The Food and Drug Administration’s approval of Turalio for tenosynovial giant cell tumors may offer significantly improved clinical benefit for select patients with these rare, benign tumors.
The Food and Drug Administration (FDA)’s approval of Turalio (pexidartinib), a CSF1R inhibitor drug for patients with certain types of tenosynovial giant cell tumors, may provide patients who are ineligible for surgical resection with a significantly improved response and clinical benefit.
Tenosynovial Giant Cell Tumors
Tenosynovial giant cell tumors are a rare, locally aggressive neoplasm that is driven by an overexpression of colony-stimulating factor 1 (CSF1), a genetic anomaly which secretes a protein into the blood that controls various white blood cell functions and plays the important role of controlling immune and inflammatory processes. This genetic abnormality can attract inflammatory cells to that area in the joints, according to Dr. William D. Tap, lead investigator of the ENLIVEN study and chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City.
“This is a disease that we have really only begun to truly understand within the last 10 years from a scientific standpoint, and from a clinical standpoint really within the last five to eight years,” said Tap. “Because of that, (tenosynovial giant cell tumor) has been very much neglected by the medical community in our understanding of it and how to approach the treatment of it. That is one of the areas of the greatest unmet medical need, as this condition has been affecting people for long periods of time but there haven’t been great medical treatments for it.”
The condition can occur anywhere in the body and be painful and debilitating for patients. The non-malignant tumor can occur in young or otherwise healthy people, and average presentation usually occurs in a person’s thirties or forties, Tap told CURE®. Symptoms include pain, inflammation, stiffness, functional impairment, swelling, joint destruction, joint instability and decreased range of motion.
Tenosynovial giant cell tumor represents two distinct clinical presentations: localized (or nodular) and diffuse. Diffuse disease in tenosynovial giant cell tumors is highly irregular tumor shape and does not grow circumferentially, making it difficult to treat with surgery and often resulting in a difficult patient journey. A typical patient with diffuse disease is likely to need over 750 days off throughout their disease, intermittent physical therapy for years or decades and an arsenal of braces, compression socks, ice machines and other anti-inflammatory tools. Ninety percent of patients with tenosynovial giant cell tumors present with localized disease, according to research presented at the FDA’s May Oncologic Drugs Advisory Committee (ODAC), which voted 12 to 3 in favor of the agency approving pexidartinib to treat adult patients with tenosynovial giant cell tumors.
The primary treatment standard for tenosynovial giant cell tumors is surgical resection; however, those with diffuse disease — widely spread throughout the joint or joints – are not always amenable to surgery. Prior to the approval of pexidartinib, there were no FDA-approved systemic therapies for tenosynovial giant cell tumors.
“The diffuse type (of symptomatic tenosynovial giant cell tumors) can be very difficult because it can be very infiltrated throughout the joints and can often be very difficult from a surgical standpoint to truly remove all of the disease,” said Tap.
“Surgeons will say it’s almost like ‘operating in mud’ and patients may need to go through large procedures to try to remove as much as possible,” he added. “There is a percentage of the diffuse type that is cured with surgery alone, but we also know that there is a high relapse rate in the diffuse type of the TCGT. Depending on the literature it’s quoted anywhere from about 40% to 55% of the time that the disease will come back.”
In extreme cases, patients with the diffuse subtype of tenosynovial giant cell tumor may require more surgeries, which can result in morbidity of the joints and in some cases, amputation, according to Tap.
FDA Approval of Turalio
Turalio showed promising phase 1 activity in patients with tenosynovial giant cell tumors. When a CSF1 receptor (CSF1R) inhibitor such as Turalio is administered in patients with tenosynovial giant cell tumors, this can prevent CSF1R activation and CSF1R-mediated signaling in these cells. This can reduce inflammation, improve T-cell infiltration and antitumor T-cell immune responses to inhibit tumor cells from multiplying.
“The thought that this CSF1 gene is upregulated in this process really brought in the idea of targeting that with drugs such as (Turalio), which can be very strong inhibitors of the CSF1 receptor,” said Tap. “So, the thought is that it can block the recruitment of these inflammatory cells that actually have the receptor on their surface for this CSF1 chemoattractant.”
CSF1R inhibitors can help potentially slow down the process and improve patient symptoms and tumor mass, sometimes within weeks, he added.
The ODAC found that the drug’s “efficacy (is) clearly established by robust tumor response rate and clinically meaningful improvement in function and disease symptoms, as measured by clinical and patient reported outcomes.”
Turalio is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumors associated with severe morbidity or functional limitations and unresponsive to treatment with surgery.
The FDA’s approval of Turalio was based on data from the phase 3 ENLIVEN trial — a global, double-blind, randomized, placebo-controlled study of Turalio in patients with advanced tenosynovial giant cell tumors, whose tumors were ineligible for surgical removal as it could cause more harm than benefit. Overall, 120 patients were analyzed in the ENLIVEN trial, 61 of which were given Turalio and 59 patients who were given a placebo.
Turalio resulted in significantly improved overall response rate (the percentage of patients with a reduction in tumor burden of a predetermined amount for a designated minimum time period) and clinical benefit in terms of functional outcomes. Compared with placebo, overall response rates by tumor volume score — which calculates tumor volume as percentage of the entire synovium (the soft tissue that lines the spaces between joints) – were 55.7% for patients who received Turalio vs 0% for those who received the placebo. The study showed improved range of motion by 15.1% with Turalio compared to 6.2% with placebo; meanwhile, worst stiffness reduced by 2.45% and .28%, respectively, and pain response improved by 31.1% and 15.3%. Thus, Turalio may offer a relevant treatment option for select patients with tenosynovial giant cell tumors.
Side Effects to Be Aware Of
Researchers observed less than 40% change in exposure in subjects with renal impairment and no effect of mild and moderate hepatic impairment upon exposure to the drug.
However, severe liver toxicity was observed in some patients: Two serious liver toxicity cases (one requiring a liver transplant and one associated with death) have been observed with Turalio across the non-tenosynovial giant cell tumors development program.
Liver toxicities were more frequent with Turalio. There were two cases of nonfatal, serious liver toxicity and eight patients discontinued Turalio due to hepatic side effects; four were serious, nonfatal side effects with increased bilirubin (an orange-yellow substance made during the normal breakdown of red blood cells, which travels through the liver and is eventually emitted out of the body), one lasting approximately seven months. Other, less severe side effects associated with Turalio included hair color changes, vomiting, fatigue, dysgeusia (a distortion or loss of taste) and periorbital edema (swelling around one or both eyes).
“This is really important for patients and prescribing clinicians to know because this is not something that should be used in every patient and really should be only considered in very specific clinical situations after discussion has been had about the potential of this liver toxicity, even though it’s very rare,” said Tap.
For more information, view CURE®’s breaking news report on the FDA’s approval.