November-December 2017, Volume 14, Issue 6
A Randomized Trial in a Rare Cancer: Targeting CD30 in Cutaneous T Cell Lymphoma Yields Therapeutic Dividends
Published on: October 11, 2017
Prince HM, Kim YH, Horwitz SM, 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;390:555-566.
Patients with cutaneous T cell lymphomas are typically managed in focused multidisciplinary clinics; therefore, the difficulties faced by patients with relapsed and refractory disease may be unfamiliar to many hemato-oncologists. The plethora of partially or temporarily effective therapies used to manage this chronic, incurable condition highlights the absence of a treatment that changes the natural history of the disease and the unmet need felt by patients with diminished quality of life.
Dr. H. Miles Prince, Dr. Youn Kim, and colleagues conducted the largest randomized trial to date in patients with cutaneous T cell lymphoma. Based on phase II data indicating response rates of 54 to 100 percent in small studies in cutaneous T cell lymphomas (including mycosis fungoides and primary cutaneous anaplastic large-cell lymphoma), the authors randomly assigned 131 patients with CD30-expressing disease (10% or more CD30+ malignant cells) in a 1:1 fashion to either intravenous brentuximab vedotin (BV) or dealer’s choice of two standard therapies (weekly oral methotrexate or bexarotene — an orally bioavailable retinoid). BV is an anti-CD30 antibody-drug conjugate that is already widely approved for use in systemic CD30+ anaplastic T cell lymphomas. BV 1.8 mg/kg was given once every three weeks for up to 16 cycles. Patients in both arms received 48 weeks of therapy in the absence of unacceptable toxicity or progression. The primary endpoint was the proportion of patients achieving an objective global response lasting at least four months (ORR4). This captures the two clinically important aspects of treatment success in this disease in a single measurement — proportion of patients achieving a response and meaningful response duration. Use of this endpoint minimizes the common confounding effect on the interpretation of progression-free survival (PFS) in this disease from the addition of other therapies for persisting symptoms in patients who have not formally progressed. Primary data used to calculate the global response score were centrally reviewed by an independent panel including dermatologists, radiologists, and pathologists. Secondary endpoints included PFS, complete response rate, safety, and a skin-specific quality of life measure. The trial was powered (>90%) to detect a 30 percent improvement in ORR4 to 70 percent for BV, from 40 percent for the standard care arms.
BV was successful at achieving a sustained objective global response in 56.3 percent of patients compared to 12.5 percent in the standard care arm (p<0.0001). Improvement of ORR4 in the BV group versus the physician’s choice group was consistent across all key subgroups, including subgroups with skin-only and extracutaneous disease. Key secondary endpoints were also superior in the BV arm, including prolonged PFS (median, approximately 17 months vs. 3.5 months; hazard ratio, 0.27; p<0.0001) and greater reduction in patient-reported skin symptom scores. However, duration of response (median of 15.1 months for BV vs. 18.3 months for standard care) and measures of overall quality of life (FACT-G) did not differ significantly between arms. After a median follow-up of 22.9 months, 24 percent of patients in the BV arm and 23 percent in the standard care arm had died. Patients were more likely to persist with BV treatment than with bexarotene or methotrexate (median durations, 279, 114, and 77 days respectively) with progression being the major cause of treatment discontinuation in the standard arm. Discontinuation due to adverse events occurred in 24 percent of patients in the BV group versus 8 percent in the physician’s choice group. Peripheral neuropathy was more common (44% vs. 6%) in the BV arm and was the most common reason for premature discontinuation of BV therapy. The overall incidences of serious and grade 3/4 adverse events appeared similar between arms.
It is an oft-heard lament that it is not possible to do adequately powered randomized studies in rare cancers. For many years this truism applied for cutaneous T cell lymphoma, but this is no longer the case. It is to the credit of the investigators, the sponsors, and the patients that this trial was conducted to completion. BV was shown to provide superior benefit versus a standard therapy that included two of several active drugs used around the world for this group of diseases. Based on these results, the sponsor is seeking U.S. Food and Drug Administration and European Medicines Agency approval. The efficacy of bexarotene and methotrexate when stringently assessed is sobering. While the open-label design of the trial means that some bias against persistence in the standard arm is plausible, the data highlight the need for more effective therapies. BV is clearly more effective than these two drugs, but still the ORR4 was lower than postulated, with more than 40 percent of patients not achieving the sustained global response. Additionally, the median PFS and median duration of response were modest at approximately 17 and 15 months, respectively. This indicates that further innovation is required to meet the needs of patients with these diseases. Other options that may be available to some patients in the United States, but less so in other countries, include drugs with different mechanisms of action such as romedepsin, vorinostat, and pralatrexate. However, the relative efficacy of these drugs cannot readily be determined in the absence of comparative trials, and when different response criteria were used in the various phase II trials of each drug. The ALCANZA trial has clearly raised the bar for clinical trials in patients with cutaneous T cell lymphomas and promising new therapies should be tested in randomized trials against accepted current standards.
Conflict of Interests
Dr. Roberts indicated no relevant conflicts of interest.
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