Nancy Bartlett, MD
Combining the CD30-directed antibody-drug conjugate brentuximab vedotin (Adcetris) with standard R-CHOP yielded objective responses in 80% of patients with advanced DLBCL in a phase II trial, including complete remissions in two-thirds of the population. The interim results from the ongoing study were presented at the 2015 ASCO Annual Meeting.
“Brentuximab vedotin in combination with R-CHOP results in a high response rate in newly diagnosed high-intermediate and high-risk DLBCL patients,” lead author Nancy Bartlett, professor of Medicine in the division of Oncology at the Washington University School of Medicine in St. Louis, said when presenting the results at ASCO.
The phase II study included 53 previously untreated patients with DLBCL. Ninety-six percent had stage III/IV disease and were categorized as high-risk (38%) or high-intermediate risk (62%). Patients were required to have an ECOG performance status ≤2. The median patient age was 67 years and 79% of patients were aged ≥60 years.
CD-30 mutation status was determined through routine IHC staining, with CD-30 positivity defined as expression on ≥1% of tumor cells. Twenty-five patients (47%) were CD-30 positive, 24 (45%) were negative, and the status was not available for four (8%) patients.
Patients were randomized in a 1:1 ratio to standard R-CHOP plus brentuximab at a dose of either 1.2 mg/kg (n = 30) or 1.8 mg/kg (n = 23). Brentuximab was administered on day 1 of each 21-day cycle, for a maximum of 6 cycles. The primary outcome measures were response and safety, with secondary endpoints focused on progression-free survival (PFS) and overall survival.
During a preplanned safety monitoring committee review after the first 10 patients in each arm completed treatment, “It was noted that in the 1.8-mg/kg arm, three patients experienced grade 3 peripheral neuropathy, as opposed to one patient in the 1.2-mg/kg arm,” said Bartlett. The rate of dose eliminations of brentuximab was also significantly higher in the 1.8-mg/kg arm. Based on these outcomes, the higher dose arm was closed and the remainder of brentuximab treatments were administered at 1.2 mg/kg.
Two patients enrolled in the trial did not initiate treatment, so the safety and efficacy analysis included 51 patients, comprising 29 and 22 patients in the 1.2-mg/kg and 1.8-mg/kg arms, respectively.
The antitumor activity was comparable between the higher- and lower-dose treatment arms. Overall, forty-one patients (80%; 95% CI, 66.9-90.2) in the trial achieved an objective response, including thirty-four (67%; 95% CI, 52.1-79.2) complete remissions and seven (14%) partial remissions. Five patients (10%) had progressive disease.
In the overall population, the 6- and 12-month PFS rates were 79% and 65%, respectively. PFS results were similar between the two dose cohorts.
ORR was comparable in CD-30–positive and –negative patients at 84% and 83%, respectively. “It does appear that there is a trend toward an improved complete remission rate in the patients who were CD-30 positive, with a 76% complete remission rate compared to 61% in the CD-30–negative patients; however, there are wide confidence intervals which do overlap.”
Six-month PFS rates were similar between the CD-30 arms. The 12-month PFS was 86% versus 58% in the CD-30–positive versus –negative cohorts, respectively; however, the confidence intervals once again overlapped.
As expected, toxicities were higher in the 1.8-mg/kg cohort. The most frequently reported all-grade adverse events in the higher-dose versus lower-dose brentuximab arms were peripheral sensory neuropathy (69% vs 55%), fatigue (68% vs 55%), nausea (68% vs 45%), diarrhea (60% vs 48%), and vomiting (55% vs 24%). Rates of peripheral neuropathy were 36% versus 13% in the two arms, respectively.
Bartlett also said it was significant that approximately 35% of patients in each cohort developed febrile neutropenia despite at least 90% of patients using prophylactic growth factors. “This rate certainly is higher than reported with standard R-CHOP with the use of prophylactic growth factors.”
The most common grade 3/4 adverse-events reported in the overall study population were neutropenia, febrile neutropenia, and anemia. There were two treatment-related deaths in the trial (both in the 1.2-mg/kg arm), and five patients discontinued treatment due to adverse events.
The protocol for the study has been amended since this initial analysis, and the trial is now only enrolling CD-30–positive patients, with a dosing regimen of 1.8 mg/kg of brentuximab plus RCHP. High rates of vincristine dose elimination occurred in the initial 51 patients, so it was removed from the chemotherapy regimen.
In her concluding remarks on the phase II data, Bartlett said, “Although the results look promising, ultimately, a randomized trial would be needed to determine the benefit of adding brentuximab vedotin to R-CHOP in CD-30–positive DLBCL as frontline therapy.”
Although not currently approved in DLBCL, brentuximab received an accelerated approval in August 2011 as a treatment for patients with Hodgkin lymphoma after failure of ASCT or after failure of at least two prior chemotherapy regimens in patients who were not candidates for ASCT. At the same time, the drug was approved for the treatment of patients with anaplastic large cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.
In April 2015, the FDA granted a priority review to brentuximab as a consolidation therapy following autologous stem cell transplantation in patients with Hodgkin lymphoma at risk of relapse or progression, based on findings from the phase III AETHERA trial. A final approval decision is scheduled to be made by August 18, 2015.
Bartlett NL, Farber CM, Yasenchak CA, et al. Updated results of a phase II trial of brentuximab vedotin combined with R-CHOP in frontline treatment of patients (pts) with high-intermediate/high-risk diffuse large B-cell lymphoma (DLBCL). J Clin Oncol. 2015;(suppl; abstr 8506).