Brentuximab combinations highly active in Hodgkin lymphoma

Attendees at ASH 2014

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.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

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.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.

Attendees at ASH 2014

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.

Investigators therefore hypothesized that brentuximab in combination with bendamustine could induce more CRs in HL patients with relapsed or refractory disease after frontline therapy.

Ann LaCasce, MD, of Dana-Farber Cancer Institute in Boston, presented the data at ASH as abstract 293.*

Ten patients were enrolled in the phase 1 portion of the study to determine the optimal dose level of bendamustine and to assess safety and tolerability.

No dose-limiting toxicities were observed. So the investigators used bendamustine at 90 mg/m² and brentuximab at 1.8 mg/kg. Patients received a median of 2 cycles (range, 1 to 6) of combination therapy.

Patients had the option to proceed to an autologous stem cell transplant at any time after cycle 2 and could receive brentuximab monotherapy thereafter for up to 16 total doses.

The phase 2 expansion portion enrolled 44 patients and assessed the best response, duration of response, and progression-free survival.

Results

Patients were a median age of 37 years (range, 27 to 51), and 57% were male. Ninety-eight percent were ECOG status 0 or 1, and 54% had stage III or IV disease at diagnosis.

The majority of patients had received ABVD as frontline therapy, Dr LaCasce pointed out.

The most common treatment-emergent adverse event was infusion-related reactions, accounting for 96% of the events. Dyspnea (15%), chills (13%), and flushing (13%) were the most common symptoms, and hypotension requiring vasopressor support also occurred.

Most reactions occurred within 24 hours of the cycle 2 infusion and were considered related to both agents. However, delayed hypersensitivity reactions also occurred, Dr LaCasce said, the most common being rash in 14 patients up to 22 days after infusion.

“Based on the number of infusion-related reactions after 24 patients, the protocol was amended to require mandatory corticosteroids and anthistamine premedication,” Dr LaCasce explained. “[T]his resulted in a significant decrease in the severity of the infusion-related reactions.”

The best clinical response for the 48 evaluable patients was 83% CR and 13% partial remission, for an objective response rate of 96%.

The median progression-free survival has not yet been reached, and the combination has had no negative impact on stem cell mobilization or engraftment to date.

The response rate compares very favorably to historical data, Dr LaCasce said, and the combination represents a promising salvage regimen for HL patients.

*Data in the presentation differ from the abstract.