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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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Long-term Data of Brentuximab Vedotin Redifines Treatment of Frontline Mature T-Cell Lymphoma.

Data highlighted at the 59th annual meeting of the American Society of Hematology (ASH) held in Atlanta, Georgia, December 9-12, 2017 shows final five-year survival results from a phase I clinical trial evaluating  brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda), a drug directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, in the treatment of patient with mature T-cell lymphoma (MTCL).

An Antibody-drug Conjugate
Brentuximab vedotin is an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology.


The current standard of care for frontline MTCL treatment has not changed for several decades and there remains a significant need for improved therapeutic options…


Unmet medical need
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.

Non-Hodgkin lymphomas 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. In the United Stated T-cell lymphomas account for approximately 15% of all non-Hodgkin lymphoma.

There are a number of different forms of T-cell lymphomas, which can be aggressive of indolent. Some of these are extremely rare. Almost all types of T-cell lymphoma fall under the category of mature T-cell lymphoma, also known as peripheral T-cell lymphoma.

According to the American Cancer Society and analysis of literature sources, approximately 4,300 patients will be diagnosed with CD30-expressing mature T-cell lymphoma in the United States during 2017. While, over the last years, a number of treatments have been developed, overall, a significant unmet medical need persists in older patients, as well as for those patients who have relapsed or refractory (R/R) disease.

Highlights
The data highlighted during the annual meeting focused on durability data from a phase I clinical trial of brentuximab vedotin in combination with chemotherapy for the treatment of patients with newly diagnosed MTCL, also known as peripheral T-cell lymphoma (PTCL).

“Approximately 4,000 patients are diagnosed with MTCL each year. The current standard of care for frontline MTCL treatment has not changed for several decades and there remains a significant need for improved therapeutic options.” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“The results of this phase I trial support the ongoing phase III ECHELON-2 clinical trial and our goal to redefine frontline MTCL treatment with a novel brentuximab vedotin combination regimen,” he added.

“The final results from the Phase I study were presented today, with five-year progression-free survival and overall survival rates of 52 and 80%, respectively. No patients have experienced any disease progression events since the three-year follow-up results. Importantly, after more than five years of follow-up, patients who remain in remission have the potential to be cured. These data continue to support the phase III ECHELON-2 trial, from which we anticipate reporting data in 2018,” Drachman concluded.

Figure 1.0: ECHELON-2 (NCT01777152) is a Clinical Trial designed to establish brentuximab vedotin (Adcetris®) as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens.

A combination
Data were reported from 26 frontline MTCL patients who received the combination regimen of brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone (CHP).

Patients who achieved at least a partial remission with combination therapy following six cycles of brentuximab vedotin plus CHP were eligible to receive up to ten additional cycles of single-agent brentuximab vedotin treatment.

The median age of patients was 56 years. Nineteen patients (73%) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients with anaplastic lymphoma kinase (ALK)-negative disease, which is typically associated with a poor prognosis.

Seven patients (27%) had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk. All patients on the trial achieved an objective response, including 92 percent with a complete response and eight percent with a partial response.

Updated key findings based on a median observation time of 60 months from first dose of therapy showed that at five-year follow-up, there have been no progression events or deaths in this trial since the three-year follow up. The results also showed that the estimated five-year progression-free survival rate was 52%, with no patients receiving a consolidative stem cell transplant in first remission. The median progression-free survival has not yet been reached.

While the media overall survival has not yet been reached, the researchers involved were able to confirm an estimated five-year overall survival rate was 80%.

Adverse events
Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 4.2 months and median time to improvement of symptoms was 2.6 months.

A global phase III study called ECHELON-2 completed enrollment in November 2016. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate brentuximab vedotin plus CHP versus CHOP as frontline therapy in patients with CD30-expressing MTCL.

The trial enrolled 452 patients (approximately 225 patients per treatment arm) randomized to receive brentuximab vedotin plus CHP or CHOP every three weeks for six to eight cycles. Data from the ECHELON-2 trial are expected in 2018.


Last Editorial Review: December 10, 2017

Featured Image: Scientists at Seattle Genetics Courtesy: © 2017. Seattle Genetics | Used with permission.

Copyright © 2017 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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