Abstract
Background
Cutaneous T cell lymphoma (CTCL) is a chronic disease that negatively impacts quality of life (QoL) and, in advanced stages, has poor prognosis. Current systemic therapies rarely provide reliable and durable responses, and to date, no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate (MTX) or bexarotene (Bex). CD30-directed antibody-drug conjugate brentuximab vedotin (BV) has demonstrated marked clinical activity in two phase 2 single-arm trials in CTCL with overall response rates (ORR) of about 70%. These results led to ALCANZA, a randomized, open-label, multicenter phase 3 trial of the efficacy and safety of BV vs physician's choice (PC) of MTX or Bex, in previously treated patients with CD30-expressing CTCL (NCT01578499). This is the first reported randomized phase 3 trial testing a new agent against standard-of-care therapy in CTCL.
Methods
Adults with CD30-expressing (≥10% of infiltrate by central review) mycosis fungoides (MF) who received ≥1 prior systemic therapy or primary cutaneous anaplastic large cell lymphoma (pcALCL) who received ≥1 prior systemic therapy or radiotherapy were enrolled. Patients were stratified by diagnosis and randomized 1:1 to receive BV 1.8 mg/kg IV, once every 3 weeks, or PC of either MTX 5-50 mg PO, once weekly, or Bex 300 mg/m² (target dose) PO, once daily, for up to 16 three-week cycles, until disease progression or unacceptable toxicity. Primary endpoint was ORR4, defined as ORR lasting ≥4 months, an endpoint that captures response rate and duration as a single measurement. ORR4 was determined by independent review of global response using the ISCL/EORTC consensus guidelines. Global response is a composite of skin evaluation (modified severity weighted assessment tool), radiographic assessment, and Sézary cell enumeration. Key secondary endpoints were CR rate, PFS, and symptom burden measured by the symptom domain of the Skindex-29 QoL tool. Sample size was calculated to provide 90% power to detect a 30% improvement in ORR4. Treatment-emergent adverse events (AEs) were evaluated according to NCI CTCAE v4.03.
Results
131 patients were randomized with 128 patients in the intent-to-treat population (97 MF, 31 pcALCL; 3 excluded for insufficient CD30 expression) and assigned to BV (n=64) or PC (n=64). Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the BV arm (Table). In BV vs PC arms, respectively, median age was 62 (22-83) vs 58 (22-83) years; ECOG performance status 0-1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies.
At a median follow-up of 17.5 months, ORR4 (primary endpoint) and PFS strongly favored BV vs PC with ORR4 of 56% vs 13% (p<0.0001) and median PFS of 16.7 vs 3.5 months (HR 0.270; 95% CI, 0.169-0.430; p<0.0001), respectively (Fig 1, 2). ORR was 67% (n=43) with CR 16% for BV, compared with ORR of 20% (n=13) with CR 2% for PC (ORR, p<0.0001; CR, p=0.0046). Skindex-29 showed significantly greater symptom reduction for BV compared with PC (-27.96 vs -8.62; p<0.0001).
Patients received a median of 12 (1-16) cycles of BV vs 5.5 (1-16) Bex and 3 (1-16) cycles of MTX. Grade 3-4 AEs, all cause / drug-related, were seen in 41% / 29% with BV vs 47% / 29% with PC. Serious AEs were seen in 29% of patients in each arm. Peripheral neuropathy (PN), any grade, was seen in 67% in the BV arm (32% grade 2, 9% grade 3) and 6% in the PC arm. At last follow-up, 36/44 (82%) patients in the BV arm had improvement or resolution of PN. Discontinuation due to AEs occurred in 24% (BV) vs 8% (PC). Four deaths in the BV arm (3 unrelated to study drug) occurred within 30 days of the last dose. Other AEs were consistent with reported safety profiles for the individual agents.
Conclusions
In this first report of a randomized phase 3 trial evaluating a new agent vs standard-of-care options in CTCL, the clinical outcome of BV was far superior to PC (MTX or Bex). Highly statistically significant improvements in ORR4 (44%) and median PFS (13.2 months) were observed with BV. Greater ORR with higher CR rate and reduction in symptoms per Skindex-29 symptom domain were also observed in the BV arm. Safety data for BV were consistent with the established tolerability profile. The data from this randomized trial provide compelling evidence favoring BV over PC of Bex or MTX in CD30-expressing CTCL.
Kim:Kyowa Kirin Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Merck: Research Funding; Soligenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Innate: Research Funding; Portola: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding. Whittaker:Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Other: Investigator in a clinical trial; Seattle Genetics: Other: Investigator in a clinical trial; Galderma: Research Funding. Horwitz:ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Takeda: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy. Dummer:Allos: Research Funding; Shape: Research Funding; Jonathan Wood & Assoc: Speakers Bureau; Soligenetics: Research Funding; Cell Medica: Consultancy, Honoraria; Therakos: Speakers Bureau; Mallinckrodt Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Covance Laboratory Services: Consultancy; Oncoceuticals: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya: Consultancy; Eisai: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scarisbrick:Millennium: Consultancy; 4SC: Consultancy. Zinzani:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Wang:Seattle Genetics: Employment, Equity Ownership. Palanca-Wessels:Seattle Genetics: Employment, Equity Ownership. Zagadailov:Takeda Pharmaceuticals: Employment, Equity Ownership; Amerisource Bergen: Equity Ownership. Trepicchio:Takeda Pharmaceuticals: Employment. Liu:Takeda Pharmaceuticals: Employment, Equity Ownership. Little:Takeda Pharmaceuticals: Employment, Equity Ownership.
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