Professor He Pengcheng: Through the fog, the innovative ADC drug Pola continues hope for DLBCL patients with CAR-T treatment failure

Every unknown world is opened with pioneers who bravely foresee; Every journey of sneaking through the dark night is fearlessly led by the lighter
.
The series of reports "Solving the Problem - Unlocking the New Standard of DLBCL Cure" digs deep into the problems in the treatment of diffuse large B-cell lymphoma (DLBCL) and explores unmet clinical needs; Combined with clinical research and real-world treatment experience at home and abroad, we jointly explore the new standard
of precision diagnosis and treatment of DLBCL.
Polatuzumab Vedotin (Pola) is transformed into a North Star (Pole Star), which helps optimize diagnosis and treatment strategies under the guidance of leading experts in the field in order to improve the survival of
DLBCL patients in China.

≥ 2 relapsed/refractory (R/R) DLBCL patients have a poor prognosis and extremely limited treatment methods, although CAR-T therapy has improved the prognosis of 3L+R/R DLBCL patients, but there are shortcomings such as high cost and low popularity, and about half of the patients still have early progression
after CAR-T treatment.
So, where should patients who fail CAR-T treatment go? Is there no way to salvage treatment?

There is a huge unmet need for 3L+R/R DLBCL patients

DLBCL is the most common non-Hodgkin lymphoma (NHL) and is one of the few curable lymphomas, with cure rates increasing from 30%~40% to 50%~60% over the past few ^decades1
.
However, after first- and second-line standard treatment, about 30%~40% of DLBCL patients still become R/R ^patients2
.

≥ patients with 2 relapses/progressions of DLBCL have very limited treatment options and can only receive allogeneic hematopoietic stem cell transplantation (allo-SCT), enrollment in clinical trials, chemotherapy that is not cross-resistant to frontline therapy, chimeric antigen receptor T cell therapy (CAR-T) therapy, or palliative ^care3
.

However, these regimens have not been effective, with the SCHOLAR-1 study showing an objective response rate (ORR) of approximately 26% for posterior line therapy and only 7% for complete response (CR), and a median overall survival (OS) of only 6.
3 months for patients with R/R DLBCL1
.
It can be seen that DLBCL patients have poor efficacy, low survival rate, and low cure possibility of post-line therapy, and there is a huge clinical demand for treatment and more effective treatment options
.

Since its inception, CAR-T cell therapy has shown great advantages and potential in the field of hematological cancer treatment, but the currently marketed CAR-T therapy generally needs personalized customization, which has shortcomings such as high price, time-consuming preparation, low popularity, and neurotoxicity also limits the widespread use of CAR-T cell
therapy4.

Unfortunately, even after receiving CAR-T therapy, most patients eventually relapse and progress
again.
A retrospective analysis showed that after a median follow-up of 12.
9 months after CAR-T treatment, 49% of patients had progression5^, and that pre-treatment tumor metabolic volume (MTV), sex (male), age, number of previous treatment lines, international prognostic index (IPI) score, and Eastern US Collaborative Oncology Group (ECOG) performance status score were associated with a higher risk of ^{recurrence5,6}
。

At present, there is no standard protocol for the follow-up treatment of patients who have failed CAR-T therapy, in a retrospective study 26% of patients received supportive care after CAR-T treatment failure, 74% of patients received further treatment, commonly used treatment regimens include immune checkpoint inhibitors, lenalidomide, chemotherapy, radiotherapy, etc.
, but the optimal ORR of patients was 29%, CR was 17%, and median PFS was only 55
。 Overall, less than 25% of patients with DLBCL who progressed after CD19 CAR-T therapy responded to subsequent treatment, with a median OS of only 3.
6 ^months7
.
So, for patients who fail CAR-T treatment, is there no way to save the treatment?

Desperate to survive, Pola brings a new option for the after-line treatment of patients with R/R DLBCL

In order to meet the treatment needs of patients with R/R DLBC, researchers continue to explore
.
Polatuzumab Vedotin (Pola) stands out as the world's first drug conjugate (ADC) targeting CD79b antibodies, and its combination therapy regimen Pola-BR (Pola, bendamustine combined with rituximab) in the treatment of R/R DLBCL patients has shown excellent efficacy
in both clinical studies and real-world studies (RWD).

GO29365 ^study8 showed that compared with BR, the Pola-BR regimen significantly improved the optimal CR rate, progression-free survival (PFS) and OS of patients with R/R DLBCL by nearly 3 times, reduced the risk of death by 58% (Figure 1), and had tolerable safety features and controllable
adverse effects.

Figure 1 GO29365 research results: PFS, OS

It is worth mentioning that 45% of the patients in the GO29365 study received ≥ 3-line therapy
.
The optimal CR rate for the Poola-BR protocol is as high as about 58% (Figure 2), which is similar to the CR rate range of 40%-58% for CAR-T (non-head-to-head comparison)^9-12
.

