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Update of ALCANZA trial: confirmed superior clinical activity of brentuximab vedotin in patients with CD30-positive cutaneous T-cell lymphoma compared to methotrexate or bexarotene

The phase III ALCANZA study previously showed a significantly higher rate of durable responses with brentuximab vedotin compared to methotrexate or bexarotene in the treatment of patients with CD30-positive cutaneous T-cell lymphoma.1 During the 2017 Annual meeting of the American Society of Hematology, updated data of this study, with 11 months of additional follow-up were presented. This updated analysis confirmed that, compared to methotrexate, or bexarotene, brentuximab vedotin was associated with a significantly higher objective response rate (ORR), a significantly longer progression-free survival (PFS) and a better quality of life (QoL). In addition to this, a significantly prolonged time to next treatment (TTNT) was reported with brentuximab vedotin compared to methotrexate or bexarotene. These data further support the integration of brentuximab vedotin into the standard management of CD30+ CTCL.2

Cutaneous T-cell lymphoma (CTCL) is generally considered to be an incurable disease and the current systemic therapies rarely provide high rates of durable responses. With the current standard of care, the ORR varies from 24–68%. The median TTNT, which is a marker for disease control in CTCL, is only 3.9 months with the current treatment regimens. The initial report of the ALCANZA study was based on a median follow-up of 22.9 months and showed a significantly higher rate of durable responses with the CD30-directed antibody-drug conjugate brentuximab vedotin compared to physician’s choice (PC: methotrexate or bexarotene).1 The data presented at ASH 2017 were based on a median follow-up of 33.9 months.

In ALCANZA, 131 adult patients with previously treated CD30+ mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) were randomized to receive either brentuximab vedotin (1.8 mg/kg IV Q3W for up to 16 cycles), or PC (up to 48 weeks: methotrexate 5–50 mg PO QW or bexarotene 300 mg/m² PO QD). The primary endpoint of the trial was the rate of objective responses lasting for 4 months or more (ORR4), while secondary objectives included the rate of complete responses (CR), PFS and the symptom burden measured by the symptom domain of the Skindex-29 QoL tool. In this study, TTNT was defined as the time from randomization to the date of the first documentation of antineoplastic therapy or the last contact date for patients who never took antineoplastic therapy, and formed a not prespecified endpoint. Finally, ALCANZA also assessed the incidence, the severity and the duration of peripheral neuropathy (PN) of patients treated with brentuximab vedotin.1,2

Of the 131 patients that were randomized in the trial, 3 were excluded for insufficient CD30 expression, resulting in an ‘intent-to treat’ population of 128 patients (97 patients with MF and 31 with pcALCL). In the updated analysis, both the ORR4 (60.9% vs. 7.8%; OR[95%CI]: 53.1[36.5-67.2]; p< 0.001) and the CR rate (18.8% vs. 0%; OR[95%CI]: 0.7-35.0]; p< 0.001) were significantly higher with brentuximab vedotin than with PC.2 Also the median PFS was found to be significantly longer with brentuximab vedotin at 15.8 months as compared to 3.6 months with PC (HR[95%CI]: 0.373[0.245-0.569]; p< 0.001). After one year, 63.9% of patients on brentuximab vedotin were still free of progression, as compared to 15.6% in the control arm. At two years, these rates were 28.8% and 8.4%, respectively. At the time of this updated analysis, 47 (73%) and 48 (75%) patients in the brentuximab vedotin and in the PC arm, respectively, had received at least 1 subsequent antineoplastic therapy. The median TTNT among these patients was significantly longer for patients randomized to brentuximab vedotin than for patients in the control arm (median TTNT: 14.2 vs. 6.1 months; HR[95%CI]: 0.335[0.218-0.515]; p< 0.001). In the brentuximab vedotin arm, the probability of patients not requiring subsequent antineoplastic therapy was 65.5% after 1 year and 24.6% after 2 years (as compared to 15.3% and 4.4% with PC). The QoL, assessed by Skindex-29, showed a significantly greater symptom reduction for brentuximab vedotin as compared to PC (mean maximum reduction -28.08 vs. -8.62; p< 0.001).2

PN is a known toxicity of brentuximab vedotin and was the most commonly reported adverse event with this agent in ALCANZA. A total of 44/66 patients (67%) in the brentuximab vedotin arm experienced PN as compared to 4/62 (6%) in the PC cohort.  At a median follow-up of 33.9 months, the PN had completely resolved in 26 of 44 patients. In an additional 12 patients the PN was improved with at least one grade. The median time to resolution of PN was 30 weeks, while the median time to an improvement of at least one grade was reported to be 13 weeks. The PN improved over time: in this updated analysis, on-going grade 1/2 PN was seen in 18 patients, while this was the case in 22 patients in the initial report (no grade 3/4 PN reported).1

In conclusion, the presented longer-term data from ALCANZA continue to provide compelling evidence of improved response rates, PFS, and QoL with brentuximab vedotin as compared to PC in CD30+ CTCL. In addition to this, an extended TTNT was shown with brentuximab vedotin compared with PC, suggesting that single-agent treatment with brentuximab vedotin not only provides high rates of response and symptom control, but also leads to durable and clinically meaningful responses in this population with relapsed/refractory CTCL.

References

1. Prince H, Kim Y, Horwitz S, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 2017 Aug 5;390(10094):555-66.
2. Horwitz S, ScarisbrickJ, Dummer R, et al. Updated Analyses of the International, Open-Label, Randomized, Phase 3 Alcanza Study: Longer-Term Evidence for Superiority of Brentuximab Vedotin Versus Methotrexate or Bexarotene for CD30-Positive Cutaneous T-Cell Lymphoma (CTCL). Presented at ASH Abstract 1509.

Speaker Steven Horwitz

Horwitz1

Steven M. Horwitz, MD, PhD, medical oncologist, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

 

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