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Phase III ECHELON-1 Clinical Trial of Brentuximab Vedotin Meets Primary Endpoint – Demonstrates a Statistically Significant Improvement in Modified Progression-Free Survival

Published on 10th December

Data from the Phase III ECHELON-1 clinical trial evaluating brentuximab vedotin (Adcetris®; Seattle Genetics | Takeda) as part of a frontline combination chemotherapy regimen in untreated advanced classical Hodgkin lymphoma were presented in the Plenary Scientific Session at the 59th American Society of Hematology (ASH) annual meeting on Sunday, December 10, 2017.[1]

The data, simultaneously published online in the New England Journal of Medicine*, demonstrates that the ECHELON-1 trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (modified PFS or mPFS) per Independent Review Facility (IRF) versus the control arm. [2]. The modification is to include, as an event, the receipt of chemotherapy or radiotherapy for patients not in complete remission at the end of initial treatment.[3]

The ECHELON-1 trial, which enrolled 1,334 patients, is a randomized, open-label, two-arm, multi-center Phase III study designed to compare brentuximab vedotin + AVD (Adriamycin [doxorubicin], vinblastine and dacarbazine) to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine) as frontline therapy in patients who had histologically-confirmed diagnosis of Stage III (36%) or IV (64%) Hodgkin lymphoma – referred to as advanced classical Hodgkin lymphoma – and had not been previously treated with systemic chemotherapy or radiotherapy.

The patients participating in the study were randomized (58% male; median age 35 year [range 18–83]; ≥45 year, 34%; ≥60 year, 14%) to receive brentuximab vedotin + AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) IV on Days 1 and 15 of up to six 28-day cycles. The multi-center trial was conducted at 218 sites in 21 countries across North America, Europe, South America, Australia, Asia and Africa.[1]

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

Novel treatment option
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma but is currently not approved as a frontline therapy for the treatment of patients with Hodgkin lymphoma. The imunoconjugate includes a payload called monomethyl auristatin E (MMAE), a spindle poison, and is approved for classical Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or ≥2 prior chemotherapy regimens and as consolidation post‑ASCT for increased risk Hodgkin lymphoma.[3]

Unmet medical need
The lymphatic system, a network of tissues and organs including lymph nodes, spleen, thymus gland, and bone marrow, helps rid the body of toxins, waste and other unwanted materials. The system is the body’s disease-fighting network. Cancers originating in the lymphatic system are generally referred to as lymphomas.[4]

Hodgkin lymphoma and non-Hodgkin lymphoma are two major categories of lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. Reed-Sternberg cells, which express CD30, are large, cancerous cells found in Hodgkin lymphoma tissues and named for the scientists who first identified them.

Although multidrug chemotherapeutic regimens, with or without radiotherapy, have been highly successful in achieving long-term remissions in the majority of patients with advanced-stage Hodgkin lymphoma – the disease is one of the most curable forms of cancer – approximately 30% of patients with advanced disease do not achieve long-term remission with front-line treatment using standard regimens, such as ABVD.[5][6][7]

The number of patients with advanced disease not achieving long-term remission can be reduced by about 5 to 10% with the use of much more intensive escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone) -therapy, developed by the German Hodgkin Study Group (GHSG) to increase dose density of chemotherapy as compared with ABVD and other regimens used in advanced-stage Hodgkin lymphoma. However, this treatment carries the risk of significant short- and long-term morbidity,

According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. The Lymphoma Coalition, estimates that worldwide over 62,000 people are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people will die each year from this cancer.

This represents a major unmet medical need.

“For patients with advanced stage Hodgkin lymphoma, approximately one in three do not achieve long-term remission after standard frontline therapy, which is why the results of ECHELON-1 could be important to this group of patients,” said Jesús Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda.

