Sorafenib Extends PFS in Desmoid Tumors

Sorafenib Extends PFS in Desmoid Tumors

Dr. Rashmi Chugh
Dr. Mrinal M. Gounder
Sorafenib resulted in significantly improved progression-free survival (PFS) compared with placebo in patients with desmoid tumors (DTs) or aggressive fibromatosis, according to results of a randomized phase III trial presented on June 4 (Abstract 11500).

DTs are rare, with approximately 1,000 patients per year in the United States. Surgery is considered the primary therapy, but is associated with high recurrence rates and surgical morbidity, said Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, during the Sarcoma Oral Abstract Session. Limited information on potential systemic therapies for this malignancy was previously available.

Previous research has shown that sorafenib, a pan–tyrosine kinase inhibitor, has activity in DTs. In one study from 2011, 25% of a small cohort had an objective response to the agent.1

The new trial randomly assigned patients 2:1 to receive either sorafenib 400 mg/day (50 patients) or placebo (37 patients); after progression with placebo, crossover to open-label sorafenib was permitted. All patients had histologically confirmed DTs and were over age 18, and all had unresectable tumors or unacceptable surgical morbidity; progressive disease; and symptomatic disease. The mean age in both groups was 39 years, and approximately 70% of patients were female. Approximately 40% of the cohort had received prior systemic therapy.

The study met its primary endpoint, with improved PFS in the sorafenib group. The median PFS with sorafenib was not reached, compared with a median PFS of 11.3 months in the placebo group (HR 0.14, 95% CI [0.06, 0.33]; p < 0.0001).

Ten patients (20%) receiving sorafenib discontinued the therapy due to adverse events. One patient discontinued in favor of an alternative therapy, five patients (10%) discontinued due to disease progression, and 22% discontinued because of withdrawal/refusal. Nineteen patients continued on sorafenib at the time of data cutoff. Most of the patients receiving placebo who discontinued (66%) did so due to disease progression.

Clinician-reported adverse events (AEs) were more common with sorafenib than with placebo. Grade 1/2 palmar-plantar erythrodysethesia was reported in 69% of patients on sorafenib (2% grade 3/4) and in 22% of patients receiving placebo. Grade 1/2 fatigue (61% vs. 47%), hypertension (55% vs. 28%), and diarrhea (47% vs. 28%) were also more common with sorafenib, among several other AEs. The most common grade 3/4 AEs with the study drug included papulopustular rash (12%), hypertension (8%), and fatigue (6%).

Dr. Gounder noted that in spite of the higher rates of patient-reported hand-foot syndrome in the sorafenib arm, including severe cases, patients reported that it did not significantly affect their daily lives.

The objective response rate was 33% with sorafenib, and all patients who achieved a complete or partial response continue to respond, Dr. Gounder said.

With placebo, the objective response rate was 20%. This result, Dr. Gounder said, supports the possibility that observation alone could be appropriate as initial treatment in select patients. He also noted that biomarker discovery is an important future avenue of research, and analysis of more than 600 MRI scans to link imaging to patient experience is ongoing.

“In appropriate patients, these data support the use of sorafenib at 400 mg once daily in the firstline or subsequent line of therapy,” Dr. Gounder concluded. He noted that there were some late responses to sorafenib, “so keeping patients on this drug is important.”

Rashmi Chugh, MD, of the University of Michigan, was the discussant for the study. She noted that the 400 mg dose is half what is approved for use in other malignancies. “I think it is important to tailor the therapy choice to the individual patients, considering the toxicities,” Dr. Chugh said, noting that other recent trials (including Abstract 11501) have also suggested pazopanib could be effective in DTs. 

–Dave Levitan