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Sorafenib improves PFS in refractory desmoid tumors
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Patients with progressive, refractory or symptomatic desmoid tumors derived a significant PFS benefit from sorafenib, according to results of a double-blind, placebo-controlled randomized phase 3 study published in The New England Journal of Medicine.
Sorafenib (Nexavar; Bayer, Onyx Pharmaceuticals) also included durable responses in this patient population, results showed.
“In a retrospective analysis, sorafenib, an oral multitargeted receptor tyrosine kinase inhibitor, at a starting dose of 400 mg once daily was shown to have acceptable safety and was associated with a response rate of 25% ... as well as with improvements in quality of life,” Mrinal M. Gounder, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “The retrospective study also highlighted that RECIST may underestimate efficacy and that a better criterion may be MRI T2-weighted signal intensity, an imaging biomarker that signifies a biologic transformation from cellular tumor to a collagenous scar.”
Desmoid tumors, also known as aggressive fibromatosis, are rare connective tissue neoplasms that commonly affect the abdominal wall, mesentery and neurovascular bundle of the extremities, according to study background. About 1,000 new cases, mostly among young adults, are diagnosed annually. There currently is no standard of care for these tumors.
“In general, desmoids are locally aggressive and often painful tumors for which there are no effective therapies,” Gary K. Schwartz, MD, chief of hematology/oncology at NewYorkPresbyterian/Columbia University Medical Center and senior study author, said in a press release. “Sorafenib is an oral agent that provides a new means to directly target the ability of desmoid tumors to grow.”
Gounder, Schwartz and colleagues evaluated 87 patients aged 18 years and older with progressive, symptomatic or recurrent desmoid tumors who had not been treated previously with sorafenib.
Researchers randomly assigned patients 2:1 to 400 mg sorafenib once daily (n = 50; median age, 37 years; range, 18-72) or matching placebo (n = 37; median age, 37 years; range, 21-67). Researchers used CT or MRI to image desmoid tumors at baseline and every 8 weeks. Treatment continued until disease progression, intolerable side effects or withdrawal of consent.
Patients in the placebo group who experienced disease progression could switch to the sorafenib group.
PFS served as the study’s primary endpoint. Secondary endpoints included adverse effects, OS and rate of radiographic response.
The final analysis included 84 patients.
With a median follow-up was 27.2 months, researchers observed 2-year PFS rates of 81% (95% CI, 69-96) in the sorafenib group vs. 36% (95% CI, 22-57) in the placebo group (HR for progression or death = 0.13; 95% CI, 0.05-0.31).
Overall, 33% of patients (n = 28 of 84) experienced disease progression, including 12% (n = 6 of 49) of the sorafenib group and 63% (n = 22 of 35) of the placebo group.
The sorafenib group had a higher objective response rate (33%; 95% CI, 20-48 vs. 20%; 95% CI, 8-37) before crossover, as well as a shorter median time to objective response (9.6 month; interquartile range, 6.6 to 16.7 vs. 13.3 months; interquartile range, 11.2-31.1) than the placebo group.
Adverse events among sorafenib-treated patients included grade 1 or grade 2 rash (73%), fatigue, (67%), hypertension (55%) and diarrhea (51%). Skin disorders were the most common reason for dose reduction in the sorafenib group.
Twenty-nine percent of patients in the sorafenib group experienced treatment-related grade 3 adverse events, compared with 14% of the placebo group. One patient in the sorafenib group died of disease-related bowel perforation.
“On the basis of the predictable toxic-effects profile and substantial PFS advantage conferred by sorafenib, the drug has antitumor activity as first line therapy or as subsequent therapy for desmoid tumors,” the researchers wrote. – by Jennifer Byrne
Disclosures : NCI funded this trial, with sorafenib provided through a research collaboration with Bayer. Gounder reports grants from American Society of Clinical Oncology – Career Development Award, Desmoid Tumor Research Foundation and FDA Orphan Products Clinical Trials Grants during the conduct of the study, as well as personal fees from Amgen, Bayer, Daiichi Sankyo, Karyopharm and TRACON; and personal fees and nonfinancial support from Epizyme outside the submitted work. Schwartz reports other support from Boehringer Ingelheim, Daiichi Sankyo and Merck; personal fees from Novartis and Roche; and grants from Foundation of the NIH outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
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