CSF-1R targeted therapies for tenosynovial giant cell tumour: Current landscape and future developments

The colony-stimulating factor 1 receptor (CSF-1R) inhibitor pexidartinib is an effective long-term treatment option for adult patients with advanced tenosynovial giant cell tumour (TGCT), but adverse events (AEs), especially liver toxicities, need to be closely monitored. While off-label use of imatinib may be considered in advanced TGCT, development of future-generation CSF-1R inhibitors with an improved AE profile is highly awaited.

“At median follow-up of 39 months, the overall response rate [ORR] with pexidartinib was high, at 60 percent as assessed by the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1, and 65 percent as assessed by tumour volume score [TVS; defined as ≥50 percent reduction in tumour size]. The median duration of response [DoR] was 46.8 months in a pooled analysis of three pexidartinib-treated TGCT cohorts,” reported Dr Tom Wei-Wu Chen of National Taiwan University Cancer Center, Taiwan, at the 4th Chinese University of Hong Kong (CUHK) Sarcoma Masterclass. [Cancer 2021;127:884-893]

The pooled analysis included 130 pexidartinib-treated patients (median age, 45 years; disease location in knee, 57 percent; ≥1 prior surgery, 59 percent; prior systemic therapy, 12 percent) with unresectable and symptomatic TGCT from the phase I PLX108-01 first-in-human extension study (n=39) and multicentre phase III ENLIVEN study (randomized cohort, n=61; crossover cohort, n=30). Treatment-emergent AEs (TEAEs) were mostly of low grade even with long-term treatment. The most common TEAEs were hair colour change (75 percent), fatigue (61 percent), nausea (47 percent), and arthralgia (39 percent). Grade ≥3 increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were reported in 8 percent and 10 percent of the patients, respectively. 

“DCC-3014 is another highly specific, oral CSF-1R inhibitor which exhibits nanomolar potency for CSF-1R. Results of a phase I/II study [dose-escalation phase] of DCC-3014 in 25 patients with TGCT showed promising activity, [with an ORR and partial response rate of 41 percent and 78 percent, respectively],” said Chen. [Razak AA, et al, CTOS Annual Meeting 2020, abstract 38]

“These results are encouraging and support the ongoing phase I/II study [dose expansion phase] in further evaluating the safety and efficacy of DCC-3014 in TGCT patients with or without prior anti-CSF1/CSF-1R treatment. The updated data from the phase I/II study are expected to be presented in the second half of 2021,” Chen added.

“Although rates of all-grade increases in AST were similar between pexidartinib in the pool analysis [31 percent] and DCC-3014 in the phase I study [44 percent], the rate of grade 3/4 increase in ALT was higher with pexidartinib than DCC-3014 [10 percent vs 0 percent],” he continued. [Cancer 2021;127:884-893; Razak AA, et al, CTOS Annual Meeting 2020, abstract 38] 

In the pooled analysis of pexidartinib, elevated AST accounted for 92 percent of liver derangement, with 3 percent of patients experiencing mixed/cholestatic hepatoxicity, which were all reversible (recovery time, 1–7 months). [Cancer 2021;127:884-893]

“TEAEs of pexidartinib, especially liver toxicities, require close monitoring,” Chen suggested.

“Despite the availability of CSF-1R–targeted agents for TGCT, the optimal treatment duration remains unknown. Results of a long-term follow-up study of CSF-1R inhibitors in TGCT patients [n=39] showed a high progression-free survival rate [56 percent] with first-line treatment at a median follow-up of 30 months, suggesting potential benefit with long-term treatment,” Chen continued. [PLoS One 2020;15:e0233046]

“Nevertheless, treatment discontinuation with imatinib mesylate was reported in 66 percent of patients after a median of 7 months, mainly driven by patient’s own decision [24 percent] and need for surgical resection [17 percent],” Chen pointed out. [Sci Rep 2019;9:14551]

“The role of neoadjuvant therapy and systemic therapy in diffuse-type TGCT also needs to be explored further, with respect to the potential in developing treatment resistance,” Chen said.