Zilovertamab/Ibrutinib Promising Activity With Tolerable Toxicity in MCL and CLL

Hun Ju Lee, MD

Encouraging clinical response and progression-free survival (PFS) rates and showcased a tolerable toxicity was observed with the combination of zilovertamab and ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), according to findings from a phase 1/2 trial presented at the 2022 ASH Annual Meeting.¹

In this trial’s dose-finding and dose-expansion cohorts, the combination elicited overall response rates (ORRs) of 89.3% (n = 25) and 91.2% (n = 31) in patients with MCL and CLL, respectively. Additionally, in the randomized portion, the ORR was 93.8% (n = 15) in patients with CLL who received the combination vs 100.0% in those who received ibrutinib alone.

“We are excited [to see these data] in the patients with MCL and CLL who were treated with this combination,” lead study author Hun Ju Lee, MD, of The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data. “[The combination] was well tolerated, and the safety profile was comparable to that of ibrutinib alone.”

ROR1, an onco-embryonic kinase-like receptor, is expressed at high levels in MCL, CLL, and marginal zone lymphoma (MZL). Zilovertamab is a fully humanized monoclonal antibody that inhibits ROR1 signaling. In preclinical studies, this agent has been shown to inhibit the CLL cell expression of genes induced by activated NF-kB, ERK1/2, NRF2, and STAT3, which may promote the growth and survival of TP53-mutated CLL cells in patients who receive BTK inhibitors such as ibrutinib.

The phase 1/2 study consists of 3 parts. Part 1 included a dose-finding cohort of patients with MCL and CLL. Here, zilovertamab was evaluated at doses of 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, 300 mg, and 600 mg. After a 1-month safety run-in, oral ibrutinib was added at 420 mg in the patients with CLL and 560 mg in those with MCL. The recommended phase 2 dose (RP2D) was determined to be 600 mg of intravenous zilovertamab given once every 2 weeks for 3 cycles and once every 4 weeks thereafter in combination with the approved doses of ibrutinib.

Part 2 included a dose-expansion cohort that had primary end points of safety, preliminary efficacy, and pharmacology at the RP2D. This part of the research aimed to confirm the RP2D dose of 600 mg of zilovertamab plus oral ibrutinib daily at 420 mg in CLL and 560 mg in MCL. The CLL and MCL arms of this part are enrolled, and the MZL arm is currently enrolling.

Part 3 randomly assigned patients with CLL in a 2:1 fashion to receive zilovertamab plus ibrutinib vs ibrutinib alone. Here, investigators aimed to evaluate objective responses, PFS, and biomarkers in this population.

Parts 1 and 2 enrolled 33 and 34 patients with MCL and CLL, respectively, all of whom were included in the safety population and 84.8% (n = 28) and 100% (n = 34) of whom were included in the efficacy population. Part 3 enrolled 21 patients with CLL to receive zilovertamab plus ibrutinib and 10 patients to receive ibrutinib alone, 18 and 10 of whom were included in the safety population, respectively. Additionally, 88.9% (n = 16) of those who received the combination and 70.0% (n = 7) of those who received ibrutinib monotherapy were included in the efficacy population.

A total of 39.4% (n = 13) of the patients with MCL from parts 1 and 2 were still receiving treatment at data cutoff. Additionally, 60.6% (n = 20) and 100% (n = 34) of the patients with MCL and CLL, respectively, discontinued treatment. A total of 11.1% (n = 2) and 10.0% (n = 1) of the patients from part 3 were still receiving the combination or ibrutinib monotherapy, respectively; 88.9% (n = 16) and 90.0% (n = 9), respectively, had discontinued treatment.

In parts 1 and 2, 51.5% (n = 17) of the patients with MCL had a median Ki-67 of at least 30%. A total of 15.2% (n = 5) of the patients with MCL from parts 1 and 2 and 10.0% (n = 1) of the patients with CLL from part 3 who received ibrutinib monotherapy had received prior ibrutinib. In total, 47.0% (n = 8), 17.6% (n = 6), 23.5% (n = 4), and 10.0% (n = 1) of the patients with MCL from parts 1 and 2, CLL from parts 1 and 2, CLL from part 3 who received the combination, and CLL from part 3 who received ibrutinib alone, respectively, had TP53 alterations.

