NSCLC (Advanced Non-small Cell Lung Cancer), Metastatic NSCLC
Conditions
Keywords
non-small cell lung cancer, NSCLC, nogapendekin alfa inbakicept, NAI, ANKTIVA, IL-15 agonist, chemoimmunotherapy, pembrolizumab, platinum chemotherapy, pemetrexed, paclitaxel, nab-paclitaxel, progression-free survival, immunotherapy, molecular profiling
Brief summary
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.
Detailed description
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.
Interventions
DRUGDrug: Nogapendekin alfa inbakicept (NAI)
1.2 mg SC q3 weeks (15 μg/kg SC if ≥100 kg), up to 35 cycles.
DRUGPembrolizumab
200 mg IV q3 weeks.
Cisplatin 75 mg/m² IV q3w OR carboplatin AUC 5-6 IV q3w (per label).
DRUGNab-paclitaxel (squamous) OR Pemetrexed (nonsquamous)
Squamous: nab-paclitaxel 100 mg/m² IV on Days 1, 8, 15 of cycles 1-4. Nonsquamous: pemetrexed 500 mg/m² IV Day 1 q3w, up to 35 cycles.
DRUGNab-paclitaxel OR Paclitaxel OR Docetaxel (squamous)
Nab-paclitaxel 100 mg/m² IV D1, 8, 15 or paclitaxel 175 mg/m² IV D1 or docetaxel 75 mg/m² IV D1 (per RHA label/local guidelines) for cycles 1-4 in squamous participants.
DRUGPemetrexed (nonsquamous)
First-line standard-of-care chemoimmunotherapy per pembrolizumab + platinum doublet regimens, histology-specific.
Sponsors
ImmunityBio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants are randomized 1:1 to two parallel treatment arms (NAI + pembrolizumab + platinum-based chemotherapy vs pembrolizumab + platinum-based chemotherapy alone). Randomization is stratified by tumor histology (squamous vs nonsquamous NSCLC) and PD-L1 tumor proportion score (TPS ≥1% vs \<1%, with "unknown" PD-L1 classified as \<1%). Each participant remains on the assigned arm throughout the study; there is no planned crossover.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) 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; 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | From first dose until death, with survival follow-up through 156 weeks (3 years) from first dose. | Time from randomization to death from any cause. |
| 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. | ORR is the proportion of participants with a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 by BICR. |
| 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. | Change from baseline in absolute lymphocyte count over time by treatment group. |
| 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 immune competence, defined as the time during treatment that ALC remains ≥1,000 cells/µL. |
| 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. | For participants with a confirmed CR or PR per RECIST v1.1 by BICR, DOR is defined as the time from the date of first documented response (CR or PR) to the date of disease progression per RECIST v1.1 by BICR or death from any cause, whichever occurs first. |
| 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. | DCR is the proportion of participants with CR, PR, or stable disease (SD) lasting at least 2 months per RECIST v1.1 as assessed by BICR. |
| 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 assessed per immune RECIST (iRECIST) as determined by BICR, using the same definitions as for RECIST v1.1 but applying iRECIST rules. |
| 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. | PFS, ORR, DOR, and DCR per RECIST v1.1 and iRECIST as assessed by site Investigators, using the same definitions as for BICR. |
| Disease-specific survival (DSS) | From first dose until death due to NSCLC, with follow-up through 156 weeks (3 years) from first dose. | DSS is defined as the time from randomization to death due to NSCLC. Deaths from other causes are censored at the date of death. |
Contacts
CONTACTJoseph Ward
CONTACTTamra Madenwald
Outcome results
None listed