •AST/ALT >1.5×ULN (or >5×ULN with liver mets).
- •ALP >2.5×ULN (or >5×ULN with bone mets).
- •Creatinine clearance <40 mL/min (Cockcroft-Gault).
- •Significant cardiovascular disease (uncontrolled HTN, recent MI, stroke, CHF ≥NYHA II, serious arrhythmia).
- •Known hypersensitivity to study drugs.
- •Concomitant medications known to interact adversely with study drugs.
- •Participation in another investigational drug/device study (except hormone-lowering therapy).
- •Pregnancy or breastfeeding.
- •Confinement by court order/authority.
- •Any condition or noncompliance that, in Investigator judgment, precludes participation.
研究组 & 干预措施
Active Comparator: Pembrolizumab + Chemotherapy
First-line standard-of-care chemoimmunotherapy per pembrolizumab + platinum doublet regimens, histology-specific.
干预措施: Nab-paclitaxel OR Paclitaxel OR Docetaxel (squamous) (Drug)
Active Comparator: Pembrolizumab + Chemotherapy
First-line standard-of-care chemoimmunotherapy per pembrolizumab + platinum doublet regimens, histology-specific.
干预措施: Cisplatin or Carboplatin (Drug)
Active Comparator: Pembrolizumab + Chemotherapy
First-line standard-of-care chemoimmunotherapy per pembrolizumab + platinum doublet regimens, histology-specific.
干预措施: Pemetrexed (nonsquamous) (Drug)
Experimental: NAI + Pembrolizumab + Chemotherapy
First-line stage IV NSCLC; induction (≤4 cycles) with pembrolizumab + platinum + nab-paclitaxel (squamous) or pemetrexed (nonsquamous) plus NAI, followed by maintenance pembrolizumab ± pemetrexed plus NAI.
干预措施: Drug: Nogapendekin alfa inbakicept (NAI) (Drug)
Experimental: NAI + Pembrolizumab + Chemotherapy
First-line stage IV NSCLC; induction (≤4 cycles) with pembrolizumab + platinum + nab-paclitaxel (squamous) or pemetrexed (nonsquamous) plus NAI, followed by maintenance pembrolizumab ± pemetrexed plus NAI.
干预措施: Nab-paclitaxel (squamous) OR Pemetrexed (nonsquamous) (Drug)
Active Comparator: Pembrolizumab + Chemotherapy
First-line standard-of-care chemoimmunotherapy per pembrolizumab + platinum doublet regimens, histology-specific.
干预措施: Nab-paclitaxel (squamous) OR Pemetrexed (nonsquamous) (Drug)
Experimental: NAI + Pembrolizumab + Chemotherapy
First-line stage IV NSCLC; induction (≤4 cycles) with pembrolizumab + platinum + nab-paclitaxel (squamous) or pemetrexed (nonsquamous) plus NAI, followed by maintenance pembrolizumab ± pemetrexed plus NAI.
干预措施: Pembrolizumab (Drug)
Experimental: NAI + Pembrolizumab + Chemotherapy
First-line stage IV NSCLC; induction (≤4 cycles) with pembrolizumab + platinum + nab-paclitaxel (squamous) or pemetrexed (nonsquamous) plus NAI, followed by maintenance pembrolizumab ± pemetrexed plus NAI.
干预措施: Cisplatin or Carboplatin (Drug)
Active Comparator: Pembrolizumab + Chemotherapy
First-line standard-of-care chemoimmunotherapy per pembrolizumab + platinum doublet regimens, histology-specific.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: Imaging every 9 weeks (±7 days) from first dose until treatment discontinuation; final PFS analysis with follow-up through 156 weeks (3 years) from first dose.
Time from randomization to disease progression (per RECIST v1.1) or death from any cause, whichever occurs first. Tumor imaging every 9 weeks (±7 days) after Cycle 1 Day 1. If progression per RECIST v1.1 is observed, confirmatory imaging 4-8 weeks later to rule out pseudoprogression; assessments also analyzed by iRECIST. Final PFS analysis per SAP with follow-up through 156 weeks (3 years) from first dose.
