Brentuximab

Brentuximab
Mass / length primary structure	149.2-151.8 kDa
Identifier
External IDs	CAS number : 914088-09-8
Drug information
ATC code	L01 XC
Drug class	Cytostatics

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Brentuximab Vedotin ( INN , trade name Adcetris ) is an antibody-drug conjugate (ADC) that has been tested as part of studies on the treatment of cancer diseases of the lymph cells . In the conjugate, a monoclonal antibody directed against human CD30 antigen is covalently bound to three to five molecules of the cytostatic agent monomethyl auristatin E. The drug was approved in the USA in August 2011. At the end of October 2012, the European Medicines Agency granted approval for the cancer drug in the European Union and expanded it in 2016. The drug approval applies to the following indications:

• In adults for the treatment of a relapse or recurrence of Hodgkin's lymphoma (HL) or of refractory (not responding to conventional therapies) Hodgkin's lymphoma a) after an autologous stem cell transplant (ASCT) or b) after at least two previous therapies, when ASCT or combination chemotherapy is not an option.
• In adults for consolidation treatment of CD30 + Hodgkin's lymphoma (HL) after autologous stem cell transplantation (ASCT) when the risk of the disease returning or getting worse .
• In adults, for the treatment of a relapse or recurrence of systemic anaplastic large cell lymphoma (sALCL) or of treatment-resistant (not responding to usual therapies) sALCL.

Brentuximab Vedotin has the status of a drug against rare diseases ( orphan drug status ).

The Federal Joint Committee (G-BA) subjected Brentuximab Vedotin to a drug benefit assessment in accordance with Section 35a of Book V of the Social Code: The G-BA resolution of May 16, 2013 established a non-quantifiable additional benefit for patients with CD30 ⁺ Hodgkin's lymphoma. The German Society for Hematology and Oncology e. V. (DGHO) has issued and published an opinion on the assessment process.

In 2013, Brentuximab Vedotin was included as a treatment option in the S3 guideline for the diagnosis, treatment and follow-up of Hodgkin's lymphoma .

Brentuximab Vedotin is manufactured by Seattle Genetics in the USA and Millennium Pharmaceuticals , a subsidiary of Takeda Pharmaceutical .

Mechanism of action

The property of monoclonal antibodies to specifically recognize certain cell characteristics can also be used in oncological therapy: Antibodies are supposed to detect the tumor cells and thus deliver the cytostatic agent to the tumor cells in a targeted manner. The antibody-drug conjugate attaches itself to the surface of the cell, which carries a certain cell characteristic ( antigen ). In brentuximab vedotin, the cell characteristic against which the monoclonal antibody is directed is the tumor antigen CD30 . After the antibody has attached to the tumor antigen, the cell membrane everts into the interior of the cell and the antibody-drug conjugate is channeled into the cell. There, enzymes in the lysosomes split the amino acid connection between the antibody and the cytostatic agent, which can now develop its effect on site. The active ingredient in brentuximab vedotin linked to the antibody is the cytostatic agent monomethyl auristatin E, which destroys the mitotic spindle and thus leads to G2 / M cell cycle arrest and apoptosis (ie cell death of cancer cells).

Studies

A dose-ranging study in 45 patients with relapse of malignant lymphoma , the CD30 expressing , was published in November of 2010. It showed a regression of the tumor in 36 patients, including eleven complete remissions .

In two pivotal Phase II studies , brentuximab vedotin was tested in 160 patients in the USA, Canada and Europe, of which 102 patients had Hodgkin lymphoma and 58 patients had sALCL . In the Hodgkin's lymphoma study, all 102 patients had already received high-dose chemotherapy with autologous stem cell transplantation (ASCT) and had been pretreated with several chemotherapy regimens. Brentuximab vedotin was given for a maximum of 16 cycles. 96% of the patients achieved disease control (ie a remission or disease stabilization), 94% of the patients showed a tumor reduction and an objective overall response (ORR = partial or complete remission ) was determined in 75% of the patients .

In the sALCL study , 58 patients who had failed at least one previous combination chemotherapy received brentuximab vedotin for a maximum of 16 cycles. Here 97% of the patients achieved a tumor reduction and in 86% of the patients an objective overall response (ORR = partial or complete remission ) was achieved.

Further results in heavily pretreated patients with CD30 + Hodgkin lymphoma are also available from a retrospective analysis by the German Hodgkin Study Group (GHSG).

At the International Conference on Malignant Lymphoma (ICMAL) 2013, a post-hoc analysis was presented that compared progression-free survival with brentuximab vedotin and previous therapy. Data from patients from the two approval-relevant phase 2 studies were included in the analysis. The study participants were diagnosed with relapsed or refractory Hodgkin lymphoma (HL) after ASCT or relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL). The comparison was made with the previous last systemic therapy. As a result, more than 60% of the heavily pretreated patients achieved an increase in progression-free survival under the antibody drug conjugate Brentuximab Vedotin.

3-year updates to the Phase II registration trials in patients with relapsed or refractory Hodgkin lymphoma (HL) or sALCL confirmed that bentuximab vedotin improved overall survival compared to previous therapies: in patients with relapsed or refractory HL the median overall survival was 40.5 months. 18 patients remained in remission and were further observed. In patients with relapsed or refractory sALCL, the median overall survival was not yet reached after 33.4 months, the estimated 3-year survival rate was 63%.

