Abstract CT147: Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors

Abstract

Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine, which is highly expressed in a subset of tumors and correlates with poor prognosis. LIF is hypothesized to contribute to tumor microenvironment immunosuppression and regulation of cancer stem cells. MSC-1 is a first-in-class humanized IgG1 monoclonal antibody that potently and selectively inhibits LIF. In pre-clinical models, MSC-1 decreases tumor growth through inhibition of STAT3 signaling, promoting immune stimulatory macrophages and increasing tumor infiltration of CD8 T and NK cells. The Phase Ia clinical study employed an accelerated 3 + 3 escalation design to explore safety and tolerability, dose-limiting toxicities (DLTs), preliminary efficacy, define a recommended phase II dose (RP2D), and evaluate exploratory tumor biomarkers. Eligible patients had advanced relapsed/refractory solid tumors and received treatment with MSC-1 intravenously (75mg-1500 mg) once every 3-weeks as a single agent until disease progression. The three highest dose cohorts were expanded to further assess safety, PK, engagement of LIF in the periphery, and assess immuno-regulatory tumor activity in matched pre- and on-treatment tumor biopsies. Forty-one patients (pts) were enrolled (14 in dose escalation; 27 in expanded cohorts) with the last pt completing the study on September 23, 2019. The most common tumor types were pancreatic (13), colorectal (5), head & neck (4) and ovarian (4). Pts had received a median of 3 prior lines of therapy. All pts experienced at least one adverse event (AE). The most common considered drug-related AEs were fatigue (N=8, 20%) and gastrointestinal disorder (N=8, 20%), and there was 1 considered drug-related SAE (Gr 2 osteonecrosis of jaw in a head and neck cancer patient who previously received radiation to the area and denosumab). There were no Dose Limiting Toxicities observed during the first cycle of treatment and 2 pts discontinued treatment due to AEs. The PK profile of MSC-1 was linear with an estimated terminal half-life of ∼13 days and benign anti-drug antibody profile. There was evidence of durable peripheral saturation of LIF binding demonstrating high level of target engagement. Results supported the selection of a RP2D of 1500 mg Q3W. Prolonged stable disease (≥ 16 weeks) was observed in 9 pts. Analysis of paired biopsies collected from matched metastatic lesions supported MSC-1 mediated STAT3 signaling inhibition, stimulatory (M1) to suppressive (M2) macrophage skewing in the majority of paired biopsies evaluated and increased CD8 T-cell infiltration in a subset of samples. Single agent MSC-1 was well tolerated in doses ranged from 75 mg to 1500 mg IV OD in patients with advanced solid tumors, showed promising activity as an anti-cancer therapy, and is Phase 1b/2 ready for combination with other agents. The updated final safety, efficacy, PK, LIF stabilization analyses, and tumor biopsy data will be presented. Citation Format: Alison Schram, Erkut Borazanci, Irene Brana, Maria Vieito Villar, Elena Garralda, Anna Spreafico, Marc Oliva, Nehal Lakhani, Robert Wasserman, Kimberly Hoffmann, Robin Hallett, Judit Anido, Dorotea Maetzel, Patricia Giblin, Enda Moran, Adrianne Kelly, Joan Seoane, Daniel D. Von Hoff, Lillian Siu, Josep Tabernero. Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT147.

Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance

“…26 Recently, the results of a phase I study investigating the safety and efficacy of MSC-1, a first-in-class humanized IgG1 MAb that potently and selectively inhibits LIF, have been reported. 32 Eligible patients had advanced relapsed/refractory solid tumors and received treatment with MSC-1 intravenously (75 mg-1500 mg) once every 3 weeks as a single agent until disease progression. Single agent MSC-1 was well tolerated with no dose limiting toxicities observed during the first cycle of treatment.…”

Next generation of immune checkpoint inhibitors and beyond

“…MSC-1, a humanized IgG1 mAb targeting LIF, is being evaluated in a phase I clinical trial as monotherapy in patients with advanced, refractory solid malignancies ( NCT03490669 ). Results available from 41 patients who received a median of 3 prior lines of therapy revealed a DCR of 22% with 9 patients achieving SD that lasted over 16 weeks [ 73 ]. In addition, tissue samples confirmed an increase in both M1:M2 ratio and cytotoxic CD8 + T cells.…”

“…Although no grading is specified, the most common AEs included fatigue (20%) and gastrointestinal symptoms (20%). There was one patient with HNSCC who developed grade 2 osteonecrosis of the jaw; however, he had previously received radiation therapy to the area and had been exposed to denosumab [ 73 ]. Unfortunately, this trial was terminated early due to safety concerns.…”

Emerging Perspectives on Leukemia Inhibitory Factor and its Receptor in Cancer

“…Overall, the study found that high levels of LIF were associated with decreased response to anti-PD1 therapies, and that LIF nAb when used in conjunction with anti-PD1 therapy could be a potential therapeutic option for patients with solid tumors exhibiting high LIF expression ( 82 ). In 2019, a humanized LIF nAb called MSC-1 entered phase 1A clinical trials and has been recommended to enter phase 2 dose trials for patients with relapsing or non-responsive solid-state tumors ( 83 ). Clearly, LIF and the LIFRβ have relevant connections to cancer growth and metastasis that warrant additional research and definition.…”