Abstract CT082: Phase (Ph) I/Ib study of NIZ985 with and without spartalizumab (PDR001) in patients (pts) with metastatic/unresectable solid tumors

Background: NIZ985 is a soluble IL-15/IL-15 receptor α heterodimer (hetIL-15) that binds IL-2/IL-15 receptor β/γ and promotes effector T-cell and NK cell expansion and activation. Spartalizumab is a humanized IgG4 mAb that blocks binding of programmed death 1 (PD-1) to programmed death ligand 1/2 (PD-L1/2). In preclinical studies, IL-15 and anti-PD-1/PD-L1 combinations demonstrated synergistic antitumor activity. Here we report dose escalation results from a Ph I/Ib study of NIZ985 as a single agent (SA) and in combination with spartalizumab (NCT02452268). Methods: Pts with metastatic/unresectable solid tumors received subcutaneous NIZ985 TIW (2 weeks on/2 weeks off); 0.25-4 μg/kg NIZ985 SA or 1 μg/kg NIZ985 with IV spartalizumab (400 mg, Q4W). Ph I endpoints: DLTs, safety, PK, pharmacodynamics (PD), preliminary efficacy, and recommended dose for expansion (RDE), statistically guided by a 3+3 study design. Results: As of Oct 9, 2018, 14 pts (median age 56.5 y [range 42.0-73.0]) received NIZ985 SA and 11 pts (median age 61 y [range 34.0-75.0]) received NIZ985 + spartalizumab. Treatment was discontinued in 13 (93%) and 10 (91%) pts receiving NIZ985 SA and NIZ985 + spartalizumab, respectively, mainly due to disease progression (57% and 82%); 1 pt in each group is ongoing. No DLTs were reported in the first cycle. AEs suspected to be drug related were reported in 100% of pts (36% grade 3/4) for NIZ985 SA and 100% of pts treated with the combination (27% grade 3/4). Common AEs [all grades; grade 3/4], defined as ≥50% of pts for any grade, were injection site reaction [100%; 7%], chills [64%; 0%], and fatigue [57%; 0%] in NIZ985 SA; and injection site reaction [100%; 9%], fatigue [82%; 0%], diarrhea [64%; 9%], and nausea [55%; 0%] in NIZ985 + spartalizumab. Median duration of NIZ985 exposure (range) across doses was 7.6 weeks (2.6-15.6) in NIZ985 SA and 21.6 weeks (5.6-53.6) in NIZ985 + spartalizumab. In 13 evaluable NIZ985 SA pts, confirmed best overall responses (BORs) were stable disease (SD; n=3, 23%), progressive disease (n=8, 62%), and unknown (n=2, 15%); SD is ongoing in 1 pt with spindle cell ocular melanoma. Confirmed BORs in 11 evaluable NIZ985 + spartalizumab pts were SD (n=5, 45%) and progressive disease (n=6, 55%); SD is ongoing in 1 pt with gastric adenocarcinoma. RDE was declared as 1 μg/kg NIZ985 (TIW; 2 weeks on/2 weeks off) for SA and with spartalizumab (400 mg, Q4W). PD analyses showed NIZ985 induces lymphocyte proliferation in peripheral bloo