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Pexidartinib: first approved systemic therapy for patients with tenosynovial giant cell tumor

Hans Gelderblom

Michiel van de Sande

Hans Gelderblom

*Author for correspondence: Tel.: +31 71 526 3486;

E-mail Address: a.j.gelderblom@lumc.nl

https://orcid.org/0000-0001-9270-8636

Leiden University Medical Center, Leiden, Netherlands

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Michiel van de Sande

Leiden University Medical Center, Leiden, Netherlands

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Published Online:23 Jul 2020https://doi.org/10.2217/fon-2020-0542

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Abstract

Pexidartinib is an orally administered small molecule tyrosine kinase inhibitor. Phase III ENLIVEN study results provided clinical evidence for US FDA approval for treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Recommended dosage is 400 mg orally twice daily on an empty stomach. Long-term follow-up in pooled analyses showed increased response rates compared with those observed in ENLIVEN. Patients on pexidartinib also experience meaningful improvements in range of motion. Side effects associated with pexidartinib are generally manageable; however, there is a risk of potentially life-threatening mixed or cholestatic hepatotoxicity and pexidartinib has a Risk Evaluation and Mitigation Strategy (REMS) program to ensure appropriate monitoring.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. de Saint Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour: localized type, diffuse type. In: World Health Organization Classification of Tumours of Soft Tissue and Bone. Fletcher CDMBridge JAHogendoorn PCWMartens F. (Eds). 100–103 IARC Press, Lyon, France (2013).
Google Scholar
2. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases and literature review. Medicine (Baltimore) 59(3), 223–238 (1980).
Medline CASGoogle Scholar
3. Mastboom MJL, Verspoor FGM, Verschoor AJ et al. Higher incidence rates than previously known in tenosynovial giant cell tumors. Acta. Orthop. 88(6), 688–694 (2017). • Highlights tenosynovial giant cell tumor (TGCT) incidence rates.
MedlineGoogle Scholar
4. Ehrenstein V, Andersen SL, Qazi I et al. Tenosynovial giant cell tumor: incidence, prevalence, patient characteristics, and recurrence. A registry-based cohort study in Denmark. J. Rheumatol. 44(10), 1476–1483 (2017).
MedlineGoogle Scholar
5. Staals EL, Ferrari S, Donati DM, Palmerini E. Diffuse-type tenosynovial giant cell tumour: current treatment concepts and future perspectives. Eur. J. Cancer 63, 34–40 (2016).
MedlineGoogle Scholar
6. Brahmi M, Vinceneux A, Cassier PA. Current systemic treatment options for tenosynovial giant cell tumor/pigmented villonodular synovitis: targeting the CSF1/CSF1R axis. Curr. Treat. Options Oncol. 17(2), 10 (2016).
MedlineGoogle Scholar
7. Mastboom MJ, Planje R, van de Sande MA. The patient perspective on the impact of tenosynovial giant cell tumors on daily living: crowdsourcing study on physical function and quality of life. Interact. J. Med. Res. 7(1), e4 (2018). • Evaluates the impact of TGCT on patient physical function and daily activities.
MedlineGoogle Scholar
8. Lopez-Bastida J, Ye X, Laeis P et al. Health-related quality of life in tenosynovial giant cell tumor (TGCT) patients in Europe and US: an observational disease registry. CTOS 22, S866 (2019).
Google Scholar
9. von Mehren M, Kane JMI, Benjamin RS et al. NCCN Clinical Practice Guidelines in Soft Tissue Sarcoma. Version 4.2019 (2019). www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
Google Scholar
10. Dangoor A, Seddon B, Gerrand C, Grimer R, Whelan J, Judson I. UK guidelines for the management of soft tissue sarcomas. Clin. Sarcoma Res. 6, 20 (2016).
MedlineGoogle Scholar
11. Casali PG, Abecassis N, Aro HT et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29(Suppl. 4), iv268–iv269 (2018).
Medline CASGoogle Scholar
