FDA Clears IND Application for Novel IL-2 Agent in Advanced NSCLC

The FDA has cleared an investigational new drug (IND) application for ILKN421H (STI-7349), a novel mRNA therapy, plus pembrolizumab (Keytruda) for patients with advanced non–small cell lung cancer (NSCLC), according to a press release from the developer, iLeukon Therapeutics, Inc.¹

Acceptance of the IND enables investigators to pursue a phase 2 trial protocol assessing the novel agent plus pembrolizumab among patients in the first-line setting or for those who previously received immunotherapy.

Developers engineered ILKN421H as a non-alpha interleukin-2 variant (IL-2v) fusion protein that may show preferential mRNA expression in patients with lymphoid organs through a half-life of approximately 20 hours. Investigators hypothesize that its non-alpha design assists with the expansion of stem-like CD8 T cells and natural killer (NK) cells. Additionally, the mRNA platform may provide enhanced efficacy while reducing systemic toxicity by mitigating cytokine-sink limitations reported with other protein-based IL-2 agents.

Investigators previously reported antitumor activity and a favorable safety profile associated with ILKN421H as part of a first-in-human, open-label phase 1 trial (NCT05978102). Whether administered with or without pembrolizumab, the investigational IL-2 therapy appeared to be well-tolerated among 45 patients with advanced solid tumors; no dose-limiting toxicities occurred, and investigators did not reach a maximum tolerated dose.

Among patients with frontline NSCLC, ILKN421H plus pembrolizumab elicited confirmed objective responses in 80% (n = 16/20) regardless of PD-L1 status. Moreover, the median progression-free survival (PFS) was not reached at the time of analysis, although investigators projected it to surpass 12 months.

Investigators will present detailed results from this phase 1 study at the 2025 Society for Immunotherapy of Cancer Annual Meeting.

“Next-generation IL-2 agents have been a major focus of the immuno-oncology field for the past decade. ILKN421H expands cytotoxic lymphocytes—CD8 T cells and NK cells—by up to 5- and 25-folds respectively; the first IL-2–based treatment that achieved this level of immune promotion safely. We believe ILKN421H can enhance the efficacy of checkpoint inhibitors, such as pembrolizumab, and may also support future modalities including TIL and in vivo CAR [T-cell] therapies,” Haining Huang, PhD, co-founder and chief executive officer of iLeukon Therapeutics, stated in the press release.¹ “With FDA clearance to proceed to phase 2, we look forward to advancing ILKN421H globally to meet the significant unmet needs and to improve the outcomes for patients with NSCLC and potentially other types of cancers in the future.”

Investigators of the first-in-human phase 2 study administered ILKN421H intravenously to patients with advanced solid tumors across 2 periods.² Period 1 included a dose-escalation component and a dose-expansion portion for ILKN421H monotherapy. Period 2 included a dose-escalation portion and a dose-expansion portion for ILKN421H plus pembrolizumab or other commercially available anti–PD-(L)1 agents.

The trial’s primary end points included the number of patients with treatment-related adverse effects following ILKN421H monotherapy or combination therapy per CTCAE v5.0 criteria. Secondary end points included pharmacokinetics, objective response rate, disease control rate, duration of response, PFS, and overall survival.

Patients 18 to 80 years old with an ECOG performance status of 0 or 1, an estimated survival of at least 12 weeks, at least 1 measurable lesion per RECIST v1.1 guidelines, and histopathologically or cytologically confirmed malignant advanced solid tumors who have progressed on or could not tolerate standard treatment were eligible for enrollment on the study. Having adequate major organ function was another requirement for study entry. Those with prior CAR T-cell therapy within 3 months of beginning study treatment or major surgery within 28 days of the first dose were ineligible for enrollment.

References

1. iLeukon receives FDA clearance of IND application for a phase II study of mRNA-based non-alpha IL-2 variant, ILKN421H, in advanced non-small cell lung cancer (NSCLC). News release. iLeukon Therapeutics, Inc. November 3, 2025. Accessed November 4, 2025. https://tinyurl.com/5hc3nymp
2. A dose escalation and dose expansion clinical study of STI-7349 in subjects with advanced solid tumors. ClinicalTrials.gov. Updated July 23, 2025. Accessed November 4, 2025. https://tinyurl.com/yf6ecd8f