Synthekine Showcases Updated Clinical and Translational Data Highlighting Strong STK-012 Activity in First-Line Non-Squamous NSCLC at AACR 2026
Synthekine, a clinical-stage biotechnology firm focused on engineering precision cytokine therapeutics, has reported updated clinical and translational findings for its investigational agent STK-012 in combination with pembrolizumab, chemotherapy agents pemetrexed and carboplatin, in the treatment of first-line PD-L1-negative, non-squamous (NSQ) non-small cell lung cancer. The data were presented at the American Association for Cancer Research Annual Meeting 2026 in San Diego, highlighting the potential of this novel immunotherapy approach to address a population of patients with historically poor outcomes.
Advancing Cytokine Engineering in Oncology
STK-012 represents a next-generation cytokine therapy designed to overcome limitations associated with traditional interleukin-2 (IL-2)–based treatments. Unlike earlier IL-2 therapies, which broadly activate multiple immune cell populations and often lead to significant toxicity, STK-012 is engineered as a first-in-class α/β IL-2 receptor–biased partial agonist. This design allows for selective activation of antigen-experienced T cells—particularly those involved in anti-tumor responses—while minimizing stimulation of other immune cells such as natural killer (NK) cells that are commonly associated with adverse effects.
This targeted mechanism is intended to enhance anti-tumor immunity while maintaining a more manageable safety profile, addressing a long-standing challenge in cytokine-based immunotherapy. The updated dataset builds on earlier findings presented at SITC 2025 and includes longer follow-up, expanded translational analyses, and new insights into durability of response, particularly in genetically defined subgroups.
Addressing an Unmet Need in PD-L1-Negative NSCLC
The majority of patients included in the study had PD-L1-negative tumors, a subgroup that has historically shown limited responsiveness to standard chemoimmunotherapy regimens. In such patients, first-line treatment with checkpoint inhibitors combined with chemotherapy typically yields objective response rates in the range of 23% to 32%. These tumors are often characterized by an “immune-cold” microenvironment, meaning they lack sufficient immune cell infiltration or activation to mount an effective anti-tumor response.
Compounding this challenge, many of these tumors harbor genetic alterations such as STK11, KEAP1, and SMARCA4 loss-of-function mutations. These mutations are associated with resistance to immunotherapy and poor clinical outcomes, making them particularly difficult to treat.
Naiyer Rizvi, Chief Medical Officer of Synthekine, emphasized the significance of these findings in this difficult-to-treat population. He noted that while chemoimmunotherapy remains the standard of care, many patients derive limited benefit, underscoring the need for new therapeutic strategies that can overcome immune resistance.
Promising Clinical Efficacy Across High-Risk Subgroups
The updated clinical data, derived from 36 efficacy-evaluable patients, demonstrate encouraging activity for STK-012 when combined with pembrolizumab and chemotherapy (commonly referred to as the PCT regimen).
In the overall study population, which included a high proportion of PD-L1-negative patients (32 out of 36), the combination achieved an objective response rate (ORR) of 50% and a disease control rate (DCR) of 97%. These results compare favorably with historical benchmarks for standard-of-care regimens in similar populations.
Even more striking results were observed in patients with high-risk genetic alterations. Among individuals with STK11, KEAP1, and/or SMARCA4 mutations (18 out of 36 patients), the combination therapy achieved a 61% ORR and a 100% DCR. Historically, response rates in this subgroup have been reported in the range of 7% to 33%, highlighting the potential of STK-012 to significantly improve outcomes.
Particularly noteworthy are the findings in the STK11/KEAP1 co-mutated subgroup, which represents approximately 10% of first-line NSQ NSCLC cases and is associated with especially poor prognosis. In this group (8 out of 36 patients), the combination therapy achieved a 50% ORR, with a median progression-free survival (PFS) of 5.5 months. At a median follow-up of 6.8 months, the median overall survival (OS) had not yet been reached, and the six-month OS rate was 88%.
These outcomes compare favorably to published benchmarks for this subgroup, where ORR typically ranges from 7% to 15%, median PFS is around three months, and median OS falls between 5.4 and 7.0 months. The durability signals observed in this study suggest that STK-012 may offer meaningful clinical benefit in a population with few effective treatment options.
Manageable Safety Profile
Safety data from 39 evaluable patients indicate that the STK-012 combination regimen was generally well tolerated. Importantly, no dose-limiting toxicities were reported, and there were no treatment discontinuations attributed to STK-012.
The most commonly observed treatment-related adverse events included rash or dermatitis (51%), nausea (51%), and fatigue (46%). These side effects were described as manageable and reversible, suggesting that the therapy can be administered safely in combination with existing standard-of-care treatments.
The favorable safety profile is particularly significant given the historical challenges associated with cytokine therapies, which have often been limited by severe toxicities. The selective mechanism of STK-012 appears to mitigate these risks while preserving therapeutic activity.
