Novel IL-2 Therapy Combo Yields Initial Responses in Nonsquamous NSCLC

"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," according to study investigator Adam J. Schoenfeld, MD.

Combining STK-012, a novel α/β-IL-2 receptor biased partial agonist, with pembrolizumab (Keytruda) and chemotherapy produced early responses in a small cohort of patients with frontline, PD-L1–negative, nonsquamous non–small cell lung cancer (NSCLC), according to a press release on findings from a phase 1a/1b trial (NCT05098132).1

Among 21 evaluable patients, the STK-012 combination produced an overall response rate (ORR) of 57%. Additionally, the ORR was 53% in 17 patients with PD-L1 expression in less than 1% of tumor cells, which exceeds the expected ORR range of 23% to 32% with standard pembrolizumab/chemotherapy.

Among 10 patients with 1 or more immune resistance mutations, data showed an ORR of 60%; this exceeds the historical ORR range of 7% to 33% with pembrolizumab/chemotherapy alone. The ORR was 80% in 5 patients with mucinous histology, surpassing the historical ORR of 21% in this population with standard pembrolizumab/chemotherapy.

The most frequent treatment-emergent adverse effects (TEAEs) among 25 evaluable patients included manageable and reversible nausea, fatigue, and rash or dermatitis. There were no treatment discontinuations of STK-012 due to TRAEs. Investigators also reported no treatment-related hypotension, capillary leak syndrome, or cytokine release syndrome.

Investigators will share detailed results from the phase 1a/1b trial in a late-breaking oral presentation at the 2025 Society for Immunotherapy of Cancer Annual Meeting.

“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,” study investigator Adam J. Schoenfeld, MD, a thoracic medical oncologist and cellular therapist & early drug development specialist at Memorial Sloan Kettering Cancer Center, stated in the press release.1 “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.”

Developers engineered STK-012 to selectively stimulate antigen-activated T cells, facilitating potent anti-tumor activity without stimulating other lymphocytes like natural killer cells, which may confer IL-2–associated toxicity.

The phase 1a portion of this first-in-human trial was designed to evaluate STK-012 as monotherapy and in combination with other agents as part of a dose-escalation scheme among patients with selected solid tumors.2 In the phase 1b portion of the study, investigators assessed STK-012 administered alone or with other agents at the recommended phase 2 dose.

The trial’s primary end points included AEs and dose-limiting toxicities. Secondary end points included ORR, progression-free survival, overall survival, immunogenicity, and the maximum concentration of STK-012.

Patients 18 years and older with selected tumor types and progression on, intolerance of, or refusal of prior standard therapy were eligible for enrollment on the STK-012 monotherapy dose-escalation and dose-expansion portions, as well as the combination therapy dose-escalation portion. Enrollment on the STK-012 dose-expansion combination therapy portion of the trial specifically required PD-L1–negative NSCLC and no prior treatment for metastatic disease.

Those with systemic anti-cancer treatment within 3 weeks of beginning study treatment or radiotherapy within 2 weeks of initiating treatment were ineligible for enrollment on the trial. Having prior treatment with IL-2–based or IL-15–based cytokine therapy was grounds for exclusion from the trial. Additionally, patients with NSCLC must not have had any known genetic aberrations that could be targeted with approved therapies.

“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. 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,” Naiyer Rizvi, MD, chief medical officer at Synthekine, the developer of STK-012, concluded.1

References

1. Synthekine presents positive initial results from phase 1a/1b clinical trial of STK-012 plus pembrolizumab and chemotherapy in first-line, PD-L1 negative nonsquamous non-small cell lung cancer. News release. Synthekine Inc. November 7, 2025. Accessed November 7, 2025. https://tinyurl.com/4fhhpk6z
2. STK-012 monotherapy and in combination therapy in patients with solid tumors. ClinicalTrials.gov. Updated August 7, 2025. Accessed November 7, 2025. https://tinyurl.com/2dumrhay