Treatment with sorafenib (Nexavar) induced durable responses and doubled the rate of progression-free survival (PFS) at 2 years in patients with advanced or refractory desmoid tumors, results of a double-blind phase III trial found.
Among 84 evaluable patients with symptomatic, progressive, or refractory tumors, the estimated 2-year 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, they reported in the .
"This establishes a new standard of care for this disease," Schwartz told ľֱ. "The progression-free survival on this study for patients on sorafenib is exceptional. In fact, we have never seen anything this good in the treatment of this disease."
In the sorafenib arm, 12% of patients had disease progression compared with 63% of those in the placebo arm. In some patients (nine in the placebo group, two on sorafenib), clinical deterioration was the only evidence of progression.
He noted that medical oncologists are already comfortable and familiar with sorafenib (the drug is approved in liver, kidney, and thyroid cancers), and believes they will immediately start using it for the treatment of patients with desmoid tumors (also called aggressive fibromatosis). While these tumors are considered benign and only occur in soft tissue (unlike sarcomas which also occur in the bone), they can be aggressive and life-threatening if they restrict vital organs.
Prior to crossover, more patients responded to the investigational agent (33% vs 20% with placebo); this included one compete response to sorafenib. Among responders, the median time to response according to RECIST was 9.6 months with sorafenib and 13.3 months with placebo. The earliest detected responses were seen at 2.2 months and 8.8 months in the two groups, respectively.
"It should be noted that responses in general to sorafenib were late," he said. "We should encourage all physicians and patients not to 'give up' on this drug too early as delayed responses are often seen."
Measuring response to treatment is difficult in sarcomas and in desmoid tumors in particular, Schwartz noted, but the researchers found that using T2-weighted MRI to detect tumor volume and changes may be better at identifying responses than classic RECIST measurements. Data on these findings are being prepared for future publication.
"Nevertheless, it is the progression-free survival that really trumps response here," he said.
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."
Skin rash and disorders were the most common reason for dose reduction among patients on sorafenib. 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.
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.
The double-blind study randomized 87 patients with desmoid tumors to 400-mg sorafenib daily or placebo. Patients in the placebo arm were allowed to crossover upon disease progression.
Baseline characteristics were well balanced between the two arms of the trial. Patients were a median age of 37, and were mostly women (69%). All patients had an ECOG status of 0-1, though 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 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.
Disclosures
The study was in part funded by the National Cancer Institute.
Schwartz reported personal fees from Bayer Health Care Pharmaceuticals outside the submitted work. Some co-authors disclosed multiple relevant relationships with industry.
Primary Source
New England Journal of Medicine
Gounder MM, et al "Sorafenib for advanced and refractory desmoid tumors" N Engl J Med 2018; 379:2417-2428.