Brentuximab Vedotin Plus Chemo Improves OS in Newly Diagnosed Advanced Hodgkin Lymphoma

Roger Dansey, MD

The combination of brentuximab vedotin (Adcetris) and chemotherapy resulted in a statistically significant improvement in overall survival (OS) when used in the frontline treatment of patients with advanced classical Hodgkin lymphoma, according to data from the phase 3 ECHELON-1 trial (NCT01712490).¹

At a median follow-up of approximately 6 years, the frontline combination of brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (A+AVD) resulted in a 41% reduction in the risk of death vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; HR, 0.59; 95% CI, 0.396-0.879).

Additionally, the toxicity profile of the antibody-drug conjugate (ADC) proved to be consistent with what has been demonstrated in prior studies, and no new safety signals have been reported.

“These groundbreaking results are important for patients with advanced classical Hodgkin lymphoma given that an improvement in OS has rarely been shown in frontline treatment of this disease,” Roger Dansey, MD, chief medical officer at Seagen Inc., stated in a press release. “We look forward to presentation of the results at an upcoming medical meeting.”

The open-label, international, phase 3 trial enrolled patients who were at least 18 years of age, had an ECOG performance status of 0 to 2, and had previously untreated stage III or IV classical Hodgkin lymphoma that was histologically confirmed via current World Health Organization classification.²

A total of 1334 study participants were randomized in a 1:1 fashion. Those in the A+AVD arm (n = 664) were given the ADC at 1.2 mg/kg of body weight, doxorubicin at 25 mg/m² of body surface area, vinblastine at 6 mg/m², and dacarbazine at 375 mg/m². Patients in the ABVD arm (n = 670) were administered doxorubicin at 25 mg/m², bleomycin at 10 U/m², vinblastine at 6 mg/m², and dacarbazine at 375 mg/m² intravenously on days 1 and 15 of each 28-day treatment cycle for up to 6 cycles.

The use of granulocyte-colony stimulating factor (G-CSF) was permitted in both arms for the treatment or prevention of neutropenia, per investigator discretion and institutional guidelines. After 75% of patients were enrolled to the trial, a recommendation was made for primary prophylaxis with G-CSF for those who would be given A+AVD to mitigate increased risk of febrile neutropenia.

The primary end point of the trial was modified progression-free survival (PFS) per independent review facility (IRF), and a key secondary end point was OS. Other secondary end points comprised rate of complete remission as best overall response, adverse effects (AEs), serious AEs (SEAs), assessments of clinical laboratory values, vital sign measurements, event-free survival, disease-free survival, overall response rate, duration of response, duration of CR per IRF, proportion of patients not in CR who received irradiation, CR rate per IRF at end of frontline treatment, proportion of patients with PET-2 negativity, patient-reported outcomes, pharmacokinetic variables for the ADC, monomethyl auristatin E and total antibody, and the presence of antitherapeutic antibodies to brentuximab vedotin.

Baseline disease characteristics and patient demographics were noted to be similar between the 2 arms. The median age of patients was 36 years (range, 26-52), with 58% of patients under the age of 40 years. Fifty-eight percent of patients were male, 50% were from Europe, 64% had Ann Arbor stage IV disease at initial diagnosis, and 53% had an International Prognostic score (IPS) ranging from 2 to 3. Moreover, 57% of patients had an ECOG performance status of 0, 62% had extranodal involvement at diagnosis, 59% had any B symptom, and 87% had negative PET-2 status.

Data from the 5-year update of the trial showed that the estimated 5-year PFS per investigator assessment in the intent-to-treat population was 82.2% (95% CI, 79.0%-85.0%) with A+AVD v s 75.3% (95% CI, 71.7%-78.5%) with ABVD (HR, 0.68; 95% CI, 0.53-0.87; P = .0017).

The 5-year PFS rates per investigator assessment proved to be generally higher with A+AVD vs ABVD across prespecified subsets, including age, PET-2 status, IPS risk group, and disease stage. In the 588 patients with PET-2 negativity, the estimated 5-year PFS rates in the investigative and control groups were 84.9% (95% CI, 81.7%-87.6%) and 78.9% (95% CI, 75.2%-82.1%), respectively (P = .0035); these rates were 60.6% (95% CI, 45.0%-73.1%) and 45.9% (95% CI, 32.7%-58.2%), respectively, in the 47 patients with PET-2 positivity (P = .23).

Investigators also evaluated treatment with anticancer treatment following frontline therapy and found that fewer patients in the investigative arm received at least 1 subsequent therapy vs those in the control arm, at 20% and 24%, respectively. Moreover, 6% and 9% of patients, respectively, received high-dose chemotherapy plus an autologous hematopoietic stem cell transplantation.

Regarding safety, 67% of 662 patients in the A+AVD group experienced peripheral neuropathy vs 43% of the 659 patients in the ABVD group. At 5 years, 19% vs 9% of patients, respectively, had ongoing peripheral neuropathy. In the A+AVD group, 85% of patients who had peripheral neuropathy achieved either complete resolution (71%) or improvement (13%).

Moreover, in the investigative arm, 11% of patients had a maximum severity of grade 1 ongoing peripheral neuropathy, 6% had a maximum severity of grade 2, 14% had a maximum severity of grade 3, and less than 1% had a maximum severity of grade 4.

In the control arm, 86% of 286 patients with peripheral neuropathy achieved complete resolution (79%) or improvement (6%). In this group, 6% had a maximum severity of grade 1, 2% had maximum severity of grade 2, and less than 1% had a maximum severity of grade 3 ongoing peripheral neuropathy.

In March 2018, the FDA approved brentuximab vedotin for use in combination with chemotherapy as a frontline treatment for adult patients with stage III or IV classical Hodgkin lymphoma.³ The regulatory decision was based on earlier data from ECHELON-1, which had shown that the A+AVD reduced the risk of disease progression, death, or initiation of new therapy by 23% vs ABVD. The 2-year modified PFS rates in the investigative and control arms were 82.1% and 77.25%, respectively (HR, 0.77; 95% CI, 0.60-0.98; P = .035).

References

1. ADCETRIS combination significantly improves overall survival in newly diagnosed patients with advanced Hodgkin lymphoma. News release. Seagen Inc.; February 3, 2022. Accessed February 3, 2022. https://bit.ly/3ojej4U
2. Straus DJ, Dlugosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021;8(6):e410-e421. doi:10.1016/S2352-3026(21)00102-2
3. FDA expands approval of Adcetris for first-line treatment of stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. News release. FDA; March 20, 2018. Accessed February 3, 2022. https://bit.ly/3gjUOEC