Zilovertamab

Matrix metalloproteinase-9 (MMP-9) facilitates the extravasation and lymphoid-tissue infiltration of chronic lymphocytic leukemia (CLL) cells. Prior studies found that high level expression of MMP-9 in CLL associates more aggressive disease. We find that circulating CLL cells that express high levels the onco-embryonic protein ROR1 express significantly higher levels of MMP-9. Stimulation of CLL cells with Wnt5a could enhance expression and the release of MMP-9 into the culture media and increase the capacity of CLL cells to invade Matrigel in a Boyden-Chamber Assay. Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. We found that siRNA silencing of NF-κB-p65 or use of an NF-κB inhibitor (CAS 545380-34-5) blocked the capacity of Wnt5a to induce MMP-9 or enhance the invasive capacity of treated CLL cells. Moreover, siRNA directed silencing of MMP9 or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-κB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking.

Background: Zilovertamab (Zilo) is a humanized monoclonal antibody that inhibits the tumor promoting activity of the cancer stem cell receptor, ROR1, which is highly expressed in many hematologic malignancies but not on normal adult tissues. Methods: Patients (Pts) with relapsed or refractory (RR) MCL or MZL or treatment-naïve (TN) or RR CLL were enrolled. Part 1 (Dose Escalation in CLL & MCL) evaluated multiple doses up to Zilo 600 mg IV q4wks + Ibr 420 mg (CLL) or 560 mg (MCL) daily which was selected for Part 2 (Dose Expansion in CLL, MCL & MZL) and Part 3 (CLL only; pts randomized 2:1 to Zilo+Ibr vs. Ibr alone). Results: To date, 33 MCL, 62 CLL & 4 MZL (99) pts were treated in Parts 1, 2 & 3. In Parts 1&2, 28 RR MCL and 34 CLL (12 TN and 22 RR) on zilo+ibr were efficacy evaluable (MZL not yet evaluable). In Part 3, 23 CLL pts on Zilo+Ibr (16) or Ibr (7) were evaluable. Safety & efficacy results were as of 11 October 2022. Safety in MCL and CLL: The most frequent (≥30%) treatment emergent adverse events (TEAEs) for all MCL & CLL pts on Zilo+Ibr (n = 85) were diarrhea & fatigue (45.9%), contusion (38.8%) and cough (30.6%). The most frequent (≥5%) grade ≥3 TEAEs were hypertension (10.6%), pneumonia (8.2%), atrial fibrillation (AF) & neutropenia (7.1%), and fatigue (5.9%). For all MCL & CLL pts on zilo+ibr, grade ≥3 hematologic lab abnormalities were decreases in neutrophils (11.8%), platelets (4.7%), and hemoglobin (3.5%). Efficacy in MCL: The ORR was 89.3% (42.9% CR); 18% had achieved CR at 3 mos which suggests rapid response; median duration of response (mDOR) was 34.1 mos. Median PFS (mPFS) was not reached (NR) (95% CI: 33.2, NE) with median follow-up (mf/u) of 19.5 mos. Pts with 1 prior line of therapy (LOT) and >1 prior LOT had mPFS of 33.2 mos and NR, respectively. In pts with poor prognostic factors, 7 pts with TP53 mutation had ORR of 85.7% with mPFS NR and 14 pts with Ki-67 ≥30% had ORR of 85.7% with mPFS 33.2 mos. Overall, median OS was NR (95% CI: 22.46, NE). Efficacy in CLL: In parts 1–3, mPFS was NR with mf/u of 40 mos for parts 1&2 and ∼30 mos in part 3. In pooled analysis of all parts, mPFS in 10 pts (5 TN, 5 R/R) with TP53/del(17p) was NR and landmark PFS and OS were 100% at 42 & 40 mos, respectively. Conclusions: Zilo+Ibr is well-tolerated with a safety profile that is comparable to Ibr alone. AF (all grades) occurred in 9.4% of all pts treated which appears lower than rate in Ibr alone studies. The combination is very promising in pts with RR MCL (ORR 89.3%, CR 42.9%, mPFS NR). For CLL pts with TP53 mut/del(17p), Zilo+Ibr is also very active, maintaining 100% PFS and OS at ∼42 mos. This Zilo+ Ibr data after >3 years of f/u is very encouraging in reference to the ALPINE results which reported estimated PFS at 36 mos of ∼55% for Zanubrutinib and ∼42% for Ibr in RR CLL pts with TP53 mutation. The study is currently enrolling MZL pts and has provided a strong rationale for conducting a Phase 3 pivotal study in RR MCL (ZILO-301). The research was funded by: California Institute for Regenerative Medicine and Oncternal Therapeutics, Inc. