IMP-MEL: a phase I first-in-human study of IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer (NSCLC)

Abstract Background IMM60 is a novel synthetic liposomal encapsulated iNKT cell agonist with enhanced potency and stability compared with the structurally similar, archetypical agonist, α-galactosylceramide. We report results from the first-in-human phase I study of liposomal-IMM60 alone and in combination with pembrolizumab in treatment-experienced patients with advanced melanoma and non-small cell lung cancer (NSCLC). Results Fourteen of fifteen enrolled patients (6 melanoma, 8 NSCLC) received 66 IMM60 infusions (median 5 per patient, range 2–6). No dose-limiting toxicities were observed and no MTD was identified. Treatment-related adverse events occurred in 10 patients (71%), all grade 1–2 and self-limiting. Pharmacokinetics were linear and dose-proportional (Cmax R² = 0.858; mean residence time 7.1 h). iNKT cell TCR downregulation was observed within 24 h, consistent with target engagement. MCP-1 peaked at 24 h (geometric mean fold-change 4.2×, p = 0.037 (one-tailed)) and IP-10 peaked at 4 h (geometric mean fold-change 2.4×, p = 0.019 (one-tailed)). Pro-inflammatory cytokines showed no consistent elevation over baseline. Stable disease was the best overall response in the majority of assessed patients, with lesion-level reductions in 30% of evaluated lesions, including in a patient with BRAF/MEK and PD-1 inhibitor-refractory melanoma. Median progression-free survival was 2.9 months (95% CI: 2.8 months to not reached). Conclusions Liposomal IMM60 is well tolerated with evidence of iNKT cell target engagement and early chemokine induction. Evidence of disease control was observed in heavily pretreated and PD-1-refractory patients, with stable disease as the best drug-attributable overall response. These findings support further evaluation of IMM60 in combination with checkpoint inhibition. Trial registration ISRCTN, ISRCTN80472712. Registered 22 January 2021, https://www.isrctn.com/ISRCTN80472712 .