High response rates were the hallmark of two clinical trials of brentuximab vedotin (BV) in combination with chemotherapy presented at the 2015 American Society of Clinical Oncology Annual Meeting, examining the outcomes in patients with non-bulky, limited-stage classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) patients.
Despite the encouraging efficacy results, treatment with BV, an anti-CD30 directed antibody-drug conjugate recently approved by the U.S. Food and Drug Administration for the treatment of HL, carried several safety concerns in both disease settings.
AVD + BV in Hodgkin Lymphoma
Patients with limited HL are typically treated with ABVD (adriamycin/bleomycin/vinblastine/dacarbazine) plus radiation, with cure rates of 85 to 90 percent, but the associated bleomycin lung toxicity and the late effects of radiotherapy threaten long-term survival and quality of life.
In the first trial, Jeremy Abramson, MD, from Massachusetts General Hospital Cancer Center, in Boston, and colleagues evaluated whether adding BV and removing bleomycin from the chemotherapy regimen would result in similar or better response rates and eliminate those late effects.1
In this multicenter, phase II trial, 34 patients (median age = 36 years) received a lead-in cycle of BV monotherapy (1.2 mg/kg) on days 1 and 15, followed by an exploratory PET-CT scan. Patients then received four to six cycles of BV + AVD, depending on PET–CT results. At baseline, 62 percent of patients had favorable risk, and 38 percent had unfavorable risk.
After the BV monotherapy lead-in, 18 of 34 patients (53%) achieved a complete response (CR) and 16 (47%) patients achieved a partial response (PR). Following two cycles of BV + AVD, the rate of CR jumped to 97 percent (33 patients), but one patient was removed from the study due to toxicity. Thirty-one patients ultimately completed treatment – one patient had experienced progressive disease and another patient was removed due to toxicity. However, Dr. Abramson noted, the patients removed from the study had achieved CR in their last treatment cycle.
At the end of treatment, eight subjects had PET–CT scans interpreted as positive. Dr. Abramson and colleagues later confirmed six of the eight were false-positive scans, a common enough occurrence to “warrant further attention,” they wrote. At a median follow-up of 14 months, one-year progression-free survival (PFS) and overall survival (OS) rates were 90 percent and 97 percent, respectively.
While the addition of BV to AVD was associated with high response rates, it was associated with treatment-related adverse events, including peripheral neuropathy (74%), fatigue (71%), neutropenia (68%), and anemia (56%). One older patient died of neutropenic sepsis in the first AVD cycle, while another patient was removed from the study after experiencing grade 2 hypersensitivity, despite premedication.
Reductions in BV were required in 38 percent of patients – mostly due to peripheral neuropathy. Neutropenia and febrile neutropenia were the most common grade 3 and 4 toxicities; however, altering the protocol to include GCSF support, Dr. Abramson noted, dramatically reduced neutropenic episodes.
Frontline BV + R-CHOP in DLBCL
In the second trial, adding BV to the standard R-CHOP (rituximab/cyclophosphamide/doxorubicin hydrochloride/vincristine sulfate/prednisone) regimen led to “encouraging” response rates in patients with intermediate or high-risk DLBCL (defined as International Prognostic Index [IPI] scores of 3-5, or age-adjusted IPI scores of 2-3 for patients younger than 60) – a patient group with typically suboptimal outcomes with R-CHOP alone – according to presenter Nancy Bartlett, MD.2
Dr. Bartlett, from Washington University School of Medicine in St. Louis, Missouri, and colleagues have previously demonstrated that single-agent BV resulted in responses in relapsed DLBCL patients.3 With the current study, they posited that the combination of BV and R-CHOP could improve outcomes in the frontline setting.
Fifty-three patients were enrolled in the study, 51 of whom received treatment. Patients were randomized to six cycles of BV + R-CHOP (1.2 or 1.8 mg/kg BV every third week with standard R-CHOP) or standard R-CHOP. After the first safety and monitoring committee review, the 1.8 mg/kg dose was reduced to 1.2 mg/kg due to high rates of grade 3 neuropathy.
At the end of the study, the overall response rate was 97 percent, with 80 percent of patients having a PET-negative CR at the end of treatment. As observed in their previous study, the investigators found that CR rates were higher in CD30-positive than in CD30-negative patients: 76 percent (95% CI 54.9-90.6) and 61 percent (95% CI 38.5-80.3), respectively.
Similar to the HL trial, the addition of BV to standard chemotherapy was associated with toxicity in these patients: Treatment-emergent adverse events (AEs) occurred in 96 percent of patients, with the most frequent being nausea, fatigue, and peripheral neuropathy. AEs led to treatment discontinuation in 10 percent of patients, and two patients died from AEs, including sepsis and hypovolemic shock. An additional three patients died following progression.
Although these results were “encouraging,” Dr. Barlett noted, a randomized trial is needed to determine the benefit of BV in CD30-positive DLBCL compared with R-CHOP as frontline therapy.
- Abramson JS, Arnason JE, LaCasce AS, et al. Brentuximab vedotin plus AVD for non-bulky limited stage Hodgkin lymphoma: A phase II trial. Abstract #8505. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 2, 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). Abstract #8506. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 2, 2015.
- Bartlett NL, Smith MR, Advani R, et al. Brentuximab vedotin monotherapy in DLBCL patients with undetectable CD30: preliminary results from a phase 2 study. Abstract #629. Presented at the 56th ASH Annual Meeting, San Francisco, CA, December 8, 2014.