【News】The ninth live broadcast of the "Drug Precision" series ended successfully, focusing on drug targets, and pharmaceutical company celebrities talked about the progress of DLBCL targeted drug research and clinical treatment!

On October 26, the ninth live broadcast of the series of live broadcast column "Drug Precision" jointly planned by Genetron and Translational Medicine Network was successfully completed, focusing on the hot content related to "DLBCL targeted drug research and clinical treatment progress
".

In the presentation session, the first speaker was Dr.
Ni Fan, Director of Medical R&D from InnoCare, who gave a keynote speech
entitled "DLBCL Targeted R&D Strategy".

First, Dr.
Fan briefly introduced the clinical features of diffuse large B-cell lymphoma (DLBCL) and the latest NCCN guidelines
.
The median age of diagnosis of DLBCL is 60-70 years, with slightly more men than women, and most patients are already in an aggressive stage
at the time of initial diagnosis.
At present, NCCN guidelines have many recommendations for different treatment lines, but the treatment outcomes of DLBCL patients are still largely inadequate, and a large proportion of patients do not achieve sustained remission and eventually die of lymphoma, so there is still an urgent clinical need
.

Dr.
Fan then introduced three cases and shared DLBCL's R&D strategy
from three different perspectives.

Firstly, based on whole exome sequencing and molecular classification of structural genomic abnormalities, DLBCL is divided into genetic subtypes characterized by targetable genetic changes, including MCD, BN2, N1, A53, ST2, EZB, etc.
, thus paving the way
for a new era of precision medicine 。 Taking MCD as an example, MCD subtypes are characterized by double mutations of MYD88 and CD79b, which have poor prognosis and short PFS time after RCHOP treatment.
The MCD subtype depends on the long-term activation of the BCR signaling pathway, and by inhibiting the activity of BTK, and then inhibiting the BCR signaling pathway, it has become a potential target for the treatment of MCD subtypes
.
Previous studies suggest that due to the high heterogeneity of DLBCL, cell-source-oriented treatment strategies cannot surpass R-CHOP with R-CHOP
+X.
Preliminary results from the Guidance-01 Phase II study ^[1] from the team of President Zhao Weiyi of Ruijin Hospital showed that the response rate of R-CHOP+X was significantly higher than that of standard treatment group (87% vs 66%, p=) according to the molecular subgroup (ibrutinib for MCD and BN2, demethylation drug deceitabine to TP53 mutant group, HDAC inhibitor in EZB group, N1, and other addition of lenalidomide).
0.
003), in the subgroup analysis, it was found that the CR rate of R-CHOP-X in the MCD, BN2, and TP53 subgroups was significantly higher than that of the control, and the significantly improved response rate was ultimately translated into a survival benefit, and the 1-year PFS rate was 96%, which was significantly higher than that of the control group (HR = 0.
22).

Despite the small sample size, this "proof-of-concept" study suggests the potential benefits of mechanism-based, tailored treatment strategies and facilitates further research
in this direction.

That's why InnoCare is conducting a randomized, double-blind, placebo-controlled phase III study (BELIEVE-01) for patients with diffuse large B who
are newly treated for MCD subtypes.
Orelabrutinib is an optimally designed BTK inhibitor that is highly selective for BTK targets, with a share of nearly 100%, which greatly reduces the toxic side effects caused by off-target effects
.
At present, no BTK inhibitor has been approved for DLBCL, and the BELIEVE-01 study is the world's first registered study targeting MCD subtypes, and it is expected that in the BELIEVE-1 study, orelabrutinib + R-CHOP combination can bring patients more durable remission and safer treatment experience
.

Dr.
Fan went on to introduce a case study
of achieving first-in-class through new targets.
Polatuzumab vedotin is an ADC
that targets the B cell surface antigen receptor CD79b.
Because POLA-vedotin acts on the microtubule system in cells, it replaces vincristine in RCHOP and becomes POLA-R-CHP
.
THE RESULTS FROM THE PHASE III POLARIX TRIAL ^[2] INDICATE THAT POLA-R-CHP SIGNIFICANTLY PROLONGS THE PFS AND EFS
OF NEWLY DIAGNOSED INTERMEDIATE- AND HIGH-RISK DLBCL COMPARED WITH STANDARD FIRST-LINE THERAPY R-CHOP.
This is one of the few treatment options
shown to surpass R-CHOP in recent years.
However, there was no significant difference in 2-year OS (88.
7 versus 88.
6 percent), possibly due to shorter follow-up and response to
subsequent salvage therapy.

Dr.
Fan then introduced the case
of developing new mechanisms of action for mature targets that can also achieve first-in-class.
CD19 is a well-established and preferred target for the treatment of B-cell malignancies
.
CAR-T targeting CD19 has shown excellent efficacy
in the field of B-cell malignancies.
Tafasitamab is an Fc-segment-enhanced humanized anti-CD19 monoclonal antibody that targets the same target, but a new mechanism of action, as a first-in-class, exhibits activity in B-cell malignancies and has a good synergistic effect
with lenalidomide.
The phase II single-arm L-MIND study evaluated tafa plus lenalidomide in relapsed, refractory diffuse large B not suitable for transplantation, with an ORR of 61%, a CR rate of 43%, and a median duration of response (DOR) of 21.
7 months
.
Based on this result, in 2020, TAFA combined with lenalidomide received accelerated FDA and EMA approval for the treatment of R/R DLBCL
that is not suitable for transplantation.
Last year, InnoCare licensed in tafasitamab, and the study of tafa-len in China is currently underway, and it is hoped that InnoCare will bring this excellent product to China as soon as possible to benefit Chinese patients
with diffuse large B lymphoma.

Dr.
Fan concluded that there will be certain differences in the distribution of molecular subtypes in different races and regions, and it is necessary to avoid the bias
of research results caused by inconsistent genetic background of the population when developing globally.
Molecular-based therapeutic strategies are a future direction, and accessibility to testing will be a challenge
.
Only by transforming whole genome sequencing into a simplified platform that can detect the relevant characteristics of different genetic subgroups can we promote the popularization
of molecular signature-based precision treatment strategies in the clinic.
Precision treatment strategies will be updated
in the near future as research progresses.

InnoCare Dr.
Fanny

Then, Director Liu Wei, deputy chief physician of the Hematology Hospital of the Chinese Academy of Medical Sciences, made a keynote report
entitled "New Progress in DLBCL Diagnosis and Treatment".
Director Liu Wei's report was launched
from two aspects: "optimization and exploration of front-line solutions" and "a hundred schools of thought contending, seeking vitality on the back line".

Director Liu first said that the first-line treatment status of R-CHOP cannot be surpassed, and most treatment programs other than R-CHOP have failed
.
Only about 60 percent of patients are cured from first-line therapy, and 30 to 40 percent of patients will relapse to refractory ^[3].

Once the patient enters the stage of relapse and refractory treatment, the proportion of re-cured in treatment is still significantly reduced
.

Director Liu then introduced some new attempts at first-line treatment, the Roche pivotal phase 3 POLARIX trial (NCT03274492) ^[2].
CD79b-targeted antibody conjugate (ADC) Polivy (polatuzumab vedotin) combined with chemotherapy regimen MabThera/Rituxan (rituximab) + cyclophosphamide + doxorubicin + prednisone regimen (abbreviation: Polivy + R-CHP regimen) were evaluated, and the standard regimen MabThera/Rituxan + cyclophosphamide + doxorubicin + was evaluated Vincristine + prednisone regimen (R-CHOP regimen) for efficacy, safety and pharmacokinetics
of first-line therapy.
In the study, Polivy+R-CHP had a similar safety profile
to R-CHOP.
In the CAVALL study, Ven+R-chop ^[4] improved outcomes in BCL2-positive patients, and the results showed that 2-year PFS had some advantages in the overall population and the IHC BCL2-positive population, but the ORR and CR rates were not significantly improved
compared with GOYA.
DA+EPOCH-R+venetoclax treatment with HGBCL may result in increased toxicity and is not recommended
for patients with DHL.
The SMART START study^[5], for RLI sequential combination chemotherapy, achieved a 2-cycle ORR of 86.
2% and a CR of 36%, bringing good survival and safety
controllability.
EPCO combined with R-CHOP in the first-line treatment of high-risk DLBCL patients also has good efficacy and safety
.
Mosunetuzumab ^[6] achieved 63.
5% and CRR of 45.
5%
for the first-line treatment of elderly DCLBL.
For relapsed and refractory DLBCL, Director Liu introduced in detail the key studies of three marketed Car-T for the treatment of LBCL, and the prognosis is still very poor
for those patients who do not respond to salvage therapy, are not suitable for sequential autologous hematopoietic stem cell transplantation (HSCT) for other reasons, and relapse after transplantation.
Patients with refractory large B lymphoma with ASCT combined with CNCT19 had a median follow-up of 15.
5 months, and PFS and OS were not achieved
.
Bispecific antibodies have become a new treatment option
for R/R DLBC.
In combination with immunotherapy and X, how to accurately define the benefit population, balance the efficacy and safety is the key
.

Director Liu finally concluded that CAR-T brings hope for re-cure of relapsed and refractory DLBCL in more than two lines, bispecific antibodies bloom brightly, and solo and combination therapy brings post-line vitality to relapsed and refractory DLBCL
.
In the later stage, ADC and new CD19 monoclonal antibody became a new option for
salvage therapy.
If patients can be individualized and the most suitable targeted therapy or cell therapy drugs can be found, it is expected to achieve clinical cure
of DLBCL patients as soon as possible.
Therefore, further analysis of its biological background is required to provide further possibilities
for the selection of targeted therapies.

Director Liu Wei, Hematology Hospital, Chinese Academy of Medical Sciences

Finally, Dr.
Wang Chunyang, Senior Translational Medicine Manager of Genetron, gave a speech
entitled "Exploration and Application of ctDNA in Precision Diagnosis and Treatment of DLBCL Patients".

Dr.
Wang first elaborated on the relevant genetic characteristics of ctDNA testing, such as gene mutation, methylation, amplification or rearrangement, fragmentation size, etc
.
ctDNA can be used as an important indicator for tumor diagnosis, treatment efficacy evaluation, prognosis risk stratification, recurrence risk prediction, and the detection methods currently applied to lymphoma liquid biopsy are mainly based on IG/TCR clonal rearrangement and targeted capture detection of second-generation sequencing
.

Dr.
Wang then introduced the application of ctDNA detection in various diagnosis and treatment links of DLBCL, ctDNA can assist in the diagnosis of lymphoma, for many types, different lymphomas have significant molecular characteristics, ctDNA can be used for genetic mutation screening of DLBCL patients, accurate detection of patient prognosis biomarkers can better guide clinical treatment
.
ctDNA overcomes the heterogeneity of tissue testing
by detecting genetic mutations that are not detected in the primary tumor tissue.
Several retrospective studies have confirmed that ctDNA levels in DLBCL patients are significantly correlated with tumor burden, and changes in tumor burden can be observed by monitoring the fluctuation of ctDNA levels during treatment and used for prognostic assessment
.

Dr.
Wang then said that ctDNA detection can guide the prediction
of efficacy in the clinical treatment of DLBCL.
After R-CHOP standard first-line treatment, although 50%~60% of DLBCL patients can achieve cure, 40%~50% of patients will enter the refractory or relapsed stage ^[3], which is an important challenge
in the current treatment of DLBCL.
Therefore, it is of great
significance for efficacy monitoring and recurrence prediction in patients with DLBCL.
Imaging detection methods such as PET-CT have low sensitivity and high false positives, so more sensitive and specific monitoring methods are key
for the clinical diagnosis and treatment of DLBCL patients.
ctDNA testing predicts clinical recurrence
by a median of 3.
5 months earlier than imaging or flow cytometry.
In DLBCL patients after first-line therapy, ctDNA VDJ detection can predict clinical recurrence early, and medium-term ctDNA can be used as a biomarker to predict patients at high risk of
treatment failure.

Finally, Dr.
Wang concluded that ctDNA detection can realize the full-cycle study
of molecular typing, drug resistance mechanism research, efficacy detection, recurrence monitoring, and clonal evolution of DLBCL patients.
Increased ctDNA levels in DLBCL patients with drug therapy may be used as an early molecular predictor marker for treatment failure, and ctDNA mutation profiling can be used as an adjunct to imaging and tissue biopsy to assess tumor response
.
It provides a reference for early clinical treatment intervention, which can improve patient survival
.

Panbiotic Dr.
Wang Chunyang

The discussion session was moderated by Director Liu Wei, with the participation of Dr.
Fan Ni and Dr.
Wang Chunyang, and the three experts discussed "Exploring the Value of Genetic Testing in DLBCL Drug Development and Clinical Diagnosis and Treatment"
.

Dr.
Fan pointed out that from the perspective of pharmaceutical companies' research and development, they all hope that every study will have positive results, but in practice it is difficult to achieve it
.
This requires the basic research of pharmaceutical R&D personnel to be based on the precise stratification of patients, better and deeper understanding of the genetic background behind the disease, in order to be able to more accurately select the beneficiary population
.
From 2018 to now, many genetic molecular detection methods and computer algorithm research results have been published, but none of them have been approved
by regulatory agencies.
The selection of targeted populations and the success rate of clinical trials need to be improved, which requires more companies with precise targeted genetic testing to invest in related fields
.

From the perspective of the testing company, Dr.
Wang said that ctDNA for lymphoma MRD monitoring has the technical advantages of convenient sampling and high sensitivity, and a large number of studies have shown that ctDNA monitoring can detect recurrence trends earlier than imaging, which has become a potential new strategy
for the management of lymphoma patients.
However, there is a lack of evidence to support
the use of ctDNA-based MRD in clinical use with large samples.
Taking solid tumors similar to lung cancer as an example, clear targets guide precise medication, and patients can bring great benefits
.
However, current clinical studies are based on molecular typing in Caucasian populations, and there are some very typical differences in
molecular characteristics from those of Chinese diffuse large B patients.
There is a need for some prospective, larger clinical studies to establish platforms
specifically for molecular typing of Chinese populations.

From the perspective of clinicians, Director Liu believes that the detection of molecular heterogeneity is a new model
to guide accurate diagnosis and efficacy evaluation in the future.
The ultimate goal is to hope that more patients can be cured through this accurate diagnosis and treatment mode, which is also the ultimate goal
of everyone.
With the continuous research and development and application of targeted drugs, the treatment of DLBCL has entered the era of targeted therapy from the era
of immune combined chemotherapy.
If patients can be individualized and the most suitable targeted therapy or cell therapy drugs can be found, it is expected to achieve clinical cure
of DLBCL patients as soon as possible.
Multi-party cooperation to achieve drug development to clinical application, so as to better improve the life cycle
of patients.

The live broadcast ended with a heated discussion among the three experts, and the tenth issue of "Medicine Precision" will be held in November, and I look forward to seeing you again!

discuss

In addition, in order to better understand everyone's interests, improve the pertinence of experts' live broadcasts, and answer users' questions in a timely manner, we have also set up communication groups
.
If you are interested in the live broadcast of the "Drug Precision" series, then you are welcome to join the group to exchange ideas, discuss problems, watch the live broadcast + review, and give multiple good gifts non-stop! Welcome to add staff WeChat, invite you to join the group, please note "name ++ department"!

This live broadcast ended successfully in the unfinished thoughts of the guests and the audience! Precision medicine, diagnosis first, this series of live broadcasts aims to promote academic exchanges in innovative drug R&D, help the high-quality research and development of innovative drugs, and jointly promote the R&D exploration and industry thinking
of Chinese pharmaceutical innovation enterprises.
The "Drug Precision" column adopts a combination of online live broadcast and offline meeting, once a month, welcome everyone to continue to obtain live broadcast information and participate in the discussion through the public account of Translational Medicine Network, Genetron Online Public Account, and "Drug Precision" WeChat group!

Past Review

Review of the first issue of Drug Precision: the regulation, value and clinical application of MRD

Wonderful review of the second issue of "Drug Precision": MRD detection accurately helps the development of CAR-T cell therapy

Review of the third issue of "Drug Precision": research progress of multiple myeloma and application of MRD

Review of the fourth issue of "Drug Precision": innovative drug research and development and development

Review of the fifth issue of Drug Precision: MET targeted drug development and progress

Review of the sixth issue of Drug Precision: NTRK targeted drug development and progress

Review of the seventh issue of Drug Precision: R&D and progress of RET-targeted drugs

Review of the eighth issue of Drug Precision: Biomarkers and Drug Development

References:

[1]:Zhang et al.
, Clin Epigent 2020/Zhang et al.
, Clin Transl Med 2022

[2]:Sawalha.
Onco Targets Ther.
2020; 13:5123.

Tilly.
ASH 2021.
Abstr LBA1.
Tilly.
NEJM.
2022; 386:351.

[3]:Scherer F.
Sci Transl Med.
2016

[4]:Davids M S, Roberts A W, Seymour J F, et al.
Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma[J].
J Clin Oncol, 2017, 35(8): 826-833.
23

[5]:Jason Westin, et al.
Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma.
Journal of Clinical Oncology.
August 11, 2022.
https://ascopubs.
org/doi/abs/10.
1200/JCO.
22.
00597

[6]:Adam J Olszewski, Abraham Avigdor, Sunil Babu, et al.
Single-Agent Mosunetuzumab Is a Promising Safe and Efficacious Chemotherapy-Free Regimen for Elderly/Unfit Patients with Previously Untreated Diffuse Large B‑Cell Lymphoma.
2020 ASH Annual Meeting, Abstract #401.