Fig.
2 GO29365 research results: optimal CR rate

Patients who have failed CAR-T therapy usually have been treated with multiple lines in the past, and the choice of subsequent treatment regimens should pay attention to the non-cross-resistance with frontline chemotherapy
regimens.
BR regimens are relatively rarely used in first- and second-line treatments for DLBCL, and Pola-BR regimens reduce cross-resistance to chemotherapy in ^patients8 while avoiding the risk of overlapping neurotoxicity of platinum-based regimens13
.
In addition, RWD has also demonstrated that the OS of BR regimen in R/R DLBCL is similar to that of the platinum-containing regimen R-GemOx (rituximab plus gemcitabine and oxaliplatin) (Figure 3), and the safety is ^{controllable14}
.

Fig.
3 The efficacy of BR and R-GemOx regimens in the treatment of R/R DLBCL is similar

As an extension of clinical research, real-world studies (RWDs) suggest that if CAR-T therapy fails, the Pola combination regimen can still be used as an effective salvage treatment
.

A multicenter retrospective study of 400 patients receiving CAR-T therapy in the United States showed that with a median follow-up of 22.
4 months, 47.
5% of patients progressed after CAR-T treatment, of which 65.
5% received follow-up treatment, and Pola-BR had the highest ORR and CR rates of 73% and 40%, respectively, and median PFS of 136 days (Figure 4).
¹⁵
。

Figure 4 Real-world research in the United States

In another UK real-world study of 133 patients, 19 patients received Pola-BR salvage therapy after CAR-T failure showed that greater than 40% of patients still had remission from Pola-BR salvage and nearly 20% achieved CR (Figure 5)¹⁶
.

Figure 5 Real-world research in the UK

In summary, the Pola combination regimen has reliable efficacy, no safety concerns such as specific CRS, and the convenient application of ready-to-use drugs, which provides a new treatment option
for patients with R/R DLBCL and CAR-T therapy failure.
And in the 2022 NCCN Clinical Practice Guidelines: B-Cell Lymphoma and Chinese Society of Clinical Oncology (CSCO) Lymphoma Diagnosis and Treatment Guidelines, the Pola-BR regimen is recommended for patients with
R/R DLBCL.
At present, Pola-BR has been approved to treat patients with R/R DLBCL in more than 60 countries around the world, and is expected to be approved for marketing in China soon, which will bring hope
to more DLBCL patients.

West China Hospital, Sichuan University

Professor Niu Ting

In recent years, despite the progress made in R/R DLBCL, there is still a huge unmet clinical need, especially for patients who have failed CAR-T therapy, which is often considered to be a loss of cure potential, and treatment options are extremely limited, and there is an urgent need for more effective, less toxic, and more widely available therapies
.
Pola-BR has been shown to be a potential treatment for patients with R/R DLBCL that induces adequate response rates, has acceptable toxicity, and can be used as an effective salvage therapy
after CAR-T therapy failure 。 In addition to the latest advances in the field of R/R DLBCL, Pola has also made a major breakthrough in the field of treatment-new DLBCL, and the POLARIX study confirmed that the Pola-R-CHP (Pola plus rituximab, cyclophosphamide, doxorubicin and prednisone) regimen can further improve the cure rate of first-line treatment of DLBCL and help more patients achieve long-term survival
.
It is expected that in the future, after the launch of Pola in China, it will benefit more patients with treatment-specific and R/R DLBCL
.

The First Affiliated Hospital of Xi'an Jiaotong University

Professor He Pengcheng

DLBCL is a curable condition, and about 60% of patients do not require further treatment after first-line standard treatment
.
However, due to the lack of effective treatment options, the overall prognosis of R/R DLBCL is poor, especially in patients above the third line, with very poor
outcomes.
CAR-T cell therapy can be said to bring a breakthrough to the cure of hematological tumors, but the pricing and patient accessibility limit the wide application of CAR-T cell therapy, and the preparation cycle is long, and the third-line and later line patients who are suitable for CAR-T therapy have a high risk of rapid disease progression during the waiting cycle, and patients may "not be able to wait"
.
The innovative ADC drug Pola is relatively more affordable and the ready-to-use drug is more convenient, providing a new treatment option
for patients on the back line.
Whether it is clinical research or real-world data, it has verified the efficacy of Pola, and it is expected that Pola will be launched in China as soon as possible, bringing new hope
to DLBCL patients.