In parts 1 and 2, 42.9% (n = 12), 46.4% (n = 13), and 3.6% (n = 1) of patients with MCL achieved a complete response (CR), partial response (PR), or stable disease (SD), respectively. Additionally, 8.8% (n = 3), 79.4% (n = 27), and 8.8% (n = 3) of patients with CLL achieved a CR, PR, or SD, respectively.

The combination demonstrated rapid responses in those with MCL. At 3, 6, 9, 12, 15, and 26 months, the ORRs were 78.6%, 82.1%, 85.7%, 89.3%, 89.3%, and 89.3%, respectively, and the CR rates were 17.9%, 25.0%, 28.6%, 39.3%, 39.3%, and 42.9%, respectively.

In parts 1 and 2, the median duration of response (DOR) was 34.1 months (95% CI, 13.84–not estimable [NE]) in those with MCL and 33.5 months (95% CI, 33.5-NE) in those with CLL. The median duration of follow-up was 19.5 months (95% CI, 19.4-28.5) in those with MCL and 40.0 months (95% CI, 38.6-43.5) in those with CLL.

In part 3, 0%, 93.8% (n = 15), and 6.3% (n = 1) of the patients with CLL who received the combination achieved a CR, PR, or SD, respectively, compared with 14.3% (n = 1), 85.7% (n = 6), and 0% of those who received ibrutinib alone. The median DOR was not reached (NR) in either arm. The median duration of follow-up was 29.2 months (95% CI, 27.4-30.3) and 30.0 months (95% CI, 19.1-33.1) in the combination and monotherapy arms, respectively.

The patients with MCL who received the combination after 1 prior line of therapy had a median PFS of 33.21 months (95% CI, 17.31-NE). In those who received the combination after more than 1 prior line of therapy, the median PFS was NR (95% CI, 4.33-NE).

In those with MCL and a Ki-67 of less than 30%, the median PFS was NR (95% CI, 35.93-NE), and in those with a Ki-67 of 30% or higher, the median PFS was 33.21 months (95% CI, 2.85-NE). Additionally, in patients with non–TP53 mutated MCL, the median PFS was 33.21 months (95% CI, 5.67-NE), compared with a median PFS that was NR (95% CI, 2.85-NE) in those with TP53 mutations.

After a median follow-up of 19.5 months, the median overall survival (OS) was NR (95% CI, 22.46-NE) in the patients with MCL. At 25 months, the OS rate in those with MCL was 70% with the combination.

After a median follow-up of 40 months, the median PFS in the patients with CLL was NR. At 24 months, the PFS rate was approximately 95% in those with relapsed/refractory CLL who received the combination.

At approximately 42 months, with a median duration of follow-up of 40 months, a pooled analysis of parts 1, 2, and 3 that looked at those with CLL with TP53 mutations or 17p deletions who received the combination revealed a 100% PFS rate (relapsed refractory CLL, n = 5; treatment-naïve CLL, n = 5). This pooled analysis also found that after a median follow-up of 40 months, both those with relapsed/refractory and treatment-naïve CLL had a 100% OS rate, with a median OS that was not reached.

Across parts 1, 2, and 3, the most common treatment-emergent adverse effects experienced with zilovertamab plus ibrutinib in the patients with MCL and CLL of grades 1 to 2 or grade 3 or higher, respectively, were diarrhea (42.4%; 3.5%), fatigue (40.0%; 5.9%), contusion (38.8%; 0%), cough (30.6%; 0%), arthralgia (25.9%; 2.4%), hypertension (16.5%; 10.6%), upper respiratory tract infection (25.9%; 0%), dizziness (24.7%; 0%), thrombocytopenia (22.4%; 2.4%), nausea (23.5%; 0%), hematuria (22.4%; 0%), rash (22.4%; 0%), anemia (16.5%; 4.7%), dyspnea (20.0%; 1.2%), gastroesophageal reflux disease (20.0%; 0%), and onychoclasis (20.0%; 0%). Additionally, 9.4% and 1.2% of patients experienced atrial fibrillation and febrile neutropenia, respectively.

This trial remains open for enrollment of patients with relapsed/refractory MZL.

Based on the data seen so far, the global, randomized, double-blind, placebo-controlled, multicenter phase 3 ZILO-301 trial (NCT05431179) investigating ibrutinib with or without zilovertamab in patients with relapsed/refractory MCL has been initiated.

_Reference

_{Lee HJ, Choi M, Siddiqi T. et al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or marginal zone lymphoma (MZL). Blood. 2022;140(suppl 1):566-568. doi:10.1182/blood-2022-167153}