Abstract 6740: Selective immune activation of antigen activated T cells with STK-012, an a/b IL-2 receptor biased partial agonist, with pembrolizumab and chemotherapy in 1L PD-L1 negative non-squamous NSCLC

Abstract Background: 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. In this phase 1a/b study, STK-012 is combined with standard of care pembrolizumab + chemotherapy (PCT) in 1L PD-L1 negative NSQ NSCLC where PCT alone has poor outcomes (ORR 32% and median PFS 6.2 months). Methods: 1L NSQ NSCLC subjects received STK-012 SC Q3W + PCT. Serial blood samples were analyzed for changes in cytokines in chemoluminescence assays, T cell proliferation and activation markers were analyzed in spectral flow cytometry, and T cell clonality was analyzed by TCR sequencing. Data are shown for a cohort of 22 efficacy-evaluable 1L NSCLC subjects (N=18 PD-L11%, N=4 PD-L1=1%) which was enriched for loss-of-function tumor suppressor gene (LoF TSG) mutations (n=11; STK11, KEAP1, SMARCA4) or mucinous histology (n=5) associated with a “cold” TME and primary immune resistance. Results: STK-012 + PCT demonstrated an ORR of 55% in all efficacy evaluable patients; 50% in patients with PD-L11% tumors; 55% in LoF TSG mutations; and 80% in mucinous histology. STK-012 + PCT induced sustained proliferation of CD8+ and CD4+ T cells (13X and 5x increase from baseline, respectively), proliferation of antigen activated T cells including PD-1+ CD8+ (14X) and 4-1BB+ CD8+ (14X) and re-invigoration and proliferation of previously exhausted CD39+ (11x) and TIM3+ (18x) CD8+ T cells. After the first cycle, 3.35% of the total T cell repertoire were T cell clones which were newly detected or expanded 10x (n=12). STK-012 + PCT induced key cytokines IFNγ and IL-18 characterizing an activated CD8+ T cell response and increased IP-10 which is associated with enhanced T cell trafficking into tumor tissues (13x,14x and 23x mean increase from baseline, respectively). Sustained elevation of cytokines across treatment cycles (IFNγ median peak of 71, 95, 96 pg/mL in C1, C2 and C6) was observed, supportive of the emerging durability of the combination. Induction of cytokines TNFα and IL-6 was limited (median peak 4, 6 pg/mL), consistent with limited activation of naïve T cells and NK cells and the lack of capillary leak syndrome with STK-012. Conclusions: STK-012 + PCT led to robust cytokine induction, proliferation and expansion of antigen activated T cells, proliferation of previously exhausted T cells, and remodeling of the T cell repertoire. The addition of STK-012 to PCT has the potential to overcome resistance in immune excluded populations including PD-L11% tumors, LoF TSG mutations and mucinous histology. A global, randomized Phase 2 study, SYNERGY-101, of STK-012 + PCT vs. PCT in 1L PD-L11% NSQ NSCLC is ongoing (NCT05098132). Citation Format: Salman Punekar, Adam Jacob Schoenfeld, Edward B. Garon, So Yeon Kim, Kai He, Jennifer Marks, Brian S. Henick, Stephen V. Liu, Nagashree Seetharamu, Alexander Spira, Justin Gainor, Tim Larson, Ticiana A. Leal, Cameron Oswalt, Benjamin Izar, Alize Marangoz-Stager, Vic Danh, Grace Lunardi, Krystle Bach, Naiyer A. Rizvi, Alex Azrilevich, Anita Mehta-Damani, Martin Oft. Selective immune activation of antigen activated T cells with STK-012, an a/b IL-2 receptor biased partial agonist, with pembrolizumab and chemotherapy in 1L PD-L1 negative non-squamous NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6740.