BRENTUXIMAB FOR CUTANEOUS T-CELL LYMPHOMA

SAN DIEGO — For patients with CD30 expressing cutaneous T cell lymphoma (CTCL), treatment with the CD30 targeting antibody brentuximab vedotin (Adcetris, Seattle Genetics) was superior to physician's choice of therapy (methotrexate or bexarotene) in the phase 3 head-to-head-comparator ALCANZA study.

The results were presented today here at the American Society of Hematology 58th Annual Meeting (abstract 182).

The authors, headed by Youn Kim, MD, from Stanford University School of Medicine, California, reported that the clinical outcomes with brentuximab vedotin were "far superior," with highly significant improvements in both overall response rates and median progression-free survival (PFS).

"These compelling results have potential practice-changing implications," Dr Kim said.

Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets CD30, which is a defining marker of classical Hodgkin lymphoma. It is comprised of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a cytotoxic agent, monomethyl auristatin E (MMAE). According to the manufacturer, it also uses a "linker system" that is designed to be stable in the bloodstream but to release MMAE when internalized into CD30-expressing tumor cells, resulting in target cell death.

The product is currently used for relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma, but recent studies are investigating other indications. One study showed that brentuximab vedotin given early after stem cell transplant significantly improves PFS compared with placebo in patients with hard-to-treat Hodgkin lymphoma, while  another study suggested that brentuximab vedotin may be an effective alternate first-line therapy in elderly patients with Hodgkin lymphoma who are unable to tolerate standard chemotherapy.

CTCL is a chronic disease that negatively impacts quality of life and has a poor prognosis in advanced stages. The systemic therapies currently used rarely provide reliable and durable responses, and to date, no therapy has proven superior to standard-of-care treatment, including methotrexate or bexarotene.

In two phase 2, single-arm trials in CTCL, however, brentuximab vedotin has shown strong activity with overall response rates (ORR) of about 70%.

"These results led to the current phase 3 ALCANZA trial," said Dr Kim.

Superior Outcomes for All Endpoints

In this study, which is the first reported randomized phase 3 trial testing a new systemic agent against standard-of-care therapy in CTCL, Dr Kim and colleagues randomized 128 patients to brentuximab vedotin 1.8 mg/kg IV, once every 3 weeks, or physician's choice of methotrexate 5–50 mg orally, once weekly, or bexarotene 300 mg/m² (target dose) orally, once daily, for up to 16 3-week cycles, until disease progression or unacceptable toxicity. 

The primary endpoint was ORR4, defined as ORR that lasts 4 months or longer, "which is a measure of clinically meaningful efficacy and combines response rate and duration in a single endpoint," explained Dr Kim.

Key secondary endpoints were complete response rate, PFS, and symptom burden measured by the symptom domain of the Skindex-29 QoL, an established and validated tool for measuring quality of life in dermatologic diseases.

The primary endpoint of ORR4 strongly favored brentuximab vedotin vs standard care (56% vs 13%; P < .0001), which extrapolated to a significant 44% improvement.

Dr Kim noted that there was superior ORR4 across all subtypes as well.

Additionally, median PFS also significantly improved with brentuximab vedotin vs standard care (16.7 vs 3.5 months; HR, 0.270;  P < .0001).

Safety data were consistent with the established tolerability profile for brentuximab vedotin, the researchers commented.

Drug-related grade 3/4 adverse events were observed in 29% of patients in both treatment arms. The rate of peripheral neuropathy of any grade, however, was far more prevalent with brentuximab vs standard care (67% vs 6%), but at the last follow-up, 82% of patients had improved or resolution of symptoms. Other adverse events were consistent with reported safety profiles for the individual agents.

"This trial shows that brentuximab vedotin has significant advantages over two commonly used treatments for this disease," commented Stephanie Lee, MD, MPH, secretary of ASH and professor of medicine at the University of Washington in Seattle.

She added that it is difficult to conduct randomized trials in rare diseases, but these investigators were able to do so and come to a fairly definitive conclusion.

Commenting on the study, Brad S. Kahl, MD, professor of medicine at Washington University School of Medicine in St Louis, Missouri, noted that these lymphomas are challenging to treat because, although a number of treatments can induce a response, but they are usually not long lasting.

"The primary endpoint in this study not only showed response, but a durable one," Dr Kahl told Medscape Medical News. "So they were trying to raise the bar — and signify a quality response."

Overall, brentuximab showed a large advantage over the other therapies, but on the downside, he cautioned, it does have toxicity. "This was particularly evident for peripheral neuropathy, and that can limit the ability to give it over time," he said.

With CTCL, the initial issues are more quality of life, rather than being a life-threatening disease, Dr Kahl explained. "But as it gets more advanced, it becomes more difficult to control."

"The skin lesions create a portal that allows for the entry of microbes, and these patients face a significant risk of infections," he said. "And that is a common cause of death."

"But peripheral neuropathy can impair quality of life, so if you are the treating physician, you need to monitor these patients closely for signs of peripheral neuropathy," he said.

The patient may need a dose reduction, or the treatment may need to be stopped, and then can be restarted as needed. "You don't want to be in the position where you create a whole new set of problems," Dr Kahl emphasized.

The study was funded by Seattle Genetics and Takeda. Dr Kim reports membership on an entity's board of directors or advisory committees, research funding for Kyowa Kirin Pharma, Takeda Eisai, Seattle Genetics; consultancy, membership on an entity's board of directors or advisory committees for Horizon Pharma, Forty Seven Inc; research funding from miRagen, Merck, Soligenix, Neumedicines, Innate, TetraLogic, Portola. Disclosures for the coauthors are listed in the abstract. 

American Society of Hematology 58th Annual Meeting. Abstract 182. Presented December 3, 2016.