Daiichi Sankyo Company, Limited announced that the phase 3 ENLIVEN study showed a statistically significant 39 per cent overall response rate (ORR) at week 25 based upon central review of MRI scans using Response Evaluation Criteria in Solid Tumours, version 1.1 (the primary endpoint) for patients treated with oral pexidartinib compared to no tumour response among patients who received placebo (P<0.0001).  Patients enrolled in the trial were those with tenosynovial giant cell tumour (TGCT) for whom surgery would be associated with potentially worse function or severe morbidity. After a median six month follow-up (longest 17 months), no responders in the ENLIVEN study had progressed.

The data presented during an oral abstract session on Monday, June 4, 2018 between 8:24 AM - 8:36 AM CDT (Abstract 11502) at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

urrent treatment options for TGCT are largely limited to surgery in order to remove as much of the tumour as possible. Despite the best surgical intervention, the recurrence rate of diffuse TGCT is high and the disease may advance to the point where surgery is no longer an option,” said William D. Tap, MD, lead investigator of the study and Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City. “Pexidartinib may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended.”

Pexidartinib is an investigational, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), a primary growth driver of abnormal cells in the synovium that cause TGCT.

In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT =3X ULN: 33 per cent, total bilirubin =2X ULN: 5 per cent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

Other AEs noted in ENLIVEN >10 per cent and more common with pexidartinib included hair colour changes, pruritus, rash, vomiting, abdominal pain, constipation, fatigue, dysgeusia, facial edema, peripheral edema, periorbital edema, decreased appetite and hypertension.

Secondary efficacy endpoints demonstrated that patients treated with pexidartinib had a 56 percent overall response rate (ORR) by Tumour Volume Score (TVS), compared to no response in patients who received placebo (P<0.0001). Clinically meaningful improvement versus placebo was observed in other secondary efficacy endpoints, including range of motion (+15% vs +6%, P=0.0043), PROMIS physical function (+4.1 vs -0.9, P=0.0019), and worst stiffness (-2.5 vs -0.3, P<0.0001).  There was also a nonsignificant improvement in pain response (31% vs 15%).

“We are encouraged by the results from the ENLIVEN study and we look forward to submitting an NDA to the U.S. FDA and engaging European regulators for review of pexidartinib,” said Gideon Bollag, PhD, CEO, Plexxikon, a member of the Daiichi Sankyo Group.”

ENLIVEN, a double-blind, randomized, global multi-cener, pivotal phase 3 study, evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumour volume score, PROMIS physical function, stiffness and measures of pain reduction.

After completing the first part of the study, patients randomized to either pexidartinib or placebo were eligible to take part in the second part of ENLIVEN, a long-term, open-label part where patients could continue to receive or start to receive pexidartinib. In October 2016, following two reported cases of serious, non-fatal liver toxicity in the ENLIVEN study, the data monitoring committee (DMC)  recommended that patients receiving placebo in the first part of the study should no longer be eligible to start pexidartinib in the second part of the study.  A total of 120 patients who were enrolled prior to the DMC recommendation continued with the study according to the revised protocol.

Tenosynovial giant cell tumor (TGCT), previously referred to as pigmented villonodular synovitis (PVNS) or giant cell tumour of the tendon sheath (GCT-TS), is a rare, usually non-cancerous tumour that affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb. It has been estimated that the incidence of TGCT is 11 to 50 cases per million, based on studies from three countries. Patients are commonly diagnosed in their 20s to 50s, and depending on the type of TGCT, women can be up to twice as likely to develop a tumor as men.

Primary treatment of TGCT includes surgery to remove the tumor. However, in patients with a diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove and may require multiple surgeries or joint replacement, eventually advancing to the point where surgical resection is no longer an option and amputation may be considered. It is estimated that the rate of recurrence for diffuse TGCT can be 20 to 55 per cent.

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib has been granted Breakthrough Therapy Designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumour of tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity and Orphan Drug Designation for PVNS/GCT-TS by the US Food and Drug Administration (FDA). Pexidartinib also has received Orphan Designation from the European Commission for the treatment of TGCT. Pexidartinib is not approved by the FDA or any other regulatory agency worldwide as a treatment for any indication. Safety and efficacy have not been established.