Results of a Phase II Trial of Brentuximab Vedotin (SGN-35) for CD30+ Cutaneous T-Cell Lymphomas and Lymphoproliferative Disorders

Brentuximab vedotin is a conjugate of CD30 monoclonal antibody (cAC10) and the tubulin inhibitor, monomethyl auristatin E (MMAE) which targets the cell surface antigen CD30. Responses in CD30+ relapsed/refractory Hodgkin lymphoma (HL; ORR 75%) and anaplastic large T-cell lymphoma (ALCL; ORR 86%) were reported.

To determine the safety and efficacy of brentuximab vedotin, we conducted a Phase II investigator initiated open label clinical trial in patients with primary cutaneous CD30+ lymphoproliferative disorders (self-regressing lymphomatoid papulosis (LyP) or primary cutaneous pc-ALCL) and CD30+ mycosis fungoides (MF) with or without large cell transformation. Eligibility was based on ECOG < 2, need for systemic therapy, expression of CD30 in baseline skin lesion by immunohistochemistry, > 10 lesions of active or scarring LyP, pc-ALCL without generalized nodes, and CD30+ MF stage > IB with ≥ 1 prior topical or systemic therapy. Brentuximab vedotin at 1.8 mg/kg was infused over 30 min every 21 days up to 8 doses with an option of up to 8 more doses for patients with PR or two cycles past a complete response. Patients receiving at least 2 doses were evaluable for response measured as 50% decrease in active lesion number (LyP), tumor measurements (pc-ALCL), or modified skin weighted assessment tool mSWAT (MF). Biopsies were taken at pre-study, day 1, and to confirm response or disease progression to correlate response with CD30 expression.

Among 46 patients receiving at least one dose there are currently 38 evaluable patients: 21 females and 25 males whose median age is 59.5 years (range 31–86 years). Their clinical diagnoses are 27 MF, 3 pc-ALCL, 9 LyP, 6 LyP/MF, and 1 pc-ALCL/LyP/MF. The overall response rate is 63% (24/38) with CR of 32% (12/38) (Table 1). Evaluable MF patients (n=24) divided into three groups based on intensity of CD30+ expression in skin tumor cells at baseline, had response rates of 30% (low < 10%; n=10), 37.5% (medium >10-<50%; n=8) and 50% (high >50%; n=6). Complete responses were noted in all primary and secondary LyP patients as well as CD30+ tumors in pc-ALCL and MF patients. Time to response for LyP and ALCL was 3 wks (range 3–6) with median duration of response (DOR) of 22 wks (range 9–30). Time to response was 12 wks (range 3–25) and median duration of response for MF was 12 wks patients (range 6–32).

The most common related adverse events of any grade were neuropathy (38%), drug rash (27%), diarrhea (24%), fatigue (24%), alopecia (16%), myalgias (16%), and nausea (14%). Grade 3–4 events were neutropenia (n=3), nausea (n=2), chest pain (n=2), deep vein thrombosis (n=1), transaminitis (n=1) and dehydration (n=1). Dose reductions to 1.2 mg/kg were made for grade 2 neuropathy (n=2), transaminitis (n=1) and arthralgias and fatigue (n=1). One pc-ALCL patient with tumor regression died from infection after one dose; one withdrew due to infusion reaction.

This phase II clinical trial demonstrates that brentuximab vedotin is an effective and safe targeted therapy for the spectrum of CD30+ CTCLs - MF, pc-ALCL, and LyP with an overall response rate of 63% in all evaluable patients and 100% in LyP/pc-ALCL. Although highest response rates correlated with highest CD30+ expression, low expression patch/plaque MF responded following additional treatment cycles.

Duvic:seattle genetics: Consultancy, Research Funding. Off Label Use: This is a conjugated antibody approved for HD and ALCL tested in a phase II trial for another indication - CTCL CD30+. Tetzlaff:Seattle Genetics: Consultancy.