481 Phase 1/2 study of THOR-707 (SAR444245), a pegylated recombinant non-alpha IL-2, as monotherapy and in combination with pembrolizumab or cetuximab in patients (pts) with advanced solid tumors

Abstract

BackgroundTHOR-707 (SAR444245) is a recombinant human IL-2 molecule irreversibly bound to a PEG chain to block alpha-binding while retaining near-native affinity for beta/gamma IL-2 receptor subunits. We report updated results from the ongoing HAMMER phase 1/2 trial.MethodsSAR444245 was given via IV infusion as monotherapy Q2W [A] or Q3W [B], with pembrolizumab 200mg IV Q3W [C], or Q3W with cetuximab 400mg/m2 IV on D1 then 250mg/m2 IV QW [D] after pre-medication and peri-infusion hydration. A 3+3 design was used to identify the MTD/RP2D in pts with advanced solid tumors. Key objectives included assessments of safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD).Results68 pts, median age 61.5 (37–78) yrs with median 3 (1–10) prior therapies enrolled. Most common tumors: melanoma (n=10), colorectal (n=11). Doses tested by cohort: [A]: 8–16 µg/kg (n=9); [B]: 8–40 µg/kg (n=29); [C]: 8–32 µg/kg (n=20); [D]: 16–24 µg/kg (n=10). The most common (>30%) AEs included pyrexia (52.5%), nausea (50.0%), flu-like symptoms (44.1%), vomiting (36.8%), chills (32.4%), fatigue (32.4%), AST elevation (30.9%). AEs generally resolved promptly with supportive care. Grade(G) 3/4 (>5%) related AEs included ALT/AST elevation (5.9%), and decreased lymphocyte count (26.5% within first 24 hrs, recovering by 48–72 hrs, this lymphocyte migration is mechanistically consistent with immune cell margination). G3/4 CRS was observed in 2 pts. Two DLTs occurred: G3 infusion reaction (32 µg/kg [B]) and G3 AST/ALT/G2 bilirubin elevation with G2 CRS (24 µg/kg [C]). No vascular leak syndrome, QTc prolongation, cardiac, or end organ toxicity was observed. Half-life was ~10 h. Sustained increases in CD8 T and NK cells were observed (fold relative to baseline): monotherapy (1–9.4x and 2–43.3x); with pembrolizumab (0.5–5.78x and 1.5–26.9x); with cetuximab (1.3–7.57x and 3.6–45.4x). Max CD4 and eosinophils increased to 136 cell/µL and 1078 cell/µL. No IL-5 elevation or ADAs were observed. Transient IL-6 increases in 4 pts (500, 627, 1000, 1100 pg/mL) were not associated with AEs. Four pts had confirmed PRs (1 PD1-treated SCC, unknown primary [B]; 2 PD1-naïve BCC and 1 PD1-treated HNSCC [C]); 3 pts had minor responses -- prostate (-24%) and PD1-treated melanoma (-17%) [B]; PD1-treated NSCLC (¬-29%) [C] -- after ≥2 scans. 23 pts completed ≥5 cycles.ConclusionsSAR444245 was well tolerated and demonstrated antitumor activity in heavily pretreated patients, including prior checkpoint inhibitor therapy. Clinical safety, efficacy and PD suggest a wide therapeutic window. Combination with pembrolizumab and cetuximab leveraged SAR44245’s effects on CD8 T and NK cells.Trial RegistrationNCT04009681Ethics ApprovalThe clinical trial was approved by each institutions ethics’ and review board prior to beginning study enrollment.

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs

“…In particular, the cytokines interleukin-2 (IL-2) and interleukin-12 (IL-12) have garnered significant interest owing to their ability to proliferate, activate, and differentiate critical effector immune cell populations unleashed by checkpoint inhibitors 9,10 . Encouraging synergy has been observed with these interleukin/checkpoint inhibitor combinations in early clinical trials, although adverse side effects have been encountered in patients [11][12][13] . As key signaling molecules between immune cells, endogenous immune-stimulating cytokines like IL-2 and IL-12 exhibit tightly controlled spatial distributions and diffusional kinetics to prevent aberrant and pathologic activation.…”

PEGylated therapeutics in the clinic

“…65 From their interim clinical data, THOR-707 is tolerated by cancer patients and showed antitumor efficacy, especially in increasing CD8 T and NK cells treated with or without pembrolizumab and cetuximab. 66 Phase III trials (Table 3). Among them, Zimura is a novel mono-PEGylated anti-C5 RNA aptamer, developed as a complement C5…”

“…THOR‐707, for instance, is a novel PEGylated investigational IL‐2 in seven active clinical trials (Table 3). 65 From their interim clinical data, THOR‐707 is tolerated by cancer patients and showed antitumor efficacy, especially in increasing CD8 T and NK cells treated with or without pembrolizumab and cetuximab 66 . There are eight PEGylated small molecules and five PEGylated NPs that have entered Phase II clinical trials, including the two camptothecin derivative‐based antitumor drugs (i.e., PLX038 and JK‐1201I), and a PLGA‐PEG NP‐based formulation with quercetin encapsulated.…”

Revitalizing Cytokine‐Based Cancer Immunotherapy through Advanced Delivery Systems

“…In the clinical trial of THOR-707 in combination with pembrolizumab and cetuximab, THOR-707 showed a half-life ≈ 10 h, and induced systemic antitumoral response including the increase of CD8+ T and NK cells, while no dose-limiting toxicity and VLS was reported. [190,191] Moreover, partial responses were found in several patients bearing different solid tumors.…”