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ASH 2018 Highlights Progress in Ongoing Development of Brentuximab Vedotin

As the premier hematology event in malignant and non-malignant hematology, the annual meeting of the American Society of Hematology (ASH), held this year from December 1 – 4, 2018 in San Diego, CA, is expected to present an invaluable educational experience and an opportunity to examine the latest clinical advances on topics covering malignant and non-malignant hematology, explore the year’s most significant scientific discoveries and relevant updates in key areas of the field, build new partnerships, stay current on industry trends and learn about the latest products and services available in research and patient care to meet the need of patients.

Brentuximab vedotin
During the annual meeting, expect to see 31 abstracts featuring data from the broad brentuximab vedotin (Adcetris®) development program.  Brentuximab vedotin is an Antibody-drug Conjugate or ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma (HL) cells and several types of non-Hodgkin lymphoma.

The drug, being developed by Seattle Genetics and Takeda, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

The data being presented includes both oral and poster presentations. Some of the presentations includes the latest updated of brentuximab vedotin in combination with other drugs, including Nivolumab (Opdivo®; Bristol-Myers Squibb)

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Schematic 1.0: The phase III ECHELON-2 clinical trial.

ECHELON-2 clinical trial
Data latest, updated from the phase III ECHELON-2 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in previously untreated patients with CD30-expressing peripheral T-cell lymphoma (PTCL) patients will be presented in an oral presentation on Monday, December 3, 2018 at 6:15 p.m. PT.

Seattle Genetics and partner Takeda reported positive top-line results from the ECHELON-2 trial in October 2018. The trial demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) of brentuximab vedotin in combination with CHP (cyclophosphamide, doxorubicin, prednisone) versus the control arm, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The brentuximab vedotin plus CHP arm also demonstrated superior overall survival (OS), a key secondary endpoint, compared to CHOP. The ECHELON-2 trial is the first trial to demonstrate an OS advantage in this difficult to treat type of non-Hodgkin lymphoma.

Seattle Genetics expects to submit in November 2018 a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for approval of brentuximab vedotin plus CHP in frontline CD30-expressing PTCL.

ECHELON-1 clinical trial

In addition to clinical trial data from the ECHELON-2 trial, expect to see several analyses from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline Stage III or IV classical HL adult patients, which formed the basis of FDA approval in this indication in March 2018.

Data presentations include additional analyses from the ECHELON-1 study, including PFS per investigator and outcomes in younger patients (18-30 years of age). These analyses are consistent with the previously reported modified PFS data and demonstrate improved outcomes in the ADCETRIS plus AVD (doxorubicin, vinblastine, dacarbazine) arm versus ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

Preliminary results from a phase II study of brentuximab vedotin in combination with nivolumab among patients with relapsed or refractory primary mediastinal large B-cell lymphoma (CHECKMATE 436 trial), as well as updated results from an ongoing phase I/II study evaluating the combination therapy in relapsed or refractory HL.

“There will be more than 30 data presentations from both corporate- and investigator-sponsored studies presented at the 2018 ASH Annual Meeting evaluating ADCETRIS in a variety of CD30-expressing lymphoma settings. These presentations are reflective of a robust ADCETRIS clinical development program that we, in partnership with the oncology community, are conducting to improve the treatment outcomes for patients,” said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics.

“[Together with our partner Takeda, we’re looking forward to presentation, on Monday, December 3rd, outlining the] results of the phase III ECHELON-2 clinical trial evaluating brentuximab vedotin in combination with CHP chemotherapy in frontline CD30-expressing peripheral T-cell lymphoma patients.  These data are the basis for our planned supplemental Biologics License Application to the FDA requesting approval of brentuximab vedotin in this setting, which we intend to submit in November 2018,” Dansey concluded.

Oral and poster presentations
Data presented during the meeting includes a series of different presentations:

