ATLANTA — Upfront treatment with the antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris) led to significantly better progression-free survival (PFS) for patients with newly diagnosed advanced Hodgkin lymphoma, investigators reported here.
Patients who received the ADC, in addition to standard first-line chemotherapy, had a 2-year PFS of 82.1% versus 77.2% for chemotherapy alone. An interim analysis of overall survival (OS) showed a trend in favor of the brentuximab regimen, but the difference did not achieve statistical significance, according to James M. Connors, MD, of the British Columbia Cancer Agency in Vancouver, and colleagues.
The addition of brentuximab to chemotherapy increased rates of neutropenia and peripheral neuropathy, which was manageable in most cases, Connors said during a presentation at the American Society of Hematology meeting. The study was published simultaneously in the New England Journal of Medicine.
The trial also provided support for omitting bleomycin from chemotherapy when brentuximab is used.
“The (brentuximab) regimen is associated with more myelotoxicity — which can be ameliorated with prophylactic G-CSF — and neurotoxicity — which is largely reversible) than ABVD but substantially less pulmonary toxicity and appears to be more effective for the frontline treatment of advanced-stage classic Hodgkin’s lymphoma,” Connors’ group wrote.
Authors of an accompanying NEJM editorial cautioned that follow-up time for the study was too brief to rule out the possibility of late side effects with brentuximab regimen. However, they gave tentative support for upfront use of the ADC.
“It appears that the addition of brentuximab vedotin to AVD combination chemotherapy … merits consideration as first-line treatment for advanced Hodgkin’s lymphoma,” wrote Daniel Longo, MD, and Vincent T. DeVita Jr., MD, both of Yale Cancer Center in New Haven, Connecticut. “Although the follow-up time has been relatively short the (ADC combination) appears to be more effective than ABVD (and is unlikely to be less effective) and is associated with fewer, more treatable toxicities.”
Outcomes for advanced Hodgkin’s lymphoma improved substantially over the past 50 years, especially after the introduction of ABVD combination chemotherapy (doxorubicin-bleomycin-vinblastine-dacarbazine) more than 40 years ago. However, 25% to 30% of patients have refractory disease or relapse after initial treatment with ABVD, Connors’ group noted. Moreover, bleomycin can cause unpredictable and potentially fatal pulmonary toxicity.
Brentuximab vedotin consists of a monoclonal antibody that targets the CD30 surface antigen — expressed by Reed-Sternberg cells in classic Hodgkin’s lymphoma — to the microtubule-disrupting agent monomethyl auristatin. The ADC has FDA approval as treatment for classic Hodgkin’s lymphoma that does not respond, or recurs after stem-cell transplantation or failure of at least two multiagent chemotherapy regimens. The drug also has approval as posttransplant consolidation therapy for high-risk patients.
The decision to include bleomycin in chemotherapy (ABVD) remains controversial, both in terms of efficacy and added toxicity, particularly pulmonary toxicity. In a phase I trial of frontline therapy for advanced Hodgkin’s lymphoma, brentuximab vedotin combined with AVD chemotherapy led to complete responses in 24 of 25 patients, a 5-year failure-free survival of 92%, and OS of 100%.
Connors presented results from a phase III randomized trials to compare brentuximab vedotin plus AVD chemotherapy with standard ABVD chemotherapy in 1,334 patients with untreated stage III or IV classic Hodgkin’s lymphoma. The trial had a primary endpoint of modified PFS — the time to disease progression, death, or non-complete response and use of subsequent anticancer therapy, adjudicated by an independent review committee.
The study population had a median age of 36, and men accounted for 58% of the patients. Two-thirds of the patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms (such as night sweats, weight loss, and fever).
After a median follow-up of 25 months, the brentuximab regimen had resulted in a 23% reduction in the hazard for the primary endpoint (95% CI 0.60-0.98, P=0.03). The preliminary survival analysis showed that 28 patients ion the brentuximab arm died versus 39 in the ABVD arm, which translated into a nonsignificant 28% reduction in the hazard ratio in favor of brentuximab (95% CI 0.44-1.17, P=0.19).
With respect to safety, the most common adverse event in both groups was neutropenia, which occurred in 58% of the brentuximab arm and 45% of the ABVD arm. Febrile neutropenia occurred in 19% and 8% of the brentuximab and ABVD groups, respectively. In the brentuximab arm, febrile neutropenia occurred less in of 83 patients who received prophylactic G-CSF (11% vs 21%). Connors said 1% of patients in each group discontinued because of febrile neutropenia.
Other common adverse events (any grade) were infection (55% vs 50%), constipation (42% with brentuximab, 37% with ABVD), vomiting (33% vs 28%), fatigue (32% in both groups), peripheral sensory neuropathy (29% vs 17%), diarrhea (27% vs 18%), pyrexia (26% vs 13%), abdominal pain (21% vs 10%), and stomatitis (21% vs 16%). Neutropenia (54% vs 39%) was the only grade 3 adverse event that occurred in more than 5% of patients in either group.
Pulmonary toxicity occurred in 2% and 7% of the brentuximab and ABVD groups, respectively, including grade ≥3 pulmonary toxicity in 1% and 3%.
The study was supported by Seattle Genetics and Millennium Pharmaceuticals.
Connors disclosed relevant relationships with Janssen, Genentech, NanoString Technologies, Merck, F Hoffmann-La Roche, Cephalon, Seattle Genetics, Bayer Healthcare, Bristol-Myers Squibb, Takeda, Amgen, and Eli Lilly.
Longo disclosed serving as deputy editor of the New England Journal of Medicine. DeVita disclosed no relevant relationships with industry.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner