Phase 1/2 Study of Zilovertamab and Ibrutinib in Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), or Marginal Zone Lymphoma (MZL)

Background: Zilovertamab (Zilo) is a humanized monoclonal antibody that inhibits the tumor promoting activity of the cancer stem cell antigen, ROR1, which is highly expressed by hematologic malignancies including MCL and CLL, and by many solid tumors but not by normal tissue specific stem cells. While pre-clinical studies showed that Zilo has additive or synergistic activity with targeted agents, such as the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (Ibr), this is the first study showing clinical synergy. Methods: Patients (Pts) with relapsed or refractory (RR) MCL with ≥1 prior line of therapy (LOT) or treatment-naïve (TN) or RR CLL with ≥1 prior LOT were enrolled. In Part 1 (Dose Escalation in MCL, CLL), multiple doses were evaluated. As a result, Zilo 600 mg IV starting q2wks x3 then q4wks + Ibr 420mg (CLL/SLL) or 560 mg (MCL/MZL) daily dosing was selected as the recommended dosing regimen for use in Part 2 (Dose Expansion) and Part 3 (CLL only; pts randomized 2:1 to receive Zilo+Ibr vs. Ibr alone). The study opened to RR MZL pts with ≥1 prior anti-CD20 based therapy as of June 2022. Results: Sixty-seven pts (33 MCL and 34 CLL) were treated in Parts 1&2 and 28 pts (CLL) were treated in Part 3 of the study. In Parts 1 and 2, there were 27 RR MCL and 34 CLL (12 TN and 22 RR) efficacy evaluable pts. In Part 3, there were 23 efficacy-evaluable CLL pts randomized to receive either Zilo+Ibr (16) or Ibr (7). Safety in MCL and CLL: The most frequent (≥30%) treatment emergent adverse events (TEAEs), regardless of causality for all pts treated with Zilo+Ibr (N=85), were fatigue (42.4%), contusion (36.5%), and diarrhea (37.6%). The most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality, were hypertension (10.6%), pneumonia (7.1%), neutropenia (5.9%), atrial fibrillation (5.9%), and fatigue (5.9%). In Parts 1 and 2, grade ≥3 hematologic laboratory abnormalities observed in pts with MCL and CLL, respectively, were neutrophils decrease (9.1% and 17.6%), platelets decrease (12.1% and 2.9%), and hemoglobin decrease (9.1% and 0%). Efficacy in MCL: The objective response rate (ORR) was 85.2% (40.7% CR, 44.4% PR) with a median duration of response (mDOR) of 34.1 months (mos) (95% CI:13.67, NE). The CR rate was 29.6%, 37% and 40.7% at 6, 12 and 26 mos, respectively. Median PFS (mPFS) was 35.9 mos (95% CI: 17.3, NE) with median follow-up (mf/u) of 15.1 mos and landmark PFS (LPFS) at 30 mos was ~70%. For 6 pts with P53 mutations, the ORR was 83.3% (1 CR, 4 PRs), mDOR was 13.84 mos (11.93, NE), mPFS was 17.3 (95% CI: 2.85, NE) and LPFS at 12 mos was >80%. In patients with Ki67≥30% (14), the ORR was 85.7% (5CRs, 7PRs) with mDOR NR (13.67, NE), for intermediate sMIPI (9) ORR was 88.9% (5 CRs, 3 PRs) with mDOR of 34.13 mos, and for high sMIPI (3) ORR was 66.7% (1 CR, 1PR) with mDOR NR (13.84, NE). Overall survival was not reached (NR; 95% CI: 18.9, NE) and landmark OS at 12 mos was ~90%. Efficacy in CLL: In Parts 1 and 2, the mPFS had not been reached for all pts with CLL with mf/u of 32.9 mos. The LPFS at 36 mos was 100% for pts with 1-2 prior LOT, ~70% for pts with >2 LOT. From pooled analysis of all Parts, the LPFS at 30 mos was 100% for the 9 pts with P53alterations.In Part 3, mPFS had not been reached in either group (Zilo+Ibr or Ibr) with mf/u of 24.1 mos Conclusions: In this study, Zilo+Ibr is well-tolerated with a safety profile that is very similar compared with Ibr alone. With respect to grade ≥3 neutropenia in RR MCL, the rate observed with Zilo+Ibr was 9.1%, which is lower than the 29% reported for Ibr alone in its Phase 3 study. The combination is very promising in pts with RR MCL (ORR 85.2%, CR 40.7%, mPFS 35.9 mos), compared with historical results for Ibr alone (ORR 66%, CR 20%, mPFS 12.8 mos; Rule 2017). For CLL pts with p53 alterations, overall efficacy with Zilo+Ibr is also very promising with LPFS at 30 mos of 100% that almost doubles historic Ibr monotherapy LPFS of ~55% (Byrd 2019). This encouraging exploratory study is ongoing, with the addition of MZL pts, and has provided the impetus for a Phase 3 registrational study evaluating Zilo+Ibr in MCL (ZILO-301).