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. H. Lee Consultant or advisory role: Century Therapeutics Honoraria: Janssen, BMS, Aptitude Health, Guidepoint Global, Cancer Experts, Curio Science, Korean Society of Cardiology, Olson Research, Deloitte Research funding: Seagen, Takeda, Celgene, Oncternal, Pharmacyclics, BMS M. Choi Research funding: Abbvie, TG Therapeutics, Geron, Merck, Oncternal, Pharmacyclics T. Siddiqi Consultant or advisory role: Astrazeneca, Beigene, BMS, Juno, Kite, Pharmacyclics, Janssen, RTP, Celgene, Seattle Genetics Research funding: Astrazeneca, Beigene, Juno, Kite, Pharmacyclics, Celgene, Oncternal, TG Therapeutics W. Wierda Research funding: Abbvie, GSK, Novartis, Genentech, Karyopharm, Pharmacyclics, Acerta, Gilead, BMS(Juno/Celgene), Kite, Sunesis, Miragen, Oncternal, Cyclacel, Loxo, Janssen, Xencor, Astrazeneca N. Lamanna Consultant or advisory role: Abbvie, Astrazeneca, Beigene, Janssen, Pharmacyclics Research funding: Genentech, Abbvie, Astrazeneca, Beigene, Loxo Oncology/Lilly, Mingsight, Octapharma, Oncternal, TG Therapeutics J. Breitmeyer Employment or leadership position: Oncternal Therapeutics Stock ownership: Oncternal Therapeutics S. Yazji Employment or leadership position: Oncternal Therapeutics Stock ownership: Oncternal Therapeutics T. Shih Employment or leadership position: Oncternal Therapeutics Stock ownership: Oncternal Therapeutics M. Wang Consultant or advisory role: Astrazeneca, Beigene, BioInvent, CSTone, Deciphera, DTRM Biopharma, Epizyme, Genentech, Janssen, Juno, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, Pepromene Bio, Pharmacyclics, Innocare, Abbvie, VelosBio Honoraria: Astrazeneca, Acerta Pharma, Beigene, BioInvent, Chinese Medical Association, Clinical Care Options, Dava Oncology, Epizyme, Eastern Virginia Medical School, Hebei Cancer Prevention Federation, Imbruvica, Imedex, Janssen, Kite Pharma, Miltenyi Biomedicine GmbH, Moffitt Cancer Center, OMI, PER, Anticancer Association, TS Oncology, Medscape, Meeting Minds Experts, Mumbai Hematology Group, OncLive, Practice Point Communications, First Hospital Zhejiang University, BGIS, CAhon Research funding: Astrazeneca, Beigene, BioInvent, Celgene, Janssen, Juno, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, Innocare, Genentech, VelosBio, Acerta Pharma, Genmab, Vincerx T. Kipps Consultant or advisory role: Astrazeneca, Celgene, Genentech/Roche, Gilead, Janssen, Loxo Oncology, Oncternal, Pharmacyclics/Abbvie, TG Therapeutics, VelosBio, Verastem Stock ownership: Oncternal provided to TJK Laboratory (UCSD) Honoraria: Pharmacyclics/Abbvie, Genentech/Roche, Janssen, Gilead, NIH, Celgene, European Research Initiative on CLL (ERIC), Dava Oncology, Breast Cancer Research Foundation, iwNHL, NCCN CLL/SLL panel meeting, OncLive Research funding: Pharmacyclics/Abbvie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal, SCOR-LLS, CIRM, NIH, VelosBio, Astrazeneca, Celgene, Genentech/Roche, Gilead, Janssen, Loxo Oncology, TG Therapeutics, Verastem Educational grants: Pharmacyclics/Abbvie, Genentech/Roche, Janssen, Gilead, NIH, Celgene, European Research Initiative on CLL (ERIC), Dava Oncology, Breast Cancer Research Foundation, iwNHL, NCCN CLL/SLL panel meeting, OncLive