Improved survival with Brentuximab vedotin plus chemotherapy in stage III/IV Hodgkin’s lymphoma

August 2021 Clinical trials Tobias Rawson

The primary analysis of the phase III ECHELON-1 study, comparing brentuximab vedotin, doxorubicin, vinblastine and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with stage III/IV classical Hodgkin’s lymphoma, previously reported an improvement in progression-free survival (PFS) with A+AVD. At five years, A+AVD continues to show robust and durable improvement in PFS versus ABVD, regardless of PET-2 status.

EXPERT OPINION OF PROF. ANN JANSSENS, HAEMATOLOGIST, UZ LEUVEN

“Today, we treat advanced Hodgkins lymphoma with ABVD and/or BEACOPP and adapt treatment according to the PET-2 status. The 5-year follow-up of the ECHELON-1 study confirms that A+AVD improved PFS versus ABVD in all stages, age groups and different risk categories. A+AVD also has a promising long-term safety profile with no excess of secondary malignancies, no fertility issues and resolution or improvement of peripheral neuropathy. Therefore, we can conclude that A+AVD is at least an alternative treatment option for advanced Hodgkin’s disease.”

The most commonly used frontline regimen for advanced Hodgkin’s lymphoma consists of the combination of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Despite treatment with this regimen, up to 30% of patients with stage III/IV Hodgkin’s lymphoma eventually relapse, or develop refractory disease. Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets the surface antigen CD30, found on the malignant Reed-Sternberg cells in classical Hodgkin’s lymphoma. Investigating this ADC in patients with stage III/IV Hodgkin’s lymphoma, the phase III ECHELON-1 trial previously reported an improvement in progression-free survival (PFS) with brentuximab vedotin, when combined with  doxorubicin, vinblastine and dacarbazine (A+AVD), when compared to ABVD. Now, a 5-year update to the trial provides updated insight into survival outcomes.

This international, phase III, open-label trial randomised 1,334 patients with previously untreated stage III or IV Hodgkin’s lymphoma to receive A+AVD (N= 664) (brentuximab vedotin, 1.2 mg/kg of bodyweight, doxorubicin 25 mg/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (N= 670) (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Eligible patients were also required to have an ECOG PS of ≤2 and be over 18 years of age. Positron emission tomography (PET) scans were conducted at screening and after 2 cycles of therapy (PET2).  The primary endpoint of this study was PFS. This 5-year analysis includes PFS analysis per investigator assessment in the intention-to-treat population, which was an exploratory endpoint.

Significantly improved five-year PFS with A+AVD

At a median follow-up of 60.9 months, the 5-year PFS was significantly improved with A+AVD, compared to ABVD (82.2% vs. 75.3%; HR[95%CI]: 0.68[0.53-0.87], P= 0.0017).

PFS was also significantly improved in PET2-negative patients with A+AVD at 5 years (84.9% vs. 78.9%; HR[95%CI]: 0.66[0.50-0.88], P= 0.0035). In addition, five-year PFS for PET-2 positive patients was 60.6% with A+ AVD versus 45.9% with ABVD (HR[95%CI]: 0.70[0.39-1.26], P= 0.23). During this analysis, 5-year PFS was also generally higher with A+AVD, compared to ABVD, across other prespecified subgroups, including age (<60 years: 84.3% vs. 77.8%; HR[95%CI]: 0.67[0.51-0.88], P= 0.0034 and ≥60 years: 67.1% vs. 61.6%; HR[95%CI]: 0.82[0.49-1.36], P= 0.44), International Prognostic Score (IPS) risk group (0-1: HR[95%CI]: 0.67[0.38-1.15]; 2-3: HR[95%CI]: 0.75[0.52-1.07] and group 4-7: HR[95%CI]: 0.60[0.39-0.90]) and disease stage (stage III: HR[95%CI]: 0.59[0.39-0.92] and Stage IV: HR[95%CI]: 0.73[0.55-0.98]). Fewer patients who received A+AVD went on to receive subsequent anticancer therapy, compared to ABVD patients (20% vs. 24%). Additionally, 6% of A+AVD patients and 9% of ABVD patients received subsequent high-dose chemotherapy plus autologous haematopoietic stem cell transplantation.

Treatment with A+AVD and ABVD saw comparable rates of improvement or resolution in peripheral neuropathy (85% and 86%, respectively), although more patients overall had ongoing peripheral neuropathy with A+AVD, compared to ABVD (19% vs. 9%). Encouragingly, fewer secondary malignancies were reported with A+AVD, compared to ABVD (3% vs. 4%). Additionally, more livebirths were reported in patients treated with A+AVD (N= 75) than in patients treated with ABVD (N= 50).

Conclusion

At this updated, 5-year analysis, A+AVD continued to show improvement in PFS compared to ABVD, irrespective of PET2 status. Combined with a manageable safety profile, A+AVD is the preferred treatment of choice in previously untreated, advanced (stage III/IV) classical Hodgkin’s lymphoma.

Reference

Straus D, Dlugosz-Daneck 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:e410-21.

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