The Role of Brentuximab Vedotin in Previously Untreated Patients with CD30-Positive T-Cell Lymphoma

 ECHELON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Brentuximab Vedotin and CHP versus CHOP in the Frontline Treatment of Patients with CD30-Positive Mature T-Cell Lymphomas

 NCT01777152

Seattle Genetics

Millennium Pharmaceuticals

More than 100 centers worldwide

300 patients

In this phase III study, adult patients are randomized 1:1 to receive either conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or 1.8 mg/kg of brentuximab vedotin (BV) plus standard-dose CHP for six to eight cycles, per investigator discretion. To be eligible, patients must have newly diagnosed CD30-positive mature T-cell lymphoma, without evidence of a concurrent CD30-positive primary cutaneous T-cell lymphoproliferative disorder or mycosis fungoides, with fluorodeoxyglucose- (FDG-) avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by CT and an Eastern Cooperative Oncology Group (ECOG) performance score of ≤2 with adequate organ function.

After four treatment cycles and at the end of therapy patients undergo reassessment with PET and CT scans. Follow-up with CT assessment is performed every three months in years one and two and every six months subsequently until disease progression, death, or analysis of the primary endpoint. The primary endpoint is progression-free survival (PFS) in patients treated with BV plus CHP (cyclophosphamide, doxorubicin, and prednisone) versus PFS in patients randomized to receive CHOP. Secondary endpoints include PFS in the subset of patients with systemic anaplastic large-cell lymphoma (sALCL), overall survival, safety, and tolerability of the two treatment arms. Interim futility analysis will be performed after 50 percent of patients have completed end-of-treatment assessments.

BV, an anti-CD30 monoclonal antibody conjugated via dipeptide linker to the inhibitor of microtubule polymerization, monomethyl auristatin E (MMAE), is highly active treatment for relapsed and refractory sALCL. In the pivotal study of the efficacy of BV in this setting, the overall and complete response rates were 85 and 57 percent, respectively, and the median duration of response was 12.6 months (Pro B et al. J Clin Oncol. 2012;30:2190-2196). A recent phase II study of BV in patients with T-cell lymphoma expressing CD30, excluding sALCL, demonstrated an overall response rate of 41 percent with 54 percent of patients with angioimmunoblastic T-cell lymphoma responding (Horwitz SM et al. Blood. 2014;123:3095-3100). Interestingly, activity did not correlate with the level of CD30 expression on the neoplastic cells. Preliminary results of a phase I study that combined BV with standard-dose CHP in patients with CD30-positive mature T- and NK-cell lymphoma suggested a maximum tolerated dose of BV of 1.8 mg/kg (Finale MA et al. Blood. ASH Annual Meeting. 2012;120:60). All patients (n=26) responded, and the complete response rate was 88 percent. Toxicity in all studies has been manageable, with peripheral neuropathy being the most significant adverse event. 

Despite attempts to improve upon the efficacy of CHOP in the upfront setting in T-cell lymphoma by using intensified chemotherapy regimens and by incorporating newer agents, the majority of patients, with the exception of those with anaplastic lymphoma kinase–positive ALCL, ultimately relapse after initial therapy. Consolidation with autologous stem-cell transplantation in first remission may improve outcomes in patients with chemotherapy-sensitive disease, but the survival of patients who subsequently relapse is dismal. Given the impressive single-agent activity of BV in sALCL and its significant response rates in other subtypes of T-cell lymphoma in the relapsed and refractory setting, comparing BV+CHP to CHOP in this patient population is a singular undertaking. The omission of vincristine from the chemotherapy regimen in patients receiving BV should result in a lower incidence of peripheral neuropathy compared with other studies in which patients received prior vinca alkaloids or receive both agents concurrently. 

Recent data suggest that BV may exert other cytotoxic effects in addition to the delivery of MMAE directly into tumor cells (Katz J et al. Brentuximab Vedotin (SGN-35). Clin Cancer Res. 2011;17:6428-6436). Antibody binding may induce CD30 ligation, which has been shown to induce apoptosis in ALCL cell lines. The diffusion of MMAE out of CD30-positive cells could result in the destruction of other cells in the microenvironment that function to support the survival of the neoplastic cells. Comparing the efficacy of BV in combination with chemotherapy across different subtypes of CD30-positive T-cell lymphoma with respect to CD30 expression may suggest that further study of BV in other lymphoid malignancies without high-density CD30 expression is warranted.