Saturday, December 1, 2018
Abstract #1647 (poster) Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 ECHELON-1 Study ()
Abstract #1618 (poster) Older Patients (pts) with Previously Untreated Classical Hodgkin Lymphoma (cHL): A Detailed Analysis from the Phase 3 ECHELON-1 Study
Abstract #1635 (poster) Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classic Hodgkin lymphoma: Part 3 (Concurrent Dosing) Results and Updated Progression-Free Survival Results from Parts 1 and 2 (Staggered Dosing) ()
Abstract #1636 (poster) Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma
Abstract #1633 (poster) Real World Prevalence of Diagnostic Revision Among Patients with Peripheral T-cell Lymphomas (PTCL) in the US: Results of an Administrative Claims and Electronic Medical Record Analyses
Abstract #1646 (poster) Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician’s Choice Irrespective of CD30 Level of Large Cell Transformation Status in the Phase 3 ALCANZA Study
Abstract #1654 (poster) A Phase II Study of Brentuximab Vedotin plus Adriamycin and Dacarbazine without Radiation in Non-Bulky Limited Stage Classical Hodgkin Lymphoma.
Abstract #1656 (poster) Treatment Patterns and Outcomes of Relapsed/Refractory Peripheral T-Cell Lymphoma (RR-PTCL) Patients Treated in the Community Oncology Setting.
Abstract #1691 (poster) Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results From the Phase 2 CheckMate 436 Trial.
Abstract #2261 (poster) The Development and Validation of an Electronic Health Record (EHR)-Based Algorithm for Identifying Treatment Failure in Newly Diagnosed Hodgkin Lymphoma (HL) Treated in a US Community Oncology Setting.
Abstract #2268 (poster) Real World Evidence in Relapsed/Refractory Classical Hodgkin Lymphoma Patients Who Are Ineligible for Stem Cell Transplant in the United States (US).
Abstract #1625 (poster) Toxicity Profile of Brentuximab Vedotin in Combination with Chemotherapy for Newly Diagnosed Patients with ALK+ ALCL: a Children’s Oncology Group Study ANHL12P1.
Abstract #1431 (poster) Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia.
Abstract #1644 (poster) Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL).
Sunday, December 2, 2018
Abstract #2904 (poster) Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study.
Abstract #2921 (poster) Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial.
Abstract #2917 (poster) Interim Analysis Results from an International, Multi-Centre, Non-Interventional Retrospective Study to Describe Treatment Pathways, Outcomes, and Resource Use in Patients with Classical Hodgkin Lymphoma: B-CD30+ Hodgkin Lymphoma International Multi-Centre Retrospective Study of Treatment Practices and Outcomes (B-HOLISTIC).
Abstract #2923 (poster) Combining Brentuximab Vedotin with DHAP as Salvage Treatment in Relapsed/Refractory Hodgkin Lymphoma: the Phase II HOVON/LLPC Transplant BRaVE Study.
Abstract #2938 (poster) Peripheral T-Cell Lymphomas in Spain: Profiling Clinical, Phenotypic and Genetic Characteristics in Spanish Population.
Abstract #2959 (poster) Primary Mediastinal B-Cell Lymphoma: Evaluation of Clinicopathologic Diagnosis Compared to Gene Expression Based Diagnosis in a Clinical Trial with CD30+ B-Cell Lymphomas.
Abstract #2978 (poster) Utilization of a Novel Method of Detection of CD30 Expression in Diffuse Large B-cell Lymphoma.
Abstract #3587 (poster) Health-Related Quality of Life (HRQL) Trajectories during Treatment for Advanced Stage Pediatric Hodgkin Lymphoma (HL).
Monday, December 3, 2018
Abstract #997 (oral presentation at 6:15 p.m. PT) The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas.
Abstract #623 (oral presentation at 8:00 a.m. PT) Longitudinal Adverse Event Assessment of the Combination of Ipilimumab, Nivolumab And Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412: Arms A-F)
Abstract #679 (oral presentation at 10:30 a.m. PT) A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A trial of the ECOG-ACRIN Research Group (E4412: Arms G-I)
Abstract #926 (oral presentation at 4:45 p.m. PT) B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)Ne) in Older Patients with Advanced-Stage Hodgkin Lymphoma: Results of a Phase II Intergroup Trial By the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG)
Abstract #927 (oral presentation at 5:00 p.m. PT) Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed by BV and Bendamustine for Suboptimal Response, in Children, Adolescents, and Young Adults with Standard-Risk Relapsed/Refractory Classical Hodgkin Lymphoma.
Abstract #975 (oral presentation at 5:00 p.m. PT) Productivity Loss Among Parent Caregivers is Associated with Poor Health-Related Quality of Life (HRQL) at the Initial Diagnosis Of Pediatric Advanced Stage Hodgkin Lymphoma (HL).
Abstract #2837 (poster) Baseline Tumor Transcriptome Characteristics Associated with the Response of Relapsed/Refractory Hodgkin Lymphoma Patients to Brentuximab Vedotin in Combination with Nivolumab (
Abstract #4786 (poster) Patient and Physician Preferences for First-Line Treatment of Classical Hodgkin Lymphoma in the United States.
Abstract #2907 (poster) Prolonged Overall Survival (OS) in a Subset of Responders to the Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL): Results of an International Multi-Center Phase I/II Experience.

Editorial Review: November 30, 2018

Featured Image: ASH – San Diego, 2018 #ASH18 Courtesy: © 2010 – 2018 American Society of Hematology. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Supplemental Biologics License Application for Brentuximab Vedotin in Frontline Treatment of CD30-Expressing Peripheral T-Cell Lymphomas Submitted to US FDA

Seattle Genetics has submitted a supplemental Biologics License Application (BLA) for brentuximab vedotin (Adcetris®) to the U.S. Food and Drug Administration (FDA).