Statistical Significant Improvement
“The trial demonstrated that combination treatment with [brentuximab vedotin] resulted in a statistically significant improvement in modified progression-free survival versus the control arm. For patients treated with brentuximab vedotin +AVD, there was a 23% reduction in the occurrence of an event, defined as progression, death or need for subsequent anti-cancer therapy for patients not in a complete response, compared to those who were treated with ABVD,” Gomez Navarro added

“We are excited about these clinical trial results and the potential impact brentuximab vedotin may have in the treatment of patients with advanced stage Hodgkin lymphoma if approved by health authorities for frontline use,” he concluded.

Standard treatment
Altough very effective in treating the disease, the original treatments for Hodgkin lymphoma were developed in the 1960s and 1970s. Some of these treatments caused serious side effects later in life, including infertility, cardiovascular problems, as well as secondary cancers, such as lung cancer and breast cancer. Overall, these long-term problems were partly caused by the types of chemotherapy and high doses of radiation therapy delivered to large areas of the body.[4]

“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades and there remains an unmet need for additional regimens in frontline treatment. Current regimens include bleomycin, which is known to be associated with unpredictable and potentially fatal pulmonary toxicity,” said Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada.

“Increasing the durable response rate with a frontline therapy that also removes bleomycin from the regimen, represents a major step forward for the Hodgkin lymphoma community. Reducing the risk of relapse, is an important concern for patients and their physicians. In the trial, 33% fewer patients treated in the [brentuximab vedotin] containing regimen required subsequent salvage chemotherapy or high dose chemotherapy and transplant compared to the patients treated with ABVD. Lastly, the safety profile of [brentuximab vedotin]+AVD in the trial was generally consistent with that known for the single-agent components of the regimen, Connors added”

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“The ECHELON-1 Phase III clinical trial results were selected by the American Society of Hematology as one of only six abstracts to be featured in the Plenary Scientific Session, and the data were also published simultaneously today in the New England Journal of Medicine. This study represents a bold effort that began more than five years ago to improve upon the current standard of care regimen that has not significantly changed in more than four decades. We’d like to thank the many patients and physicians who participated in this landmark trial,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“These data demonstrate statistically superior activity of an brentuximab vedotin-containing regimen over ABVD, the current standard of care, including the primary endpoint of modified PFS per IRF, and secondary endpoints trended in favor of the brentuximab vedotin-containing regimen as well. Importantly, patients treated with the brentuximab vedotin-containing regimen required fewer subsequent therapies after frontline treatment,” Siegal further said.

“The results of the ECHELON-1 study supported FDA Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma, and we recently submitted a supplemental Biologics License Application to the FDA. Our goal is to make this regimen available to patients in the U.S. with advanced Hodgkin lymphoma in the first half of 2018,” Siegal concluded.

Key findings
The key findings, presented during the annual meeting and published in the New England Journal of Medicine confirm that the trial achieved its primary endpoint with the combination of [brentuximab vedotin]+AVD resulting in a statistically significant improvement in modified Progessive Free Survival (mPFS) versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; p-value=0.035). This corresponds to a 23% percent reduction in the risk of progression, death or need for additional anticancer therapy.

Per IRF assessment, the two-year modified PFS rate for patients in the [brentuximab vedotin] +AVD arm was 82.1% compared to 77.2 percent in the control arm. Furthermore, per investigator assessment, the two-year modified PFS rate for patients in the [brentuximab vedotin]+AVD arm was 81.0% compared to 74.4% in the control arm (HR 0.73; p-value=0.007). This corresponds to a 27% reduction in the risk of progression, death or need for additional anticancer therapy.

