Hodgkin Lymphoma: Antibody-Drug Conjugate Tested in the Front Line

ECHELON-1: A Randomized, Open-Label, Phase III Trial of A+AVD Versus ABVD as Frontline Therapy in Patients With Advanced Classical Hodgkin Lymphoma

NCT01712490

Millennium Pharmaceuticals

Seattle Genetics (USA) and Millennium Takeda (worldwide)

More than 100 centers worldwide

1,040 patients

Adult patients with histologically confirmed classical Hodgkin lymphoma who are treatment-naïve; have Ann Arbor III or IV disease staged by FDG-PET/CT; have bi-dimensional measureable disease; and have an ECOG performance score of ≤ 2 are randomized 1:1 (stratified by geographic region and prognostic factor score) to receive either conventional ABVD, or AVD plus brentuximab vedotin 1.2 mg/kg on days 1 and 15 of each 28-day cycle. After two cycles, patients undergo reassessment with PET/CT, and those with FDG uptake not markedly above that of the liver (Deauville scores 1-4) continue the same therapy to complete six cycles, while those with markedly FDG-avid disease (Deauville score 5) are eligible to receive alternative salvage therapy. Further PET/CT assessment is performed at the end of therapy. Radiotherapy is permitted to sites of PET-positive residual disease at the end of treatment. Follow-up with CT assessment is performed every three months in year one, and every six months subsequently.

The primary endpoint is modified progression-free survival (mPFS) obtained with brentuximab vedotin plus AVD versus that obtained with ABVD. The modification is to include, as an event, the receipt of chemotherapy or radiotherapy for patients not in complete remission at the end of initial treatment. Overall survival is the secondary endpoint, and the study will also include brentuximab vedotin pharmacokinetics, tumor biomarkers for response and drug clearance, fertility assessment, and analyses of patient-reported outcomes for lung toxicity.

Planned enrollment is 1,040 patients, which will give the power to detect a hazard ratio in the three-year mPFS of 0.67 with 90 percent power at a significance level of 0.025. This outcome measure would correspond to a change in mPFS from 75 percent to 82.5 percent in the experimental arm.

Brentuximab vedotin, an immunoconjugate that targets CD30 on Reed-Sternberg cells with a payload of monomethyl auristatin E (MMAE), a spindle poison, has been a notable success. High response rates were seen after single-agent therapy in relapsed and refractory Hodgkin lymphoma (Younes A et al. J Clin Oncol. 2012;30:2183-9), and a strikingly high response rate on FDG-PET scanning was observed in a phase I/II combination study with chemotherapy (Ansell SM et al. Blood. ASH Annual Meeting Abstracts. 2012;120:798). In most subjects, toxicity has been confined to a cumulative peripheral neuropathy, thanks to a stable linker between the antibody and the toxin that minimizes systemic exposure to MMAE. There was, however, an important note of caution that came from the combination study: brentuximab vedotin given concomitantly with ABVD produced severe pulmonary toxicity, with two deaths among 25 patients. Based on these observations, use of brentuximab in combination with bleomycin is not recommended. Thus, the experimental arm in the current study uses AVD concommitantly with brentuximab, a combination that was shown to be tolerable, and without apparent additive neurotoxicity.

Although the outcomes of chemotherapy for patients with advanced Hodgkin lymphoma are generally good, about 25 percent of patients are not cured by initial therapy with ABVD. This proportion can be reduced by about 5 to 10 percent with the use of much more intensive escalated BEACOPP therapy, but this treatment carries the risk of significant short- and long-term morbidity, and alternative approaches to maximize control of the lymphoma are still being sought. The demonstration that brentuximab vedotin can be given safely in combination with AVD, and that this combination results in a high rate of metabolic remission, provides a sound basis for testing the combination in first-line therapy.

This study should determine whether a higher response rate will translate into superior PFS without the toxicity that attends the intensification of conventional cytotoxics. The increasing role of interim PET/CT scanning is reflected in the re-assessment after two months of treatment, with the opportunity to switch to salvage protocols for the small proportion of patients with persistently FDG-avid disease, although some investigators may feel that all subjects with uptake higher than that of the liver (Deauville score 4 as well as 5) are at a relatively high risk of treatment failure, and this concern may be a source of imbalanced early protocol withdrawals. Another important consideration will be the long-term toxicity of the immunoconjugate in a patient group that has a high expectation of cure and many years of life ahead. To date, there are very limited data available addressing this issue, and there are theoretical concerns over the depletion of T-cell memory that may result from targeting CD30. So far, T-cell depletion has not resulted in clinically significant sequelae, although a small number of cases of progressive multifocal leukoencephalopathy have been reported in patients treated with brentuximab. Accordingly, this serious adverse event requires continuing vigilance.