Translational Insights Support Mechanism of Action
In addition to clinical outcomes, the study included extensive translational analyses that provide biological validation for the observed efficacy. These data offer insight into how STK-012 modulates the immune system and supports anti-tumor activity.
One key finding is the sustained pharmacokinetic profile of STK-012, with a half-life of approximately 5.7 days. This allows for continuous pharmacodynamic activity throughout the three-week dosing cycle, ensuring consistent immune stimulation.
The therapy was also associated with targeted cytokine induction, characterized by robust increases in interferon-gamma (IFN-γ) and IP-10—markers of T-cell activation—while maintaining low levels of pro-inflammatory cytokines such as IL-6 and TNF-α. This pattern is consistent with selective activation of T cells rather than broad, systemic immune activation.
Further analyses demonstrated significant expansion of activated CD8+ T cells expressing 4-1BB, a marker associated with antigen-specific immune responses. Importantly, this expansion occurred without substantial increases in NK cells or regulatory T cells, which can dampen anti-tumor immunity or contribute to toxicity.
Clonal expansion of T cells was also observed, with approximately 3.5% of circulating T cells derived from newly expanded clonotypes after just one treatment cycle. Notably, greater clonal expansion was correlated with clinical response, suggesting that this metric may serve as a biomarker for treatment efficacy.
Overcoming Immune Resistance in Challenging Tumors
One of the most compelling aspects of the translational data is the evidence of immune reactivation in tumors with STK11/KEAP1 co-mutations. These tumors are typically characterized by a highly suppressive microenvironment that limits the effectiveness of immune checkpoint inhibitors.
Martin Oft, Chief Scientific Officer of Synthekine, explained that despite having a high neoantigen burden, these tumors often fail to respond to immunotherapy due to dysfunctional immune signaling. The data presented at AACR suggest that STK-012 can help overcome this barrier by restoring T-cell proliferation, reinvigorating exhausted T cells, and driving robust clonal expansion.
Specifically, the therapy increased the activity of PD-1–positive CD8+ T cells—often referred to as “exhausted” T cells—and reactivated their ability to participate in anti-tumor responses. This re-engagement of the immune system may be key to achieving meaningful clinical responses in resistant tumors.
Implications for the Future of Lung Cancer Treatment
The findings presented at AACR 2026 highlight the potential of STK-012 as a novel immunotherapeutic strategy for patients with PD-L1-negative NSCLC and other high-risk molecular subtypes. By combining targeted cytokine signaling with checkpoint inhibition and chemotherapy, the approach aims to address multiple aspects of tumor biology simultaneously.
If these results are confirmed in larger, later-stage trials, STK-012 could represent a significant advancement in the treatment of lung cancer, particularly for patients who currently have limited options. The ability to convert “immune-cold” tumors into more responsive, “immune-active” states could have broad implications not only for NSCLC but also for other cancers with similar resistance mechanisms.
Moreover, the integration of translational biomarkers into clinical development provides a framework for more personalized treatment approaches. By identifying patients most likely to benefit from therapy based on molecular and immune profiles, clinicians may be able to optimize outcomes and minimize unnecessary treatment.
In summary, Synthekine’s updated data for STK-012 in combination with pembrolizumab and chemotherapy demonstrate promising efficacy, manageable safety, and strong biological rationale in a challenging patient population. The therapy’s ability to selectively activate T cells, overcome immune resistance, and deliver durable responses positions it as a potentially transformative option in the evolving landscape of immuno-oncology.
As development continues, further studies will be critical to validate these findings and determine the full clinical potential of STK-012. Nevertheless, the data presented at AACR 2026 provide a compelling glimpse into the future of precision cytokine therapy and its role in redefining cancer treatment.
About the SYNERGY-101 Randomized Phase 2 Clinical Trial
Development of STK-012 is ongoing in SYNERGY-101, a global, randomized Phase 2 study evaluating STK-012 plus pembrolizumab and chemotherapy versus pembrolizumab and chemotherapy alone in first‑line, PD‑L1-negative non‑squamous NSCLC. The study is currently enrolling with the first patient dosed in November 2025. Synthekine has entered into a clinical trial collaboration and supply agreement with Merck, under which Merck provides Keytruda® (pembrolizumab) for use in the trial. Synthekine retains all commercial rights to STK-012.
For additional information about the SYNERGY-101 trial, please visit www.clinicaltrials.gov and use the identifier NCT05098132.
About Synthekine
Synthekine is harnessing the potential of cytokine therapeutics to develop selective immunotherapies designed to improve the treatment paradigm of cancer and inflammatory disease. Using insights on cytokine structure and function, the company engineers therapeutics designed to unlock the full efficacy potential of cytokines while avoiding their associated toxicities. Synthekine is applying principles of cytokine partial agonism and immunological specificity across multiple therapeutic areas to create a broad and deep pipeline of product candidates. These novel immunotherapies include modified cytokines and surrogate cytokine agonists.
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