Pexidartinib Gets Receives Support to Treat Giant Cell Tumors

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Committee: Oncologic Drugs Advisory Committee

Indications: the treatment of adult patients with symptomatic tenosynovial giant cell tumor also referred to as giant cell tumor of the tendon sheath or pigmented villonodular synovitis, which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery

Drug/Device: Drug (pexidartinib capsule)

Sponsor: Daiichi Sankyo Inc.

Question 1: Does the demonstrated benefit of pexidartinib outweigh the risks of the drug in the proposed indication?

Vote Results: Yes 8 No 5 abstain 0

FDA Documents:

Background:

Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the synovium, bursae, or tendon sheaths that is driven by overexpression of colony-stimulating factor-1 (CSF-1). The current standard of care for TGCT is surgical resection. However, diffuse disease often has more extensive involvement and a poorer likelihood of successful cure with surgery, and therefore often may not be amenable to surgical resection due to the risk of morbidity or high risk of recurrence. In the United States (US), the annual incidence of new cases is estimated to be ~15,000 for localized TGCT and ~1500 for diffuse TGCT.

Conducted in patients with locally advanced, symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity, the new drug application is seeking approval for pexidartinib capsule with a two-part, multicenter, randomized (1:1), double-blind, placebo-controlled trial PLX108-10 (ENLIVEN) for the proposed indication. Part 1 was a double-blind phase, the patients either received placebo or pexidartinib capsule for 24 weeks. The dosage for part 1 patient was 1000 mg per day for two weeks, then 400 mg twice a day for the rest of 22 weeks. The patients who completed Part 1 were to enter Part 2 for efficacy and safety assessment of long-term pexidartinib treatment. In Part 2, patients received open-label pexidartinib at the same pexidartinib dose or equivalent dose of placebo as at the end of Part 1. Part 2 also evaluated efficacy and safety of pexidartinib in patients starting pexidartinib after crossover from placebo, all started pexidartinib at the 400-mg twice daily dose.

Unique Challenges

Efficacy

The primary efficacy outcome measure in ENLIVEN was overall response rate (ORR) at Week 25. Efficacy assessments included tumor imaging by MRI, assessment of ROM of the affected joint, and PRO assessments. In submitted study, primary efficacy endpoint was met. There were statistically significant improvements in all secondary endpoints for the patients randomized to pexidartinib arm compared to the patients randomized to placebo arm. However, the evaluation of the effects of pexidartinib on the symptomatic aspects of the disease requires COAs (Clinical Outcome Assessment) that are valid, reliable and clinically relevant.

A key challenge for this application is whether the results of the COA measures provide evidence of benefit for the functional aspects of the disease. While the analysis of the COA secondary endpoints of ROM, physical function, and worst stiffness demonstrated a statistically significant improvement in mean change from baseline to Week 25 for the pexidartinib arm compared to the placebo arm, the interpretability of these results is limited due to several factors, including uncertainty regarding the threshold for what constitutes a clinically meaningful within-patient change in ROM, and a high level of missing data at Week 25. A primary concern regarding missing COA data is that the assessments may not be missing at random, therefore imputation may lead to a biased interpretation of the benefit of pexidartinib based on COA data.

Safety

A key issue for this application has been to define the risk of liver injury in patients who receive pexidartinib. A majority of patients who received this drug experienced elevations in transaminase values. While the majority of patients in the TGCT population who experienced transaminase elevations and total bilirubin increase had improvement to baseline levels with dose reductions, dose interruption, and/or discontinuation of pexidartinib.

Across the overall development program (commercial-sponsored and investigator-initiated trials), two of 768 pexidartinib-treated patients experienced irreversible liver injury, resulting in liver transplantation in one patient and death in another. Furthermore, it is unclear in what proportion of patients pexidartinib causes subacute or chronic injury and if any ongoing subacute or chronic injury may result in clinically important sequelae such as liver failure resulting in the need for liver transplantation or death.

An additional area of uncertainty is the lack of understanding of the potential long-term effects of pexidartinib given that patients with TGCT will likely be exposed to pexidartinib as a chronic medication. In the ENLIVEN trial, a small number of patients had long-term exposure to pexidartinib.

Next Steps: