Novel ADC Delivers Responses and a Manageable Safety Profile in R/R Non-Hodgkin Lymphoma

Michael Wang

Zilovertamab vedotin (MK-2140) was tolerable and generated early efficacy signals in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to findings from the phase 1, first-in-human waveLINE-001 trial (NCT03833180) that were presented at the 17th Annual International Conference on Malignant Lymphoma.

At a median follow-up of 14.3 months (range, 0.5-48.5), 96% (n = 54) of patients who received zilovertamab vedotin at 0.5 mg/kg to 2.5 mg/kg intravenously (IV) on day 1 every 3 weeks experienced all-cause adverse effects (AEs) of any grade, and 70% (n = 39) of patients had at least 1 grade 3, 4, or 5 AE.

“Zilovertamab vedotin continued to demonstrate a manageable safety profile and promising antitumor activity in patients with heavily pretreated diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], and Richter transformation [RT],” lead study author Michael Wang, of The University of Texas MD Anderson Cancer Center in Houston, and coinvestigators, wrote in a poster of the data.

Several aggressive hematologic malignancies contain upregulated ROR1 oncofetal transmembrane proteins. Zilovertamab vedotin is an antibody-drug conjugate (ADC) containing the humanized ROR1-directed monoclonal antibody UC-961, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E (MMAE).

Eligible patients for waveLINE-001 included those at least 18 years of age with an ECOG performance status (PS) of 0 to 2 and relapsed/refractory NHL, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, acute lymphocytic leukemia, or acute myeloid leukemia (AML).

This trial consisted of 3 dosing schedules. At schedule 1, patients received zilovertamab vedotin at 0.5 mg/kg to 2.5 mg/kg IV on day 1 every 3 weeks. At schedule 2, patients received the agent at 1.0 mg/kg to 2.25 mg/kg IV on days 1 and 8 every 3 weeks. At schedule 3, patients received the agent at 1.0 mg/kg to 2.25 mg/kg IV on days 1, 8, and 15 every 4 weeks.

The coprimary end points of this trial were the establishment of the maximum tolerated dose and/or recommended dosing regimen. Key secondary end points included safety, objective response rate (ORR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Initial schedule 1 findings established 2.5 mg/kg IV on day 1 every 3 weeks as the recommended dosing regimen of zilovertamab vedotin, which was received by 54% (n = 30) of the 56 patients in the schedule 1 cohort.

At the data cutoff date of April 7, 2023, all patients in schedule 1 had discontinued treatment, 70% (n = 39), 18% (n = 10), 5% (n = 3), 2% (n = 1), and 5% (n = 3) because of progressive disease (PD), AEs, investigator decision, patient withdrawal, and other reasons, respectively.

The schedule 1 population had a median age of 70 years (range, 40-91); 66% (n = 37) of patients were 65 years of age or older. Additionally, 59% (n = 33) of patients were male and 80% (n = 45) had an ECOG PS of 0 or 1. In total, 82% (n = 46) of patients had NHL, of whom 30% (n = 17), 30% (n = 17), 13% (n = 7), and 9% (n = 5) had DLBCL, MCL, RT, and other NHL types. Furthermore, 13% (n = 7) of patients in the schedule 1 cohort had CLL/SLL, and 5% (n = 3) of patients had AML.

When stratified by NHL subtype, the median follow-ups were 8.9 months (range, 0.5-44.3), 12.2 months (range, 1.1-47.1), and 15.6 months (range, 2.7-26.9) in patients with DLBCL, MCL, and RT, respectively.

In the DLBCL population, 47% (n = 8), 35% (n = 6), and 18% (n = 3) of patients had germinal center B cell–like (GCB), non-GCB, and unknown disease, respectively.

In the MCL population, 53% (n = 9), 24% (n = 4), 12% (n = 2), and 12% (n = 2) of patients had blastoid, pleiomorphic, classical, and unknown morphology, respectively. TP53 mutations were detected in 53% (n = 9) of patients.

All patients in the RT population had DLBCL.

The patients in the DLBCL cohort had a median of 4 prior lines of therapy (range, 1-9), including transplant, CAR T-cell therapy or CAR natural killer (NK)–cell therapy, an MMAE-directed ADC, and a BTK inhibitor in 12% (n = 2), 71% (n = 12), 24% (n = 4), and 18% (n = 3) of patients, respectively. Of the patients with prior BTK inhibitor exposure, 2 discontinued this treatment because of PD and 1 discontinued this treatment because of treatment-related AEs (TRAEs).

The patients with MCL had a median of 4 prior lines of therapy (range, 1-9). In total, 24% (n = 4) of patients had received prior transplant, and all patients had received a prior BTK inhibitor, of whom 14, 2, and 1 discontinued this treatment because of PD, TRAEs, and other reasons, respectively.

The patients with RT had a median of 6 prior lines of therapy (range, 1-10). In total, 29% (n = 2) of patients had received prior CAR T-cell therapy or CAR NK-cell therapy, and 71% (n = 5) of patients had received prior BTK inhibitors, 3, 1, and 1 of whom discontinued this treatment because of PD, other reasons, and unknown reasons, respectively.

The investigators observed TRAEs of any grade in 73% (n = 41) of patients. A total of 48% (n = 27) and 21% (n = 12) of patients experienced grade 3/4 or serious AEs, respectively. The most common TRAEs were fatigue, decreased neutrophil counts, nausea, diarrhea, peripheral sensory neuropathy, myalgia, decreased appetite, dizziness, peripheral neuropathy, dyspnea, decreased hemoglobin, decreased platelet counts, abdominal pain, alopecia, asthenia, constipation, stomatitis, and vomiting. Peripheral neuropathy occurred in 48% (n = 27) of patients, and the estimated median time to first peripheral neuropathy was 15.6 weeks.

