For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. .