12. Gelhorn HL, Tong S, McQuarrie K et al. Patient-reported symptoms of tenosynovial giant cell tumors. Clin. Ther. 38(4), 778–793 (2016). • Describes patient-reported symptoms of TGCT and identifies patient-reported outcomes instruments for assessing the effects of TGCT treatments.
MedlineGoogle Scholar
13. Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr. Opin. Oncol. 23(4), 361–366 (2011).
Medline CASGoogle Scholar
14. Tap WD, Wainberg ZA, Anthony SP et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N. Engl. J. Med. 373(5), 428–437 (2015). •• Reports results from a Phase I trial of pexidartinib in patients with TGCT.
Medline CASGoogle Scholar
15. Cassier PA, Gelderblom H, Stacchiotti S et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer 118(6), 1649–1655 (2012).
Medline CASGoogle Scholar
16. Gelderblom H, Cropet C, Chevreau C et al. Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, Phase 2 trial. Lancet Oncol. 19(5), 639–648 (2018).
Medline CASGoogle Scholar
17. Mastboom MJL, Palmerini E, Verspoor FGM et al. Surgical outcomes of patients with diffuse-type tenosynovial giant-cell tumours: an international, retrospective, cohort study. Lancet Oncol. 20(6), 877–886 (2019). •• Provides a comprehensive overview of TGCT and assesses the clinical profile and management of the disease.
MedlineGoogle Scholar
18. Lin F, Qian C, Kwong J. Treatment patterns of tenosynovial giant cell tumor among commercially insured patients: a retrospective claims analysis. J. Clin. Oncol. 36(Suppl. 15), e18737–e18737 (2018).
Google Scholar
19. Daiichi-Sankyo Company Limited. TURALIO™ full prescribing information (2020). https://dsi.com/prescribing-information-portlet/getPIContent?productName=Turalio&inline=true
Google Scholar
20. West RB, Rubin BP, Miller MA et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad. Sci. USA 103(3), 690–695 (2006).
Medline CASGoogle Scholar
21. Patwardhan PP, Surriga O, Beckman MJ et al. Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin. Cancer Res. 20(12), 3146–3158 (2014).
Medline CASGoogle Scholar
22. Ao JY, Zhu XD, Chai ZT et al. Colony-stimulating factor 1 receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma. Mol. Cancer Ther. 16(8), 1544–1554 (2017).
Medline CASGoogle Scholar
23. Yin O FJ, Polhamus D, Zahir H et al. Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor (TGCT). Presented at: Tenth American Conference on Pharmacometrics (ACoP10). FL, USA (2019). Poster W-017.
Google Scholar
24. Yin O, Kang J, Knebel W et al. Population pharmacokinetic analysis of pexidartinib in healthy subjects and patients with tenosynovial giant cell tumor (TGCT) or other solid tumors. Presented at: Tenth American Conference on Pharmacometrics (ACoP10). FL, USA (2019). Poster M-028.
Google Scholar
25. Lin C-C, Guo J, Tap WD et al. Population pharmacokinetic analysis for comparison of pexidartinib exposure in Asian and non-Asian patients. Presented at: 2019 Connective Tissue Oncology Society (CTOS) Annual Meeting. Tokyo, Japan (2019). Abstract 3253949.
Google Scholar
26. Peterfy C, Tap WD, DiCarlo J et al. MRI assessment of oral CSF1 receptor inhibition with PLX3397 for tenosynovial giant cell tumor using novel modified RECIST, tumor volume scoring and tissue damage scoring methods. Presented at: Orthopaedic Research Society Annual Meeting 2015. NV, USA (2015). Poster 2028.
Google Scholar
27. Tap WD, Gelderblom H, Palmerini E et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised Phase 3 trial. Lancet 394(10197), 478–487 (2019). •• Reports results from the Phase III registrational study of pexidartinib in patients with TGCT.
Medline CASGoogle Scholar
28. Tap WD, Gelhorn HL, Ye X et al. Improvement in patient-reported pain in a Phase iii trial of pexidartinib (PLX3397) among patients with tenosynovial giant cell tumor (TGCT). Presented at: 2019 Connective Tissue Oncology Society (CTOS) Annual Meeting. Tokyo, Japan (2019).
Google Scholar
