Synthekine Unveils Encouraging Early Clinical Results for STK-012 in Combination Therapy for First-Line PD-L1–Negative Non-Squamous NSCLC at SITC 2025
Synthekine Inc., a biotechnology company advancing a new generation of engineered cytokine therapeutics, released promising initial findings from its Phase 1a/1b clinical trial evaluating STK-012 administered alongside pembrolizumab and standard chemotherapy in patients with previously untreated, PD-L1–negative nonsquamous non-small cell lung cancer (NSCLC). The results mark a meaningful step forward in a patient population historically characterized by profound resistance to immune-based therapies and poor clinical outcomes.
Data from this ongoing study will be highlighted during a late-breaking oral presentation at the 2025 Society for Immunotherapy of Cancer (SITC) Annual Meeting on November 8. The presentation will be delivered by lead investigator Adam J. Schoenfeld, M.D., from Memorial Sloan Kettering Cancer Center (MSKCC), in National Harbor, Maryland.
STK-012: A Novel IL-2 Pathway–Focused Cytokine Therapeutic
STK-012 is a first-in-class engineered cytokine designed as an α/β IL-2 receptor biased partial agonist. Unlike conventional IL-2–based agents, which broadly activate multiple lymphocyte subsets and are often limited by toxicities driven by nonspecific activation, STK-012 was deliberately engineered to selectively stimulate antigen-activated T cells. These T cells are widely recognized as central drivers of anti-tumor response.
Traditional IL-2 therapies can trigger broad immune activation, including stimulation of natural killer (NK) cells and non-tumor-specific lymphocytes, which can lead to elevated toxicity such as capillary leak syndrome or severe systemic inflammatory reactions. STK-012’s tailored receptor selectivity aims to reduce these risks by restricting signaling to tumor-specific T cell populations. This design intends to enhance efficacy while alleviating safety challenges that have historically limited IL-2–based approaches.
By focusing activation on the immune cells most likely to initiate targeted tumor destruction, STK-012 aspires to reshape how cytokine modulation is integrated into cancer therapy. Its development underscores a broader translational trend across oncology: pairing rational immune engineering with established therapeutic backbones to break through immune resistance barriers.
A Challenging Patient Population: First-Line PD-L1–Negative Non-Squamous NSCLC
NSCLC accounts for approximately 85% of lung cancer cases, and nonsquamous histology—including adenocarcinoma—is the most common subtype. For newly diagnosed patients, standard front-line therapy typically consists of platinum-based chemotherapy combined with PD-1/PD-L1 checkpoint blockade.
Yet despite progress over the past decade, PD-L1–negative tumors remain an area of significant unmet medical need. These tumors often display immunologically “cold” tumor microenvironments with low T cell infiltration, rendering them less responsive to checkpoint inhibitors. First-line response rates for this population remain modest even with pembrolizumab chemotherapy combinations.
Clinical outcomes are further diminished when the disease features genomic markers associated with immune resistance, including loss-of-function (LoF) mutations affecting STK11, KEAP1, or SMARCA4 tumor suppressor genes. These alterations are strongly correlated with reduced responsiveness to immunotherapy and poorer survival. Another negative prognostic feature—mucinous histology—is also known to confer resistance to immunotherapy and cytotoxic chemotherapy alike.
Consequently, first-line treatment choices for PD-L1–negative nonsquamous NSCLC patients with such high-risk features are limited, and innovative therapeutic solutions are urgently needed.
Phase 1a/1b Overview: Trial Design and Treatment Regimen
In this early-stage study, Synthekine is evaluating STK-012 delivered at a dose of 2.25 mg via subcutaneous injection every three weeks, paired with standard‐of‐care pembrolizumab, pemetrexed, and carboplatin—the frontline therapeutic backbone for nonsquamous NSCLC irrespective of PD-L1 status.
The Synthekine Phase 1a/1b trial aims to characterize safety, tolerability, dose optimization, and preliminary anti-tumor activity. Twenty-five patients have been treated to date, forming the safety evaluable population; 21 of these were considered efficacy evaluable.
The study population was heavily enriched for patients expected to respond poorly to immunotherapy. Among the 21 efficacy evaluable individuals:
- 17 (81%) were PD-L1 negative (<1%)
- 4 (19%) were PD-L1 low–positive (≥1%), including 3 with 1% expression and 1 with 5% expression
Notably, 15 of 21 (71%) patients exhibited additional resistance-linked features, having LoF mutations in STK11, KEAP1, and/or SMARCA4, or mucinous tumor histology. These markers typically correlate with suboptimal response to standard therapy and reduced clinical benefit.
The fact that this population was heavily skewed toward immune-resistant disease highlights the level of therapeutic challenge—and the potential significance of STK-012’s early clinical signals.
Efficacy Results Demonstrate Encouraging Anti-Tumor Activity
Early clinical data demonstrate that the combination of STK-012 with pembrolizumab and chemotherapy (PCT) achieves clinically meaningful response rates in a patient group where standard therapies have historically produced limited benefit.
Overall Efficacy
Among 21 efficacy evaluable subjects, the objective response rate (ORR) was 57%—notably higher than the expected 23–32% ORR for PD-L1–negative or low-expressing patients receiving SoC pembrolizumab with chemotherapy. Responses were observed across both PD-L1–negative and PD-L1–low subgroups.
