Frontline Brentuximab Vedotin Generates 76% Complete Remission Rate in DLBCL

Christopher Yasenchak, MD

Adding brentuximab vedotin (Adcetris) to frontline R-CHOP produced a greater than 80% response rate—including complete remissions in three-fourths of patients—as a treatment for CD30+ diffuse large B-cell lymphoma (DLBCL), according to updated interim data from an ongoing phase II clinical trial recently presented at the 2015 ASH Annual Meeting.

The trial was designed to assess antitumor activity and the safety profile of frontline brentuximab vedotin plus R-CHOP. Exploratory endpoints included CD30 expression measured by immunohistochemistry testing and the relationship between CD30 expression and response.

At ASH, data were reported from 51 DLBCL patients with a median age of 67 years. Seventy-one percent of patients in the trial had stage IV disease, 37% were considered high-risk, and 63% were considered high-intermediate risk.

Patients were randomized to receive standard R-CHOP with either 1.2 mg/kg or 1.8 mg/kg of brentuximab vedotin. However, after the first 10 patients experienced significant neurotoxicity with the 1.8-mg/kg dose, the remaining patients were all given the 1.2-mg/kg dose.

Of the 25 evaluable patients who had CD30-expressing disease, defined as 1% expression or greater, 21 patients (84%) had an objective response, including 19 patients (76%) who experienced a complete remission and 2 patients (8%) who experienced a partial remission.

The estimated progression-free survival rate for CD30-positive patients at both 12 and 15 months was 83%.

These are patients who are very much in need of novel treatment options, said study author Christopher Yasenchak, MD, an oncologist with Willamette Valley Cancer Institute and Research Center and associate chair of the Hematology Research Program with US Oncology Research, who presented the data at ASH.

“These are the worst of the worst in terms of long-term outcomes,” says Yasenchak. “Three-year progression-free survival is roughly about 55%. Many of these patients are destined to fail frontline therapy and eventually will require salvage chemotherapy, autotransplant, mini-allo transplant, and subsequently still die of their disease. RCHOP in this context, is a non-adequate treatment.”

Brentuximab vedotin also showed favorable outcomes in subsets of patients known to have a poor prognosis, according to Yasenchak.

Among eleven patients with CD30-positive activated B-cell like (ABC) DLBCL, the complete remission rate of 73% (n = 8). The estimated PFS rate for these patients at both 12 and 15 months was 80%. Among 6 patients with Epstein-Barr virus (EBV)¬—positive lymphoma, the complete remission rate was 83% (n = 5). The estimated PFS rate for these patients at 12 months was also 83%.

“The PET-negative complete response rates were higher than what we would normally expect,” said Yasenchak. “What we did not see is that patients had inferior outcomes with ABC as opposed to GBC DLBCL and several patients in the study where also EBV-positive and historically they’ve done quite poorly. EBV drives CD30 expression and CD30 is the target for brentuximab vedotin.”

The most common treatment-emergent adverse events of any grade were fatigue and peripheral sensory neuropathy (63% each), diarrhea and nausea (57% each), and neutropenia and vomiting (37% each). The most common grade III or IV adverse events were febrile neutropenia (31%), neutropenia (33%), and anemia (24%).

Based on these efficacy and safety data, the phase II trial has been amended to add a randomized cohort exploring the activity and safety of brentuximab vedotin plus RCHP (without vincristine) versus RCHOP in frontline patients with CD30-expressing high-intermediate or high-risk DLBCL. Separately, a randomized phase II trial is also ongoing evaluating rituximab and bendamustine with or without brentuximab vedotin in relapsed or refractory DLBCL.

Brentuximab vedotin is also being investigated in combination with CHP (cyclophosphamide, doxorubicin, and prednisone) as a frontline treatment for CD30-positive peripheral T-cell lymphomas. Three-year durability and survival data was recently reported at ASH 2015 from 26 mature T-cell lymphoma (MTCL) patients.

Patients who achieved at least a partial remission with combination therapy were eligible to receive continued 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 (62%) with anaplastic lymphoma kinase (ALK) negative disease, which is typically associated with a poor prognosis. Seven patients had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk.

After a median of 38.7 months from first dose of therapy, the estimated 3-year PFS rate was 52% with no patients receiving a consolidative stem cell transplant in first remission. The estimated median PFS has not yet been reached and the estimated 3-year overall survival rate was 80%.

The most common adverse events of any grade occurring in more than 30% of patients were nausea and peripheral sensory neuropathy (69% each), diarrhea (62%), fatigue (58%) and hair loss (54%). The most common Grade III or higher adverse events occurring in more than 10% of patients were febrile neutropenia (31%), neutropenia (23%), anemia (15%) and pulmonary embolism (12%).

Seventy-three percent of patients 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 1.3 months.

According to Seattle Genetics, the manufacturer of brentuximab vedotin, the drug has 3 approved FDA indications: (1) regular approval for the treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen.

Brentuximab vedotin does not currently have approved indications for DLBCL and MTCL.

“There is a significant need to improve frontline treatment options in aggressive non-Hodgkin lymphomas. In particular, newly diagnosed patients with high-intermediate and high-risk DLBCL and MTCL have estimated 3-year progression-free survival rates of approximately 55% and 30%, respectively,” said Jonathan Drachman, MD, chief medical officer and executive vice president, Research and Development at Seattle Genetics, in a statement.

“Adcetris has demonstrated high complete remission and progression-free survival rates when added to frontline chemotherapy regimens for DLBCL and MTCL. Our efforts to redefine frontline therapy for these diseases are part of our goal to establish Adcetris as the foundation of care for all CD30-expressing lymphomas.”

References

1. Yasenchak CA, Halwani A, Advani R, et al. Brentuximab vedotin with RCHOP as frontline therapy in patients with high-intermediate/high-risk diffuse large B cell lymphoma (DLBCL): results from an ongoing phase 2 study. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 814.
2. Horwitz SM, Shustov AR, Forero-Torres A, et al. Frontline treatment of CD30+ peripheral T-cell lymphomas with brentuximab vedotin in combination with CHP: 3-year durability and survival follow-up. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 1537.