ResQ1010-NSCLC: NAI + Chemoimmunotherapy vs Chemoimmunotherapy for First-Line Advanced/Metastatic NSCLC

This randomized, open-label Phase 3 trial evaluates whether adding nogapendekin alfa inbakicept (NAI), an IL-15 receptor agonist that stimulates NK and T cells and preserves/augments lymphocyte counts, to current first-line chemoimmunotherapy improves progression-free survival (PFS) in adults with untreated, advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations. Participants are randomized 1:1 to standard first-line chemoimmunotherapy containing an approved checkpoint inhibitor (pembrolizumab 200 mg IV q3w) plus platinum-based chemotherapy and histology-specific agent (squamous: nab-paclitaxel 100 mg/m2 IV or paclitaxel 175 mg/m2 IV; nonsquamous: pemetrexed 500 mg/m2 IV) with or without NAI. NAI is given subcutaneously Day 1 of each 3-week cycle at 1.2 mg SC flat dose (participants ≥100 kg receive 15 µg/kg SC); preferred injection site is the lower abdominal quadrants, alternating sides. Treatment includes up to 4 cycles of induction followed by maintenance therapy for cycles ≥5 and may continue up to \~35 cycles (≈2 years) unless there is unacceptable toxicity, withdrawal of consent, or confirmed progression per protocol.

Key design features include stratified randomization by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and PD-L1 tumor proportion score (≥1% vs 0); tumor imaging by CT/MRI every 9 weeks (±7 days) after Cycle 1 Day 1 with confirmatory imaging 4-8 weeks for suspected progression to rule out pseudoprogression; and centralized oversight by an Independent Data Monitoring Committee (IDMC). The primary endpoint is PFS by RECIST v1.1. Key secondary endpoints (hierarchical testing) include overall survival (OS) and objective response rate (ORR). Other secondary endpoints include change in absolute lymphocyte count (ALC) over time, duration of immune competence (on-treatment ALC ≥1,000 cells/µL), duration of response, disease control rate, iRECIST analyses, disease-specific survival, and safety (AEs graded per NCI CTCAE v6.0).

An interim PFS analysis will be performed at \~50% of planned PFS events using an alpha-spending approach (0.1% interim / 4.9% final two-sided for PFS). The study includes a predefined "promising-zone" adaptive sample-size increase (CPmin = 37%) that may increase enrollment up to a maximum of 960 participants to restore target power if interim results are promising; futility stopping rules apply (conditional power \<15%). Safety monitoring includes routine AE/SAE collection, labs, ECGs, extended follow-up for immune-related AEs (90 days after last dose), and prompt SAE reporting to Sponsor Drug Safety.

Exploratory objectives include molecular profiling (tumor tissue and serial blood) and digital whole-slide image analyses to identify biomarkers correlated with clinical outcomes. Participants will be followed for survival through at least 3 years (156 weeks) from first dose; Sponsor may extend follow-up at its discretion.