29. van de Sande M, Staals E, Gronchi A et al. Pexidartinib for advanced tenosynovial giant cell tumor: patient subgroup results from the Phase 3 ENLIVEN study. Presented at: 2019 European Musculo-Skeletal Oncology Society (EMSOS) Annual Meeting. Florence, Italy (2019). Abstract 2250.
Google Scholar
30. Gelderblom H, Tap WD, Palmerini E et al. Pexidartinib for advanced tenosynovial giant cell tumor (TGCT): long-term efficacy and safety from the Phase 3 ENLIVEN and Phase 1 PLX108-01 (TGCT cohort) studies. Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. IL, USA (2019). Abstract 11042.
Google Scholar
31. Healey JH, Gelderblom H, Wagner AJ et al. Pexidartinib for locally advanced tenosynovial giant cell tumor (TGCT): overall long-term pooled efficacy and safety with characterization of hepatic adverse reactions (ARs) from ENLIVEN and other studies. Presented at: 2019 Musculo Skeletal Tumor Society (MSTS) Annual Meeting. OR, USA (2019). Presentation 46.
Google Scholar
32. Healey JH, Gelderblom H, Wagner AJ et al. Pexidartinib for locally advanced tenosynovial giant cell tumor: overall long-term pooled efficacy and safety with characterization of hepatic adverse reactions from ENLIVEN and other studies. Presented at: 2019 Connective Tissue Oncology Society (CTOS) Annual Meeting. Tokyo, Japan (2019). Abstract 3208650.
Google Scholar
33. Butowski N, Colman H, De Groot JF et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium Phase II study. Neuro. Oncol. 18(4), 557–564 (2016).
MedlineGoogle Scholar
34. Colman H, Raizer JJ, Walbert T et al. Phase 1b/2 study of pexidartinib (PEX) in combination with radiation therapy (XRT) and temozolomide (TMZ) in newly diagnosed glioblastoma. J. Clin. Oncol. 36(Suppl. 15), 2015–2015 (2018).
Google Scholar
35. Wesolowski R, Sharma N, Reebel L et al. Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. Ther. Adv. Med. Oncol. 11, 1758835919854238 (2019).
MedlineGoogle Scholar
36. Manji GA, Tine BAV, Lee SM et al. Phase 1 combination therapy with pexidartinib (PEX) and sirolimus (S) to target tumor-associated macrophages in pigmented villonodular synovitis, malignant peripheral nerve sheath tumors, and other soft tissue sarcomas. J. Clin. Oncol. 37(Suppl. 15), 11055–11055 (2019).
Google Scholar
37. Rosenbaum E, Kelly C, D'Angelo SP et al. A Phase I study of binimetinib (MEK162) combined with pexidartinib (PLX3397) in patients with advanced gastrointestinal stromal tumor. Oncologist 24(10), e1309–e1983 (2019).
Medline CASGoogle Scholar
38. Wagner AJ TW, Shields AF, Patnaik A et al. A Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of PLX9486 alone and in combination (combo) with the KIT inhibitors pexidartinib (pexi) or sunitinib (su) in patients (Pts) with advanced solid tumors and gastrointestinal stromal tumor (GIST). J. Clin. Oncol. 36(Suppl.15), 11509 (2018).
Google Scholar
39. Hittson L, Glod J, Amaya M, Derdak J, Widemann BC, Kaplan R. Phase I study of pexidartinib (PLX3397) in children with refractory leukemias and solid tumors including neurofibromatosis type I (NF1) related plexiform neurofibromas (PN). J. Clin. Oncol. 35(Suppl. 15), 10546–10546 (2017).
Google Scholar
40. Zahir H, Darpo B, Gu X et al. A concentration-QTc analysis to determine the effect of pexidartinib on the QTc interval. Presented at: 2019 American College of Clinical Pharmacology (ACCP) Annual Meeting. IL, USA (2019).Poster 073.
Google Scholar
41. Bauer S, Lewis JH HG, van de Sande M et al. Pexidartinib (Pex) for locally advanced tenosynovial giant cell tumour (TGCT): characterization of hepatic adverse reactions (ARs). Presented at: ESMO Congress 2019. Barcelona, Spain (2019).Poster 1696P.
Google Scholar
42. Radi ZA, Koza-Taylor PH, Bell RR et al. Increased serum enzyme levels associated with kupffer cell reduction with no signs of hepatic or skeletal muscle injury. Am. J. Pathol. 179(1), 240–247 (2011).
MedlineGoogle Scholar
43. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5(1), 53 (2017).
