Key takeaways
- TGCT is a rare giant cell tumor that causes pain, swelling, stiffness and limited range of motion.
- Researchers discovered a signaling protein that gave hope for a non-surgical treatment therapy for the benign tumor.
- In a trial, researchers measured a drug’s effect on tumor size as well as patient-reported experiences of physical function.
- The first iteration of a new drug to treat TGCT received FDA approval in 2019.
Tynosynovial giant cell tumor, or TGCT, is a rare disease, affecting three to four people per 100,000 per year. It’s also considered an “orphan disease,” due to the high cost of developing treatments for the small population that might benefit.
But when the discovery of a signaling protein called CSF1 – a pathway for tumor growth investigated as a potential cancer treatment – showed promise for treating TGCT, it created the possibility for a new oral therapy for this painful inflammatory condition that was once only treated surgically.
“It turned out that TGCT patients had very high overexpression of this pathway,” says UCLA Health orthopedic oncologic surgeon Nicholas Bernthal, MD, chair and executive medical director of the Department of Orthopedic Surgery at the David Geffen School of Medicine at UCLA. “So that left the field in this really interesting spot, because TGCT is not a cancer. It’s benign.”
Getting approval for what would be a game-changing medication for TGCT would require convincing the Food and Drug Administration to consider metrics beyond survival.
When a tumor is malignant, patients are willing to accept myriad medication side effects to shrink it – their lives are on the line. Oncologic drug development doesn’t typically deal with benign conditions, Dr. Bernthal says.
Still, having a drug to help people with TGCT would make a significant difference in their quality of life, because otherwise the only remedy is repeated surgeries as the tumors recur. Dr. Bernthal cites one patient who underwent 15 surgical procedures to treat TGCT, ultimately moving across the country to Los Angeles for repeated operations at UCLA Health.
Unlike a cancer drug that would prolong life, with a TGCT medication, “the fundamental question is do they feel better,” Dr. Bernthal says. “And is their function higher?”
A paradigm shift
The journey to earn approval for the first oral therapy for TGCT included a component not typically seen in oncologic trials: patient-reported outcomes.
TGCT primarily affects adults ages 20 to 40. It causes pain, swelling, stiffness and limited range of motion. And it’s unpredictable, with “flares of massive inflammatory bouts” that severely limit function and mobility, Dr. Bernthal says.
Researchers designed the ENLIVEN trial to measure the drug’s effect on tumor size – “The consensus of our group was that the FDA isn’t going to approve a drug without shrinking the tumor,” Dr. Bernthal says – and, as a secondary outcome, patient-reported experiences of physical function.
Such qualitative measures of patient experience are central to orthopedic practice, Dr. Bernthal says.
“A patient walks into an orthopedic office, and the first question every time is, ‘How do you feel?’” he says. “Within five seconds, you know if you have a happy patient or a frustrated patient. But to run a trial, you need these (responses) to be quantitative – you need them to be evaluable and reproducible.”
The Patient-Reported Outcomes Measurement Information System-Physical Function scale (PROMIS), developed by the National Institutes of Health in 2004, standardized patient-reported health measures for clinical research.
Researchers incorporated this scale into the trial for pexidartinib, which received FDA approval to treat TGCT in 2019. The drug was found to reduce tumor size, increase range of motion, and improve patient-reported physical function, pain, stiffness and overall health.
But that was only the beginning.
Educating doctors and patients
Pexidartinib, sold under the brand name Turalio, isn’t without side effects, and it isn’t ideal for all people with TGCT.
“Oncologists, when a tool is given to them, are all interested in using it, but there’s a lot of TGCT tumors that you don’t want the drug – you can just operate on and still remove it,” Dr. Bernthal says. “So there becomes a huge educational campaign about who not to use the drug on, and then going to surgeons and educating them that there is a drug. We have to figure out which patients are going to benefit from each track.”
The new drug was a daily pill that came with dietary restrictions, which were potentially invasive for people’s lives, he says. It also had the unusual side effect of lightening people’s hair.
A second medication, vimseltinib, was approved in 2025. It only requires twice weekly doses and has no dietary limitations.
A third and fourth iteration of the drug are in the works, Dr. Bernthal says, aimed at “making it easy for a really active, really informed, really mobile, really vibrant patient population that is not interested in sitting around and managing their life around pills.”
Trials for these medications are all using a framework of elevating patient-reported outcomes, he says, which represents a paradigm shift in FDA oncologic drug considerations.
“It’s getting people across fields to really think about that piece of things, and a benign but locally aggressive neoplastic disease was the perfect foil to get us to look at the world a little differently,” Dr. Bernthal says. “It’s just not enough to say: does it shrink the tumor? That can't be our only goal.”
He thinks of his mentor at UCLA Health, Jeffrey Eckardt, MD, who taught him that orthopedic surgery isn’t just about survival. It’s about quality of life.
“Orthopedic surgeons are the patient-reported outcome experts,” Dr. Bernthal says. “So getting our field involved in oncologic drug discovery as we shift from just prolonging life … is just such a gift for all these patients with rare diseases who were virtually ignored by industry.”
