In the ECHELON-1 study that involved patients with previously untreated stage III or IV Hodgkin’s lymphoma, treatment with a CD30-directed antibody–drug conjugate, brentuximab vedotin, plus doxorubicin, vinblastine, and dacarbazine (AVD), resulted in a risk of death that was significantly lower than that observed with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen. This result translated to an overall difference in mortality of 4.5% in favour of brentuximab vedotin plus AVD at 6 years of follow-up. Dr. Stephen M. Ansell of the Mayo Clinic in Rochester, MN, US and the ECHELON-1 investigators, who reported the results on 13 July 2022 in The New England Journal of Medicine, wrote that the treatment of advanced Hodgkin’s lymphoma has been a success story in oncology, but only modest progress has been made in past decades. However, in the ECHELON-1, treatment with brentuximab vedotin plus AVD resulted in an improvement in both progression-free survival (PFS) and overall survival (OS).

For decades, first-line treatment with ABVD has been the standard of care for advanced stage classic Hodgkin’s lymphoma. However, a substantial proportion of patients with stage III or IV disease have a relapse or disease that is refractory to ABVD. For patients with advanced stage, high-risk disease, debates regarding the best currently available approach have centred on ABVD regimen, escalated BEACOPP regimen, and risk-adapted approaches that use PET scans, usually after two cycles of therapy, as the basis of either intensifying or deescalating treatment. It was hoped that brentuximab vedotin, when substituted for bleomycin in the ABVD regimen, would lead to better survival when used as primary therapy, without the serious side effects that are associated with escalated BEACOPP.

In the phase III, ECHELON-1 study, first-line treatment with brentuximab vedotin, a CD30-directed monoclonal antibody conjugated by protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E, plus AVD significantly improved modified PFS, defined as a time to progression, death, or non-complete response and use of subsequent therapy, as compared with ABVD, among patients with newly diagnosed stage III or IV Hodgkin’s lymphoma, and a planned interim analysis indicated a potential benefit with regard to OS. At 5 years, a long-term benefit with regards to PFS with brentuximab vedotin plus AVD as compared with ABVD was shown (hazard ratio [HR] for disease progression or death 0.68; 95% confidence interval [CI] 0.53 to 0.87). In the latest article, the study team reports the results of the OS analysis of brentuximab vedotin plus AVD as compared with ABVD, as well as long-term safety data, after approximately 6 years of follow-up.

The ECHELON-1 investigators randomly assigned patients in a 1:1 ratio to receive up to 6 cycles of brentuximab vedotin plus AVD or ABVD. The primary endpoint modified PFS has been reported previously. The key secondary endpoint was OS in the intention-to-treat population. Safety was also assessed. A total of 664 patients were assigned to receive brentuximab vedotin plus AVD and 670 to receive ABVD.

At a median follow-up of 73.0 months, 39 patients in the brentuximab vedotin plus AVD arm and 64 in the ABVD arm had died (HR 0.59; 95% CI 0.40 to 0.88; p = 0.009). The 6-year OS estimates were 93.9% (95% CI 91.6 to 95.5) in the brentuximab vedotin plus AVD arm and 89.4% (95% CI 86.6 to 91.7) in the ABVD arm. PFS was longer with brentuximab vedotin plus AVD than with ABVD (HR for disease progression or death 0.68; 95% CI 0.53 to 0.86).

Fewer patients in the brentuximab vedotin plus AVD arm than in the ABVD arm received subsequent therapy, including transplantation, and fewer second cancers were reported with brentuximab vedotin plus AVD (23 versus 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with brentuximab vedotin plus AVD. More patients had peripheral neuropathy with brentuximab vedotin plus AVD than with ABVD, but most patients in the two arms had resolution or amelioration of the event by the last follow-up.

In an accompanied editorial, Drs Dan L. Longo and James O. Armitage of the University of Nebraska in Omaha, US wrote that the authors deserve congratulations on completing a phase III study that included 1334 patients. Except for some German Hodgkin Study Group studies, an international study of such size involving 218 sites in 21 countries has never before been completed. 

They discussed the issues that might affect the interpretation of these results or their application to practice. In particular, the imbalance in deaths from second cancers: in the ABVD arm, 11 deaths were due to second cancers, as compared with only 1 death in the brentuximab vedotin plus AVD arm. More patients in the ABVD arm than in the brentuximab vedotin plus AVD arm received salvage therapy, including 15 more of the patients (59 [9%] in the ABVD arm versus 44 [7%] in the brentuximab vedotin plus AVD arm) undergoing autologous stem-cell transplantation, which is known to be associated with risks of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, the number of AML or MDS was 3 in the ABVD arm and 2 in the brentuximab vedotin plus AVD arm. Since brentuximab vedotin cannot plausibly be thought to protect against death from second cancer, and since bleomycin is not recognised as a cause of second cancers, it seems likely that this imbalance was by chance.

Another concern is the imbalance in the deaths from pulmonary side effects: 11 in the ABVD arm as compared with none in the brentuximab vedotin plus AVD arm. Since almost 2% of the patients in the ABVD arm died from pulmonary side effects and since diffusion capacity of the lung for carbon monoxide monitoring is not mentioned in the study protocol, it seems likely that careful monitoring was not routinely done.

If the 10 excess deaths from second cancer and the 11 deaths from pulmonary side effects in the ABVD arm were eliminated, the survival advantage with brentuximab vedotin plus AVD might be smaller than it appears. However, the higher initial cure rate and a lower likelihood of subsequent therapy (20% in the brentuximab vedotin plus AVD arm versus 24% in the ABVD arm) could still be a reason to favour using brentuximab vedotin plus AVD.

Other factors could also affect decision to use the brentuximab vedotin–containing regimen. These include the increased incidence of neurotoxic effects and myelosuppression and the cost. Although many patients have mild symptoms, the neurotoxicity of brentuximab vedotin can be severe and may have a considerable effect on quality of life. Unfortunately, the neurotoxic effects do not always completely resolve after the drug is discontinued. Furthermore, safe administration of the brentuximab vedotin plus AVD regimen requires routine administration of white-cell growth factors and prompt attention to neutropenic fever. Key subgroups of patients, such as women and patients with better prognosis stages, did not benefit from brentuximab vedotin plus AVD treatment and had no advantage from exposure to a more complicated and expensive regimen.

The editorialists commented that it seems reasonable that some patients who would not be cured with the ABVD regimen might be cured with the incorporation of brentuximab vedotin into primary therapy. But many patients might be able to avoid the neurotoxic effects, increased myelosuppression, and increased cost associated with brentuximab vedotin by using PET-guided therapy. It seems reasonable to consider that patients who do not have a complete remission after two cycles of ABVD might include those who could uniquely benefit from brentuximab vedotin plus AVD therapy.

The ECHELON-1 study was supported by Takeda Development Center Americas and Seagen.