The submission is based on data from the phase III ECHELON-2 trial evaluating brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with CD30-expressing peripheral T-cell lymphoma (PTCL). The positive topline results of the Phase III ECHELON-2 clinical trial were announced in October 2018 and full data will be presented at the upcoming annual meeting of the American Society of Hematology (ASH), held December 1-4, 2018 in San Diego, California.

Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. There are more than 60 subtypes of non-Hodgkin lymphomas which are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing).


Results from the ECHELON-2 trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival and importantly, overall survival, in patients with previously untreated CD30-expressing peripheral T-cell lymphoma who were treated with [brentuximab vedotin] in combination with CHP chemotherapy over standard of care CHOP chemotherapy.


Peripheral T-cell lymphoma, which accounts for approximately 10% of non-Hodgkin lymphoma cases in the United States and Europe and may be as high as 24% in parts of Asia, is defined as a diverse group of aggressive lymphomas that develop from mature-stage white blood cells called T-cells and natural killer (NK) cells.

The disease is classified as a subtype of non-Hodgkin’s lymphoma (NHL). NHL affects two particular types of white blood cells: B-cells and T-cells. Peripheral T-cell lymphoma specifically affects T-cells, and results when T-cells develop and grow abnormally.

It is the origin of the disease in the lymphatic system that gave it the name peripheral T-cell lymphoma. In the case of peripheral T-cell lymphoma, the term “peripheral” does not refer to the extremities, but identifies the disease as a cancer that arises in the lymphoid tissues outside of the bone marrow such as lymph nodes, spleen, gastrointestinal tract, and skin.

Frontline treatment
The proposed treatment option, brentuximab vedotin, is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of several types of peripheral T-cell lymphoma. The drug, which is on of four approved and commercially available antibody-drug conjugates is currently not approved for the frontline treatment of patients with peripheral T-cell lymphoma.

“CD30 is expressed in several subtypes of peripheral T-cell lymphoma, an aggressive type of non-Hodgkin lymphoma, and the current standard of care for frontline treatment consisting of a multi-agent chemotherapy regimen called CHOP has not changed in several decades,” explained Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Results from the ECHELON-2 trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival and importantly, overall survival, in patients with previously untreated CD30-expressing peripheral T-cell lymphoma who were treated with [brentuximab vedotin] in combination with CHP chemotherapy over standard of care CHOP chemotherapy. We believe these superior results over standard of care represent a significant advance for patients with CD30-expressing peripheral T-cell lymphoma and for the medical community, and we look forward to working with the FDA during the review process of this application to bring this potential new treatment regimen to patients as quickly as possible.”

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Illustration: The randomized, double-blind, placebo-controlled ECHELON 2 is a phase III trial is investigating brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as frontline therapy in patients with CD30-expressing peripheral T-cell lymphoma, also known as mature T-cell lymphoma. The primary endpoint is progression-free survival (PFS) per Independent Review Facility assessment, with events defined as progression, death, or receipt of chemotherapy for residual or progressive disease. Secondary endpoints include PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate, overall survival and objective response rate, in addition to safety. The multi-center trial was conducted at sites across North America, Europe and Asia and was designed to enroll 450 patients, approximately 75% of whom were to be diagnosed with sALCL. The ECHELON-2 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and the trial also received European Medicines Agency (EMA) scientific advice.

ECHELON-2 trial
The phase III ECHELON-2 clinical trial evaluated the combination of [brentuximab vedotin] plus CHP (cyclophosphamide, doxorubicin, prednisone) compared to a recognized standard of care chemotherapy regimen, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), in previously untreated CD30-expressing peripheral T-cell lymphoma. The ECHELON-2 study met its primary endpoint demonstrating a statistically significant improvement in progression-free survival (PFS) as assessed by an Independent Review Facility (IRF; hazard ratio=0.71; p-value=0.0110).

The brentuximab vedotin plus CHP arm also demonstrated superior overall survival (OS), a key secondary endpoint, compared to CHOP (hazard ratio=0.66; p-value=0.0244). All other key secondary endpoints, including PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate and objective response rate were statistically significant in favor of the brentuximab vedotin plus CHP arm. The safety profile of brentuximab vedotin plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of brentuximab vedotin in combination with chemotherapy.

Reference
Oral Session: Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: T-Cell Lymphoma: Chemotherapy and Targeted Approaches (Abstract #997) | Date/Location: Monday, December 3, 2018 at 6:15 p.m. PT, San Diego Convention Center, Room 6F | Presenter: Steven Horwitz, M.D.,Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York.


Last Editorial Review: November 6, 2018

Featured Image: Clinical trial. Courtesy: © 2010 – 2018 Fotolia. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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