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Brentuximab vedotin combination superior to standard chemotherapy in Hodgkin lymphoma
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ATLANTA — Brentuximab vedotin in combination with doxorubicin, vinblastine and dacarbazine induced superior modified PFS compared with standard chemotherapy, according to results from the phase 3 ECHELON-1 clinical trial presented at the ASH Annual Meeting and Exposition.
“It’s important to understand Hodgkin lymphoma is one of the success stories of modern oncology with a large percentage of patients being cured with standard multiagent chemotherapy,” Joseph M. Connors, MD, FRCPC, medical oncologist and clinical director of the Centre for Lymphoid Cancer at British Columbia Cancer Agency in Vancouver, said during his presentation. “However, approximately a quarter to a third of patients wind up requiring secondary treatment to accomplish that goal and, still, some of the patients do die of progressive or refractory disease.”
Relapse after standard-of-care treatment with ABVD chemotherapy — or doxorubicin, bleomycin, vincristine and dacarbazine — occurs in approximately 30% of patients with high-risk Hodgkin lymphoma.
An anti-CD30 antibody-drug conjugate, brentuximab vedotin (Adcetris, Seattle Genetics) is approved for classical Hodgkin lymphoma after previous failure of autologous stem cell transplantation or a minimum of two prior chemotherapy regimens is a new option to explore in frontline therapy.
“In a phase 1 dose-escalation trial with coinvestigators, we demonstrated very high response rates and OS when [brentuximab vedotin] was combined with the three agents — adriamycin, vinblastine and dacarbazine — in a four-drug recipe,” Connors said. “So, we brought this forward to test this in comparison to standard chemotherapy, which is used in most of the world for advanced disease.”
Researchers randomly assigned 1,334 patients (median age, 36 years; 58% men) with previously untreated stage III (36%) or IV (64%) classical Hodgkin lymphoma to 1.2 mg/kg brentuximab vedotin plus AVD (25 mg/m2 doxorubicin, 6 mg/m2 vinblastine, 375 mg/m2 dacarbazine; n = 662), or to standard ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine and 375 mg/m2 dacarbazine; n = 659) on days 1 and 15 of up to six 28-day cycles.
Patients with a PET scan Deauville score of 5 after two cycles of treatment could switch to alternative therapy at discretion of the treating physician.
Patients assigned brentuximab plus AVD later in the study were mandated to have granulocyte colony-stimulating factor primary prophylaxis based on higher incidence for febrile neutropenia in that arm.
Modified PFS — defined as time to progression, death or evidence of incomplete response followed by subsequent anticancer therapy — determined by independent review facility assessment, served as the primary endpoint.
Secondary endpoints included complete response rate, overall response rate at the end of randomization regimen, CR rate at the end of frontline therapy, the rate of PET negativity at the end of cycle two, duration of response and complete response, and EFS.
Results showed modified PFS improved in the brentuximab plus AVD arm, with 117 events in that arm compared with 146 events in the ABVD arm (HR = 0.77; 95% CI, 0.6-0.98). This appeared consisted with investigator-reported modified PFS (HR = 0.72; 95% CI, 0.57-0.91).
Twoyear modified PFS rates per independent review were 82.1% (95% CI, 78.7-85) in the brentuximab plus AVD arm compared with 77.2% (95% CI, 73.7-80.4) in the ABVD arm.
Investigator-reported modified 2-year PFS rates were 81% (95% CI, 77.6-83.9) in the brentuximab plus AVD arm, and 74.4% (95% CI, 70.7-77.7) in the ABVD arm.
Secondary endpoints also trended in favor of the brentuximab vedotin arm.
Thirty-three percent fewer patients in the brentuximab vedotin arm received more than one subsequent chemotherapy, and 33% fewer received subsequent high-dose chemotherapy and transplant.
At the interim OS analysis, there were 28 deaths in the brentuximab vedotin arm and 39 in the ABVD arm (HR 0.72; 95% CI 0.44-1.17).
Safety profiles appeared consistent with known toxicities of the single agents, Connors said.
Among patients in the brentuximab vedotin arm, 67% of patients with peripheral neuropathy had resolution or improved by one grade at last follow-up. Among those with ongoing peripheral neuropathy at the last follow-up, 64% had grade 1, 29% had grade 2 and 7% had grade 3.
