2021EHA/ASCO/ICML|Otuzumab-based program opens up new ideas for lymphoma treatment

Otuzumab is the world's first humanized type II anti-CD20 monoclonal antibody with an innovative structure and mechanism.

Compared with type I rituximab, the direct cell death effect of the type II antibody, Ortuzumab, is enhanced; due to the structural modification of glycosylation, the antibody of Otuzumab depends on cell-mediated cytotoxicity (ADCC).
)/Antibody-dependent phagocytosis (ADCP) is more than 35 times stronger than rituximab.

Otuzumab has been approved abroad for multiple indications including newly-treated and relapsed and refractory follicular lymphoma (FL) and first-line treatment of chronic lymphocytic leukemia (CLL); it has been given priority by the FDA for lupus nephritis Approval qualifications.

At the same time, otuzumab is also a hot spot combination drug in the current clinical research of indolent lymphoma.

There are a number of otuzumab-related studies at the upcoming 2021 American Society of Clinical Oncology Annual Meeting (ASCO), the 26th European Hematology Annual Meeting (EHA) and the 16th International Conference on Malignant Lymphoma (ICML) Update.

Yimaitong has sorted out some important developments first, and will take you a quick glance.

New method: rapid infusion of otuzumab, safe and tolerable [ASCO-7545/EHA-EP807] GAZELLE study: the 2nd cycle and afterwards give FL patients rapid infusion of otuzumab, safe and feasible GAZELLE study is A prospective, open-label, multi-center, single-group, phase IV clinical study, which included 113 newly-treated FL patients, and there was no infusion-related level ≥3 after the first cycle (C1, standard infusion rate) treatment Response (IRR) patients receive Otuzumab (Obi) 90-minute rapid infusion (SDI) from C2.

The safety of FL patients receiving Obi 90-minute SDI from the second cycle was evaluated.

The primary endpoint is the incidence of IRR ≥ grade 3 during C2.

Secondary endpoints include adverse events (AE) and the overall response rate (ORR) at the end of induction as assessed by the researchers at the end of induction (EOT).

Of the 110 patients who received Obi SDI after the onset of C2, no patient had an IRR of grade ≥3 due to SDI in C2 (table).

One patient developed SDI-related grade 3 IRR in C5, which was manifested as hypertension.

Other IRR using SDI was 1/2 grade, and no 4/5 grade IRR occurred.

Other AEs are similar to those previously reported.

At the clinical deadline, 104 patients had been evaluated for effectiveness at EOI, 67.
3% of patients achieved complete remission (CR), and 19.
5% achieved partial remission (PR).

New era: Otuzumab combination regimen, "no chemotherapy" new choice for indolent lymphoma [ASCO-7544] LYSA Phase II clinical study: Otuzumab + venecola + atelizumab for the treatment of R/ R FL/MZL has good efficacy and safety.
The study has enrolled 78 patients with relapsed and refractory (R/R) FL and marginal zone lymphoma (MZL) until January 8, 2021, and received 24 cycles of Obi + Atelizumab (ATE) + Venecla (VEN) treatment.

The primary endpoint was ORR assessed by Lugano criteria.

The median follow-up time of the FL cohort (n=58) was 14.
5 months, the ORR was 53.
6%, including a 30.
4% molecular response (CMR).

The median follow-up time of the MZL cohort (n=20) was 11.
9 months, and the ORR was 66.
76%, including 16.
7% CR and 50% PR.

The effectiveness of the triple regimen in both the R/R FL and MZL cohorts was relatively long-lasting, with only 21.
4% of patients experiencing recurrence/progress.

The triple scheme did not bring unexpected toxicity.

Among 78 patients, a total of 55 patients had Grade 3-4 AEs, and 1 patient was discontinued due to AEs.

Adverse events of grade ≥3 were mainly hypocytopenia.

 Chronic lymphocytic leukemia [EHA-S146/ICML137] CLL14 study 4 years follow-up: Otuzumab + Venecla treatment for newly treated CLL, better curative effect: PFS longer, higher remission rate This report provides the CLL14 study According to the latest follow-up data, all patients have stopped the study treatment for at least 3 years.

432 newly-treated CLL patients with comorbidities randomly received 12 cycles of VEN + 6 cycles of Obi (VEN-Obi) or 12 cycles of chlorambucil + 6 cycles of Obi (Clb-Obi) at a 1:1 ratio .

The primary endpoint is PFS assessed by the investigator.

The key secondary endpoints are safety, remission rate, minimal residual disease (MRD) rate, and overall survival (OS).

After a median follow-up of 52.
4 months, the PFS of VEN-Obi was better than that of Clb-Obi (less than 36.
4 months, HR 0.
33 [95% CI 0.
25-0.
45], P <0.
0001) (left in the figure below).

Four years after randomization, the estimated PFS of the VEN-Obi group was 74.
0%, and that of the Clb-Obi group was 35.
4%.

Improvements in PFS were observed in all clinical and biological risk groups.

The time to next treatment in the VEN-Obi group was significantly longer (4-year TTNT: 81.
1% vs 59.
9%, HR 0.
46, 95% CI [0.
32-0.
65], P <0.
0001) (right in the figure below).

Thirty months after the end of treatment, 26.
9% of patients in the VEN-Obi group still had uMRD (< 10-4), while the uMRD rate in the Clb-Obi group was 3.
2%.

No difference in OS was observed between the two groups.

No new safety signals were observed.

[EHA-EP632/ICML31] The results of the MRD model of the CLL14 study: Otuzumab+Venecla can more effectively regulate the growth of MRD and eradicate MRDLL14.
The study established a stable, population-based MRD growth kinetics model.

The purpose of this report is to use this model to analyze the growth kinetics of MRD after drug withdrawal, and to compare the growth trajectory between targeted therapy and chemoimmunotherapy.

Studies have shown that the model is well calibrated, and the observed and predicted values ​​are in good agreement (Figure C).

The median MRD level at EOT in the VEN-Obi group was significantly lower than that in the Clb-Obi group (10-6.
00 vs 10-3.
26, P<2e-16); the median MRD doubling time was also significantly longer than that of the Clb-Obi treatment (84 days vs.
67 days, P=3.
3e-5) (Figure D); the median time from EOT to MRD level rising to 10-2 was also significantly longer than Clb-Obi (1225 days vs 227 days, P<2e-16) (Figure D).

The final model showed that VEN-Obi treatment, high MRD levels at the beginning of treatment, high CLL-IPI, 11q loss, high disease burden, treatment response and IGHV status have a significant impact on MRD growth kinetics.

After adjusting all covariates in the model, the effect of VEN-Obi treatment on MRD growth is still significant (Figure E, F).

[EHA-S149] HOVON 139/GIVE study: CLL patients who are not suitable for FCR tolerate otuzumab+venecla treatment well, and >50% of patients reached the primary study endpoint.
67 patients were included in this phase II study.
Newly-treated CLL patients who are suitable for FCR treatment receive VEN-Obi treatment.

Including 4 treatment phases: 2 cycles of Obi, 6 cycles of VEN-Obi (IND-1); 6 cycles of VEN (IND-2); and 1:1 random allocation phase: 12 cycles of VEN maintenance treatment, and Regardless of MRD (group A) or MRD-guided VEN maintenance (treatment is limited to patients without uMRD after IND-2, group B).

The primary endpoint is uMRD in the bone marrow, and there is no progression after up to 24 cycles of VEN treatment.

The results showed that 53% and 57% of patients in group A and group B reached the primary endpoint, and both met the preset requirements.

After 2 cycles of Obi, ORR was 43%, and improved to 94% after IND-2.

At the primary endpoint, the ORR of group A was 88% and group B was 97%.

Before randomization, AEs were mainly hematology and infection (mainly grade 2-3).

Finally, 62 patients underwent randomization.

The uMRD in the bone marrow after IND-2 was 79%; at the primary end point, it was 59% in group A and 57% in group B (below).

The estimated overall survival rate at 48 months is 94%.

[ASCO-TPS7567] EVOLVE CLL/SLL study (SWOG S1925, NCT04269902): Early intervention of VEN-Obi vs.
delayed treatment (ongoing) This study aims to use VEN-Obi as an early stage for asymptomatic, high-risk CLL patients Intervention programs to potentially prolong OS and thereby change the natural course of the disease.

On December 14, 2020, the researchers launched the study and enrolled adult patients diagnosed with CLL or SLL within 12 months.

Eligible patients include: CLL-IPI score ≥ 4 or complex cytogenetics (≥ 3 cytogenetic abnormalities), and do not meet the criteria for the treatment initiated by the CLL International Working Group.

The enrolled patients were randomized to receive early and delayed VEN-Obi treatment (when the indications for IWCLL treatment are met) in a 2:1 manner, and the treatment period is 12 months.

247 patients will be enrolled, and the estimated benefit time is 4 years.

The primary endpoint is OS; secondary endpoints include effective rate, PFS, recurrence-free survival, safety, time to the second CLL targeted therapy, and quality of life (FACT-Leukemia total score).

At present, the study has been open to join the group.

Summary The GALLIUM study proved that otuzumab combined with chemotherapy has brought new breakthroughs to the first-line treatment of FL, and the rapid infusion data announced this time has brought convenience and safety to FL patients from the method of administration.
Still good.

In addition, the good efficacy and safety of otuzumab combined with venecla and atelizumab in indolent lymphomas such as FL also brings "no chemotherapy" treatment for patients with relapsed and refractory indolent lymphomas.
may.

The update of the 4-year follow-up data of the CLL14 study once again verified the high efficiency and low toxicity of the fixed course of Otuzumab+Veneclax in the first-line treatment of CLL, and the benefits are durable.
The "limited treatment" yields long-term benefits.
CLL patients who are not suitable for FCR treatment are equally well tolerated, which provides more directions for the treatment of CLL patients in the era of new drugs.

In addition, there will be more otuzumab related research progress announced at the ICML conference, such as CLL14 research markers, prognostic risk index subgroup analysis, and otuzumab combined with bendamustine and acatinib Please look forward to the ICML follow-up report on the CLL2-BAAG trial of the "quadruple" treatment of CLL with Venecla.

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