STK-012 Plus Pembrolizumab, Chemo Demonstrate Safety and Efficacy in NSCLC

Data from a phase 1a/1b clinical trial (NCT05098132) show that STK-012 in combination with standard-of-care pembrolizumab (Keytruda) and chemotherapy yields favorable safety and efficacy in patients with first-line, PD-L1–negative nonsquamous non–small cell lung cancer (NSCLC).¹ 

The data was presented by Adam J. Schoenfeld, MD, Memorial Sloan Kettering Cancer Center, at the 2025 Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, MD, on Saturday, November 8, 2025.

The efficacy-evaluable patients (n = 21) included a highly immune resistant population with 17 patients who were PD-L1 < 1% and 4 patients that were PD-L1 ≥1%. Of the 21 patients, 15 also had loss-of-function tumor suppressor gene mutations (TSG) or mucinous histology.²

Of the total patients, the overall response rate (ORR) was 57%, and the disease control rate (DCR) was 90%. Of patients who were PD-L1 < 1%, ORR was 53% and the DCR was 94%. The minimum follow-up was 1.3 months as of the efficacy cut-off date of September 15, 2025. Of the total patients, 10 had a ≥1 TSG (STK11, KEAP1, SMARCA4), with an ORR of 60% and DCR of 80%. Partial response was observed in 3 patients with STK11/KEAP1 co-variants.

“We set a high bar by enrolling 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 of Synthekine, sponsor of the study, in a news release.¹ “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]. STK-012’s unique selectivity for antigen-activated T cells, while sparing bystander lymphocytes, enables delivery of the critical IL-2 signal without the associated toxicity. These compelling data position STK-012 for advancement into a randomized phase 2 trial.”

The most frequent any-grade treatment related adverse events (AEs) were nausea (44%), fatigue (40%), and rash/dermatitis (40%). One grade 4 AE of neutropenia was observed. There were no grade 5 AEs, dose-limiting toxicities, or discontinuations observed due to AEs.²

As of the safety cut-off date of August 8, 2025, 25 patients were treated with 2.25 mg subcutaneously of STK-012 every 3 weeks, plus standard-of-care pembrolizumab and chemotherapy across phase 1a (n = 10), and phase 1b (n = 15).

The primary end point is safety, and the secondary end points include ORR.

“Despite advances that have improved outcomes for newly diagnosed lung cancer patients, a significant unmet need persists–most notably among PD-L1 negative nonsquamous NSCLC and tumors with immune resistance mutations,” said Schoenfeld in a news release.¹ “Early STK-012 + [standard-of-care pembrolizumab and chemotherapy] data in these hard to treat populations are encouraging; if replicated in larger cohorts, they could reshape the treatment landscape.”

The phase 2 portion of the trial, SYNERGY-101, is recruiting patients with nonsquamous NSCLC who have stage 3b/3c of 4 disease and are treatment naive.

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. Published November 7, 2025. Accessed November 11, 2025. https://tinyurl.com/vzekk88d 

2. Schoenfeld A, Garon E, Chiang A, et al. 1345 Initial phase 1a/1b results of the STK-012, an α/β IL-2 receptor biased partial agonist, with pembrolizumab, pemetrexed, and carboplatin in 1L PD-L1 negative non-squamous NSCLC. JImmunoTherCanc.2025;13. doi:10.1136/jitc-2025-SITC2025.1345