Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT

Abstract

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.

Patients and methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies.

Results: Ninety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study.

Conclusions: These results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.

Trial registration: ClinicalTrials.gov NCT01004861.

Figure 1.

Tumor response assessed by local RECIST, treatment duration, and disposition for patients with TGCT. Data cutoff: January 31, 2018. Each line represents 1 patient in the study. Patients received an initial dose of 1,000 mg/day. Treatment duration in months is calculated as treatment duration in days divided by 30.4167. RECIST, Response Evaluation Criteria in Solid Tumors; TGCT, tenosynovial giant cell tumor.

Figure 2.

Maximum percentage change from baseline in TVS for patients with TGCT. The graph shows the maximum percentage change in TVS score from baseline by individual patient for the 31 MRI-evaluable patients with TGCT. Data cutoff: January 31, 2018. CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TGCT, tenosynovial giant cell tumor; TVS, tumor volume score.

Figure 3.

Mean change from baseline: pain by NRS for patients with TGCT. Data cutoff: January 31, 2018. n drops below 10 after cycle 39, and the results are not shown. NRS, numeric rating scale; TGCT, tenosynovial giant cell tumor.

Figure 4.

TGCT biopsy-targeted RNA-seq identified abnormal CSF1 transcripts. Ten specimens showed evidence of alteration at exon 8 or within the 3′UTR, with 6 strong-evidence events (A) and 4 low-confidence events (B). CA11, carbonic anhydrase 11; CD101, CD101 molecule; CD99, CD99 molecule (Xg blood group); CDH13, cadherin 13; Chr, chromosome; CSF1, colony-stimulating factor 1; ENG, endoglin; FN1, fibronectin 1; SM, sample; TGCT, tenosynovial giant cell tumor; TM, transmembrane; UTR, untranslated region.

Figure 5.

CSF1 RNA expression in TGCT relative to lung. Relative to the lung RNA control library, all 25 TGCT libraries had higher CSF1 expression; all 25 exceeded 2× lung CSF1 expression (A–C). There was no obvious expression difference between the distinct fusion categories. CSF1, colony-stimulating factor 1; SM, sample; TGCT, tenosynovial giant cell tumor; WT, wild-type.