Progression-Free Survival (PFS) by BICR (RECIST v1.1)
时间窗: Imaging every 9 weeks (±7 days) from first dose (after initial assessments at week 6 and week 12) until treatment discontinuation; final PFS analysis with follow-up through 156 weeks (3 years) from first dose.
PFS is defined as the time from randomization to the first documentation of disease progression per RECIST v1.1 by blinded independent central review (BICR) or death from any cause, whichever occurs first.
次要结局
- Duration of response (DOR)(DOR measured from date of first confirmed response; tumor assessments every 9 weeks (±7 days); DOR censored or followed through 156 weeks (3 years) from first dose.)
- Overall survival (OS)(Assessed continuously; survival status collected every 12 weeks (±2 weeks) through 156 weeks (3 years) from first dose or until death.)
- Objective response rate (ORR, RECIST v1.1)(Response assessments every 9 weeks (±7 days); responses must be confirmed ≥28 days after initial documented CR/PR; ORR summarized through 156 weeks (3 years) from first dose.)
- Change in absolute lymphocyte count (ALC) over time and maintenance of immune competence.(Baseline (Cycle 1 Day 1 prior to dosing) and Day 1 of each 3-week cycle (lab window: ≤3 days prior to Day 1 during induction cycles 1-4; ≤7 days during maintenance cycles ≥5) through treatment (up to 35 cycles, ≈104 weeks); summary and comparative analys)
- Disease control rate (DCR, RECIST v1.1)(Tumor assessments every 9 weeks (±7 days); DCR assessed through 156 weeks (3 years) from first dose.)
- PFS, ORR, DOR, and DCR by iRECIST(Assessed per iRECIST at the same imaging schedule (every 9 weeks ±7 days); suspected progression requiring confirmatory imaging performed 4-8 weeks after initial PD; endpoints analyzed through 156 weeks (3 years) from first dose.)
- Disease-specific survival (DSS)(Survival status collected every 12 weeks (±2 weeks) through 156 weeks (3 years) from first dose or until death.)
- Change in Absolute Lymphocyte Count (ALC) Over Time(At scheduled study visits from first dose through 156 weeks (3 years) from first dose or end of treatment, whichever occurs first.)
- Duration of Immune Competence (ALC ≥1,000 cells/µL)(From first dose until treatment discontinuation; duration of immune competence assessed up to 156 weeks (3 years) from first dose.)
- Duration of Response (DOR) by BICR (RECIST v1.1)(Tumor imaging at week 6 and week 12 following Cycle 1 Day 1, then every 9 weeks (±7 days) from first dose until treatment discontinuation; DOR assessed up to 156 weeks (3 years) from first dose.)
- Disease Control Rate (DCR) by BICR (RECIST v1.1)(Tumor imaging at week 6 and week 12 following Cycle 1 Day 1, then every 9 weeks (±7 days) from first dose until treatment discontinuation; DCR assessed up to 156 weeks (3 years) from first dose.)
- PFS, ORR, DOR, and DCR by BICR Using iRECIST(Tumor imaging at week 6 and week 12 following Cycle 1 Day 1, then every 9 weeks (±7 days) from first dose until treatment discontinuation; each endpoint assessed up to 156 weeks (3 years) from first dose.)
- PFS, ORR, DOR, and DCR by Investigator Assessment (RECIST v1.1 and iRECIST)(Tumor imaging at week 6 and week 12 following Cycle 1 Day 1, then every 9 weeks (±7 days) from first dose until treatment discontinuation; each endpoint assessed up to 156 weeks (3 years) from first dose.)
- Disease-specific survival (DSS)(From first dose until death due to NSCLC, with follow-up through 156 weeks (3 years) from first dose.)
- Overall survival (OS)(From first dose until death, with survival follow-up through 156 weeks (3 years) from first dose.)
- Objective Response Rate (ORR) by BICR (RECIST v1.1)(Imaging every 9 weeks (±7 days) from first dose (after initial assessments at week 6 and week 12) until treatment discontinuation; ORR assessed up to 156 weeks (3 years) from first dose.)