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A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large
B-cell lymphoma
Download PDF
Download PDF
 * Letter to the Editor
 * Open Access
 * Published: 16 April 2020


A PHASE 3 STUDY OF RITUXIMAB BIOSIMILAR HLX01 IN PATIENTS WITH DIFFUSE LARGE
B-CELL LYMPHOMA

 * Yuankai Shi1,
 * Yongping Song2,
 * Yan Qin1,
 * Qingyuan Zhang3,
 * Xiaohong Han1,
 * Xiaonan Hong4,
 * Dong Wang5,
 * Wei Li6,
 * Yang Zhang7,
 * Jifeng Feng8,
 * Jianmin Yang9,
 * Huilai Zhang10,
 * Chuan Jin11,
 * Yu Yang12,
 * Jianda Hu13,
 * Zhao Wang14,
 * Zhengming Jin15,
 * Hang Su16,
 * Huaqing Wang17,
 * Haiyan Yang18,
 * Weijun Fu19,
 * Mingzhi Zhang20,
 * Xiaohong Zhang21,
 * Yun Chen22,
 * Xiaoyan Ke23,
 * Li Liu24,
 * Ding Yu25,
 * Guo’an Chen26,
 * Xiuli Wang27,
 * Jie Jin28,
 * Tao Sun29,
 * Xin Du30,
 * Ying Cheng31,
 * Pingyong Yi32,
 * Xielan Zhao33,
 * Chaoming Ma34,
 * Jiancheng Cheng34,
 * Katherine Chai34,
 * Alvin Luk34,
 * Eugene Liu34 &
 * …
 * Xin Zhang34 

Show authors

Journal of Hematology & Oncology volume 13, Article number: 38 (2020) Cite this
article

 * 2995 Accesses

 * 18 Citations

 * 1 Altmetric

 * Metrics details


ABSTRACT

Rituximab in combination with chemotherapy has shown efficacy in patients with
diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was
developed as the rituximab biosimilar following a stepwise approach to
demonstrate biosimilarity in analytical, pre-clinical, and clinical
investigations to reference rituximab. With demonstrated pharmacokinetic
similarity, a phase 3 multi-center, randomized, parallel, double-blind study
(HLX01-NHL03) was subsequently conducted to compare efficacy and safety between
HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP)
and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve,
CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was
best overall response rate (ORR) within six cycles of treatment in the
per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes,
safety, and immunogenicity profile. The results showed difference in ORRs
[H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95%
confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the
pre-defined equivalence margin of ± 12%. The safety profile was comparable
between the treatment groups, with a similar overall incidence of
treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and
serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study
established bioequivalence in efficacy and safety between HLX01 and reference
rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26
August 2015 [#CTR20150583].

Treatment with rituximab, a monoclonal antibody against CD20, in combination
with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has
been used in patients with diffuse large B-cell lymphoma (DLBCL) for more than
15 years with proven efficacy and safety [1]. With demonstrated highly similar
analytical characterization and bioequivalence in pharmacokinetics and
pharmacodynamics [2], we conducted this phase 3, multi-center, randomized,
parallel, double-blind study (HLX01-NHL03) to establish the equivalence in
clinical efficacy, safety, and immunogenicity between HLX01 plus CHOP (H-CHOP)
and R-CHOP every 21 days for up to six cycles in treatment-naïve patients with
CD20-positive DLBCL.

Eligible patients were treatment-naïve adults (≥ 18 to ≤ 80 years) with
International Prognostic Index of 0-2, clinical stages I–IV (Ann Arbor Staging)
and histologically confirmed CD20-positive DLBCL. The primary efficacy endpoint
was best overall response rate (ORR) within six cycles of treatment in the
per-protocol set (PPS), and secondary efficacy endpoints included complete
response rate, 1-year duration of response, 1-year event-free survival, 1-year
progression-free survival, 1-year disease-free survival, 1-year overall
survival, and depletion of CD19-positive B-cells in peripheral blood.

From October 9, 2015 to March 10, 2017, a total of 560 patients were screened,
of whom 407 patients were randomized (1:1) at 33 investigational sites; 361
patients (H-CHOP 173; R-CHOP 188) completed six cycles of treatment, and 328
patients (H-CHOP 157; R-CHOP 171) completed the study (Fig. 1a). Baseline
characteristics are well balanced between two treatment groups (Fig. 1b). In the
PPS, the best ORRs within six cycles of treatment in the PPS were 94·1% (95%
confidence interval [CI], 89.77 to 97.04) and 92·8% (95% CI, 88.19 to 96.00) in
the H-CHOP and R-CHOP groups, respectively, with an intergroup difference of
1.4% (95% CI, − 3.59 to 6.32, p = 0.608). The efficacy equivalence between HLX01
and reference rituximab was demonstrated with 95% CIs falls entirely within the
pre-defined margin of ± 12%. The results of using the full analysis set (FAS)
were consistent with the primary efficacy analysis in the PPS. Previous reports
of R-CHOP in patients with DLBCL have shown ORRs ranging between 83% and 88% [3,
4], which is comparable with the result from this study. No significant
differences were observed in the 1-year analysis of all secondary efficacy
endpoints, in either the PPS or the FAS (Table 1).

Fig. 1

a Patient disposition of all screened patients. b Baseline patient demographics
and disease status of full analysis dataset (FAS)

Full size image
Table 1 Efficacy outcomes
Full size table

The safety analysis set (Table 2) comprised 406 patients who received at least
one treatment. 199/200 in H-CHOP group and 204/206 in R-CHOP group (H-CHOP
99.5%, R-CHOP 99.0%, p = 1.000) experienced at least one treatment-emergent
adverse event; 68/200 in H-CHOP and 67/206 in R-CHOP (H-CHOP 34.0%, R-CHOP
32.5%, p = 0.752) experienced at least one serious adverse event; 14/200 in
H-CHOP and 9/206 in R-CHOP (H-CHOP 7.0%, R-CHOP 4.4%, p = 0.252) discontinued
treatment because of adverse events (AEs). The most common AEs were
hematological events such as decreased white blood cell count (H-CHOP 85.5%;
R-CHOP 85.9%), decreased neutrophil count (H-CHOP 79.0%; R-CHOP 81.6%), and
anemia (H-CHOP 38.5%; R-CHOP 35.0%).

Table 2 Safety profiles in the safety analysis dataset
Full size table

Among the patients observed with infusion-related reactions (IRRs), 61/200 in
H-CHOP group and 61/206 in R-CHOP group (H-CHOP 30.5%; R-CHOP 29.6%), the most
common reactions were those affecting skin and subcutaneous tissues. Most IRRs
were grade 1 or 2, and no grade 4 or 5 IRRs were reported. Increases in
hepatitis B virus (HBV) DNA titer were observed in five patients in H-CHOP group
and eight patients in R-CHOP group, and nine of whom were receiving antiviral
therapy for chronic HBV; however, no patients developed signs or symptoms of
fulminant hepatitis.

Anti-drug antibodies (ADAs) were detected in one patient (< 1%) in each
treatment group at baseline and immediately before administration of the second
treatment cycle. After 6 months of follow-up, ADAs were detected in one patient
in H-CHOP group and two patients in R-CHOP group (H-CHOP 1.0%, R-CHOP 1.7%, p =
1.000), and after 8 months of follow-up in seven patients in H-CHOP group and
six patients in R-CHOP group (H-CHOP 7.1%, R-CHOP 5.5%, p = 0.629). During the
entire study, only one patient in R-CHOP group had both ADAs and neutralizing
antibodies.

In conclusion, this study demonstrated therapeutic equivalence between HLX01 and
reference rituximab. The analysis of the primary and secondary efficacy
endpoints did not reveal any statistically significant differences between two
treatment groups. The safety and immunogenicity profiles of HLX01 were
comparable with reference rituximab with no clinically meaningful differences
observed between two treatment groups.


AVAILABILITY OF DATA AND MATERIALS

The data that support the findings of this study are available from the
corresponding author upon reasonable request.


ABBREVIATIONS

R-CHOP:

Rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and
prednisone

DLBCL:

Diffuse large B-Cell lymphoma

H-CHOP:

HLX01 plus cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and
prednisone

ORR:

Best overall response rate

PPS:

Per-protocol set

CI:

Confidence interval

FAS:

Full analysis set

AE:

Adverse event

IRR:

Infusion-related reaction

HBV:

Hepatitis B virus

ADA:

Anti-drug antibody


REFERENCES

 1. Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, et al.
    CHOP Chemotherapy plus rituximab compared with CHOP alone in elderly
    patients with diffuse large-B-Cell lymphoma. The N Engl J Med.
    2002;346(4):235–42.
    
    Article  CAS  PubMed Central  Google Scholar 

 2. Xu Y, Xie L, Zhang E, Gao W, Wang L, Cao Y, et al. Physicochemical and
    functional assessments demonstrating analytical similarity between rituximab
    biosimilar HLX01 and the MabThera®. MAbs. 2019;11(3):606–20.
    
    Article  CAS  PubMed Central  Google Scholar 

 3. Pfreundschuh M, Kuhnt E, Trümper L, Österborg A, Trneny M, Shepherd L, et
    al. CHOP-like chemotherapy with or without rituximab in young patients with
    good-prognosis diffuse large-B-cell lymphoma: 6-year results of an
    open-label randomised study of the MabThera International Trial (MInT)
    Group. Lancet Oncol. 2011;12(11):1013–22.
    
    Article  CAS  PubMed Central  Google Scholar 

 4. Pfreundschuh M, Truemper L, Gill D, Osterborg A, Pettengell R, Trneny M, et
    al. First analysis of the Completed Mabthera International (Mint) Trial in
    young patients with low-risk diffuse large B-cell lymphoma (DLBCL): addition
    of rituximab to a CHOP-like regimen significantly improves outcome of all
    patients with the identification of a very favorable subgroup with IPI=O and
    no bulky disease. Blood. 2004;104(11):157.
    
    Article  Google Scholar 

Download references


ACKNOWLEDGEMENTS

We thank all the patients and families who were involved in the HLX01-NHL03
study and the clinical study teams and Hangzhou Tigermed Consulting Co., Ltd.
for providing support for the study.


FUNDING

The study was supported by the sponsor, Shanghai Henlius Biotech, Inc., and by
grants from the China National Major Project for New Drug Innovation (Grant No.
2015ZX09501008, 2017ZX09304015) and the Chinese Academy of Medical Sciences
(CAMS) Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2016-I2M-1-001).


AUTHOR INFORMATION


AUTHORS AND AFFILIATIONS

 1.  National Cancer Center/National Clinical Research Center for Cancer/Cancer
     Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular
     Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical
     College, Beijing, China
     
     Yuankai Shi, Yan Qin & Xiaohong Han

 2.  Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital,
     Zhengzhou, China
     
     Yongping Song

 3.  Harbin Medical University Cancer Hospital, Harbin, China
     
     Qingyuan Zhang

 4.  Fudan University Shanghai Cancer Center, Shanghai, China
     
     Xiaonan Hong

 5.  Daping Hospital, Third Affiliated Hospital of the Army Medical University,
     Chongqing, China
     
     Dong Wang

 6.  The First Bethune Hospital of Jilin University, Changchun, China
     
     Wei Li

 7.  The Second Hospital of Dalian Medical University, Dalian, China
     
     Yang Zhang

 8.  Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing,
     China
     
     Jifeng Feng

 9.  Changhai Hospital, Shanghai, China
     
     Jianmin Yang

 10. Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
     
     Huilai Zhang

 11. Cancer Center of Guangzhou Medical University, Guangzhou, China
     
     Chuan Jin

 12. Fujian Provincial Cancer Hospital, Fuzhou, China
     
     Yu Yang

 13. Fujian Medical University Union Hospital, Fuzhou, China
     
     Jianda Hu

 14. Beijing Friendship Hospital, Capital Medical University, Beijing, China
     
     Zhao Wang

 15. The First Affiliated Hospital of Soochow University, Soochow, China
     
     Zhengming Jin

 16. The 307th Hospital of Chinese People’s Liberation Army, Beijing, China
     
     Hang Su

 17. Tianjin People’s Hospital, Tianjin, China
     
     Huaqing Wang

 18. Zhejiang Cancer Hospital, Hangzhou, China
     
     Haiyan Yang

 19. Shanghai Changzheng Hospital, Shanghai, China
     
     Weijun Fu

 20. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
     
     Mingzhi Zhang

 21. The Second Affiliated Hospital of Zhejiang University School of Medicine,
     Hangzhou, China
     
     Xiaohong Zhang

 22. Jinan Central Hospital Affiliated to Shandong University, Jinan, China
     
     Yun Chen

 23. Peking University Third Hospital, Beijing, China
     
     Xiaoyan Ke

 24. Tangdu Hospital, Air Force Medical University, Xi’an, China
     
     Li Liu

 25. Hubei Cancer Hospital, Wuhan, China
     
     Ding Yu

 26. The First Affiliated Hospital of Nanchang University, Nanchang, China
     
     Guo’an Chen

 27. The Second Hospital of Jilin University, Changchun, China
     
     Xiuli Wang

 28. The First Affiliated Hospital, College of Medicine, Zhejiang University,
     Hangzhou, China
     
     Jie Jin

 29. Liaoning Cancer Hospital & Institute, Shenyang, China
     
     Tao Sun

 30. Guangdong Provincial People’s Hospital, Guangzhou, China
     
     Xin Du

 31. Jilin Cancer Hospital, Changchun, China
     
     Ying Cheng

 32. Hunan Cancer Hospital, Changsha, China
     
     Pingyong Yi

 33. Xiangya Hospital, Central South University, Changsha, China
     
     Xielan Zhao

 34. Shanghai Henlius Biotech, Inc., Shanghai, China
     
     Chaoming Ma, Jiancheng Cheng, Katherine Chai, Alvin Luk, Eugene Liu & Xin
     Zhang

Authors
 1.  Yuankai Shi
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CONTRIBUTIONS

YKS was the lead principal investigator and contributed to the design and
conception, interpretation data, and writing of the manuscript. YKS, YPS, YQ,
QYZ, XHH, XNH, DW, WL, YZ, JFF, JMY, HLZ, CJ, YY, JDH, ZW, ZMJ, HS, HQW, HYY,
WJF, MZZ, XHZ, YC, XYK, LL, DY, GAC, XLW, JJ, TS, XD, YC, PYY, and XLZ
contributed to data collection. XHH contributed to detecting CD19- and
CD20-positive B-cells in peripheral blood. JCC contributed to statistical data
analysis and interpretation of the data. EL contributed to the design and
conception of the research. CMM, AL, EL, and XZ contributed to the
interpretation of data and the completeness and accuracy of the data. KC and AL
provided writing assistance for the initial manuscript and editorial assistance
for reviewing and editing subsequent versions of the manuscript. The authors
read and approved the final manuscript.


CORRESPONDING AUTHOR

Correspondence to Yuankai Shi.


ETHICS DECLARATIONS


ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The protocol was developed by the sponsor of the study, Shanghai Henlius
Biotech, Inc. The study protocol was reviewed and approved by the relevant
independent ethics committee at each participating study center. Written
informed consent was obtained from all study participants prior to screening.
Data were collected by the site investigators who vouch for the completeness and
accuracy of the data and the fidelity of the trial to the protocol. The sponsor
analyzed the data. The study was conducted in accordance with the Declaration of
Helsinki, Guideline for Good Clinical Practice, and applicable national and
local regulations for clinical trials.


CONSENT FOR PUBLICATION

Not applicable.


COMPETING INTERESTS

CMM, JCC, KC, AL, EL, and XZ are employees of Shanghai Henlius Biotech, Inc. All
other authors declare no competing interests.


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ABOUT THIS ARTICLE


CITE THIS ARTICLE

Shi, Y., Song, Y., Qin, Y. et al. A phase 3 study of rituximab biosimilar HLX01
in patients with diffuse large B-cell lymphoma. J Hematol Oncol 13, 38 (2020).
https://doi.org/10.1186/s13045-020-00871-9

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 * Received: 11 February 2020

 * Accepted: 01 April 2020

 * Published: 16 April 2020

 * DOI: https://doi.org/10.1186/s13045-020-00871-9


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KEYWORDS

 * Rituximab biosimilar
 * DLBCL
 * Efficacy equivalence


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 * Fig. 1
   
   View in articleFull size image

 1. Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, et al.
    CHOP Chemotherapy plus rituximab compared with CHOP alone in elderly
    patients with diffuse large-B-Cell lymphoma. The N Engl J Med.
    2002;346(4):235–42.
    
    Article CAS PubMed Central  Google Scholar 

 2. Xu Y, Xie L, Zhang E, Gao W, Wang L, Cao Y, et al. Physicochemical and
    functional assessments demonstrating analytical similarity between rituximab
    biosimilar HLX01 and the MabThera®. MAbs. 2019;11(3):606–20.
    
    Article CAS PubMed Central  Google Scholar 

 3. Pfreundschuh M, Kuhnt E, Trümper L, Österborg A, Trneny M, Shepherd L, et
    al. CHOP-like chemotherapy with or without rituximab in young patients with
    good-prognosis diffuse large-B-cell lymphoma: 6-year results of an
    open-label randomised study of the MabThera International Trial (MInT)
    Group. Lancet Oncol. 2011;12(11):1013–22.
    
    Article CAS PubMed Central  Google Scholar 

 4. Pfreundschuh M, Truemper L, Gill D, Osterborg A, Pettengell R, Trneny M, et
    al. First analysis of the Completed Mabthera International (Mint) Trial in
    young patients with low-risk diffuse large B-cell lymphoma (DLBCL): addition
    of rituximab to a CHOP-like regimen significantly improves outcome of all
    patients with the identification of a very favorable subgroup with IPI=O and
    no bulky disease. Blood. 2004;104(11):157.
    
    Article  Google Scholar 

JOURNAL OF HEMATOLOGY & ONCOLOGY

ISSN: 1756-8722

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