2024 - Phase 1/2 Study of Zilovertamab and Ibrutinib: Durable responses suggest a novel mechanism for synthetic lethality in TP53 aberrant disease.

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 in the overall trial. Part 1 (Dose Escalation in CLL & MCL) evaluated multiple doses up to Zilo 600 mg IV q4wks + Ibrutinib (Ibr) 420mg (CLL) or 560mg (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 from the CLL cohorts, including the subgroup with del(17p) or TP53 mutation (TP53 mut) are updated.

Patient Characteristics: To date, 62 pts with CLL were treated. 34 patients (12 TN and 22 RR) in parts 1 & 2 were efficacy evaluable. In Part 3, 23 CLL pts on Zilo+Ibr (16) or Ibr (7) were evaluable. Across these parts, 10 pts (5 TN and 5 R/R) with CLL had TP53 mutation or del(17p).

Safety: AEs are summarized for all pts in both the CLL and MCL cohorts. The most frequent (≥30%) treatment emergent adverse events (TEAEs) for all MCL & CLL pts on Zilo+Ibr (n=85) were diarrhea (45.9%), 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, 7.1%), neutropenia (7.1%), and fatigue (5.9%). Grade ≥3 hematologic lab abnormalities (not all treatment emergent) were decreases in neutrophils (11.8%), platelets (4.7%), and hemoglobin (3.5%).

Efficacy in CLL: In parts 1-3, mPFS was not reached (NR) with median f/u of 40 mos for parts 1&2 and ~30 mos in part 3. Post-hoc analysis of the pts with del(17p) or TP53 mut showed a 100% landmark PFS and OS at 42 and 40 mos, respectively. To date, no patient with CLL with del(17p) or mutTP53 has had disease progression.

Correlative Science: Preclinical studies have previously shown that cancer cells with TP53 mut are more dependent on NRF2 for stress and antioxidant response. Samples from patients treated with Zilo+Ibr (but not Ibr alone) showed suppression of NRF2 gene expression, supporting the hypothesis that CLL cells with TP53 mut or del(17p) are more sensitive to the effects of NRF2 inhibition.

Conclusions: Zilo+Ibr is well-tolerated with a safety profile that is comparable to Ibr alone. For pts with CLL, Zilo+Ibr is very active and results in durable remissions. The PFS and OS for the subgroup with TP53 mut/del(17p) are particularly encouraging in reference to other trials of BTK inhibitors, maintaining 100% PFS and OS at ~42 mos. Suppression of NRF2 via inhibition of ROR1 may represent a novel strategy for treatment of TP53 mut CLL.