A novel interleukin-2 therapy combination has demonstrated promising early efficacy in patients with PD-L1-negative nonsquamous non-small cell lung cancer (NSCLC), a population known for poor response to standard immunotherapy. STK-012, an engineered α/β-IL-2 receptor biased partial agonist, combined with pembrolizumab and chemotherapy achieved a 57% overall response rate (ORR) in 21 evaluable patients in a phase 1a/1b trial.
The results are particularly noteworthy given the challenging patient population enrolled in the study. Among 17 patients with PD-L1 expression in less than 1% of tumor cells, the combination produced a 53% response rate, substantially exceeding the expected ORR range of 23% to 32% with standard pembrolizumab and chemotherapy alone.
Strong Performance in Immune-Resistant Populations
The STK-012 combination showed exceptional activity in patients with known immune resistance features. Among 10 patients with one or more immune resistance mutations, the ORR reached 60%, far surpassing the historical ORR range of 7% to 33% with pembrolizumab and chemotherapy alone. The therapy demonstrated even more impressive results in patients with mucinous histology, achieving an 80% response rate in 5 patients compared to the historical ORR of 21% in this population with standard treatment.
"Despite advances that have improved outcomes for [patients with] newly diagnosed lung cancer, a significant unmet need persists—most notably among PD-L1–negative nonsquamous NSCLC and tumors with immune resistance mutations," stated study investigator Adam J. Schoenfeld, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center. "Early STK-012 [plus standard-of-care pembrolizumab/chemotherapy] data in these hard-to-treat populations are encouraging; if replicated in larger cohorts, they could reshape the treatment landscape."
Favorable Safety Profile
The safety profile of the STK-012 combination appeared manageable across 25 evaluable patients. The most frequent treatment-emergent adverse effects included nausea, fatigue, and rash or dermatitis, all described as manageable and reversible. Notably, there were no treatment discontinuations of STK-012 due to treatment-related adverse events.
Investigators reported no treatment-related hypotension, capillary leak syndrome, or cytokine release syndrome—toxicities commonly associated with traditional IL-2 therapies. This improved safety profile stems from STK-012's engineered selectivity for antigen-activated T cells while avoiding broad stimulation of other lymphocytes such as natural killer cells, which are associated with IL-2 toxicity.
Mechanism and Trial Design
STK-012 was specifically engineered to selectively stimulate antigen-activated T cells, facilitating potent anti-tumor activity without stimulating other lymphocytes that may contribute to IL-2-associated toxicity. This selective mechanism represents a departure from traditional IL-2 approaches.
The phase 1a portion of the first-in-human trial evaluated STK-012 as monotherapy and in combination with other agents through dose escalation in patients with selected solid tumors. The phase 1b portion assessed STK-012 at the recommended phase 2 dose, either alone or in combination.
Primary endpoints included adverse events and dose-limiting toxicities, while secondary endpoints encompassed overall response rate, progression-free survival, overall survival, immunogenicity, and maximum concentration of STK-012.
Advancing to Phase 2
Based on these encouraging results, Synthekine has initiated SYNERGY-101, a global randomized Phase 2 study comparing standard of care with and without STK-012 in PD-L1 negative nonsquamous NSCLC.
"We set a high bar by enrolling [patients with] first-line PD-L1–negative nonsquamous NSCLC—a population marked by intrinsic immune resistance where standard-of-care therapies have consistently underperformed," said Naiyer Rizvi, MD, chief medical officer at Synthekine. "The high response rate observed with STK-012 in this setting is particularly encouraging and supports its potential to convert immune desert tumors into responders when added to [standard of care]. These compelling data position STK-012 for advancement into a randomized phase 2 trial."
Detailed results from the phase 1a/1b trial were presented as a late-breaking oral presentation at the 2025 Society for Immunotherapy of Cancer Annual Meeting.
