Patients with the rare cancer, advanced tenosynovial giant cell tumour (TGCT) showed promising response rates with pexidartinib compared to placebo and dramatically improved physical function according to phase III trial results presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held 1 to 5 June in Chicago, USA.
There is a vast unmet need for treatment options in TGCT since no approved systemic therapy is currently available. TGCT targets the joint/tendon sheath and is associated with pain, loss of range of motion, and other physical function disability.
William D. Tap, Department of Medicine, Memorial Sloan Kettering Cancer Centre, New York, USA presented final results from the phase 3 ENLIVEN trial (NCT02371369) on behalf of colleagues.
ENLIVEN was a global, double-blind, randomised, placebo-controlled study of pexidartinib in patients with advanced TGCT. In part 1 of the study, 59 patients were randomised to placebo and 61 patients to oral pexidartinib at 1000 mg per day for 2 weeks followed by pexidartinib at 800 mg per day for 22 weeks. All patients were ≥18 years and had symptomatic TGCT. It was determined that surgery in these patients would be associated with potentially worsening function or severe morbidity. Patients completing part 1 were eligible to continue in an open-label extension phase of pexidartinib treatment (part 2).
Pexidartinib is a selective inhibitor of the colony-stimulating factor 1 (CSF-1) receptor, KIT, and FLT3-ITD that has shown promising phase I activity in patients with TGCT, which is characterised by overexpression of CSF-1.
The primary endpoint was overall response rate (ORR) according to RECIST at week 25 by central review; the study was powered to detect a 25% difference. Secondary endpoints included ORR by tumour volume, range of motion, physical function as evaluated on the Patient Reported Outcomes Measurement Scale (PROMIS), worst stiffness, and pain response.
The ENLIVEN study was halted despite meeting the primary endpoint
Enrolment into the pexidartinib arm was halted 6 patients short of target due to 2 cases of non-fatal, serious hepatic toxicity, and the entry of patients into the part 2 placebo arm was also stopped. During the non-TGCT pexidartinib development programme, two severe cases of liver toxicity, of which one required liver transplant and one was associated with death, had been reported.
Results from the end of part 1 of the study were presented at ASCO. The ORR by RECIST in the intent to treat (ITT) population was 39.3% with pexidartinib compared to 0% with placebo (p < 0.0001). After a median 6-month follow-up no responders had progressed; the longest follow-up of responders was 17 months, which also revealed no disease progression.
Significant clinical benefit in terms of physical function were observed with pexidartinib
All secondary endpoints were also met: The ORR by tumour volume scores were 55.7% with pexidartinib versus 0% with placebo (p < 0.0001). Range of motion was increased by +15.1% versus +6.2% (p = 0.0043), PROMIS physical function scores were +4.0 versus -0.89, (p =0.0019), worst stiffness decreased by -2.45 versus -0.28, (p < 0.0001), and pain response was 31.1% versus 15.3% (1-sided p = 0.032) for pexidartinib versus placebo, respectively.
Hepatic toxicities were more frequent with pexidartinib than placebo, with both AST and ALT increased to more than 5 times the upper limit of normal (ULN) at 11.5% and 19.7%, respectively. Total bilirubin was also increased to ≥2X ULN at 4.9%. Hepatic effects resulted in pexidartinib discontinuation in 8 patients. Of these, 4 were serious non-fatal adverse events (AEs) consisting of increased bilirubin, with one AE lasting approximately 7 months.
Non-hepatic AEs occurring in ≥15% of patients that were more common with pexidartinib than placebo included hair colour changes, vomiting, fatigue, dysgeusia, and periorbital oedema.
The authors concluded that treatment with pexidartinib provided significantly improved ORR in patients with TGCT. These patients also demonstrated clinical benefit in terms of functional outcomes.
According to study team, these findings suggest that, despite the serious liver toxicity observed in some patients, pexidartinib may offer a relevant treatment option for select patients with advance TGCT.
The ENLIVEN study was sponsored by Daiichi Sankyo, Inc.
Tap WD, Gelderblom H, Stacchiotti S, et al. Final results of ENLIVEN: A global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT). J Clin Oncol 36, 2018 (suppl; abstr 11502).