Targeted Therapy, Sorafenib, Shows Promise as First-Line Treatment for Previously Untreatable Rare Tumors

Bottom Line: In patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib (Nexavar®) significantly improved progression-free survival (PFS) and induced durable responses. This study defined an active therapy for desmoid tumors that appears effective in slowing disease progression.

Findings and Method: This study provided randomized data on the efficacy of sorafenib in progressive or symptomatic desmoid tumors. In the double-blind, phase III trial, 87 individuals with progressive, symptomatic, or recurrent desmoid tumors were randomized to receive either sorafenib or a placebo. There were 50 people randomized to sorafenib and 37 to placebo. Consistent with the incidence of desmoid tumors, a higher number of women were entered (69 percent), with a median age of 37 years. The primary outcome was investigator-assessed PFS.

With a median follow-up at 27.2 months, the two-year PFS rate was 81 percent for sorafenib and 36 percent for placebo. Crossover to sorafenib was permitted for individuals in the placebo arm who had disease progression. Before crossover, the objective response rate was 33 percent in the sorafenib arm and 20 percent in the placebo arm. Median time to objective response in responding people was 9.5 months for sorafenib and 13.3 months for placebo. Among individuals who received sorafenib, the most frequently reported adverse events were rash, hypertension, and diarrhea.

Although median PFS has not yet been reached, the one- and two-year estimates of PFS are 89 percent and 81 for sorafenib and 46 and 28 percent for the placebo, respectively. PFS favored sorafenib with a 7.7-fold reduction in risk of progression or death. Given the predictable toxicity profile and substantial PFS advantage of sorafenib, these results confirm that sorafenib has antitumor activity as a first-line or subsequent therapy for desmoid tumors.

Author Comment: “Until now there hasn’t been a standard way to treat people with desmoid tumors, and there haven’t been many studies because it’s such a rare disease,” explained Mrinal Gounder, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and corresponding author of the study. “Although individually uncommon, rare cancers account for 25 percent of all cancers. Despite the challenges faced in the design and execution of rare disease studies, this work has allowed us to set a new standard of care for desmoid tumors and provide a treatment option where there previously wasn’t one.”

Background: Desmoid tumors are a type of soft tissue sarcoma. These tumors are rare, locally aggressive neoplasms arising from connective tissues. Also called aggressive fibromatosis, this type of growth usually occurs in the arms, legs, or torso. An estimated 1,000 people in the United States are diagnosed each year, most of whom are in their teens, 20s, or 30s. Desmoid tumors are more common in women than in men. They do not metastasize and pose a low risk of mortality but confer significant morbidity. Though a number of agents have activity, there is no accepted standard of care for the systemic treatment of desmoid tumors. In many people, an upfront watch-and-wait strategy is increasingly advocated. Surgery has been the gold standard for primary treatment, but the risk of local recurrence remains unacceptably high.

This trial was the first to evaluate the use of sorafenib to treat desmoid tumors. Sorafenib is a targeted therapy that was originally developed to treat kidney cancer but is also known to block proteins that frequently drive the growth of desmoid tumors. Targeted therapies such as sorafenib tend to have fewer side effects than chemotherapy because their activities in cells are more specific.

Journal: “Sorafenib for Advanced and Refractory Desmoid Tumors” was published in the New England Journal of Medicine on December 20, 2018.

Authors: Dr. Gounder served as the paper’s corresponding author.

Funding: This research was supported by National Cancer Institute grants (P30 CA008748, U10CA180821, U10CA180882, U24CA196171, U10CA180833, U10CA180838, U10CA180857, U10CA180858, UG1CA189850, UG1CA189957, U10CA180820, U10CA180868, U10CA180888, and U10CA180826). It was also supported by funds from Bayer Pharmaceuticals and grants to Dr. Gounder from an American Society of Clinical Oncology Career Development Award, the Desmoid Tumor Research Foundation, and the US Food and Drug Administration Orphan Products Clinical Trials Grants Program (R01 grant).