Sponsor decision

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.

Inclusion Criteria:

• 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 0-1.
• At least one measurable lesion per RECIST v1.1.
• Able to attend visits and follow-up.
• Contraception requirements for women of childbearing potential and nonsterile males, with 7 month post-last-dose window.

Exclusion Criteria:

• 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.

De-identified participant-level data to be shared include: unique study ID; demographics and baseline characteristics (age, sex, ECOG, histology, PD-L1, AGA status); treatment assignment and exposure (dates offset, doses, modifications); efficacy outcomes and dates (tumor measurements, RECIST/iRECIST responses, PFS, OS, DOR, DCR); safety data (AEs/SAEs with MedDRA codes, CTCAE grade, relatedness); lab results, vitals/ECGs, concomitant meds; processed biomarker datasets and derived pathology/image features. Raw direct identifiers and physical specimens require separate agreements.

Start date: Data will be made available within 6 months after primary study results are published and any required regulatory review is complete.

End date: Data access will be provided for 5 years from the start date.

Qualified researchers with approved proposals and ethics approval may access de-identified IPD (participant IDs, demographics, treatment/exposure, efficacy/safety outcomes, labs, processed biomarker and derived imaging data) and supporting documents (protocol, SAP, data dictionary) after signing a data use agreement. Data are provided via a secure controlled-access platform; requests are reviewed by the Sponsor.