Will Replacing Bleomycin With Brentuximab Vedotin Revolutionize Frontline Hodgkin Lymphoma Treatment?

For patients with advanced-stage Hodgkin lymphoma (HL), eliminating bleomycin (and its associated risks of pulmonary toxicity) from the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen and replacing it with brentuximab vedotin and AVD (A+AVD) could prolong modified progression-free survival (mPFS). Though the risks of pulmonary toxicity were lower with A+AVD, the regimen appeared to be associated with increased risks of peripheral neuropathy and neutropenia, according to research presented as a plenary abstract at the 2017 ASH Annual Meeting.

“The anti-CD30 antibody drug conjugate brentuximab vedotin is the most active agent for the treatment of HL in decades, so we wanted to know, ‘Where is the best place to put a new targeted agent that we’ve been using in relapsed and subsequent settings for some time?’” lead author Joseph M. Connors, MD, from the British Columbia Cancer Agency Centre for Lymphoid Cancer in Vancouver, Canada, told ASH Clinical News. “If this new regimen is widely adopted, it will change firstline treatment of advanced HL.” Dr. Connors presented results from the phase III ECHELON-1 trial, which were simultaneously published in the New England Journal of Medicine.

From November 19, 2012, through January 13, 2016, ECHELON-1 investigators randomized 1,344 patients with previously untreated, stage III or IV classic HL to receive up to six cycles of either ABVD (n=670) or A+AVD (n=664). The median age was 36 years (range = 18-83 years), 64 percent of patients in each group had stage IV disease, and 58 percent in each group had B symptoms.

Response was evaluated via computed tomography scans obtained at screening, at the end of cycle two, after administration of the last dose of frontline therapy, and every three months during follow-up. Patients with a positive scan after cycle two (defined as a Deauville score of 5) could switch to alternative therapy at the treating physician’s discretion.

Treatment success was determined by independently-reviewed mPFS (defined as the time to progression, death, or non-complete response and use of subsequent anticancer therapy). By selecting mPFS as the study’s primary endpoint, “we asked ‘What is the point that defines success, and after which we can avoid the need for subsequent therapy?’” While some cases of treatment failure are straightforward, Dr. Connors explained, “there are scenarios in which patients have loss of response to therapy, but the disease has not progressed and the patient has not died.”

After a median of 24.9 months follow-up (range not provided), rates of two-year mPFS were significantly higher in the A+AVD group: 82.1 percent (95% CI 78.7-85.0) versus 77.2 percent (95% CI 73.7-80.4; p values not reported). This corresponded to a 23 percent lower risk for progression, death, or modified progression in the A+AVD group than the ABVD group (hazard ratio [HR] = 0.77; 95% CI 0.60-0.98; p=0.03).

The need for subsequent therapy appeared to be nearly doubled in the ABVD group (8% [n=9] and 15% [n=22], respectively), Dr. Connors noted.

Though A+AVD was only modestly superior to ABVD in mPFS, “it means that one-quarter of the patients who would have relapsed or had a lack of success of their primary treatment can avoid that by taking newer experimental treatment,” Dr. Connors said.

The most common adverse events (AEs) in each arm were neutropenia, constipation, vomiting, fatigue, and peripheral neuropathy. As expected, pulmonary toxicity was more frequent and more severe with ABVD than A+AVD (3% vs. <1%), but neutropenia and peripheral neuropathy were more common in the A+AVD arm. Eighty-eight (13%) and 105 (16%) patients, respectively, discontinued treatment because of AEs.

There were 22 on-treatment deaths; seven of nine deaths (78%) in the A+AVD group were associated with neutropenia, and 11 of 13 (85%) in the ABVD group were associated with pulmonary toxicity.

“Of the deaths that occurred during treatment, the entire excess number of deaths in the ABVD arm were due to pulmonary toxicity,” Dr. Connors reported. “When the bleomycin is out, there isn’t the risk of unexpected pulmonary toxicity – which is already low, even in the ABVD arm, because our clinicians are smart and know how to manage bleomycin – but wasn’t completely eliminated.”

With the addition of prophylactic granulocyte colony-stimulating factor in the A+AVD arm toward the end of the study (based on a higher incidence of febrile neutropenia in this group), febrile neutropenia incidence decreased from 21 percent (n=119/579) to 11 percent (n=9/83). Grade ≥3 infections also dropped from 18 percent (n=107/579) to 11 percent (n=9/83).

Peripheral neuropathy was also more frequent in the A+AVD arm, but the authors wrote, “two-thirds of patients experiencing peripheral neuropathy in the A+AVD arm had resolution or improvement in pain at last follow-up.”

“In the past, the only [alternative regimens] that have demonstrated superiority over ABVD have come with an unacceptably high price of toxicity,” he concluded. “[These data] allow us to move forward with some confidence that, without asking our patients to put up with increased burden of long-term toxicity, we can do something that improves the likelihood that they can be cured the first time around.”

The study’s findings will need to be confirmed with longer-term follow-up, and the use of physician discretion may have introduced bias. Questions about the salvageability of frontline A+AVD also remain unanswered.

As several attendees noted during the plenary scientific session, the costs associated with adding brentuximab vedotin to AVD, particularly without an equally substantial increase in survival, are a concern. In addition, only 9 percent of patients in each group were 65 years or older, and these patients saw no significant benefit in efficacy, which limits the applicability of these findings to the older HL population.

“Ultimately, our most severe test will be the impact on overall survival (OS),” Dr. Connors concluded. A preplanned OS analysis is ongoing, but results were not sufficiently matured before the presentation. He hinted, though, that the results were “encouraging in favor of the experimental arm.”

On January 2, 2018, the U.S. Food and Drug Administration granted priority review to the supplemental biologics license application for brentuximab vedotin in the frontline setting, supported by data from ECHELON-1.

The authors report financial relationships with Janssen, Genentech, Merck, Roche, Seattle Genetics, Amgen, and Bristol-Myers Squibb.


Reference

Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 Echelon-1 study. Abstract #6. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.

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