Seven percent of patients in the brentuximab vedotin arm discontinued treatment due to peripheral neutropenia compared with 2% in the ABVD arm.
Interstitial lung disease was more common (7% vs. 2%) and severe (grade 3, 3% vs. <1%) in the ABVD arm than the brentuximab vedotin arm.
Of the on-study deaths, nine occurred in the brentuximab vedotin arm, seven of which were associated with neutropenia. These deaths occurred among patients who had not received G-CSF primary prophylaxis. Of 13 on-study deaths in the ABVD arm, 11 were due to, or associated with, pulmonary toxicity.
G-CSF primary prophylaxis is recommended for all patients in the brentuximab vedotin arm, Connors said during his presentation.
“We think ECHELON establishes that there is a significantly superior outcome for patients treated with brentuximab in combination with AVD,” Connors said. “This leads to a 23% reduction as measured by independent review, and 28% as measured by investigators themselves conducting the trial, which indicates superiority in likelihood of remaining free of disease after primary therapy.”
Bleomycin, the toxic drug that causes interstitial lung disease, may be omitted, Connors said.
“The most troublesome of side effects that can linger, such as peripheral neuropathy, if managed properly sufficiently diminished over time as to not remain troublesome for the patient,” he said.
Tatyana A. Feldman, MD, co-investigator on the study and hematologist at John Theurer Cancer Center of Hackensack Meridian Health in New Jersey, called the results of ECHELON-1 “bittersweet”.
“They are important because we did detect a 5% difference in modified PFS at 2 years between ABVD and brentuximab plus AVD, in favor of brentuximab plus AVD. The question now is, is it good enough to become new standard of care,” Feldman told HemOnc Today.
There is a clear-cut signal brentuximab plus AVD may be superior, Feldman added, it is also important that the study showed bleomycin can be safely omitted to avoid increased pulmonary toxicities.
“It is an important beginning and I think brentuximab plus AVD will play a role in the frontline setting in patient subsets,” Feldman said. “ECHELON1 collected a huge amount of data and when more of it is analyzed, we will be able to gain more insight. I don’t think it should be blankly used for everyone, but the data is there that you have a 23% decrease in death or progression compared with AVBD.” – by Melinda Stevens
Reference:
Connors JM, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Connors reports research funding from Amgen, Bayer, Bristol-Myers Squibb, Cephalon, F. Hoffman-La Roche, Genentech, Janssen, Lilly, Merck, NanoString Technologies, Seattle Genetics and Takeda. Feldman reports a speaker role with AbbVie, Celgene, Janssen, Kite Pharma, Pharmacyclics; speaker bureau honoraria, consultancy and research funding from Seattle Genetics; honoraria from Takeda and a consultant role with Bristol-Myers Squibb. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Stefan K. Barta, MD, MS, MRCP(UK)
In this large international phase 3 study of 1,334 patients with untreated advanced Hodgkin lymphoma, the investigators showed treatment with brentuximab vedotin plus AVD resulted in a reduction of the composite endpoint of death, progression or additional anticancer therapy for incomplete responses at 2 years (77.2% vs. 82.2%). Although the substitution of bleomycin by brentuximab resulted in higher rates of grade 3 or higher infectious complications (grade 3 or higher, 11% vs. 2%) — especially if used without the routine administration of growth factors — and neuropathy (grade 3 or higher, 18% vs. 10%), the incidence of grade 3 or higher pulmonary toxicity was less (grade 3 or higher, <1% vs. 3%). An OS benefit has not been established.
This study demonstrated that brentuximab plus AVD is a highly effective regimen; however, the benefit comes at the price of increased toxicities, specifically infections and neuropathy. Avoiding potentially crippling lung toxicity that we have seen in the past with bleomycin certainly is important. However, the administration of six cycles of ABVD is no longer considered standard of care for approximately 80% of patients with advanced Hodgkin lymphoma who have a negative PET CT after cycle 2. For those patients, the incidence of pneumonitis is also less than 1%, similar to brentuximab plus AVD in the ECHELON-1 trial. Further, it is not clear at this point whether patients who experience relapse after ABVD can be salvaged with a brentuximab-containing regimen, which would abrogate the initial 5% PFS benefit seen with brentuximab plus AVD.
Reference:
Johnson P, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1510093.
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