ASH's new "shi" Li Hu Yu and Professor Jing Hongmei: Glofitamab is ready to go, providing rich reverie for the treatment of B-cell lymphoma

The 63rd annual meeting of the American Society of Hematology (ASH), the largest international event in the field of hematology in the world, was held in Atlanta, USA from December 11 to 14, 2021
.

The publication of a number of major studies and the latest results at the ASH annual meeting has greatly promoted the development of the field of hematology, and provided an opportunity for academic exchanges to promote the diagnosis and treatment of blood system diseases for clinicians
.

Just in time, closely following international hotspots, focusing on the frontiers of diffuse large B-cell lymphoma (DLBCL) and immunotherapy, Yimaitong sincerely invites professors Hu Yu and Jing Hongmei to share the CD20/CD3 bispecific antibody (BsAbs) Glofitamab Prospects in the field of aggressive lymphoma (aNHL) for readers
.

Key Contents CD20/CD3 is one of the most promising dual-antibody-target combinations for relapsed or refractory (R/R) aggressive B-cell lymphoma, and many drugs at home and abroad are in the research stage, among which Glofitamab is the most advanced in development in China.
Quick, registered clinical studies are already underway
.

At this year's ASH meeting, the progress of Glofitamab in the aNHL field has attracted much attention.
The clinical research data of monotherapy, combined with light chemotherapy or chemotherapy in the treatment of R/R aNHL patients are encouraging, and first-line treatment is also being deployed
.

Glofitamab has carried out two studies in China and obtained CDE breakthrough therapy designation: Phase I GLOSHINE study and Phase III STARGLO study.
The research and development in China is synchronized with the world, and it is expected to benefit Chinese patients earlier
.

Ready-to-use immunotherapy persists, and the CD20/CD3 bispecific antibody Glofitamab stands out.
Since the 1990s, the anti-CD20 monoclonal antibody rituximab has completely changed the treatment model for B-cell lymphoma
.

Twenty years later, cell-engineered chimeric antigen receptor (CAR) T-cell therapy was approved for third-line treatment of aggressive B-cell lymphomas or other hematologic malignancies
.

With the continuous in-depth understanding of tumor immune mechanisms, many ready-to-use immunotherapies in the aNHL field are also in the rapid development stage
.

As a new type of ready-to-use immunotherapy, bispecific antibodies have obvious efficacy in R/R aNHL patients including relapse after CAR-T treatment, and can avoid the challenges faced by customized products 1
.

CD20/CD3 is one of the most promising dual-antibody target combinations for lymphoma treatment.
In the field of R/R aggressive B-cell lymphoma, the dual-antibodies under development include Glofitamab, Mosunetuzumab, Epcoritamab and Odronextamab, among which development progress in China The fastest is Glofitamab, an IgG1-like fully humanized, Fc-segmented, CD20/CD3 bispecific antibody with a unique 2:1 structure that binds to both CD20 on B cells and CD3 on T cells , induce the activation of T cells and immune responses against tumor cells, thereby achieving anti-tumor effects
.

Different from the CD19/CD3 bispecific T cell engager (BiTE) blinatumomab, which does not contain an Fc segment, the CD20/CD3 bispecific antibody Glofitamab with an Fc segment has a longer half-life and is more in line with the needs of routine clinical administration.
/R invasive B-cell lymphoma has the potential to improve remission rate and ensure good safety in clinical application 1
.

Figure 1.
Development prospects of customized cell engineering and ready-to-use immunotherapy in the aNHL field.
In the field of aggressive lymphoma, Glofitamab has achieved good results.
At this year's ASH meeting, the progress of Glofitamab in the aNHL field has attracted much attention, and multiple drug regimens have performed well: single drug Data from clinical studies in patients with R/R aNHL have been encouraging with treatment, combined with light chemotherapy, or chemotherapy regimens
.

In addition, the first-line treatment of the Glofitamab combination regimen has also begun to be deployed in the field of DLBCL, with a view to providing more treatment options in the future
.

"Chemo-free" Glofitamab monotherapy may become a new option.
The NP30179 study (NCT03075696) 2 is a phase I/II dose escalation/expansion study, including a total of 258 patients with R/R NHL, with median prior treatment The number of lines is 3 (1-13)
.

With a median follow-up of more than 13 months, in 175 patients with evaluable aNHL, a single-agent fixed course of Glofitamab after pretreatment with otuzumab showed high antitumor activity, demonstrated high response rates and Durable deep remission: The recommended phase II trial dose (RP2D: 2.
5/10/30mg) has the highest degree of remission, with an objective remission rate (ORR) of 78.
6%, of which the complete remission (CR) rate is 71.
4%; the median duration of CR Time has not been reached, 72.
5% of patients who achieved CR were still in persistent CR after 12 months of follow-up, and the median duration of response (DoR) of patients who achieved remission (n=94) was 29.
4 months (95% CI: 6.
0–NE )
.

This dataset is the largest DoR dataset to date for CD20/CD3 bispecific antibodies
.

Figure 2.
Response rates of Glofitamab monotherapy in aNHL.
Sixty-nine percent of patients with mantle cell lymphoma (MCL) enrolled in the aNHL cohort of the NP30179 study had failed prior BTK inhibitor therapy, among 21 evaluable patients with R/R MCL.
, ORR was 81.
0%, complete metabolic remission (CMR) rate was 66.
7%
.

Although most previous BTK inhibitor therapy failed, the response rates in these patients were comparable to those in BTK inhibitor-naïve patients 3
.

Figure 3 Response rate of Glofitamab monotherapy in R/R MCL In terms of safety, the study confirmed that Glofitamab is safe and controllable in the treatment of aNHL patients, and no new safety signals were detected
.

The most common adverse reaction was cytokine release syndrome (CRS) (58.
9%), and the duration of CRS was mostly mild (grade 1-2), mainly limited to cycles 1 and 2
.

None of the 4 Glofitamab-related neurological adverse events were serious and recovered by the clinical cutoff date 2
.

Strong Combination, "Chemo-light" Glofitamab + Pola Innovative Combination Program NP39488 Study 4 is a Phase Ib/II dose escalation and expansion study of 59 adult patients with R/R DLBCL, mostly high-risk, and/or Patients who are refractory to previous treatment
.

Among 49 patients who could be evaluated for efficacy, the combination therapy of Glofitamab + Polatuzumab Vedotin (Pola) showed a high response rate, and in transformed follicular lymphoma (trFL), high-grade B-cell lymphoma (HGBCL) Remissions were also observed in many patients (trFL: ORR 8/11, including 7 CR; HGBCL: ORR 5/8, including 4 CR)
.

Although the follow-up time has been limited so far, the median 3.
7 months, 23/25 patients continued to CR until the data cut-off time
.

No new safety signals were detected in the Glofitamab+Pola combination regimen, and the safety was consistent with that of the single drug, which supports further confirmatory studies
.

Figure 4 The remission rate of Glofit+Pola in the treatment of R/R DLBCL is not limited to relapse and refractory.
Glofitamab explores more DLBCL first-line combination regimen NP40126 study (NCT03467373) 5 is an ongoing phase Ib study, preliminary results of first-line DLBCL safety trial It has been shown to have a tolerable safety profile
.

A total of 26 patients with newly diagnosed DLBCL who received Glofitamab-R-CHOP were included in the study, with a median age of 68 years, Ann Arbor stage III/IV, and 46.
1% of the patients were intermediate and high-risk patients
.

In 9 patients who could be evaluated, the CMR rate was 89% (8/9), the DoR was not currently reached (range: 1-12), the CRS rate was very low and there were no neurotoxic adverse events, so it may be suitable for outpatient environment
.

The research is still in progress, and more detailed research data are expected to be released in the future
.

Table 1 Response rate of Glofit+R-CHOP in first-line DLBCLTable 2 Safety results -CHOP or Pola-R-CHP) safety and preliminary efficacy of first-line therapy in young high-risk DLBCL
.

The primary criteria for inclusion were: 18-65 years of age, diagnosed with DLBCL or high-grade B-cell lymphoma (HBGL), with high-risk features (IPI ≥ 3 or NCCN-IPI ≥ 4 or presence of DHL/THL), untreated Or only received 1 cycle of R-CHOP treatment, ECOG score 0-3
.

Patients will receive R-CHOP in cycle 1, followed by 5 cycles of combined induction therapy and 2 cycles of Glofitamab single-agent consolidation therapy
.

The study is currently recruiting.
Whether Glofitamab can continue to be the icing on the cake, this study is worth looking forward to
.

*Pola-R-CHP: Pola combined with rituximab, cyclophosphamide, doxorubicin, prednisone; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine , Prednisone Figure 5 COALITION study design Glofitamab research and development in China is synchronized with the world, and it is expected to benefit Chinese patients earlier.
Glofitamab mainly focuses on aNHL, especially in the field of DLBCL.
Other innovative combinations such as chemotherapy or Pola explore the benefits of treatment in the front-line population, and gradually provide more Chinese patients with new treatment options through solid clinical exploration and evidence-based evidence.
Currently, two clinical studies have been launched in China and will be launched in 2021.
On August 7, 2018, it was officially granted Breakthrough Therapy Designation (BTD) by CDE for adult patients with R/R DLBCL after two or more lines of systemic treatment of its monotherapy, including DLBCL-NOS, HGBCL, trFL and original Mediastinal large B-cell lymphoma (PMBCL) is expected to benefit Chinese DLBCL patients earlier
.

The GLOSHINE study (CTR20202232)7 is a phase I, open-label, Chinese multicenter, single-arm study to evaluate Chinese patients with R/R DLBCL (including DLBCL-NOS, HGBCL, trFL and PMBCL) Pharmacokinetics, Safety, Tolerability, and Efficacy of Glofitamab Monotherapy Following a Single Otuzumab Pretreatment
.

Figure 6 The design of the Phase I GLOSHINE study in China The STARGLO study (NCT04408638)8,9 is a Phase III, open-label, randomized, global multicenter trial.
Chinese patients are an important enrollment population.
A total of 10 research centers participated in the study.
To evaluate the safety and efficacy of Glofitamab in combination with gemcitabine + oxaliplatin (Glofitamab-GemOx) and R-GemOx in patients with R/RDLBCL who have received ≥1 line of systemic therapy
.

The two groups were randomized 2:1 to receive up to 8 cycles of Glofitamab-GemOx or R-GemOx, followed by up to 4 cycles of Glofitamab monotherapy.
The primary endpoint of the study was overall survival (OS).

.

Figure 7 The global phase III STARGLO research design expert commented on Professor Hu Yu As a hot spot in the field of immunotherapy, the development of bispecific antibodies has always attracted attention
.

Since the concept was first proposed, bispecific antibody technology has been developed for more than 60 years, and bispecific antibodies targeting CD20/CD3 have become increasingly mature, becoming one of the most interesting research and development directions in the field of aggressive lymphoma
.

The latest progress of the CD20/CD3 bispecific antibody Glofitamab announced at this year's ASH meeting further demonstrates the strength of the bispecific antibody in the field of aggressive lymphoma, and is expected to provide new treatment options for more patients
.

Currently, Glofitamab is conducting two clinical studies in the Chinese R/R DLBCL population, gradually exploring the application prospects in third-line and second-line relapsed and refractory patients.
Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology is participating in its Phase III STARGLO study It is expected that Glofitamab will continue to enrich the deployment of clinical treatment drugs and benefit more Chinese DLBCL patients
.

Professor Jing Hongmei With the advancement of antibody engineering technology, bispecific antibodies targeting multiple antigen-binding sites have been developed and entered the clinical research stage
.

Preliminary results in Glofitamab monotherapy in R/R aNHL have demonstrated Glofitamab's excellent performance in improving remission rate and prolonging remission duration, with a manageable safety profile
.

From the latest progress of ASH, a variety of innovative combination regimens of Glofitamab are being deployed in the field of aggressive lymphoma.
The mechanisms of action of Glofitamab and Pola are unique and complementary, and the toxicity characteristics of the two drugs hardly overlap.
The study shows the same safety as the single drug regimen.
It is believed that the application prospect of Glofitamab will be very broad in the future.
We look forward to the release of more research data, expand more clinical indications, and provide more safe and effective treatment options for patients with hematological tumors
.

ASH's new "shi" force | Prof.
Zhu Jun and Huang Huiqiang: Glofitamab data is eye-catching in the field of relapsed and refractory aggressive lymphoma with "recovery" 3.
ASH's new "shi" force I Ma Jun, Song Yuqin: global phase III POLARIX study The result topped the LBA list, opening up a new pattern for first-line DLBCL treatment! 4.
ASH's new "shi" force | Prof.
Li Jianyong: Ortuzumab fixed-course regimen leads the future treatment direction of CLL "0 Bleeding" New Life for Patients with Friends A 7.
ASH's new "shi" force | Professor Sun Jing: Classical research and clinical practice strength demonstration, emicizumab helps patients with hemophilia A inhibitor to break through the restricted area of ​​surgery 8.
ASH's new "shi" force | Zhang Wei, Prof.
Zhang Liling: Inheriting the classics and continuing with a new chapter, Pola-R-CHP explores new heights of first-line cure for DLBCL Unique dosing method can effectively improve the safety profile ", we progress together