The final data of the brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda Oncology) monotherapy pivotal phase II clinical trial in relapsed or refractory (R/R) classical Hodgkin lymphoma were published in the July 18, 2016 edition of Blood, a peer reviewed journal published by the American Society of Hematology[1] The article, which summarizes the five-year, end-of-study results, highlights data showing that patients who attained a complete response achieved long-term disease control.

Brentuximab vedotin is an antibody-drug conjugate or ADC that targets CD30, a protein on the surface of some Hodgkin lymphoma cells and a key driver of classical Hodgkin lymphoma tumor pathogenesis. As an ADC, the drug delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, directly to CD30-expressing cells.

The drug, approved in 2011 for relapsed or treatment-resistant Hodgkin lymphoma, is commonly prescribed to patients whose disease has progressed after autologous stem cell transplant, a procedure that replenishes the bone marrow with the patient’s own healthy stem cells after therapy, and is being evaluated globally as the foundation of therapy for Hodgkin lymphoma in more than 45 ongoing corporate- and investigator-sponsored clinical trials.

MabPlex
 

… this is the first study to observe long-term success in patients who have exhausted all other treatment options…


Hodgkin lymphoma
Classical Hodgkin lymphoma, known to spread by the lymphatic system, is one of the most unique types of hematological malignancies known. In Hodgkin lymphoma, the surrounding environment plays an important role in influencing the behavior of the malignant cells. And unlike non-Hodgkin lymphoma, Hodgkin lymphoma spreads in a very predictable manner, and is not considered a systemic disease at diagnosis. [2]

An estimate by the American Cancer Society, suggests that there will be about 8,500 new cases (3,710 women and 4,790 men) of  Hodgkin lymphoma in the United States in 2016.  Based on the same estimate, about 1,120 patients are expected to die (480 women, 640 men) from this disease, which is characterized by the presence of CD30‑positive Reed-Sternberg cells.

While progress in treating Hodgkin lymphoma is often presented as one of the great accomplishments in all of cancer medicine, only about 70% of patients can really expect to be cured. For those patients cured with conventional chemotherapy, the disease can be managed, and sometimes becomes more indolent and chronic in nature.

Standard of care
The standard of care for patients with relapsed or refractory (R/R) Hodgkin lymphoma is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT).  Achieving and maintaining a complete remission (CR) prior to transplant is generally considered a major aspect resulting in a favorable progression-free and overall survival (OS) after transplant.

Approximately 50% of patients treated for relapsed or refractory Hodgkin lymphoma will experience relapse or progression after auto-SCT. This usually occurs within the first year, and represents a significant therapeutic challenge. [3] In this category of patients, treatment outcomes have, historically, been very poor, with median Overall Survival (OS) from time of relapse ranging from 10.5 to 27.6 months. [2][3]

“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said Robert Chen, M.D., City of Hope National Medical Center’s Department of Hematology & Hematopoietic Cell Transplantation in Duarte, California, and lead author of the study published in Blood.

“The median survival of the patients on brentuximab vedotin monotherapy in this pivotal Phase II trial exceeds these historic figures, and I am pleased to see the publication of the final data,” Chen further noted.

“For a patient population that typically only sees an overall survival of one to two years after relapse from autologous stem cell transplantation, the fact that we can report such durable results after five years is incredible,” Chen added

“Each day that these individuals continue to spend with their loved ones is a testament to the strides our community is making in understanding and beating treatment-resistant lymphomas,” he observed, referencing the 15 patients still in remission at the close of this longitudinal study.

Commitment to improvement
“For over a decade, we have demonstrated our commitment to improve treatment outcomes in Hodgkin lymphoma through numerous clinical trials evaluating novel therapeutic approaches. Today’s final publication of the [brentuximab vedotin] monotherapy pivotal study in Hodgkin lymphoma patients represents a significant milestone for the trial that supported approval in more than 60 countries globally and established current use as standard-of-care in the relapsed setting,” noted Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Foundation of care
“The long-term safety and efficacy data from the pivotal trial are supportive of our ongoing development of [brentuximab vedotin] for other classical Hodgkin lymphoma settings, including the frontline setting. Our broad clinical program is investigating [brentuximab vedotin] as a foundation of care for Hodgkin lymphoma and potentially other CD30-expressing malignancies,” Drachman further added.

“The positive final results from this trial of [brentuximab vedotion] demonstrated that of the patients who had a complete response, 38% achieved long-term disease control for the duration of the study,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

Patients’ median progression-free survival (PFS) on brentuximab vedotin was longer than the median PFS, increasing it by more than 3 months.

“In addition, the median overall survival of 40.5 months and progression-free survival of 9.3 months observed across the trial further establish the role of [brentuximab vedotin] in improving outcomes for patients with relapsed Hodgkin lymphoma,” Huber observed.

Table 1.0: NCT00848926 is a single-arm, open-label, multicenter, pivotal clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin as a single agent in patients with relapsed or refractory (R/R) Hodgkin lymphoma. © 2016 Michael Bonert (Nephron). Licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Pivotal trial
The pivotal, single-arm trial, which supported the U.S. Food and Drug Administration’s (FDA) approval in 2011 of brentuximab vedotin for this indication, was conducted in 102 patients with relapsed or refractory classical Hodgkin lymphoma who had previously received an autologous stem cell transplant (ASCT) to assess the efficacy and safety of single-agent brentuximab vedotin. Enrolled patients had received a median of more than three prior chemotherapy regimens. [5]

After a five-year follow-up period, the final results from the pivotal trial showed a median overall survival and progression-free survival of 40.5 months (95% confidence interval [CI]: 28.7, 61.9) and 9.3 months (95% CI: 7.1, 12.2), respectively. The estimated five-year overall survival and progression-free survival rates were 41% and 22%.

Of the 102 patients treated, 34 patients (33%) had a complete remission, with the median response duration not reached. For patients who had a complete remission (CR), the estimated five-year overall survival rate was 64% (95% CI: 48, 80) and the estimated five-year progression-free survival rate was 52 percent (95% CI: 34, 69).

Thirteen of the 34 patients (38%) who achieved a complete remission (CR) continued to be followed and remained in remission for over five years at study closure. Of these patients, four underwent consolidative allogeneic stem cell transplants while in remission, and nine received no further therapy.

“It is critical to note that nine of patients [achieving a complete remission] have been in remission for over five years after receiving only brentuximab vedotin,” Chen noted.

“The fact that these patients are doing so well, even five years out, provides a new perspective for prognosis,” he pointed out.

Most common adverse events
The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia and diarrhea. Treatment emergent peripheral neuropathy, a common adverse event characterized by tingling in the extremities, reported among patients treated with brentuximab vedotin, was experienced by 56 patients (55%).  However, these toxicities were considered manageable. Eighty-eight percent of these patients in the study experienced improvement of their peripheral neuropathy symptoms, including 73% with complete resolution, Chen concluded.

Previously, primary results and 3-year follow-up of the data were reported earlier. [6][7][8]

While brentuximab vedotin is becoming standard care, this is the first study to observe long-term success in patients who have exhausted all other treatment options. The final data and end-of-study results of the pivotal trial demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with R/R Hodgkin lymphoma, particularly in patients who achieve Complete Response.[9]

These results suggests that the targeted therapy with brentuximab vedotin should be standard of care for patients with relapsed or treatment-resistant Hodgkin lymphoma.