Brentuximab Vedotin Extends Survival Benefit of Standard Chemo in Advanced HL

Stephen M. Ansell, MD

The combination of brentuximab vedotin (Adcetris) and doxorubicin, vinblastine, and dacarbazine (AVD) demonstrated a survival advantage over doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III or IV Hodgkin lymphoma, according to published findings from the ECHELON-1 clinical trial (NCT01712490).¹

“Our randomized study showed that the addition of an antibody drug conjugate, brentuximab vedotin, to standard chemotherapy in patients with advanced stage classical Hodgkin lymphoma improved overall survival for patients with Hodgkin lymphoma, when compared to patients who received standard chemotherapy alone,” stated Stephen M. Ansell, MD, professor of Medicine, chair of Faculty Development and Recruitment, Division of Hematology, Department of Internal Medicine, and consultant, Division of Hematology, Department of Internal Medicine at Mayo Clinic, in a press release.²

With the current standard-of-care, ABVD, many patients with stage III or IV disease still relapse or become refractory to the regimen. Several clinical trials have failed to bring therapies that are superior to ABVD-based treatment in terms of survival while limiting toxicities. For example, the HD9 trial showed that treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had a longer 10-year survival compared with COPP-ABVD. But when BEACOPP was tested against ABVD, there was no survival advantage and the BEACOPP-based regimen had added toxicity.¹

According to investigators of the ECHELON-1 trial led by Ansell, there has been success with regimens that include targeted therapies. It was previously shown after the 5-year follow-up in ECHELON-1 that brentuximab vedotin plus AVD prolonged progression-free survival in patients with (HR, 0.68; 95% CI, 0.53-0.87).^1,3

“Brentuximab plus AVD chemotherapy was previously reported to improve progression-free survival in patients with classical Hodgkin lymphoma, so its impact on overall survival was not completely surprising,” noted Ansell, in the press release.² “However, he says patients who relapse are often successfully treated with additional treatments so previous comparative studies of other drug combinations failed to show an overall survival benefit.”

The most recent findings from the ECHELON-1 study are based off approximately 6 years of follow up.¹

ECHELON-1 is a multicenter, randomized, open-label trial of 664 adult patients with stage III or IV Hodgkin’s lymphoma. Patients in the study were assigned 1:1 to receive either brentuximab vedotin plus AVD in the experimental arm or ABVD in the control arm. The experimental cohort received 1.2 mg of brentuximab vedotin per kg of body weight, 25 mg of doxorubicin per square meter of body-surface area, 6 mg of vinblastine per square meter of body-surface area, and 375 mg of dacarbazine per square meter of body-surface area. In the control arm, patients were treated with 25 mg of doxorubicin per square meter of body-surface area, 10 U of bleomycin per square meter of body-surface area, 6 mg of vinblastine per square meter of body-surface area, and 375 mg of dacarbazine per square meter of body-surface area. All drugs in both treatment arms were administered via intravenous infusion on days 1 and 15 of each 28-day cycle. Treatment continued in both arms for up to 6 cycles.

Patients were stratified according to their geographic region and International Prognostic Score (IPS) risk group of 0 or 1 for low risk, 2 or 3 for intermediate risk, and/or ≥ 4 for high risk.

At a median follow-up of 73 months (range, 0.0-100.6), the were 39 deaths in the brentuximab vedotin plus AVD group compared with 64 in the ABVD, showing that the addition ofbrentuximab vedotin to standard chemotherapy reduces the risk of death vs ABVD in patients with stage III or IV Hodgkin lymphoma (HR, 0.59; 95% CI, 0.40-0.88; P =.009). At the 6-year mark, the OS estimates for the experimental arm vs the control arm were 93.9% (95% CI, 91.6-95.5) vs 9.4% (95% CI, 86.6-91.7), respectively.

When OS was assessed based on patients’ geographic region, patients from the North and South America and Asia had longer survival with brentuximab vedotin plus AVD vs ABVD, but European patients had longer survival with ABVD. In terms of the IPS risk score, both the intermediate- and high-risk subgroups had longer survival with the experimental treatment compared the control. Patients with low-risk disease favored the ABVD regimen.

PFS findings at the 6-year timepoint were consistent with previous reports. At a median follow-up of 72.6 months, the 6-year PFS were 82.3% with brentuximab vedotin plus AVD and 74.5% with ABVD (HR, 0.68; 95% CI, 0.53-0.86). The PFS advantage of brentuximab vedotin plus AVD was also seen across all prespecified subgroups.

Overall, 89.3% of patients in the experimental arm and 90.7% of control arm completed all 6 cycles of trial therapy. Of the 39 deaths in the brentuximab vedotin plus AVD group, 32 were caused by Hodgkin lymphoma. The remaining causes of death in the experimental arm were second cancer (n = 1), unknown cause (n =1), accident or suicide (n = 3), heart failure (n =1), and intracranial hemorrhage (n =1). Forty-five of the 64 deaths in the ABVD arm were caused by either Hodgkin lymphoma or complications. Notably, there were 11 additional deaths in the ABVD caused by secondary cancers.

“The impact on overall survival with brentuximab vedotin plus AVD chemotherapy is somewhat surprising, but it confirms that the use of novel agents in the frontline treatment of patients with Hodgkin lymphoma has a long-term impact,” added Ansell.²

_REFERENCES:

_{1. 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.Published online July 13, 2022. doi:10.1056/NEJMoa2206125}

_{2. Brentuximab vedotin may improve overall survival in patients with Hodgkin lymphoma. News release. Mayo Clinic. July 14, 2022. Access July 19, 2022.}

_{3. 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 Hematol. 2021;8(6):e410-e421. doi:10.1016/S2352-3026(21)00102-2}