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.

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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.

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.


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