Desmoid tumors are among "the most confusing of tumors," says an expert in the field.
These rare, locally aggressive tumors arise from fibroblast cells and can occur anywhere in the body — and they have an unpredictable natural history. While they can occasionally become life-threatening when they press down on organs, they can also stop growing or even regress spontaneously, without any intervention.
"There is a 20% known remission rate in patients receiving placebo," commented Laurence H. Baker, DO, from the department of internal medicine, University of Michigan Medical School and the Michigan Medicine Sarcoma Program in Ann Arbor.
"It rarely kills patients, but makes life unpleasant," he told Medscape Medical News.
About one third of patients with desmoid tumors will have progressive or highly symptomatic disease, or both, and will need therapeutic intervention.
However, there is also no consensus on the best treatment plan: it ranges from doing nothing and observing through to surgery, with a range of drug treatments. Historically, patients with desmoid tumors may be treated with tamoxifen (hormonal therapy); anti-inflammatory drugs such as NSAIDs; chemotherapy with a methotrexate–vinblastine regimen; and more recently with tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec, Novartis) and sorafenib (Nexavar, Bayer).
Pazopanib (Votrient, Novartis) should now be added to the list of treatment options, say researchers reporting what they describe as the first randomized trial of this condition.
The study was published online July 19 in Lancet Oncology.
Not so fast, suggests Baker, who wrote the accompanying editorial. Speaking with Medscape Medical News, he said, "The conclusion that pazopanib could be considered a valid treatment option is premature."
DESMOPAZ Trial Results
The new trial, known as DESMOPAZ, was led by Antoine Italiano, MD, PhD, of the Institut Bergonié, Bordeaux, France, on behalf of the French Sarcoma Group.
This was an open-label, noncomparative, phase 2 study that randomly assigned 72 patients with progressive desmoid tumors to receive either daily pazopanib 800 mg (n = 48) or standard chemotherapy with methotrexate and vinblastine (n = 24) for 1 year.
After a median follow up of 23.4 months, 46 patients in the pazopanib group and 20 patients in the chemotherapy group were assessable for activity.
More than twice the number of patients receiving pazopanib completed the 1-year treatment schedule (52% vs 23% in the methotrexate–vinblastine group).
The median progression-free survival (PFS) was not reached for either group, but at 6 months, more patients on pazopanib had not progressed. The 6 month PFS was 83.7% for patients on pazopanib vs 45% for patients on methotrexate–vinblastine.
However, Baker noted that the 12-month PFS was similar in the two groups and was higher at 24 months for patients receiving methotrexate–vinblastine (79% vs 67.2% for patients on pazopanib).
"The study investigators fortuitously picked an endpoint that showed benefit for pazopanib," he said, but he also pointed out that this was decided upon before the study was initiated. "However, a more appropriate endpoint would have been to analyze PFS as a continuous variable, which turned out to be quite similar in effect to the survivorship curves" he said.
A partial response (PR) was reported for 37% of patients on pazopanib vs 25% on methotrexate–vinblastine, and stable disease (SD) for 58.7% on pazopanib and 50% on methotrexate–vinblastine.
Dose modifications due to adverse events were reported for 73% of patients on pazopanib and 77% of patients on methotrexate–vinblastine. The investigators noted that the toxicity with pazopanib was manageable and the toxicity profile of the methotrexate–vinblastine used was in line with previous studies.
However, Baker commented: "If three of four patients need dose reductions, how is pazopanib considered tolerable?"
Italiano and colleagues conclude that "pazopanib has clinical activity in patients with progressive desmoid tumors and might be considered a valid treatment option in this rare and disabling disease."
However, Baker says that "other therapeutic options with higher progression-free survival at each time point or with overall survival results challenge this claim."
He also suggested that DESMOPAZ was a flawed study in several ways.
First, he pointed out that the statistical plan stated it was a noncomparative study, but the investigators presented the activity of pazopanib alongside chemotherapy, inviting comparison.
If comparisons were going to be made, the investigators should have used another agent, he suggested. "There are several other TKIs such as imatinib and sorafenib, which have shown activity in desmoid tumors, including a PFS of greater than 80% at 6 months," he said.
He also questioned the 800 mg daily dose of pazopanib used in the study. "The dose of 800 mg is more than most patients can tolerate and thus patients have been overdosed," Baker said. Most other studies used the TKIs at a dose of 50% below the approved dose, namely 400 mg, he pointed out.
"The study was designed to ensure that pazopanib came out as a winner," he said, suggesting that the pharmaceutical companies had a hand in the design of the study and in the writing of the manuscript. However, the DESMOPAZ investigators state that the pharmaceutical companies that funded the study had "no role in the study design, data collection, data analysis, data interpretation, or writing of the report."
Medscape Medical News reached out to Italiano for comments, but received no response at press time.
Baker also had some praise for the investigators. They should be commended, he said, for publishing the survival curves (which showed no difference), collecting blood samples for proteomics (never been done before in desmoid tumors), and for rigorous assessment of tumor shrinkage or progression based on central review by radiologists blinded to the study (which costs money and time, but provides quality control).
He also suggested that a better study to assess long-term durability and clinical benefit would be to compare pazopanib 400 mg daily with sorafenib 400 mg daily. "The pharmaceutical companies involved would never do this study," Baker said, and conceded that a randomized, controlled, adequate-powered study — the gold standard — is unlikely.
"Independent funding is badly needed to support the extent of collaboration needed to recruit the sufficiently large study population that rigorous inquiry requires," he writes in his commentary.
The study was sponsored by Institut Bergonié and funded by GlaxoSmithKline (GSK) and Novartis, which acquired pazopanib from GSK in 2016 . All relevant financial relationships for the investigators are listed at the end of the article. Italiano reports research grant and personal fees from Ipsen, Novartis, Bayer, Bristol-Myers Squibb, Epizyme, Immune Design, Daiichi Sankyo, and MSD. Baker has disclosed no relevant financial relationships.
Medscape Medical News © 2019
Cite this: 'Most Confusing' Desmoid Tumors: Pazopanib Now an Option? - Medscape - Jul 30, 2019.