After a 5-year follow-up, both Phase II registration studies were closed. The final data showed an estimated 5-year survival rate of 41% for relapsed / refractory (r / r) Hodgkin lymphoma (HL) and 60% for r / r sALCL .

A phase III study (AETHERA) investigated the use of brentuximab vedotin as consolidation therapy in patients with advanced Hodgkin lymphoma who were at increased risk of relapse or progression after an autologous stem cell transplant (ASCT) . Patients who received brentuximab vedotin in addition to Best Supportive Care (BSC) after ASCT lived 18.8 months longer disease-free.

Adverse effects (side effects)

The WHO divides the severity of side effects with cytostatics into grades 0 (no side effect) to 5 (death from chemotherapy ). The treatment-related side effects with brentuximab vedotin in the studies were mainly of severity grade 1 (minor side effects) or 2 (general condition worsened, chemotherapeutic agent must be reduced). Side effects of severity grade 3 (interruption of chemotherapy necessary) or 4 (inpatient hospital treatment required) were mostly due to cytopenias (especially neutropenia ). Most common side effects were WHO grade 3 or 4

• in the pivotal study on Hodgkin lymphoma (102 patients): neutropenia 20%, peripheral neuropathy 9% (severity 4 did not occur), thrombocytopenia 8%, anemia 6%.
• in the pivotal study on sALCL (58 patients): neutropenia 21%, thrombocytopenia 14%, peripheral sensory neuropathy 12% (grade 4 did not occur), anemia 7%.
• Neuropathies usually regressed over time: Neuropathy symptoms had completely subsided or had improved in 88% and 91% of the patients with r / r HL or r / r sALCL by the 5-year update.

During treatment with brentuximab vedotin, progressive multifocal leukoencephalopathy (PML) occurred in three cases (as of June 2012 ). PML is described under treatment with various immunosuppressants (including monoclonal antibodies ). Whether and how brentuximab vedotin contributes to PML is still unclear.

See also

Nomenclature of monoclonal antibodies , convention for naming monoclonal antibodies

Web links

• Christine Vetter: Deutsches Ärzteblatt: Brentuximab Vedotin: Option for previously treated patients . In: Deutsches Ärzteblatt . tape 109 , no. 20 . Deutscher Ärzte-Verlag , 2012, p. A-1041 ( aerzteblatt.de ).
• Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Brentuximab

Individual evidence

1. ↑ FDA News Release of August 19, 2011.
2. ↑ Summary of the European public assessment report (EPAR) for Adcetris
3. ↑ ^{a b} Characteristics (PDF; 863 kB) European Medicines Agency.
4. ↑ Orphanet: Orphan Drugs Authorized in Europe (PDF; 1020 kB).
5. ↑ G-BA, resolution text Brentuximab Vedotin .
6. ↑ DGHO, assessment (PDF; 77 kB).
7. ↑ Hodgkin lymphoma. S3 guideline for diagnosis, therapy and aftercare of adult patients German Society for Hematology and Oncology (DGHO) 2013.
8. ^ Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 2012; 30: 631-7, PMID 22781692 .
9. ↑ Younes A et al. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas. N Engl J Med 2010; 363: 1812-21, PMID 21047225 .
10. ↑ ^{a b} Younes A et al. Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma. J Clin Oncol 2012; 30: 2183-9, PMID 22454421 .
11. ↑ ^{a b} Pro B et al. Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study. J Clin Oncol 2012; 30: 2190-6, PMID 22614995 .
12. ↑ Rothe A et al. Brentuximab vedotin for relapsed or refractory CD30 + hematologic malignancies: the German Hodgkin Study Group experience. Blood 2012; 120: 1470-2, PMID 22786877 .
13. ↑ Radford J et al. Progression-free survival analyzes of two pivotal phase 2 studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. 12th International Conference on Malignant Lymphoma (ICML), June 19-22, 2013 in Lugano, Switzerland. Poster # 303
14. ↑ Takeda and Seattle Genetics Highlight Post-Hoc Analysis Examining Progression-free Survival with ADCETRIS® (brentuximab vedotin) Versus Prior Therapy at the International Conference on Malignant Lymphoma  ( page no longer available , search in web archives )  Info: The link was automatically identified as broken marked. Please check the link according to the instructions and then remove this notice. . English. Takeda and Seattle Genetics press release June 19, 2013. Online at investor.seattlegenetics.com.  
15. ↑ Gopal AK et al. Three-Year Follow-Up Data and Characterization Of Long-Term Remissions From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Hodgkin Lymphoma. Blood 2013; 122: 4382.
16. ↑ Pro B et al. Three-Year Survival Results From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Systemic Anaplastic Large Cell Lymphoma. Blood 2013; 122: 1809.
17. ↑ ^{a b} Chen R et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 2016; 128: 1562-6, PMID 27432875 .
18. ↑ ^{a b} Pro B et al. Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma. 58th Annual Meeting of the American Society of Hematology (ASH), 2016. Poster # 4144.
19. ↑ Moskowitz CH et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; 385: 1853-62, PMID 25796459 .
20. ↑ Wagner-Johnston ND et al. Progressive multifocal leukoencephalopathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma 2012; 53: 2283-6, PMID 22424602 .

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