Overall, 23% (n = 13) 45% (n = 25), and 7% (n = 4) of patients, respectively, discontinued treatment because of AEs, required treatment interruption or reduction because of AEs, and died because of AEs, all of which were unrelated to the study treatment. No patients experienced tumor lysis syndrome or infusion-related reactions.

In all patients in the schedule 1 cohort, the ORR was 32% (95% CI, 20%-46%), including best responses of complete response (CR; 13%; n = 7), partial response (PR; 20%; n = 11), stable disease (SD; 25%; n = 14), PD (25%; n = 14), and not evaluable (NE; 18%; n = 10).

In the DLBCL cohort, the ORR was 29% (95% CI, 10%-56%), including best responses of CR (18%; n = 3), PR (12%; n = 2), SD (24%; n = 4), PD (35%; n = 6), and NE (12%; n = 2). In the patients with GCB DLBCL, non-GCB DLBCL, and unknown DLBCL subtypes, the ORRs were 25% (95% CI, 3%-65%; 2 CRs/0 PRs), 33% (95% CI, 4%-78%; 1 CR/1 PR), and 33% (95% CI, 1%-91%; 0 CR/1 PR), respectively.

In the MCL cohort, the ORR was 53% (95% CI, 28%-77%), including best responses of CR (12%; n = 2), PR (41%; n = 7), SD (18%; n = 3), PD (12%; n = 2), and NE (18%; n = 3). In the patients with blastoid, pleomorphic, classical, and unknown MCL morphologies, the ORRs were 33% (95% CI, 8%-70%; 1 CR/2 PRs), 50% (95% CI, 7%-93%; 0 CR/2 PRs), 100% (95% CI, 16%-100%; 0 CR/2 PRs), and 100% (95% CI, 16%-100%; 1 CR/1 PR), respectively. In patients with TP53-mutated MCL, the ORR was 44% (95% CI, 14%-79%).

In the RT cohort, the ORR was 57% (95% CI, 18%-90%), including best responses of CR (29%; n = 2), PR (29%; n = 2), PD (29%; n = 2), and NE (14%; n = 1).

In the patients with NHL who received prior CAR T-cell or CAR NK-cell therapy (n = 14), the ORR was 36% (95% CI, 13%-65%), including best responses of CR (21%; n = 3), PR (14%; n = 2), SD (14%; n = 2), PD (43%; n = 16, and NE (7%; n = 1).

The median TTRs in the DLBCL, MCL, and RT cohorts were 2.3 months (range, 1.8-4.6), 2.3 months (range, 1.8-11.5), and 2.0 months (range, 0.6-2.1), respectively.

The median DOR was 9.6 months (range, 0.03-30.7) in all patients who achieved an objective response.

In the DLBCL cohort, the median DOR was 4.6 months (range, 2.9-21.5). In patients with GCB DLBCL, non-GCB DLBCL, and unknown DLBCL subtypes, the median DORs were 9.6 months (range, 2.9-16.3), not reached (NR; range, 4.6-21.5 months), and 2.9 months (range, 2.9-2.9), respectively.

In the MCL cohort, the median DOR was 10.0 months (range, 0.0-30.7). In patients with blastoid, pleomorphic, classical, and unknown MCL morphologies, the median DORs were 10.0 months (range, 2.3-30.7), 8.9 months (range, 2.1-15.7), NR (range, 3.9-11.6 months), and 9.6 months (range, 0.0-9.6), respectively.

In the RT cohort, the median DOR was 2.3 months (range, 0.0-2.8).

The median PFS was 4.5 months (95% CI, 3.3-7.5) in all patients.

In the DLBCL cohort, the median PFS was 3.3 months (95% CI, 0.7-7.0). In patients with GCB DLBCL, non-GCB DLBCL, and unknown DLBCL subtypes, the median PFSs were 0.7 months (95% CI, 0.5-0.7), 3.3 months (95% CI, 2.0-NR), and 4.5 months (95% CI, 0.3-NR), respectively.

In the MCL cohort, the median PFS was 11.4 months (95% CI, 4.0-NR). In patients with blastoid, pleomorphic, classical, and unknown MCL morphologies, the median PFSs were 4.5 months (95% CI, 1.1-NR), 4.2 months (95% CI, 4.0-NR), NR (95% CI, NR-NR), and 11.4 months (95% CI, NR-NR), respectively.

In the RT cohort, the median PFS was 2.3 months (95% CI, 0.7-NR).

The median OS was 20.5 months (95% CI, 10.1-NR) in all patients.

In the DLBCL cohort, the median OS was 9.1 months (95% CI, 2.7-29.0). In patients with GCB DLBCL, non-GCB DLBCL, and unknown DLBCL subtypes, the median OSs were 7.2 months (95% CI, 0.5-NR), NR (95% CI, 2.7-NR), and 4.5 months (95% CI, 1.0-NR), respectively.

In the MCL cohort, the median OS was 18.0 months (95% CI, 7.1-NR). In patients with blastoid, pleomorphic, classical, and unknown MCL morphologies, the median OSs were 12.2 months (95% CI, 3.3-NR), 18.0 months (95% CI, 5.4-NR), NR (95% CI, NR-NR), and NR (95% CI, 12.2-NR), respectively.

In the RT cohort, the median OS was 19.4 months (95% CI, 2.7-NR).

“These results are consistent with prior findings of waveLINE-001 and support continued investigation of zilovertamab vedotin in patients with heavily pretreated relapsed/refractory NHL,” the study authors concluded.

Reference

Wang ML, Mei M, Barr PM, et al. Zilovertamab vedotin (MK-2140) in relapsed or refractory non-Hodgkin lymphoma: 14-month follow-up of the phase 1 waveLINE-001 study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 427.