Results of the phase III ALCANZA trial – brentuximab vedotin found to be superior compared to methotrexate or bexarotene in patients with R/R CD30+ Cutaneous T-Cell Lymphoma

On 6^th June 2017, Prof. Miles Prince from the Peter MacCallum Cancer Centre, Victoria, Australia, and colleagues published in The Lancet the results of the phase III, open-label, randomized, multicenter ALCANZA trial (NCT01578499).¹

This trial took place in 52 different centers across 13 countries, and aimed to compare brentuximab vedotin (BV) to Investigator’s Choice (IC) of methotrexate or bexarotene in adult (≥18 years of age) patients with R/R CD30+ Cutaneous T-Cell Lymphoma (CTCL), which included Mycosis Fungoides (MF) and Primary Cutaneous Anaplastic Large-Cell Lymphoma (pALCL). 

Overall, of the 131 patients who enrolled, 128 were included in the ITT analysis (median age, 60 years; range, 48–69). Patients were randomly assigned (1:1) to either IV BV 1.8mg/kg once every 3 weeks for up to 16 3-week cycles (n=64), or IC (n=64) of oral bexarotene 300mg/m² (target dose) once per day for up to 48 weeks or oral methotrexate 5–50mg once per week for up to 48 weeks (median methotrexate dose found to be 21.7mg/week; IQR, 16.7–30.6). Therapy continued until unacceptable toxicity or disease progression. Median follow-up was 22.9 months (95% CI, 18.4–26.1).

Key Highlights:

ITT Analysis

• BV arm = 64 pts; IC arm = 64 pts; pts with MF = 97; pts with pALCL = 31
• BV compared to IC:
  • ORR of at least 4 months (ORR4) overall = 56.3% (36/64 pts) vs. 12.5% (8/64 pts); between group difference of 43.8% (95% CI, 29.1–58.4; P<0.0001)
  • ORR4 in MF pts = 50% (24/48 pts) vs. 10% (5/49 pts)
  • ORR4 in pALCL = 75% (12/16 pts) vs. 20% (3/15 pts)
  • ORR (lasting any duration) = 67% (43/64 pts]) vs. 20% (13/64 pts); P < 0.0001
  • CR = 16% (10/64 pts) vs. 2% (1/64 pts); P = 0.0046
  • Proportion of pts achieving 50% reduction in Modified Severity Weighted Assessment Tool (mSWAT) = 77% (37/48 pts) vs. 41% (20/49 pts)
  • Median PFS per EMA criteria = 16.7 months vs. 3.5 months; HR, 0.270; 95% CI, 0.169–0.430; P < 0.001)
  • Median PFS per FDA criteria = 17.2 months vs. 3.5 months; HR, 0.181; 95% CI, 0.101–0.324; P < 0.0001)
  • Number of pts who received subsequent anti-cancer therapies = 38 vs. 47
  • Mean maximum reduction of symptoms (measured by Skindex-29) = –27.96 (SD, 26.877) vs. –8.62 (SD, 17.013; P < 0.0001); difference in mean maximum reduction = –18.9 (95% CI, –26.6 to –11.2)
  • Median EFS = 9.4 months vs. 2.3 months; HR, 0.285; 95% CI, 0.189–0.429; P < 0.0001)
  • Median DoR = 15.1 months (95% CI, 9.7–25.5; of 43 responders) vs. 18.3 months (95% CI, 3.5–18.4; of 13 responders)
  • Median duration of skin response = 20.6 months (95% CI, 14.1–25.7) vs. 18.3 months (95% CI, 3.5–18.9)

Safety Analysis

• BV arm = 66 pts; IC arm = 62 pts
• BV compared to IC:
  • Median treatment duration = 269 days (12 3-week cycles; IQR, 2–6) for BV vs. 114 days (5.5 3-week cycles; IQR, 3–11) for bexarotene vs. 77 days (3 3-week cycles; IQR, 2–6) methotrexate
  • Median relative dose intensity = 99.6% (IQR, 92.7–100.0) for BV vs. 94.3% (IQR, 73.6–100.0) for bexarotene
  • Most common reason for treatment discontinuation = completion of 16 cycles of therapy (35%; 23/66 pts) vs. progressive disease (62%; 40/65)
  • Incidence of grade 3–4 AEs = 41% (27/66 pts) vs. 47% (29/62 pts)
  • Incidence of peripheral neuropathy = 67% (44/66 pts) vs. 6% (4/62 pts)
  • Incidence of elevated triglycerides = 2% (1/66 pts) vs. 30% (11/37 pts)
  • Incidence of SAEs = 29% (19/66 pts) vs. 29% (18/62 pts)
  • Discontinuation due to AEs = 24% (16 pts) vs. 8% (5 pts)
  • Discontinuation due to peripheral neuropathy = 9 pts vs. 0 pts
  • Deaths = 24% (16 pts) vs. 23% (14 pts)

Other findings of note included 63% of patients (10/16) with pALCL treated with BV achieved a 100% reduction in skin disease, and the 3 patients who remained on treatment at the time of data analysis were all in the BV group. Additionally, at last follow-up, 82% (36/44) of patients receiving BV demonstrated improvement by ≥1 or resolution of peripheral neuropathy.

Toward the end of the paper, the authors discussed the limitations of the ALCANZA trial such as the limited choice of drugs available in the IC group. However, the authors explained that methotrexate and bexarotene were chosen as acceptable comparators to BV as they are the most commonly used options for CTCL and currently there is a lack of standard monotherapy for MF and pALCL around the world. Moreover, it was noted that the study population was relatively low-risk, with approximately one-third having early-stage disease and the median number of prior systemic therapy was two. Additionally, patients with high blood Sézary cell count were not eligible for the trial and a cut-off of 10% for CD30-positivity was selected. During the course of this trial, phase II trials conducted by other groups found that patients with high Sézary cell counts and patients with low CD30 expressing lesions respond to BV;^2,3 therefore, the ALCANZA trial might have excluded patients with MF or Sézary syndrome who could have achieved responses to BV.

The authors concluded that, compared to IC, BV significantly improved the numbers of patients achieving an objective response lasting 4 months or more and complete responses, as well as improving PFS and reducing patient-reported symptom burden. Furthermore, no new safety signals were encountered; similar numbers of SAEs were observed between BV and IC treated patients. However, more AEs and discontinuations because of AEs took place among patients treated with BV, although this could be explained by BV having a considerably longer duration of exposure compared to IC therapies. Overall, these findings “provide compelling evidence favoring BV over methotrexate or bexarotene for the treatment of relapsed or refractory CD30-positive cutaneous T-cell lymphoma.”

Abstract:

Background: Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.

Methods: In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5–50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499.

Findings: Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4–26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1–58·4; p<0·0001). Grade 3–4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.

Interpretation: Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.

Funding: Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.