Adcetris plus doxorubicin, vinblastine and dacarbazine is the first regimen to improve overall survival compared to the current standard of care for patients with advanced-stage classical Hodgkin lymphoma.
Patients with untreated stage 3/4 classical Hodgkin lymphoma had a decreased risk of death on a drug combination consisting of Adcetris (brentuximab vedotin) plus doxorubicin, vinblastine and dacarbazine (a combination referred to as A+AVD), compared to those prescribed doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), according to six-year follow-up data from the phase 3 ECHELON-1 clinical trial.
Results of the trial, which led to the 2018 approval of the Adcetris-based combination, were presented at the 2022 ASCO Annual Meeting, and also showed that A+AVD had a manageable safety profile as well.
At an average follow-up of 73 months, the estimated six-year overall survival (OS) rates were 93.9% with A+AVD, compared to 89.4% with ABVD. The median overall survival was not yet reached in either group.
“(Adcetris) plus AVD is the first regimen to show an improvement in overall survival compared with standard ABVD chemotherapy in patients with previously untreated, advanced stage classical Hodgkin lymphoma,” lead study author Dr. Stephen Ansell, professor of medicine, consultant, and chair of Faculty Development and Recruitment in the Division of Hematology and Department of Internal Medicine at Mayo Clinic, said during a presentation on the findings. “Based on these data, AVD chemotherapy plus (Adcetris) should be considered a preferred first-line treatment in patients with previously untreated, advanced stage classical Hodgkin lymphoma.”
In ECHELON-1, 1,334 patients were randomly assigned receive up to six cycles of A+AVD (664 patients) or ABVD (670 patients) intravenously on days 1 and 15 every 28 days.
Modified progression-free survival (time from treatment until the disease gets worse) was the main goal of the study, and it was met. Five-year follow-up analyses supporting the long-term progression-free survival benefit with first-line A+AVD compared to ABVD in patients with stage 3/4 classical Hodgkin lymphoma.
Overall survival was the key secondary endpoint.
Long-term follow-up assessments included progression-free survival per investigator, subsequent treatment use and safety outcomes including second malignancies, outcomes of pregnancy among patients and their partners, and peripheral neuropathy resolution and improvement rates.
Additional findings revealed a consistent overall survival benefit for A+AVD over ABVD across prespecified subgroups. Moreover, the overall survival benefit still existed in an analysis adjusting for baseline demographic and disease factors. Notably, age, non-White race, ECOG performance status (which indicates how well someone can perform their daily tasks) and PET2 status had the greatest association with overall survival.
The six-year progression-free survival estimates were 82.3% with A+AVD, compared to 74.5 with ABVD.
In terms of safety, no new side effects were identified that haven’t previously been associated with the drugs, and A+AVD had a comparable long-term safety profile to that of ABVD.
Fewer patients died from Hodgkin lymphoma and disease- or treatment-related complications with A+AVD (39 patients; 5.9%) versus ABVD (64 patients; 9.7%). Other reasons for death were unknown (one patient), accident or suicide (three patients), heart failure (one patient) and intracranial hemorrhage (one patient) in the A+AVD group and unknown (five patients), COVID-19 (one patient), heart failure (one patient) and lower respiratory tract infection (one patient) in the ABVD group.
In the A+AVD group, 19 patients who died had prior disease progression and 18 received subsequent therapy. In the ABVD group, 28 patients who died had prior disease progression and 25 received subsequent therapy (Adcetris, 13 patients).
Notably, the use of at least one subsequent therapy was less common with A+AVD (135 patients; 20%) compared to ABVD (157 patients; 24%). The type of subsequent therapy in the A+AVD and ABVD groups, respectively, included Adcetris or chemotherapy regimens (78 patients, 12%; 108 patients, 16%), radiation (54 patients, 8%; 54 patients, 8%), chemotherapy and radiation (one patient, less than 1%; four patient, less than 1%), high-dose chemotherapy and transplant (44 patients, 7%; 59 patients, 9%), allogeneic transplant (four patients, less than 1%; 12 patient, 2%), immunotherapy (18 patients, 3%; 24 patients, 4%) or other (zero patients, 0%; one patient, less than 1%).
Additionally, 23 patients in the A+AVD group experienced secondary malignancies (9 hematologic malignancies; 14 solid tumors). Meanwhile, 32 patients in the ABVD group experienced secondary malignancies (17 hematologic malignancies and 14 solid tumors), mirroring earlier study findings. Two patients in each group with second malignancies underwent transplant, and three patients in the ABVD group received prior radiation.
Furthermore, pregnancy and peripheral neuropathy data were consistent with prior findings. More female patients in the A+AVD reported pregnancies (49 patients vs 28 patients in the A+AVD and ABVD groups, respectively) and live births (56 patients vs 23 patients).
Among partners of male patients, 33 pregnancies and 40 live births were reported in the A+AVD group, compared to 33 pregnancies and 36 live births in the ABVD groups. No stillbirths were reported in either group.
The two-year incidence of peripheral neuropathy was 67% with A+AVD and 43% with ABVD. However, treatment-emergent peripheral neuropathy continued to resolve or improve in both groups, with 86% and 87% of cases in the A+AVD and ABVD groups, respectively, either completely resolving or improving by last follow-up.
The median time to resolution was 16 and 10 weeks, respectively.
Patients with ongoing peripheral neuropathy at last follow-up in the A+AVD and ABVD groups, respectively, consisted of grade 1 (71 patients, 11%; 39 patients, 6%), 2 (38 patients, 6%; 16 patients, 2%), 3 (15 patients, 2%; four patients, less than 1%), and 4 (one patient, less than 1%; zero patients) events.
“A+AVD improved overall survival vs ABVD despite the wide availability and use of active salvage treatment, including substantial use of subsequent (Adcetris) in the ABVD arm. The overall survival benefit with A+AVD was coupled with fewer second malignancies vs ABVD,” Ansell concluded. “The observed overall survival benefit with A+AVD, fewer disease-related deaths, and a concomitant reduction in disease progression, suggests that A+AVD has potentially cured more patients of their disease.”
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