MedlineGoogle Scholar
44. Piawah S, Hyland C, Umetsu SE, Esserman LJ, Rugo HS, Chien AJ. A case report of vanishing bile duct syndrome after exposure to pexidartinib (PLX3397) and paclitaxel. NPJ Breast Cancer 5, 17 (2019).
MedlineGoogle Scholar
45. ClinicalTrials.gov. A Phase I study to assess safety, pharmacokinetics, and pharmacodynamics of PLX3397 in patients with advanced, incurable, solid tumors in which the target kinases are linked to disease pathophysiology. ClinicalTrials.gov, number NCT01004861. https://clinicaltrials.gov/ct2/show/NCT01004861
Google Scholar
46. ClinicalTrials.gov. Phase 3 study of pexidartinib for pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS) (ENLIVEN). ClinicalTrials.gov, number NCT02371369. https://clinicaltrials.gov/ct2/show/NCT02371369
Google Scholar
47. ClinicalTrials.gov. Tenosynovial giant cell tumors (TGCT) observational platform project (TOP). ClinicalTrials.gov, number NCT02948088. https://clinicaltrials.gov/ct2/show/NCT02948088
Google Scholar
48. ClinicalTrials.gov. PLX3397 KIT in Acral aNd mucOsal Melanoma (PIANO). ClinicalTrials.gov, number NCT02071940. https://clinicaltrials.gov/ct2/show/NCT02071940
Google Scholar
49. ClinicalTrials.gov. Evaluation of safety and activity of an anti-PDL1 antibody (DURVALUMAB) combined with CSF-1R TKI (PEXIDARTINIB) in patients with metastatic/advanced pancreatic or colorectal cancers (MEDIPLEX). ClinicalTrials.gov, number NCT02777710. https://clinicaltrials.gov/ct2/show/NCT02777710
Google Scholar
50. ClinicalTrials.gov. PLX3397 in children and young adults with refractory leukemias and refractory solid tumors including neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN). ClinicalTrials.gov, number NCT02390752. https://clinicaltrials.gov/ct2/show/NCT02390752
Google Scholar
51. ClinicalTrials.gov. Phase Ib/II study of PLX 3397 and eribulin in patients with metastatic breast cancer. ClinicalTrials.gov, number NCT01596751. https://clinicaltrials.gov/ct2/show/NCT01596751
Google Scholar
52. ClinicalTrials.gov. A Phase 1b/2 study of PLX3397 + radiation therapy + temozolomide in patients with newly diagnosed glioblastoma. ClinicalTrials.gov, number NCT01790503. https://clinicaltrials.gov/ct2/show/study/NCT01790503
Google Scholar
53. ClinicalTrials.gov. PLX3397 plus sirolimus in unresectable sarcoma and malignant peripheral nerve sheath tumors (PLX3397). ClinicalTrials.gov, number NCT02584647. https://clinicaltrials.gov/ct2/show/NCT02584647
Google Scholar
54. ClinicalTrials.gov. PLX9486 as a single agent and in combination with PLX3397 or PLX9486 with sunitinib in patients with advanced solid tumors. ClinicalTrials.gov, number NCT02401815. https://clinicaltrials.gov/ct2/show/NCT02401815
Google Scholar
55. ClinicalTrials.gov. A study of MEK162 (Binimetinib) in combination with pexidartinib in patients with advanced gastrointestinal stromal tumor (GIST). ClinicalTrials.gov, number NCT03158103. https://clinicaltrials.gov/ct2/show/NCT03158103
Google Scholar

Vol. 16, No. 29

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History

Received 26 May 2020

Accepted 23 June 2020

Published online 23 July 2020

Published in print October 2020

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Author contributions

Both authors contributed to the drafting and critical revision of this manuscript and gave final approval to submit it for publication.

Financial & competing interests disclosure

H Gelderblom: research grant to institution from Daiichi Sankyo, Inc. M van de Sande: research grant to institution from Daiichi Sankyo, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing and editorial assistance were provided by M Tradewell and H Nyce of SciFluent Communications, Inc., and were financially supported by Daiichi Sankyo.

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This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

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