Professor Niu Ting

• Doctor of Medicine, Chief Physician, Professor, Doctoral Student (Post) Supervisor

• Director of the Department of Hematology, West China Hospital, Sichuan University

• Postdoctoral Visiting Scholar, MD Anderson Cancer Center, USA

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Association, Deputy Head of the Lymphocytic Disease Group

• Vice Chairman of China Hematology Specialist Alliance

• Member of the Standing Committee of the Hematology and Oncology Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Expert Committee of Hematology Public Welfare Project of China Primary Healthcare Foundation

• Vice Chairman of the Hematology Committee of the Chinese Medical Education Association, Vice Chairman of the Hemostasis and Thrombosis Branch

• Deputy Editor-in-Chief of the International Journal of Blood Transfusion and Hematology, Chinese Medical Association

• External expert of the Drug Evaluation Center of the State Medical Products Administration

• He is the chairman-elect of the Hematology Branch of Sichuan Medical Association

• Business Director of Sichuan Hematology Medical Quality Control Center

• Academic and technical leader of Sichuan Province and Sichuan Provincial Health Commission

Prof.
Pengcheng He

• Professor, MD, PhD supervisor

• He is currently the deputy director of the Department of Internal Medicine, the director of the Department of Hematology, and the director of the Stem Cell Clinical Research Laboratory of the First Affiliated Hospital of Xi'an Jiaotong University

• Member of the Lymphocytic Disease Group of the Hematology Branch of the Chinese Medical Association

• Member of the Lymphatic Hematology Group of the Oncology Branch of the Chinese Medical Association

• Member of Hematologist Branch of Chinese Medical Doctor Association

• Member of Hematology and Oncology Professional Committee of Chinese Anti-Cancer Association

• Member of the Standing Committee and Secretary of the Hematology Branch of Shaanxi Medical Association

• Chairman of the Tumor Immunology Diagnosis and Treatment Professional Committee of Shaanxi Anti-Cancer Association

• He is the chairman-elect of the Leukemia Professional Committee of Shaanxi Anti-Cancer Association

• Mainly engaged in the diagnosis, treatment and research of malignant hematological diseases
  .
  Presided over a number of new CART international single-center clinical research projects with optimized structure; He has presided over a total of 12 scientific research projects such as the National Natural Science Foundation of China
  .
  He has published more than 50 scientific research papers, including more than 20 in
  SCI.
  He is the chief editor of one book, "Standardized Application and Progress of Hematopoietic Stem Cell Transplantation"
  .
  He won 1 first prize for scientific and technological progress of Shaanxi Provincial Department of Education and 2 second prizes for
  scientific and technological progress of Shaanxi Provincial Department of Science and Technology.
  

References:

1.
Crump M, et al.
Blood.
2017; 130(16):1800-1808.

2.
Ying ZT, et al.
Zhonghua Xue Ye Xue Za Zhi.
2018; 39(5):382-386.

3.
Nagle SJ, et al.
Am J Hematol.
2013.

4.
Zhu Fangming ,et al.
China Journal of New Drugs,2021,30(13):1192-1199.

5.
Spiegel JY, et al.
Blood.
2021 Apr 1; 137(13):1832-1835.

6.
Michael D.
Jain, et al.
Blood.
2022 Aug 4; 140(5): 491-503.

7.
John H Baird , et al.
Blood.
2021 Apr 29; 137(17):2321-2325.

8.
Sehn LH, et al.
Blood Adv.
2022; 6(2):533-543.

9.
Schuster SJ, et al.
N Engl J Med 2019; 380:45-56.

10.
Aquilen Race Instruction Manual.

11.
Abramson JS, et al.
Lancet 2020; 396: 839–52.

12.
Ying Z, et al.
Cancer Medicine.
2021; 10:999–1011.

13.
Sehn LH, et al.
J Clin Oncol.
2020; 38(2):155-165.

14.
Felipe Castro, et al.
2020 ASH Oral and Poster 3042.

15.
Joanna C.
Zurko, et al.
2021ASH Oral 884.

16.
M Northend, et al.
2021 ICML Abstract 174.

Bridge Star Solution | Professor Zhao Weiyi and Professor Liu Yanyan: How to break through the R/R DLBCL problem? Chinese and foreign experience unlocks new solutions

Professor Zhu Jun and Guo Ye: Pola's three major offensive weapons (I) - MMAE bystander effect lays a mechanism foundation for breaking through DLBCL heterogeneity

Bridge Star Solution | Professor Ma Jun: The more classic the effect, the more curative, 1L DLBCL treatment is ushering in a new standard

Bridge Star Solution | Zhang Huilai and Professor Tao Rong: Pola's three major offensive weapons (II) - CD79b innovative target accurately broke the game, DLBCL world's first "magic bullet" to lead a new course

Bridge Star Solution | Professor Huang Huiqiang: Pola helps non-transplantable R/R DLBCL patients rekindle hope

Bridge Star Solution | Professor Wu Depei and Zhang Xi: Relay together, continue hope, and open up a new pattern of treatment suitable for transplanting R/R DLBCL

Bridge Star Solution | Professor Zhang Qingyuan: Pola's three major offensive weapons (3) - can cleave the linker, the guarantee of "strong and low toxicity" of ADC drugs

Feng Jifeng and Professor Qiu Lugui: Turn the tide, and Pola will guide the repeated progress of DLBCL

Zhou Daobin and Professor Li Zhiming: Searching for sand, Pola brings new treatment options to elderly patients with DLBCL who are frailty/intolerant

Song Yongping and Professor Zhang Wei: Climb the peak bravely and innovate ADC drugs Pola to empower transplantation and CAR-T therapy to explore more therapeutic potential