Patients with desmoid tumors, a rare form of sarcoma for which, until now, there was no standard of care, may benefit from treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar, Bayer/Onyx), say US researchers reporting a landmark phase 3 trial.
Gary K. Schwartz, MD, chief of hematology/oncology at New York–Presbyterian/Columbia University Medical Center, New York City, and colleagues from the Alliance Clinical Trials in Oncology Group randomly assigned almost 90 patients with desmoid tumors to receive either sorafenib or placebo.
The results, published online December 19 in the New England of Journal of Medicine, showed that the drug was able to reduce the risk for death or disease progression by 87% relative to placebo.
Moreover, the objective response rate was substantially higher with sorafenib than placebo, the median time to response was shorter, and there were no major safety concerns.
Sorafenib "provides a new means to directly target the ability of desmoid tumors to grow," Schwartz said in a statement.
He told Medscape Medical News that, crucially, patients are able to continue taking the drug for 2 or more years "with minimal toxicity," and, given that high doses are not required to achieve a major effect, the results compared to placebo "are pretty exceptional."
"Overall, the outcome here is very compelling and argues strongly that this represents a new drug in the treatment of this disease," he commented.
Schwartz added: "Sorafinib has been around a while in other cancers, but this is the first evidence of its activity in desmoid tumors, and we think it will change the course of therapy in the treatment of cancer.
"We think that the new data would suggest that this becomes the new standard of care for the treatment of patients with this cancer," he added.
Coauthor Mrinal M. Gounder, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, agreed.
"Although individually uncommon, rare cancers account for 25% of all cancers," he noted in a statement.
"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."
Schwartz explained that desmoid tumors arise in the fat, the muscle, or the bone, typically in the arms and the legs, although they occasionally occur in the abdomen.
These slow-growing tumors rarely metastasize; rather, they grow locally, where they can cause symptoms.
"The primary therapy for this form of connective tissue cancer is usually surgery," Schwartz said, "but the problem with this is, despite surgical resection, they often do come back."
This is because it is difficult to achieve a complete resection with a negative margin. As a result, local recurrence rates are very high.
Patients consequently "are facing treatments trying to control the growth of the cancer," Schwartz noted.
"There have been many attempts over time to control these cancers, and there are some chemotherapies we've used, but there's nothing that's officially approved to treat desmoids," he commented.
Previous studies have suggested that sorafenib may have activity in this disease. The current study was a double-blind, phase 3 trial that involved 87 patients from 24 centers. The patients had progressive, symptomatic, or recurrent desmoid tumors.
Patients were randomly assigned in a 2:1 ratio to receive sorafenib 400 mg once daily (n = 50) or matching placebo (n = 37). Patients in the placebo group who experienced progression could cross over to the sorafenib group.
The median age of the patients was 37 years, 69% were women, and 80% were white.
Dose interruptions were recorded in 65% of sorafenib patients and in 34% of those in the placebo group. Dose reductions due to toxic effects occurred in 31% of the patients who took sorafenib and in 11% of those who received placebo.
Median follow-up was 27.2 months among the 83 surviving patients.
The progression-free survival rate at 2 years was 81% with sorafenib and 36% with placebo, at a hazard ratio for disease progression or death with sorafenib vs placebo of 0.13 (P < .001).
Prior to crossover, the overall objective response rate was 33% in the sorafenib group and 20% with placebo, at a median time to a RECIST-defined response of 9.6 months and 13.3 months, respectively.
The most common adverse events with sorafenib were grade 1/2 rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). For patients taking placebo, the most common adverse events were fatigue (61%), rash (42%), hypertension (39%), and nausea (39%).
Treatment-related grade 3 adverse events occurred in 29% of patients given sorafenib vs 14% of those in the placebo group. Grade 4 events among the patients taking sorafenib included thrombocytopenia and anemia, which each occurred in 2% of patients.
The team notes: "Our prospective trial, in which desmoid tumors in patients who were taking placebo were evaluated, provides evidence in support of an initial period of observation in patients with newly diagnosed desmoid tumors, given that 20% of the patients in the placebo group had disease regression.
"In this trial, late responses were observed in the sorafenib group, and response rates may increase with further data maturation," the authors write.
Can Sorafenib Extended Overall Survival?
Schwartz would next like to be able show that sorafenib can extend overall survival in patients with desmoid tumors.
"These patients live a long time even with the cancer, so it's a matter of almost quality-of-life improvement as well as survival," he said.
"Survival data will follow, but it's going to take a long time of follow-up to see a survival benefit, we believe," he said.
"The initial gains are control the cancer, symptomatic improvement, and avoiding the need for surgery, which often happens in this patient population," he added.
"As the tumor grows, there's a need for a resection of the disease, and with use of this drug, we think we're avoiding surgeries that are often somewhat futile in this point, because it's just not possible to get this cancer out without a lot of morbidity associated with the surgery," he said.
The study was supported by grants from the National Cancer Institute, the National Institutes of Health, Bayer Pharmaceuticals, the Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, the Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the US Food and Drug Administration. Dr Schwartz has disclosed no relevant financial relationships. Several coauthors report relationships with various pharmaceutical companies, as noted in the original article.
N Engl J Med. Published online December 19, 2018. Abstract
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Cite this: Desmoid Tumors: Treatment Breakthrough With Sorafenib - Medscape - Dec 19, 2018.