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Background Standard of care in 1L NSQ NSCLC without actionable genetic alterations (AGAs) is chemo-immunotherapy however 1/3 of patients are PD-L1<1% and derive modest benefit (ORR 23-32%). 1 2 These PD-L1<1% tumors are enriched for loss-of-function mutations in tumor suppressor genes (TSGs) including STK11, KEAP1, SMARCA4 (ORR 7% to 33%) and mucinous subtype (ORR 21%) that contribute to immune resistance.3–5 STK-012 is a first-in-class α/β-IL-2R biased partial agonist that drives antitumor activity by selectively stimulating CD25+ antigen-activated T-cells and avoids hallmark IL-2 toxicities by sparing pleiotropic activation of lymphocytes including NK cells.Methods In Ph1a (PD-L1 unselected) and Ph1b (PD-L1<1%), subjects with treatment-naïve, stage IV NSQ NSCLC without AGAs received STK-012 subcutaneously (SC) Q3W + standard of care pembrolizumab, pemetrexed, and carboplatin (SoC). The primary endpoint is safety and secondary endpoints include ORR.Results As of 08AUG25 safety cut-off, 25 subjects were treated with STK-012 2.25 mg SC Q3W + SoC across Ph1a (N=10) and Ph1b (N=15). No CLS or CRS was observed. The most frequent treatment related AEs (TRAEs) were nausea (44% All Grade, 0% Gr3), fatigue (40% All Grade, 4% Gr3), and rash/dermatitis (40% All Grade, 16% Gr3). There was one Gr4 TRAE (ANC decrease) and no Gr5 AEs, DLTs, or discontinuations due to TRAEs.Twenty-one efficacy evaluable subjects included N=8 in Ph1a (N=4 PD-L1<1%, N=3 PD-L1 1%, N=1 PD-L1 5%) and N=13 in Ph1b (all PD-L1<1%) with minimum follow-up of 1.3 months as of 15SEP25 efficacy cut-off. In all 21 subjects, the ORR and DCR was 57% and 90%. In the PD-L1<1% group (n=17), the ORR and DCR was 53% and 94%. In N=10 with ≥1 TSG mutation (STK11, KEAP1, SMARCA4), the ORR and DCR was 60% and 80%, with PR in all 3 subjects with STK11/KEAP1 co-variants. In N=5 with mucinous subtype, the ORR and DCR was 80% and 100%.Conclusions These are initial Phase 1a/b results of STK-012 + SoC in 1L NSQ NSCLC. STK-012 was well tolerated in combination with SoC and demonstrated a 57% ORR in highly immune resistant 1L NSQ NSCLC populations. This included subjects with PD-L1 <1% tumors (ORR 53%), STK11, KEAP1, SMARCA4 mutations (ORR 60%), and mucinous subtype (ORR 80%). Preliminary safety and efficacy data combining STK-012 with SoC are encouraging in difficult-to-treat 1L NSQ NSCLC populations. A global, randomized Phase 2 is ongoing to evaluate STK-012 + SoC vs SoC in 1L PD-L1<1% NSQ NSCLC (NCT05098132).Trial Registration NCT05098132References Gadgeel S, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020 May 10;38(14):1505–1517.Makharadze T, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in advanced NSCLC: 2-year follow-up from the phase 3 EMPOWER-lung 3 part 2 trial. J Thorac Oncol. 2023 Jun;18(6):755–768.Skoulidis F, et al. CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors. Nature. 2024 Nov;635(8038):462–471.Alessi JV, et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced NSCLC. J Thorac Oncol. 2023 Jun;18(6):731–743.Di Federico A, et al. Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors. Ann Oncol. 2025 Mar;36(3):297–308.Ethics Approval This study, STK-012-101, obtained institutional review board approvals at every participating site (see sites below). All participants gave informed consent before taking part. Memorial Sloan Kettering Cancer Center, New York, NY University of California, Los Angeles, Los Angeles, CA Yale Cancer Center, New Haven, CT The James Cancer Center, Ohio State University, Columbus, OH Dana Farber Cancer Institute, Boston, MA, Columbia University Irving Medical Center, New York, NY, Georgetown Lombardi Cancer Center, Washington, DC Northwell Health Center for Advanced Medicine NEXT Oncology Virginia, Fairfax, VA, HealthPartners, St. Paul, Minnesota Massachusetts General Hospital, Boston, MA NYU Grossman School of Medicine, New York, NY Duke Cancer Institute, Durham, NC Emory University, Atlanta, GA Baptist Cancer Center, Bartlett, Tennessee Northwest Medical Specialists, Tacoma, WA Hoag Family Cancer Institute, Newport Beach, CA Beverly Hills Cancer Center, Los Angeles, CA Providence Crosson Cancer Center, Fullerton, CA The University of Arizona Cancer Center, Tuscon, AZ Renovatio Clinical, Houston, TX Oncology Consultants, Houston, TX