Brentuximab combinations highly active in Hodgkin lymphoma
Photo courtesy of ASH
SAN FRANCISCO—Two recent studies have shown combination therapy with brentuximab vedotin to be highly active in newly diagnosed patients with Hodgkin lymphoma (HL) and in relapsed or refractory patients after frontline therapy.
The first study evaluated brentuximab with ABVD or AVD and the second with bendamustine.
Objective response rates were 95% with ABVD, 96% with AVD, and 96% with bendamustine.
Both studies were presented at the 2014 ASH Annual Meeting, and both were sponsored by Seattle Genetics, Inc., the company developing brentuximab vedotin.
Brentuximab with ABVD or AVD
Standard frontline therapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) or AVD (the same regimen without bleomycin) fails to cure up to 30% of patients with HL.
So investigators decided to try a new approach to increase efficacy and reduce toxicity—combining brentuximab with standard therapy.
Joseph M. Connors, MD, of the BC Cancer Agency and University of British Columbia in Vancouver, Canada, presented long-term outcomes of the brentuximab-ABVD combination as abstract 292.*
Phase 1 dose-escalation study
The key initial study of the combination determined the maximum tolerated dose of brentuximab to be 1.2 mg/kg delivered on a 2-week schedule to match the other agents in the ABVD regimen. Brentuximab was delivered for up to 6 cycles.
Of the 50 patients treated, 75% were males with an ECOG status of 0 or 1. Their median age was 32.5 years (range, 18 to 59). Approximately 80% were stage III or IV.
“We learned several key lessons from that initial study,” Dr Connors said. “The first was that when one adds brentuximab vedotin to the full-dose combination ABVD, unacceptable levels of pulmonary toxicity occurred, with 44% of the patients eventually experiencing pulmonary toxicity, typically manifest between the third and sixth cycle of treatment.”
The toxicity resolved in 9 of the 11 patients, but was fatal in 2. The median time to resolution was 2.6 weeks.
Eight patients discontinued bleomycin but were able to complete treatment with AVD and brentuximab.
“When we dropped bleomycin from the combination and shifted to AVD without bleomycin, no patients experienced pulmonary toxicity,” Dr Connors added.
Ultimately, the combination produced a response rate of 95% with ABVD and 96% with AVD.
Long-term follow-up
Investigators then assessed the durability of the response and the time distribution of any relapses.
All but 1 patient was available for follow-up. Patients were followed for a median of 45 months in the ABVD arm and 36 months in the AVD arm.
In the ABVD arm, 22 of 24 patients are living, and all 26 patients in the AVD group are alive. Altogether, there have been 5 relapses—3 in the ABVD arm (occurring at 9, 22, and 23 months) and 2 in the AVD arm (occurring at 7 and 22 months).
The 3-year failure-free survival is 79% with ABVD and 92% with AVD. And the 3-year overall survival is 92% in the ABVD arm and 100% in the AVD arm.
No deaths from HL have occurred, and all 5 relapsed patients have undergone autologous stem cell transplant. One of those has subsequently relapsed.
“So far,” Dr Connors said, “survival has been excellent.” And responses are durable.
“This has encouraged activation of the large, international trial,” Dr Connors said, comparing AVD plus brentuximab to standard ABVD in frontline treatment of HL.
Brentuximab with bendamustine
Brentuximab is also active as a single agent in relapsed/refractory HL, producing a 34% complete response (CR) rate. And the alkylating agent bendamustine produces a 33% CR rate in these patients. Furthermore, both agents have manageable safety profiles and different mechanisms of action.
