Abstract LB041: THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study
Authors: Janku Filip , Abdul-Karim Raghad , Azad Arun , Bendell Johanna , Falchook Gerald , Gan Hui K. , Tan Tira , Wang Judy S. , CHEE Cheng Ean , Ma Lina , Mooney Jill , Marina Neyssa , Abbadessa Giovanni , Milla Marcos , Meniawy Tarek 
Published: July 2021

Abstract
THOR-707 (SAR444245) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Here we report safety, PK/PD, and preliminary anti-tumor activity for THOR-707 as monotherapy and combined with pembrolizumab in the ongoing HAMMER Phase 1/2 trial.
THOR-707 was administered via IV infusion as monotherapy Q2W (Cohort A), Q3W (Cohort B), or combined with pembrolizumab 200 mg IV Q3W (Cohort C); escalation follows a 3 + 3 schema to identify the maximum tolerated dose and/or the recommended Phase 2 dose.
As of 16 November 2020, 28 pts were enrolled: ECOG 0-1; median age 62 (37-76) yrs; median lines of prior therapies were 3 (1-9; 11 pts had prior anti-PD1). Most common tumor types: colorectal (n=5), melanoma (n=4). Cohort enrollment was A: 8 µg/kg (n=4); B: 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=7); C: 8 µg/kg (n=4), 16 µg/kg (n=3).
No dose-limiting toxicity (DLT) or vascular leak syndrome (VLS) was observed. Most common treatment-emergent adverse events (TEAEs) were flu-like symptoms (46.4%), fever (46.4%), vomiting/nausea (35.7%), chills (32.1%), following the first dose and resolved with standard supportive care. No cumulative toxicity, end organ toxicity, QTc prolongation, or other cardiac toxicity was observed. Grade (G) 3-4 related toxicities in B: 1 G3 rash (8 µg/kg); 1 G4 AST increase, 2 G3 increase in AST/ALT & 1 G4 decrease in lymphocytes (16 µg/kg); 2 G4 decrease in lymphocytes, 1 G4 CRS with G3 hypertension (led to discontinuation), and 1 G3 acute kidney injury (24 µg/kg); C: 1 G3 & 1G4 decrease in lymphocytes (16 µg/kg). CD8 cells (effector & memory) and NK cells increased in Cycle 1 by a median (range) respectively of 3.1 (1.04 - 5.91) and 7.93 (1.71 - 26.85) fold and were sustained until next cycle. There was no meaningful increase in CD4 Tregs or eosinophil counts (a marker of potential VLS), 1.89 (0.86- 5.36) and 1.77 (0.47- 3.65) fold. No anti-drug antibodies (IL-2 or PEG) and no meaningful IL-5 elevations were found. One IL-6 increase at 24 hrs (to 1,000 pg/mL) was observed. Half-life is ~ 10 hours.
Three pts have confirmed partial responses: 1 PD-1-naïve basal cell carcinoma; 1 head & neck squamous cell carcinoma with progression after a prior anti-PD-1, ongoing for 9+ mos in C (8 µg/kg); 1 squamous cellular carcinoma of unknown origin, unresponsive to prior anti-PD-1, ongoing for 3+ mos in B (24 µg/kg). Two pts had stable disease for 9 and 6 mos, respectively, with pancreatic (in A, 8 µg/kg) and prostate cancer (in B, 16 µg/kg); 11 pts remained on treatment for ≥5 cycles.
Preliminary encouraging results with THOR-707 monotherapy and in combination with pembrolizumab support IL-2 not-alpha preferential activity, validating preclinical models, with initial efficacy and a tolerable safety profile. Dose escalation continues. NCT04009681
Citation Format: Filip Janku, Raghad Abdul-Karim, Arun Azad, Johanna Bendell, Gerald Falchook, Hui K. Gan, Tira Tan, Judy S. Wang, Cheng Ean CHEE, Lina Ma, Jill Mooney, Neyssa Marina, Giovanni Abbadessa, Marcos Milla, Tarek Meniawy. THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB041.