695P - A phase I/Ib study evaluating the safety and tolerability of NIZ985 alone and in combination with spartalizumab (anti–PD-1) in patients (pts) with solid tumors or lymphoma

Background

NIZ985, an investigational recombinant heterodimer of interleukin (IL)-15 and IL-15 receptor alpha, binds the IL-2/IL-15 receptor on immune cells. NIZ985 activates immune cells in pts with advanced cancer and may help overcome resistance to checkpoint inhibitors (CPIs).

Methods

This is a phase I/Ib, open-label, multicenter, dose-escalation (ESC)/-expansion (EXP) study (NCT04261439) of NIZ985 alone and with spartalizumab (SPA) in pts with advanced solid tumors or lymphoma. Eligible pts had previously responded and progressed on a CPI. ESC comprised two arms: (1) single-agent (SA), subcutaneous NIZ985 at 2–16 μg/kg weekly, 3 weeks on/1 week off and (2) in combination with SPA 400 mg (N+S) intravenously on Day 1 of each 28-day cycle. Study objectives were to evaluate safety, tolerability, preliminary antitumor activity and PK.

Results

Fifty-six pts have been treated in the ESC SA NIZ985 (n=27) and N+S (n=29) arms. Pts received a median 3 (1–7) and 4 (1–9) prior therapies, with a median 1 prior CPI-containing regimen (ranges 1–3 and 1–4), respectively. At data cut-off, 21 (77.8%) and 24 (82.8%) pts had discontinued treatment in each arm respectively, mainly due to progressive disease (66.7% and 48.3%). Three DLTs during the first cycle included grade (gr) 3 fatigue, gr 2 bullous dermatitis and gr 2 injection site reaction. Gr ≥3 treatment-related AEs (TRAEs) were reported in 4 (14.8%) pts in the SA arm (pyrexia, fatigue, increased ALT, cutaneous vasculitis, and linear IgA disease) and in 4 (13.8%) pts in the N+S arm (increased ALT, hyperprogression, soft tissue infection, and increased transaminases). Of the 42 pts evaluated, 2 had a PR and 16 had SD. PK were dose proportional up to 12 μg/kg NIZ985, and overlapping exposures were observed with 16 μg/kg NIZ985. Biomarker data showed strong peripheral immune activation; increased Ki67 expression in CD8+ and NK cells and increases in systemic pro-inflammatory cytokines were noted.

Conclusions

NIZ985 +/- SPA was generally well tolerated with evidence of immune activation. The RDE was declared as 12 μg/kg NIZ985 SA and in combination. Additional pts with NSCLC have enrolled in EXP with tislelizumab.

Clinical trial identification

EudraCT 2109-0040690-42.

Editorial acknowledgement

Legal entity responsible for the study

Novartis.

Funding

Novartis.

Disclosure

E. Garralda: Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant and Advisory Role.Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: iTeos; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role.Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Institutional, Funding, Clinical Trial: Pfizer/Array, Roche Genentech, Sanofi; Financial Interests, Personal, Advisory Board: Erasca; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Member of Board of Directors, November 2017-December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, SMR, AIOM. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics. L.H. Lee, A. Reynolds: Financial Interests, Personal, Full or part-time Employment: Novartis. T. Shimizu: Financial Interests, Personal, Advisory Board: AbbVie, Chordia Therapeutics, Daiichi Sankyo; Financial Interests, Personal, Other, Safety Review Committee: Chugai; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Local PI: AbbVie, Eli Lilly, Loxo Oncology, Novartis, Daiichi Sankyo, Takeda, Bristol Myers Squibb, Eisai, Incyte, AstraZeneca, Pfizer, Chordia Therapeutics, Astellas, Symbio Pharmaceuticals, 3D-Medicine, PharmaMar; Non-Financial Interests, Other, Joint Scientific Committee Review External IRB Member of Phase 1 Trials in Hong Kong, HKSAR, China: HKU/CUHK, HKSAR, China. All other authors have declared no conflicts of interest.