All secondary endpoints trended in favor of the [brentuximab vedotin]+AVD arm, including interim analysis of overall survival (OS; HR 0.72; p-value=0.19). Other secondary endpoints include:

  • Complete response (CR) rate at the end of randomized regimen in the [brentuximab vedotin]+AVD arm was 73% compared to 70% in the control arm (p-value=0.22).
  • Objective response rate (ORR) at the end of randomized regimen in the [brentuximab vedotin]+AVD arm was 86% compared to 83% in the control arm (p-value=0.12).
  • Deauville score ≤2 after completion of frontline therapy was 85% in the [brentuximab vedotin]+AVD arm compared to 80% in the control arm (p-value=0.03).
  • Certain pre-specified subgroups of patients appeared to benefit more with [brentuximab vedotin]+AVD versus ABVD including: patients treated in North America; patients with involvement of >1 extranodal site; patients with International Prognostic Score (IPS) 4 – 7; males; patients with Stage IV disease; and patients aged <60 years.
  • In the [brentuximab vedotin]+AVD arm, 33% fewer patients received subsequent salvage chemotherapy or high-dose chemotherapy and transplant

Safety and adverse events
The safety profile of [brentuximab vedotin]+AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.

The most common clinically relevant adverse events of any grade that occurred in at least 15 percent of patients in the [brentuximab vedotin]+AVD and ABVD arms were: neutropenia (58 and 45%, respectively), constipation (42 and 37%, respectively), vomiting (33 and 28%, respectively), fatigue (both 32%), peripheral sensory neuropathy (29 and 17%, respectively), diarrhea (27 and 18%, respectively), pyrexia (27 and 22%, respectively), peripheral neuropathy (26 and 13%, respectively), abdominal pain (21 and 10%, respectively) and stomatitis (21 and 16%, respectively).

In both the [brentuximab vedotin]+AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia and neutrophil count decrease.

Febrile neutropenia was reduced through the use of prophylactic growth factors (G-CSF) in a subset of patients. In the [brentuximab vedotin]+AVD arm of the study, the rate of febrile neutropenia without the use of G-CSF was 21 percent and with the use of G-CSF was reduced to 11 percent. G-CSF primary prophylaxis with [brentuximab vedotin]+AVD resulted in overall comparable safety profile to ABVD, decreasing incidence of febrile neutropenia, neutropenia and serious adverse events. Primary prophylaxis with G-CSF was recommended for all patients.

On the [brentuximab vedotin]+AVD arm, peripheral neuropathy events were observed in 67% of patients compared to 43% on the control arm. In the [brentuximab vedotin]+AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2. Grade ≥3 events were reported in 11 percent of patients and Grade 4 events were reported in less than one percent of patients. In the control arm, Grade ≥3 events were reported in two percent of patients and there were no Grade 4 events.

Two-thirds of the patients with peripheral neuropathy in the [brentuximab vedotin]+AVD arm reported resolution or improvement at last follow-up. Pulmonary toxicity was reported in two percent of patients in the [brentuximab vedotin]+AVD arm versus seven percent of patients in the ABVD arm; Grade ≥3 events were reported in less than one percent versus three percent, in the brentuximab vedotin and control arms respectively.

Nine on study deaths occurred in the [brentuximab vedotin]+AVD arm, of which seven were due to neutropenia or associated complications (all occurred in patients who had not received primary prophylaxis with G-CSF with the exception of one patient who entered the trial with pre-existing neutropenia).

The remaining two deaths were due to myocardial infarction. In the control arm, there were 13 on study deaths, of which 11 were due to or associated with pulmonary-related toxicity, one was due to cardiopulmonary failure and one death had unknown cause.

Regulatory approval
The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize brentuximab vedotin in the rest of the world. Based on this devision, Seattle Genetics submitted a supplemental Biologics License Application to the FDA on November 1, 2017, while Takeda has begun to submit data from the ECHELON-1 trial to regulatory agencies in its territories, starting with the European Medicines Agency (EMA) on November 29, 2017.


* The data will be published in the January 25, 2018 print edition of the New England Journal of Medicine.
**

Last Editorial Review: December 11, 2017

Featured Image: American Society of Hematology | Anual Meeting. Courtesy: © 2017. American Society of Hematology. Used with permission. Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017. Seattle Genetics. Used with permission.

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