Novel Treatment Shows Promise, Manageable Safety in MCL, CLL

NVG-111, an ROR1-targeting bispecific T-cell engager (BiTE), produced promising responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) with a tolerable safety profile, according to data from the phase 1 NVG111-101 trial (NCT04763083).

The novel, humanized, tandem single-chain variable fragment ROR1 x CD3 BiTE has been found to produce potent activity against tumors by engaging a membrane-proximal epitope in the membrane proximal frizzled domain of ROR1 and in redirecting T-cell activity.

Among 5 patients with CLL, NVG-111 produced responses in 4, with a complete response (CR) observed in 2 patients and a partial response in 2 patients, according to data presented at the 2022 ASCO Annual Meeting.

Among those who experienced a CR, both patients showed undetectable minimal residual disease (MRD) at the last analysis. A long-term follow-up with 1 of the complete responders found that the patient still had undetectable MRD at 6 months post completion of NVG-111. The other complete responder will begin long-term follow-up after finishing the final cycle of NVG-111.

The 2 patients who were partial responders are already in long-term follow-up, whereas the fifth patient only achieved a cytokine response and was off study treatment after disease progression. NVG-111 produced a PR in the patient with MCL and that patient is currently in long-term follow-up.

NVG111-101 is a first-in-human trial analyzing the safety and efficacy of the novel treatment in hematological malignancies prior to being evaluated in solid tumors. The first part of the trial will enroll up to 36 patients with relapsed/refractory CLL, small lymphocytic lymphoma, or MCL, who were previously administered at least 2 lines of systemic therapy and who had stable disease or a PR after their last line of therapy.

The first cohorts included 1 patient each, who were administered an accelerated dose titration, with treatment given daily for 21 days on, 7 days off, in every 28-day cycle. Patients were administered the therapy for 3 cycles, or up to 6 cycles when applicable for each cohort.

The patient in cohort 1 received 0.3 μg of intravenous (IV) NVG-111 per day for each cycle. The patient in cohort 2 received 1 μg of IV NVG-111 per day in cycle 1, 3 μg in cycle 2, and 10 μg in cycle 3. The patient in cohort 3 was administered 3 μg of IV NVG-111 per day in cycle 1, 10 μg in cycle 2, and 30 μg in cycle 3.

In cohort 4, 3 patients were administered 30 μg of IV NVG-111 per day in all 3 cycles. All of the enrolled patients remained on salvage ibrutinib (Imbruvica) during study treatment.

The primary end point of NVG111-101 was safety, including adverse effects (AEs), serious AEs, and dose-limiting toxicities, with secondary end points that include anti-tumor activity, pharmacokinetics, and biomarkers. The 3 patients in cohort 4 experienced grade 1 cytokine release syndrome (CRS), which was resolved. None of the patients in the other cohorts experienced CRS.

In cohort 4, a patient with CLL experienced grade 3 immune effector cell-associated neurotoxicity syndrome during the first cycle of treatment. NVG-111 was subsequently stopped after 48 hours and the patient was administered dexamethasone and tocilizumab (Actemra).

There were no grade 3 or higher AEs or serious AEs reported, nor were any grade 2 AEs observed in any patients in cohorts 1-3. All patients in cohort 4 experienced multiple grade 1/2 AEs.

A pharmacokinetics analysis found that circulating NVG-111 levels from patients administered fewer than 10 μg per day were below the 250 pg/mL threshold for detection. At 10 μg/day, the average steady state (Avgcss) serum concentration was 168 pg/mL to 228 pg/mL. At 30 μg/day, the Avgcss serum concentration was 425 pg/mL to 610 pg/mL.

A biomarker analysis found a transient increase in cytokines detected with varying kinetics through all dosing levels.

The phase 1 trial is ongoing and an additional cohort expansion is planned for patients with CLL and MCL. The recommended phase 2 dose has not yet been determined.

Reference

Jasani P, Townsend W, Asher S, et al. First-in-human phase 1 study of a ROR1 targeting bispecific T cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL. J Clin Oncol. 2022;40(suppl 16):7535. doi:10.1200/JCO.2022.40.16_suppl.7535