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Pexidartinib induces responses for tenosynovial giant cell tumor
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CHICAGO — Pexidartinib showed significant antitumor activity among patients with tenosynovial giant cell tumors compared with placebo, according to results of the ENLIVEN trial presented at the ASCO Annual Meeting.
However, serious liver toxicity occurred in some patients.
Tenosynovial giant cell tumors — a rare neoplasm of the joint/tendon sheath — are associated with colony-stimulating factor 1 (CSF-1). Pexidartinib (Daiichi Sankyo) is a selective tyrosine kinase inhibitor of CSF-1 receptor, KIT and FLT3 internal tandem duplication.
“Tenosynovial giant cell tumors are rare, locally aggressive, inflammatory neoplasms that occur mainly in the synovium joints, bursae or tendon sheaths,” William D. Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center, said during his presentation. “Patients can often present with large tumors that can cause significant pain, swelling, limited range of motion and stiffness. Surgical resection is the standard primary treatment; however, relapse rates, specifically in the diffuse type, can be as high as 50% to 60%.
There are currently no approved systemic therapies for this population.”
The ENLIVEN trial included 120 patients with symptomatic tenosynovial giant cell tumor, for whom surgery would be associated with potentially worse function or severe morbidity.
For part 1 of the study, researchers randomly assigned patients 1:1 to 1,000 mg pexidartinib per day for 2 weeks then 800 mg per day for 22 weeks or placebo. Open-label crossover was permitted in part 2 of the study after 24 weeks per the trial design.
Overall response rate by RECIST criteria served as the primary endpoint.
In part 1, 98% of patients treated with pexidartinib had adverse events compared with 93% of patients in the placebo arm.
The most common adverse events included hair color changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), alanine aminotransferase increase (28%), dysgeusia (25%), vomiting (20%), headache (18%) and periorbital edema (18%).
Hepatic toxicities occurred more frequently with pexidartinib (aspartate aminotransferase five or more times the upper limit of normal, 11.5%; alanine aminotransferase five or more times the upper limited of normal, 19.7%; total bilirubin two or more times the upper limit of normal, 4.9%). Eight patients discontinued pexidartinib due to hepatic effects; four of these included serious nonfatal adverse events with increased bilirubin, one that listed for approximately 7 months.
All serious hepatic events emerged during the first 2 months of treatment.
Due to nonfatal, serious hepatic toxicity, the data monitoring committee halted enrollment and stopped entry of patients on placebo for part 2.
At the end of part 1, patients treated with pexidartinib had an ORR of 39% (95% CI, 28.1-51.9) compared with 0% (95% CI, 0-6.1) in the placebo arm. Fifteen percent of patients in the treatment arm had complete response at 25 weeks.
No responders had progressed after a median follow-up of 6 months.
Researchers also observed significant improvements in ORR when assessed via tumor volume scores (56% vs. 0%; P <.0001).
Pexidartinib appeared associated with improvements in:
- range of motion (+1 5.1% vs. + 6.2%; P =. 0043);
- PROMIS physical function (+ 4.06 vs. –0.89; P = .0019);
- worst stiffness (-2.45 vs. –0.28; P < .0001); and
- pain response (31.1% vs. 15.3%, 1-sided P = .032).
“Pexidartinib, a novel CSF1-R inhibitor, may offer a relevant treatment option for patients with tenosynovial giant cell tumor, which is associated with severe morbidity and functional limitations and for whom surgery is not recommend,” Tap said. – by Cassie Homer
Reference:
Tap WD, et al. Abstract 11502. Presented at ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Tap reports consulting/advisory roles with Adaptimmune, Blueprint Medicines, Daiichi Sankyo, Eisai, EMD Serono, Immune Design, Janssen, Eli Lilly, Loxo Oncology, Novartis, Plexxikon and TRACON Pharma. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Seth M. Pollack, MD
Tenosynovial giant cell tumor (TGCT) is a benign but locally aggressive tumor that, in some cases, can be painful, disabling or disfiguring. Surgical resection is the standard treatment, but the relapse rate is high and there are no approved systemic treatments. This tumor is driven by a specific genetic translocation (COL6A3-CSF1) and is driven by CSF1. Pexidartinib blocks the CSF1 receptor and, thus, can block the main driving signal that drives these tumors. A phase 2 trial had shown that TGCT could respond to pexidartinib and the ENLIVEN study is a phase 3 placebo controlled trial to test the efficacy of pexidartinib. One-hundred-twenty patients were on the study (61 randomized to pexidartinib, 59 to placebo). The treatment was extremely effective. Twenty-four patients responded overall to the treatment — whereas none responded to placebo — including nine patients (15%) who had a complete response and 15 patients who had a partial repose (25%).
However, liver toxicity was a very significant complication in some patients. Adverse events were common and eight patients had to stop pexidartinib because of liver toxicity. One of these patients died and one required a liver transplant.
In summary, this is a very effective treatment for patients with TGCT. However, because the toxicity of the treatment can be very serious, its use should be limited to severe cases and patients need to understand the risks.
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