Phase 3 Study of Nogapendekin Alfa Inbakicept Plus Standard of Care vs Standard of Care in First-Line Advanced or Metastatic NSCLC

Overview

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.

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.

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