Efficacy outcomes in first-line (1L) non–small cell lung cancer (NSCLC) with maintenance of immune competence: QUILT-2.023 randomized phase 3 study of IL-15R agonist nogapendekin alfa inbakicept (NAI) with checkpoint inhibitor (CPI) ± chemotherapy.

8588 Background: Baseline and treatment-induced lymphopenia are adverse prognostic factors in NSCLC and may limit CPI durability. CPI and chemo-IO can reduce peripheral absolute lymphocyte counts (ALC) over time. NAI expands NK and effector/memory T cells and increases ALC, a biological marker of immune competence. In QUILT-3.055 (≥2L NSCLC after CPI failure), sustained ALC increases were associated with prolonged overall survival (OS). QUILT-2.023 tests whether preserving immune competence with NAI improves response rate, progression-free survival (PFS), and OS when added to 1L standards of care (SOC). To inform the design of the ongoing registrational-intent QUILT-2.023 study, results from 98 enrolled subjects were unblinded for exploratory analysis. Methods: QUILT-2.023 (NCT03520686) is an ongoing randomized multicohort phase 3 trial in untreated advanced/metastatic NSCLC (ECOG 0–1; squamous or nonsquamous). Cohort A (PD-L1 TPS ≥1%) was randomized 1:1 to CPI+NAI vs CPI; ALC over time was analyzed using a mixed model for repeated measures. The primary efficacy endpoint was PFS with hierarchical testing (TPS ≥50% then TPS ≥1%). PFS was analyzed at 8 months to evaluate the temporal relationship of ALC through 27 weeks of CPI alone versus CPI+NAI. Cohorts B (squamous) and C (nonsquamous), with any PD-L1 TPS, were randomized 1:1 to SOC platinum chemo-IO ± NAI; pooled Cohort B+C efficacy (ORR, DCR, PFS, OS) was assessed per RECIST v1.1. Results: Cohort A (N = 63): baseline ALC was comparable between arms; CPI+NAI showed significant, sustained ALC increase vs CPI alone over 27 weeks (P = 0.0065), regardless of PD-L1 TPS. In TPS ≥50% (N = 45), ALC over time significantly improved with CPI+NAI vs CPI alone (P = 0.0420). Correlating with this increased ALC, PFS in the CPI+NAI arm demonstrated median PFS of 7.0 vs 2.2 months (HR 0.40; 95% CI 0.17–0.94; p = 0.0298). Grade ≥3 CPI-related TEAEs occurred in 16% of subjects in both arms. In pooled Cohorts B+C (ITT N = 36), ORR (CR+PR) was 56% with chemo-IO+NAI vs 33% chemo-IO alone; DCR was 83% vs 78%. Median PFS was 18.9 vs 10.6 months (HR 0.48; 95% CI 0.19–1.23; p = 0.1192) and median OS reached significance of 34.7 vs 20.2 months (HR 0.38; 95% CI 0.15–0.98; p = 0.0394). Conclusions: Adding NAI to CPI-based SOC increased ALC and improved PFS in PD-L1 TPS ≥50% 1L NSCLC, with manageable safety. In platinum chemo-IO cohorts, pooled efficacy shows improved response and a significant OS signal, consistent with immune-competence preservation as a modifiable determinant of CPI durability. Enrollment and follow-up are ongoing. These interim findings are consistent with the single-arm trial QUILT-3.055 and support continued accrual in QUILT-2.023 and ResQ201A (NCT06745908), randomized NAI+CPI studies across 1L and ≥2L advanced NSCLC. Clinical trial information: NCT03520686 .