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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
  1. Gerald Falchook1,
  2. Hui Gan2,
  3. Siqing Fu3,
  4. Meredith McKean1,
  5. Arun Azad4,
  6. David Sommerhalder5,
  7. Judy Wang6,
  8. Tira Tan7,
  9. Chen Chee8,
  10. Minal Barve9,
  11. charlotte Lemeque10,
  12. Nicole Acuff11,
  13. Helene Pham11,
  14. Jill Mooney11,
  15. Rui Wang12,
  16. Neyssa Marina12,
  17. Giovanni Abbadessa12 and
  18. Tarek Meniawy13
  1. 1Sarah Cannon Research Institute, Denver, CO, USA
  2. 2Olivia Newton-John Cancer Wellness, Melbourne, Australia
  3. 3MD Anderson Cancer Center, Houston, TX, USA
  4. 4Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  5. 5NEXT Oncology, Texas Oncology, San Antonio, TX, USA
  6. 6Florid Cancer Specialists and Research, Sarasota, FL, USA
  7. 7National Cancer Center Singapore, Singapore, Singapore
  8. 8National Cancer University Centre, Singapore, Singapore
  9. 9Mary Crowley Cancer Research, Dallas, TX, USA
  10. 10Scientia Clinical Research, Randwick, Australia
  11. 11Synthorx, A Sanofi Company, San Diego, CA, USA
  12. 12Sanofi, Cambridge, MA, USA
  13. 13Linear Clinical Research, Nedlands, WA, Australia


Background THOR-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.

Methods SAR444245 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).

Results 68 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.

Conclusions SAR444245 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 Registration NCT04009681

Ethics Approval The clinical trial was approved by each institutions ethics’ and review board prior to beginning study enrollment.

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