The Type II Glycoengineered Humanized Anti-CD20 Monoclonal Antibody MIL62 Combined with Lenalidomide in Chinese Patients with Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma: Results of a Multicenter, Single-Arm, Phase 1b/2 Trial
Authors: Shi Yuankai , Qin Yan , Song Yongping , Zhou Keshu , Zhou Hui , Jing Hongmei , Xiang Ying , Wang Zhao , Wang Zhen , Zang Aimin , Bai Ou , Li Zhenyu , Zhang Huilai 
Published: November 2021

Abstract
Background: A novel glycoengineered type II anti-CD20 antibody, MIL62 with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Lenalidomide combined with anti-CD20 antibody is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin lymphoma. This open-label, multicenter, phase 1b/2 trial (ClinicalTrials.gov, identifier NCT04110301) aims to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL).
Methods: Eligible patients included those who had histopathological confirmed CD20 positive MZL or FL of WHO grades 1-3a and had received one to four prior systemic regimens (with at least one rituximab-containing therapy). Patients received oral lenalidomide (15-20 mg; 28-day cycles; days 2-22) plus intravenously infused MIL62 as induction therapy (1000 mg; eight 28-day cycles; cycle 1: day 1, 15; cycle 2-8: day 1) for 8 cycles, maintenance therapy with lenalidomide (10 mg) once a day, and on Days 2-22 plus MIL62 (1000 mg) every 8 weeks on day 1 for 4 cycles. The primary endpoint was objective response rate, defined as a complete response or partial response assessed by investigator per Lugano 2014 criteria every 12 weeks. The secondary endpoints were duration of response, pharmacokinetics, and safety. Adverse events (AEs) were graded by CTCAE criteria version 5.0.
Results: From November 29 th, 2019 to December 22 th, 2020，54 patients enrolled from 11 centers in China received at least one dose of either MIL62 or lenalidomide. Median age was 50.0 (range: 28 to 85) years. A total of 51 patients (94.4%) had FL, and 3 patients (5.6%) had MZL. The median number of prior therapies was 1.0 (range: 1 to 4) and 20 (37%) patients were refractory to rituximab. Overall, 23 patients (42.6%) were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index 2 (FLIPI-2). The median treatment time of MIL62 and lenalidomide was 28.6 (range: 0.1-53.7) weeks and 27.9 (range: 2.0-56.6) weeks, respectively.
At the data cut-off date (June 30 th, 2021), the median follow-up time was 8.4 (range: 5.8-9.1) months. Overall, 42 (84.0%) of 50 assessable patients had an objective response, including 8 (16.0%) with complete response and 34 (68.0%) with partial response (Table 1). Especially, among 20 patients refractory to rituximab, 16 (80.0%) patients had an objective response, including 3 (15.0%) with complete response and 13 (65.0%) with partial response. The 9-month remission rate and 12-month progression-free survival rate were 80.2% (95%CI 58.1-91.4) and 71.2% (95%CI 50.6-84.4), respectively.
Among 54 safety-evaluable patients, all experienced at least one treatment-emergent adverse event (TEAE). Most common treatment-related adverse event (TRAEs) occurring in ≥10% of patients were neutropenia (85.2%), leukopenia (72.2%), thrombocytopenia (57.4%), infusion-related reactions (16.7%), lymphopenia (27.8%), increases in alanine/aspartate aminotransferase (14.8%/13%). Grade 3 or above TEAEs were observed in 40 (74.1%) patients, among which related to MIL62 in 35 (64.8%) patients, including neutropenia in 25 (46.3%) patients, leukopenia in 10 (18.5%) patients, thrombocytopenia in 9 (16.7%) patients, lymphopenia in 4 (7.4%) and herpes zoster, infusion related reaction, tumor lysis syndrome and abdominal pain in 1 (1.9%) patient, respectively. Severe adverse events (SAEs) were observed in 13 (24.1%) patients, and MIL62- and lenalidomide-related SAEs occurred in 8(14.8%) and 8(14.8%) patients, respectively.
Conclusion: MIL62 combined with lenalidomide showed promising efficacy in previously treated patients with relapsed or refractory FL and MZL, including those with early relapse, and has a manageable safety profile. A multi-center, randomized, open-label, phase III trial of MIL62 plus lenalidomide versus lenalidomide in rituximab refractory FL patients is ongoing (NCT04834024).
Keywords: MIL62; type II anti-CD20 monoclonal antibody; recurrent/refractory follicular lymphoma; recurrent/refractory marginal zone lymphoma
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.