Photo by Larry Young
SAN FRANCISCO—The phase 3 ALCANZA trial is the first to convincingly demonstrate that a new systemic agent can be more effective than standard of care (SOC) options for cutaneous T-cell lymphoma (CTCL), according to a speaker at the 9th Annual T-cell Lymphoma Forum.
The trial showed significant improvements in response, symptom burden, and progression-free survival (PFS) in patients with CD30-expressing CTCL who received brentuximab vedotin (BV), as compared to patients who received either bexarotene or methotrexate.
“[These are] compelling results that potentially may have practice-changing implications for the use of brentuximab in managing CD30-expressing CTCL patients who require systemic therapy,” said Youn H. Kim, MD, of Stanford University School of Medicine in California.
Dr Kim presented these results at this year’s T-cell Lymphoma Forum. The data were also presented at the recent ASH Annual Meeting (abstract 182).
The ALCANZA trial was sponsored by Millennium Pharmaceuticals, Inc. (now a part of Takeda Pharmaceutical Company Limited) and Seattle Genetics, Inc.
The study was designed to compare BV to the SOC options of methotrexate or bexarotene in patients with CD30-positive CTCL, including mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL).
There were 128 patients in the intent-to-treat and safety populations. Sixty-four patients (48 with MF and 16 with pcALCL) were randomized to receive BV at 1.8 mg/kg IV every 3 weeks for up to 48 weeks.
The other 64 patients (49 with MF and 15 with pcALCL) were randomized to receive methotrexate at 5 mg to 50 mg PO weekly or bexarotene at a target dose of 300 mg/m² PO daily for up to 48 weeks.
Patients received BV for a median of 36 weeks (12 cycles), bexarotene for a median of 17 weeks, and methotrexate for a median of 9 weeks. Three patients in the BV arm were still on treatment at the time of analysis.
Patient characteristics
The median age was 62 (range, 22-83) in the BV am and 59 (range, 22-83) in the SOC arm. More than half of patients in each arm were male—52% and 58%, respectively. And most patients in both arms had an ECOG performance status of 0-1—95% and 97%, respectively.
The median number of prior therapies was 4 (range, 0-13) in the BV arm and 3.5 (range, 1-15) in the SOC arm. The median number of systemic therapies was 2 in the BV arm (range, 0-11) and the SOC arm (range, 1-8).
“It was pretty well balanced in terms of baseline characteristics between the 2 arms,” Dr Kim said. “The brentuximab arm had more stage IV patients—in fact, 7 stage IVB in brentuximab and none in the standard of care. And more patients with ALCL [treated with BV] had extracutaneous disease.”
Among pcALCL patients, 44% in the BV arm had extracutaneous disease, compared to 27% in the SOC arm. Among MF patients, 67% in the BV arm had stage IIB-IVB disease, compared to 61% in the SOC arm.
Response
The study’s primary endpoint was the rate of objective response lasting at least 4 months (ORR4).
“[ORR4] was felt to be more meaningful than ORR because it includes not only the response rate but also a duration element in a single endpoint,” Dr Kim said.
ORR4 was significantly higher with BV than with SOC—56.3% and 12.5%, respectively (P<0.0001).
For patients with MF, the ORR4 was 50% with BV and 10% with SOC. For patients with pcALCL, the ORR4 was 75% with BV and 20% with SOC.
Overall, the complete response (CR) rates were 15.6% in the BV arm and 1.6% in the SOC arm (P=0.0046).
For patients with MF, the CR rate was 10% with BV and 0% with SOC. For patients with pcALCL, the CR rate was 31% with BV and 7% with SOC.
Symptoms
“In CTCL, there’s significant quality of life issues that are not captured adequately by objective response measures, and this patient outcome is very important,” Dr Kim said. “[Quality of life in this study] was captured by Skindex-29, which is an established quality of life measure in skin diseases.”
Patients in the BV arm had a significantly higher reduction in symptom burden according to Skindex-29 than patients receiving SOC. The mean maximum reduction in Skindex-29 symptom domain was -27.96 points in the BV arm and -8.62 points in the SOC arm (P<0.0001).
PFS
PFS was significantly longer in the BV arm than the SOC arm. The median PFS was 16.7 months and 3.5 months, respectively. The hazard ratio was 0.270 (P<0.0001).
For patients with MF, the median PFS was 15.9 months with BV and 3.5 months with SOC. For patients with pcALCL, the median PFS was 27.5 months with BV and 5.3 months with SOC.
Safety
The overall rate of adverse events (AEs) was 95% in the BV arm and 90% in the SOC arm. The rate of grade 3 or higher AEs was 41% and 47%, respectively. And the rate of serious AEs was 29% in both arms.
AEs resulting in discontinuation occurred in 24% of patients in the BV arm and 8% in the SOC arm. In the BV arm, this included peripheral neuropathy (n=9), skin-related hypersensitivity (n=3), E coli infection (n=1), impetigo (n=1), pulmonary embolism (n=1), urticaria (n=1), and vertigo (n=1).
In the SOC arm, AEs leading to discontinuation included maculo-papular rash (n=1), asthenia (n=1), hematuria (n=1), hypernatremia (n=1), neutropenia (n=1), periorbital infection (n=1), and somnolence (n=1). One patient in each arm experienced more than 1 AE resulting in discontinuation.
The most common AEs of any grade (occurring in 15% or more of patients in the BV and SOC arms, respectively) were peripheral neuropathy (67% and 6%), nausea (36% and 13%), diarrhea (29% and 6%), fatigue (29% and 27%), vomiting (17% and 5%), alopecia (15% and 3%), pruritus (17% and 13%), pyrexia (17% and 18%), decreased appetite (15% and 5%), and hypertriglyceridemia (2% and 18%).
The majority of the peripheral neuropathy events in the BV arm were grade 1 or 2—26% and 32%, respectively. The rate of grade 3 peripheral neuropathy events was 9%, and there were no grade 4 events.
Eighty-two percent of patients reported resolution or improvement in peripheral neuropathy events in the BV arm at a median of 22.9 months of follow-up.
There were no on-study deaths (occurring within 30 days of the last dose) in the SOC arm, but there were 4 in the BV arm. Three of the BV deaths were considered unrelated to the drug.
The 1 BV-related death was a result of multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites in a patient with T3bN0M1 pcALCL. The other 3 deaths were due to lymphoma progression, pulmonary embolism, and sepsis.
