ROR1-Directed ADC Generates Clinical Activity in First-In-Human Study of MCL and DLBCL

Michael L. Wang, MD

The novel ROR1-targeted antibody-drug conjugate (ADC) VLS-101 induced encouraging clinical efficacy, consistent pharmacokinetics, and a favorable safety profile as treatment of heavily pretreated patients with mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), in a phase 1 dose-escalation study, according to the findings presented during the 2020 ASH Annual Meeting.

The objective response rate (ORR) among patients with MCL (n = 15) was 47%, including 5 partial responses (PRs) and 2 complete responses (CRs). The ORR in patients with DLBCL (n = 5) was 80%, including 2 PRs and 2 CRs.

Moreover, patients with MCL who had prior high-dose therapy or hematopoietic stem cell transplant (HSCT) and patients with DLBCL who had prior high-dose therapy, HSCT, or CAR T-cell therapy derived PRs or CRs.

“The VLS-101 efficacy results provide the first clinical proof of concept for targeting ROR1, demonstrating durable objective responses in patients with advanced MCL or large B-cell lymphoma, including those with prior BTK inhibitor therapy or cellular therapies,” said lead study author Michael L. Wang, MD, a professor in the Department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center.

ROR1 is an oncofetal protein that plays a role in embryonic development. Although physiologic expression of ROR1 disappears before birth, pathologic expression of the protein can reappear in aggressive cancers, where it is expressed on the tumor cell surface.

VLS-101 utilizes the humanized IgG1k monoclonal antibody with a cleavable linker that delivers the anti-microtubule toxin monomethyl auristatin E (MMAE) to the ROR1 target through rapid internalization and lysosomal trafficking. The mean MMAE-to-antibody ratio is 4.

The phase 1 trial explored an every-3-week dosing regimen in a 3+3 design. VLS-101 was administered in 30-minute intravenous infusions. The initial dose given was 0.5 mg/kg of VLS-101 (n = 1), followed by 1.0 mg/kg (n = 3), 1.5 mg/kg (n = 3), 2.25 mg/kg (n = 11), and 2.5 mg/kg (n = 14). Intrapatient dose escalation was permitted, and interpatient and intrapatient dose modulation was used to inform starting dose selection.

Adult patients with relapsed/refractory B-cell cancers likely to express ROR1 were eligible for enrollment. Patients had to have progressive cancer or intolerance to standard therapies, as well as adequate organ function.

Evaluable patients (n = 32) had a median age of 70 (range, 54-84) and more than half (n = 19; 59.4%) were male. Patients had ECOG performance statuses of 0 (n = 18; 56.3%) 1 (n = 10; 31.3%), or 2 (n = 4; 12.5%).

The study enrolled patients with B-cell malignancies, including MCL (n = 15; 46.9%), chronic lymphocytic leukemia (n = 7; 21.9%), DLBCL (n = 5; 15.6), follicular lymphoma (n = 3; 9.4%), marginal zone lymphoma (n = 1; 3.1%), and Richter transformation lymphoma (n = 1; 3.1%).

Patients had a median of 4 prior lines of systemic therapy (range, 1-24), including anti-CD20 antibodies (n = 31; 97%), alkylators (n = 28; 88%), BTK inhibitors (n = 22; 69%), corticosteroids (n = 20; 63%), anthracyclines (n = 18; 57%), vinca alkaloids (n = 18; 56%), antimetabolites (n = 16; 50%), cereblon inhibitors (n = 8; 25%), proteasome inhibitors (n = 8; 25%), topoisomerase 2 inhibitors (n = 8; 25%), BCL-2 inhibitors (n = 7; 21%), and PI3K inhibitors (n = 4; 12%).

Additionally, 16% (n = 5) of patients had prior autologous transplant and 19% (n = 6) had prior CAR T- or NK-cell therapy.

The pharmacokinetics of VLS-101 were consistent with expected profiles of MMAE-containing ADCs.

Similarly, the safety profile of VLS-101 was in line with expected MMAE-related adverse effects (AEs).

Grade 3 and 4 neutropenia, the primary acute toxicity, was observed in 25% and 28% of patients, respectively. Prophylactic or reactive granulocyte colony-stimulating factor therapies, such as pegfilgrastim (Neulasta) and filgrastim (Neupogen), were effective in preventing or treating neutropenia.

Grade 2 and 3 neuropathy was observed in 22% and 13% of patients, respectively, and was the primary cumulative toxicity observed. Neuropathy was manageable with dose interruptions or dose modifications.

Grade 3 diarrhea was observed in 9% of patients, but it is unclear whether the toxicity was due to VLS-101. Moreover, diarrhea was managed with evaluation for alternate causes, antidiarrheals, and dose modifications.

Finally, grade 1 and grade 2 alopecia was observed in 3% and 6% of patients, respectively.

Of note, no instances of infusion reaction, venous irritation, tumor lysis syndrome, ocular, skin, cardiac, pulmonary, renal, hepatic, or metabolic toxicities, drug- or exposure-related cardiac QT interval prolongation, or clinically consequential immunogenicity was observed with VLS-101. Additionally, negligible cases of emetogenic potential, such as nausea and vomiting, were observed despite not giving routine antiemetic prophylaxis.

Ultimately, these findings confirmed that the phase 2 starting dose of VLS-101 will be 2.5 mg/kg administered every 3 weeks.

Phase 1 and 2 studies of VLS-101 as a single agent and in combination regimens in patients with hematologic malignancies, as well as solid tumors, are ongoing or planned, Wang concluded.

_Reference

_{Wang ML, Barrientos JC, Furman RR, et al. VLS-101, a ROR1-targeting antibody-drug conjugate, demonstrates a predictable safety profile and clinical efficacy in patients with heavily pretreated mantle cell lymphoma and diffuse large B-cell lymphoma. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; virtual. Abstract 121.}