Outcomes in PD-L1–Negative Patients
In the 17 PD-L1–negative (<1%) patients, the ORR reached 53%—again significantly exceeding typical response levels observed with standard therapy alone. The ORR in this subgroup provides a compelling indication that STK-012 may help overcome one of the most entrenched resistance mechanisms in lung cancer immunotherapy.
Outcomes in Additional High-Risk Subgroups
A striking trend was observed among patients harboring tumor suppressor gene LoF mutations—long recognized as biomarkers of immune resistance.
- 10 patients with STK11, KEAP1, or SMARCA4 LoF mutations:
ORR = 60%
This notably contrasts with historical response ranges of ~7–33% in similar populations treated with SoC therapy.
STK-012 also demonstrated pronounced activity among patients with mucinous lung cancer, a rare histology associated with particularly low response rates.
- 5 mucinous-histology patients:
ORR = 80%, strongly outperforming the historical ~21% ORR benchmark for SoC.
These Synthekine findings suggest that STK-012’s mechanism—selective targeting of antigen-activated T cells—may provide immune stimulation where checkpoint inhibitors alone fall short.
Although median duration of response, median progression-free survival, and overall survival data remain immature, the observed ORR in this heavily resistant population supports continued drug development.
Safety Profile Indicates Good Tolerability
The tolerability profile of STK-012 in combination with pembrolizumab plus chemotherapy has thus far been favorable.
Among 25 safety evaluable subjects, the most commonly observed treatment-related adverse events (TRAEs) included:
- Nausea
- Fatigue
- Rash or dermatitis
These TRAEs were generally manageable and reversible. No patient discontinued study treatment due to toxicity associated with STK-012. Importantly, adverse events commonly linked to systemic IL-2 pathway activation—such as hypotension, capillary leak syndrome, or cytokine release syndrome—were not observed.
These Synthekine early safety findings reinforce the rationale behind STK-012’s receptor-biased engineering: maximize anti-tumor immune activation while minimizing toxicities traditionally associated with cytokine therapies.
Expert Commentary Highlights High-Bar Clinical Design and Promise of Results
According to Synthekine’s Chief Medical Officer, Naiyer Rizvi, M.D., the company intentionally selected a patient cohort marked by profound immune resistance to validate STK-012’s ability to enhance response to checkpoint blockade. Rizvi explained that standard-of-care therapy in this population has been unable to consistently produce meaningful outcomes, emphasizing the significance of the observed response rates.
He added that STK-012’s selective targeting of antigen-activated T cells enables delivery of the IL-2 signal to the most relevant immune subsets while sparing Synthekine bystander immune populations. This distinction could underpin its emerging efficacy and manageable safety profile.
The encouraging findings, he noted, offer a strong developmental path forward and support advancing STK-012 into a randomized Phase 2 trial.
Lead presenter Dr. Adam Schoenfeld of MSKCC echoed this sentiment, noting that PD-L1–negative nonsquamous NSCLC remains a formidable clinical challenge. He stressed that early results showing efficacy in both PD-L1–negative tumors and tumors carrying LoF mutations—two Synthekine scenarios resistant to current therapies—could mark a turning point if validated in larger studies.
Late-Breaking Presentation at SITC 2025
The Phase 1a/1b data are being showcased as part of a prestigious late-breaking oral abstract at SITC 2025:
- Abstract Title:
“Initial Phase 1a/1b Results of STK-012, an α/β IL-2 Receptor Biased Partial Agonist, with Pembrolizumab, Pemetrexed, and Carboplatin in 1L PD-L1 Negative Non-Squamous NSCLC” - Abstract Number: 1345
- Presentation Time:
Saturday, November 8, 2:00 PM ET - Location:
Potomac Ballroom, Gaylord National Resort and Convention Center
Following the SITC session, Synthekine plans to make the slide deck publicly available via its website. Prospective investigators and clinical researchers can also find detailed study information on ClinicalTrials.gov (NCT05098132).
Path Toward Phase 2 Development
The biological construct of STK-012 and the strength of these early efficacy signals strengthen confidence in the drug’s potential to address unmet needs in first-line NSCLC, particularly among PD-L1–negative and genetically resistant subsets. A Synthekine randomized Phase 2 study is being prioritized to Synthekine further assess the therapy’s performance and quantify clinical benefit across broader treatment settings.
Future development plans will likely focus on:
- Better defining optimal dosing strategies
- Assessing durability of response
- Evaluating survival endpoints
- Potentially expanding investigation into other tumor types where immune resistance is common
If validated, STK-012 could Synthekine establish a new foundation for IL-2–based cytokine therapies as part of first-line combination regimens for NSCLC.
Synthekine’s STK-012 represents an emerging generation of rationally engineered cytokine therapies designed to overcome resistance barriers in solid tumors. In this early Phase 1a/1b trial, STK-012 combined with pembrolizumab and chemotherapy produced encouraging clinical activity and a favorable safety profile in a highly Synthekine challenging patient population dominated by PD-L1–negative disease and tumor suppressor gene mutations.
The ORR improvements over historical benchmarks, coupled with manageable toxicity, suggest that targeted IL-2 pathway engagement may play a meaningful role in enhancing immune responsiveness in NSCLC. These initial findings justify continued clinical development and set the stage for more definitive evaluation in upcoming Phase 2 studies.
With further validation, STK-012 may emerge as a Synthekine valuable option in reshaping the treatment paradigm for PD-L1–negative nonsquamous NSCLC—offering new hope for patients with few effective alternatives today.
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