CME Author: Vicki Brower
Study Authors: Mrinal M. Gounder, Michelle R. Mahoney, et al.
Target Audience and Goal Statement:
Oncologists, pediatric oncologists, internists, and family medicine specialists
The goal was to evaluate the safety and efficacy of sorafenib (Nexavar) in the treatment of patients with progressive or symptomatic desmoid tumors.
- What is the efficacy (primary endpoint) and safety (secondary endpoint) of sorafenib in patients with progressive, symptomatic, or recurrent desmoid tumors?
- Are the side effects manageable?
Study Synopsis and Perspective:
In this international phase III double-blind, randomized placebo-controlled study of 84 patients with advanced or refractory desmoid tumors, patients who received sorafenib had double the rate of progression-free survival (PFS) at 2 years, compared with those in the placebo group. The estimated 2-year progression-free survival (PFS) rate was 81% in the sorafenib-treated group compared with 36% for those on placebo (HR 0.13, 95% CI 0.05-0.31, P<0.001), according to Gary Schwartz, MD, of NewYork-Presbyterian/Columbia University Medical Center in New York, and colleagues.
At a median follow-up of 27.2 months, PFS was 11.3 months in the placebo arm but not reached in the sorafenib arm, the team reported in the New England Journal of Medicine.
“The progression-free survival on this study for patients on sorafenib is exceptional,” Schwartz told MedPage Today. “In fact, we have never seen anything this good in the treatment of this disease. This establishes a new standard of care for this disease.”
Objective responses are ongoing, he added.
Until now, there has been no real standard of care for these rare and difficult-to-treat and sometimes lethal tumors (due to complications, not usually metastases), nor have there been accepted predictive biomarkers, or validated desmoid-specific patient-reported outcome measures.
Also known as aggressive fibromatosis, desmoid tumors arise from connective tissue, and about 1,000 new cases are estimated to occur in the U.S.; the incidence is 0.3 cases per 100,00 persons per year. The tumors affect mostly young people, but may also appear in children and older adults, and over 90% are sporadic — i.e., without a family history or an inherited genetic change.
Desmoid tumors are often treated with surgery, but typically recur and are then treated with radiation or systemic treatments. Response to systemic treatment has generally been disappointing, in the range of 0-40%. Similarly, small studies of patients with desmoid tumors treated with the targeted drug imatinib have been disappointing, and researchers in those trials did not find any predictive biomarkers.
In the study by Schwartz’s group, only 12% of patients treated with sorafenib had disease progression, compared with 63% of patients on placebo. In some patients (nine in the placebo group, two in the sorafenib group), clinical deterioration was the only evidence of progression.
While sorafenib is generally well tolerated and the investigators used a 400-mg dose of sorafenib (half the recommended starting dose for other cancers), adverse events (AEs) still led to one-fifth of patients discontinuing the treatment during the trial; no patients in the placebo arm discontinued due to AEs.
“Even at this dose, a modest degree of toxicity, especially skin toxicity, can be seen,” said Schwartz. “Dose reductions, though, did not seem to compromise the benefits to this therapy.”
The most common reason for dose reduction among patients on sorafenib was skin rash and disorders. But the researchers found that some patients could reduce their dosage to 200 mg, re-escalate, and then had better tolerance to the original starting dose.
“Overall, with discussions between the patient and the oncologist, the sorafenib dose should be able to be titrated to avoid toxicity and obtain the optimal advantage of this drug to treat this disease,” said Schwartz.
In addition, while grade 1/2 AEs were higher in the placebo arm (69% vs 53%), grade 3/4 AEs occurred in 47% of patients in the sorafenib group and 25% of those in the placebo group. Grade 3/4 events, rash, and skin disorders occurred in 14% of patients on sorafenib but none of the placebo patients.
Source Reference: New England Journal of Medicine, Dec. 20, 2018; 379: 2417-2428
Study Highlights: Explanation of Findings
The double-blind study by Schwartz and colleagues randomized 87 patients with desmoid tumors to 400 mg of sorafenib daily or placebo. Patients in the placebo arm were allowed to cross over on disease progression. The authors noted the importance of randomized trials for this cancer in particular due to the phenomenon of spontaneous regression; in addition, these tumors can have late responses, and about 20% of patients on placebo have tumor regression.
Baseline characteristics were well balanced between the two arms of the trial, the team noted: Patients were a median age 37, and were mostly women (69%). All patients had an ECOG status of 0-1, although more patients in the sorafenib arm were ECOG 0 (70% vs 59%). Patients had a higher median number of target lesions in the sorafenib group (8.4 vs 7.6) and both arms of the study were roughly split between newly diagnosed patients and those with recurrent disease.
Among the various criteria for study entry, 76% and 88% of patients in the placebo and sorafenib groups, respectively, had disease that was either unresectable or would leave a patient with an unacceptable degree of surgery-related morbidity. Radiographic progression within the 6 months prior to randomization was seen in 43% and 38% of patients in the two groups, respectively.
Schwartz noted that because medical oncologists are already comfortable and familiar with sorafenib — it is approved in liver, kidney, and thyroid cancers — he thinks these results will encourage clinicians to immediately start using the drug for patients with desmoid tumors.
Prior to crossover, more patients in the study responded to the investigational agent (33% vs 20% with placebo); this included one complete response to sorafenib. Of note, the researchers said, among responders, the median time to response according to Response Evaluation Criteria for Solid Tumors (RECIST) guidelines was 9.6 months with patients in the sorafenib group and 13.3 months in the placebo group. The earliest detected responses were seen at 2.2 and 8.8 months in the two groups, respectively.
“It should be noted that responses in general to sorafenib were late,” Schwartz said. “We should encourage all physicians and patients not to ‘give up’ on this drug too early as delayed responses are often seen.”
The issue of using RECIST criteria to measure efficacy and disease progression is problematic and controversial for a number of solid tumor types, including desmoid cancers, Schwartz and co-authors noted. Measuring response to sarcoma treatment is often difficult, and especially so for desmoid tumors in particular, the team explained.
In this study, the researchers also used T2-weighted magnetic resonance imaging to detect tumor volume and changes, which may be better at identifying responses than classic RECIST measurements are. In these and other tumors types, measuring tumor volume and density may give a more accurate picture of what is occurring in the tumor as it is killed — “a shift from a cellular mass to a collagenous scar,” the authors wrote, noting that data on these findings are being prepared for future publication.
“Nevertheless, it is the progression-free survival that really trumps response here,” Schwartz said.
He and his co-authors also noted that the mechanism of action of sorafenib in desmoid tumors is not clear. To investigate that, the researchers said, they are now conducting ongoing research into changes in gene expression, protein phosphorylation of receptor tyrosine kinases such as fibroblast growth factor receptor, platelet-derived growth factor receptor, and transforming growth factor beta receptor, and the Wnt signaling pathway in 25 sets of paired biopsy specimens.
Ian Ingram wrote the original story for MedPage Today
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner