Brentuximab Vedotin Shows Promising Activity as First-Line Use in Classical Hodgkin Lymphoma

Results from the phase 3 ECHELON-1 trial determined brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine should be used as first-line treatment in patients with stage III or IV classical Hodgkin lymphoma.

The use of brentuximab vedotin (Adcetris) was analyzed in the phase 3 ECHELON-1 trial (NCT01712490) for patients with Hodgkin lymphoma.¹ In March 2018, the FDA approved brentuximab vedotin for patients with stage III or IV classical Hodgkin lymphoma in combination with chemotherapy.²

At the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies, David J. Straus, MD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, presented the most updated findings of the trial, and debated if this was the best course of action for treating Hodgkin lymphoma. The presentation focused on results from the trial, and how to implement the findings into treatment plans.

A total of 1334 patients were enrolled and randomized 1:1 to either the brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) group or brentuximab vedotin plus bleomycin, doxorubicin, vinblastine, and dacarbazine (ABVD) group. In the A+AVD group (n = 664), patients were given 1.2 mg/kg of brentuximab vedotin intravenously on days 1 and 15 compared with the ABVD group (n = 670) where patients received matched dosing. Patients then continued to end-of-treatment CT/PET scans with follow-up every 3 months for 36 months then every 6 months until the study ended.

The primary end point of the trial was modified progression-free survival (PFS) and the key secondary end point was alpha-controlled event-driven analysis of overall survival (OS). Long-term follow-up assessments included exploratory analysis of OS in patients who were PET2-positive and PET2-negative, PFS per investigator, subsequent treatment use, and safety.

In the A+AVD arm, the 5-year PFS was 84.9% (95% CI, 81.7%-87.6%) compared with 78.9% (95% CI, 75.2%-82.1%) in the ABVD group (HR, 0.66; 95% CI, 0.50-0.88; P = .0035). In those who were PET2-positive, PFS was inferior (HR, 0.70; 95% CI, 10.39-1.26 ; log-rank P = .2) compared with those who were PET2-negative (HR, 0.66; 95% CI, 0.50-0.88; log-rank P = .0035). Straus noted that only about a third of the patients who were PET2-positive relapsed.

At 6 years, the estimated PFS rates for the A+AVD group was 82.3% (95% CI, 79.1%-85.0%) vs 74.5% (95% CI, 70.8%-77.7%) in the ABVD group (HR, 0.68; 95% CI, 0.53-0.86; log-rank P = .002). The median follow-up was 73 months.

The OS rates at 6 years was 93.9% (95% CI, 91.6%-95.5%) in the A+AVD group vs 89.4% (95% CI, 86.6%-91.7%) in the ABVD group (HR, 0.59; 95% CI, 0.40-0.88; log-rank P = .009). The median OS was not reached at 73 months of follow-up. Additionally, the subgroup analysis showed OS remained consistent. The multivariate analysis was adjusted for baseline characteristics and disease factors (HR, 0.53; 95% CI, 0.34-0.83). The covariates with the greatest association with OS was age, non-White race, ECOG performance status, and PET2 status.

In the A+AVD group, 5.9% of patients died compared with 9.7% in the ABVD group. The main causes of death included Hodgkin lymphoma or complications in 32 patients vs 45 patients, and second malignancies in 1 patient vs 11 patients in the A+AVD and ABVD groups, respectively. In the A+AVD group, other causes of death included accident or suicide (n = 3), unknown cause (n = 1), heart failure (n = 1), and intracranial hemorrhage (n = 1). In the ABVD group, other causes of death included unknown causes (n = 5), COVID-19 (n = 1), heart failure (n = 1), and lower respiratory tract infection (n = 1).

Second malignancies in the A+AVD group included 9% hematologic malignancies and 14% had solid tumors. In the ABVD group, 17% had hematologic malignancies and 14% had solid tumors. Transplants occurred in 2 patients in each arm. In 3 patients in the ABVD arm, prior radiation was received.

Pregnancy and peripheral neuropathy were one of the safety end points assessed. Among the patients enrolled in the trial, 191 pregnancies occurred in patients or their partners.³ There were no still births reported. In the A+AVD group, 67% of patients had peripheral neuropathy at 2-year follow-up vs 43% in the ABVD group.⁴ At follow-up grade 3 peripheral neuropathy occurred in 2% of patients in the A+AVD group vs less than 1% in the ABVD group, while grade 4 occurred in less than 1% vs 0%.

Strauss concluded the presentation statin OS was improved in the A+AVD arm, with the trial being the first to show it. Additionally, patients experienced fewer secondary malignancies as well as disease-related deaths. These data cement the fact that A+AVD should be used as first-line treatment for patients with stage III or IV classical Hodgkin lymphoma.

_References:

_{1. Straus DJ, Długosz-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. Published Correction appears in Lancet Haematol. 2022 Feb;9(2):e91].}

_{2. Brentuximab vedotin. News Release. FDA. March 20, 2018. Accessed October 16, 2022. https://bit.ly/3yM9gim}

_{3. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984. Published Correction appears in N Engl J Med. 2018 Mar 1;378(9):878].}

_{4. Ansell SM, Radford J, Connors JM, et al. Overall survival with brentuximab vedotin in stage III or IV Hodgkin's lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125}