SON-1010（IL12-F H AB）与曲贝替定在晚期软组织肉瘤中协同增效

Introduction: IL-12 is a potent multifunctional regulator of cell-mediated immunity that activates NK, NKT, Th1, and CTL cells to produce IFNgamma and efficiently kill tumor cells in mice, yet clinical studies of rhIL-12 at the MTD of 500 ng/kg have failed to show adequate benefit. Single-chain native IL‑12 linked to a fully-human albumin binding (F H AB ® ) scFv domain (SON-1010) provides enhanced targeting and retention of the cytokine in the tumor microenvironment (TME) through albumin binding to locally over-expressed FcRn, GP60, and SPARC, with an improved PK profile and broader therapeutic index. SON-1010 was given as monotherapy in the dose-escalation portion of study SB101 in advanced solid tumors and 1 patient had a PR at the maximum dose of 1200 ng/kg. In the second part of this study, SON-1010 was used with trabectedin (Yondelis ® ) in metastatic soft-tissue sarcoma (STS). Trabectedin, a DNA-binding chemotherapy, is approved as 2nd line in unresectable or metastatic STS and is associated with a median PFS of 4.2 months. It also activates macrophages toward a pro-inflammatory phenotype in the TME. Methods: SB101 is a first-in-human Phase 1 study that initially assessed the safety, PK, PD, and efficacy of SON-1010 dosed SC every 3 weeks using a 3+3 design (NCT05352750). A relatively low desensitizing 1 st dose of SON-1010 activates the tachyphylaxis associated with IL-12, followed by higher maintenance doses in each cohort. Safety was reviewed in each group before dose escalation. An expansion cohort was enrolled that alternated trabectedin with SON-1010 at 1200 ng/kg in 3 week cycles. This cohort was designed to establish benefit using a Simon 2-stage approach with alpha of 0.1 and 80% power in 18 patients with STS. The first stage required at least one of the first 7 patients to show clinical benefit, defined as a RECIST response or stable disease (SD) at 4 months. The second stage required at least 4 patients to show the same. Results: All adverse events (AEs) have been transient and dosing was well tolerated; most have been mild or moderate. There were no dose-limiting toxicities and no patients were discontinued due to related AEs. The most common AEs considered related to SON-1010 were fatigue, fever, chills, and myalgia. Fourteen of the 18 patients (78%) in the combination cohort had clinical benefit at 4 months, including 1 confirmed PR. Eight patients have progressed to date and one stopped due to surgery. Nine patients remain on study, so the median PFS has not yet been reached; the mean PFS is currently 6.9 months. Conclusion: SON-1010, an extended half-life version of rhIL-12 that targets the TME, acts safely and synergistically with trabectedin to augment the potential for tumor control in STS, addressing a significant unmet medical need. The responses achieved with monotherapy or in combination could increase with higher doses. SON-1010 may act by immunologically ‘warming' the TME to improve the effectiveness of trabectedin in extending the PFS.