Background

cGvHD is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. CSF-1R-driven macrophage signaling plays a critical role in fibrosis, which is a hallmark of cGvHD. Thus, blocking this signaling may be beneficial in treating cGvHD. Pimicotinib (Pimi), an oral, highly selective and potent small molecule CSF-1R inhibitor has demonstrated efficacy in macrophage-driven tenosynovial giant cell tumor, may also have potential in cGvHD treatment (Tx). Herein, we report the preliminary results from the first study evaluating an oral CSF-1R inhibitor Pimi in the Tx of cGvHD (NCT06186804).

Methods

This is a phase II, open-label, multicenter study to evaluate safety and efficacy of Pimi in adult cGvHD patients (pts) who have failed after ≥1 prior line of therapy. The study comprises two parts, Part A includes dose-escalation and backfill cohorts, aiming to establish the recommended doses (RDs), and additional pts will be treated under the RDs in Part B. All pts receive Pimi QD in repeated 28-day cycles. The primary efficacy endpoint is the overall response rate (ORR) over six months, defined per the 2014 NIH Consensus Criteria. Secondary endpoints include safety, pharmacokinetics (PK), pharmacodynamics (PD), duration of response (DOR), time to response (TTR), Lee Symptom Scale (LSS) score, and failure-free survival (FFS).

Results

As of June 21, 2024, 28 pts were enrolled. In Part A, four dose levels were evaluated including 5 mg (n=1), 10 mg (n=3), 20 mg (n=13, including 9 pts from backfill cohort), and 25 mg (n=3). No dose-limiting toxicities were observed, 20 mg was selected as the RD, thereafter 8 pts were enrolled in Part B.

Pts had a median age of 34.5 years (range, 20-63), 60.7% were female. The median time from cGvHD diagnosis to enrollment was 20.2 months (range, 2.7-101.7). 64.3% of pts had severe cGvHD. Pts had received a median of 4 prior systemic treatment (range, 1-9), including ruxolitinib (67.9%, n=19), ibrutinib (10.7%, n=3), and belumosudil (3.6%, n=1); with a median of 4 organs involved at baseline (range, 2-7). At data cutoff, median Tx duration was 8.4 weeks (range, 0.3-45.6) and 71.4% (20/28) pts remained on Tx.

In response assessable pts, responses were observed across all dose levels 5mg (1/1, 100%), 10mg (2/3, 66.7%), 20mg (11/19, 57.9%) and 25mg (1/3, 33.3%) with an overall 57.7% (15/26) ORR in total. ORRs were similar between moderate (66.7% [6/9]) and severe cGvHD pts (52.9% [9/17]). Responses were also seen in pts who prior received ibrutinib (33.3% [1/3]) and ruxolitinib (55.6% [10/18]) Tx. Specific organ responses were observed in nearly all evaluated organs. The median TTR was 4 weeks. Median DOR and FFS were not reached. 38.5% (10/26) pts reported a ≥ 7-points improvement in the LSS score.

At the 20 mg, responses were reported not only in inflammation-dominated organs, including mouth (44.4%, 4/9), eyes (30.8%, 4/13) and liver (8.3%, 1/12), but also in fibrosis-dominated organs, including joints/fascia (60%, 6/10), skin (21.4%, 3/14, 1 scleroderma remission) and esophagus (16.7%, 1/6). Additionally, improvements in pulmonary function tests were observed over time.

Pimi was well tolerated, treatment emergent adverse events (TEAEs), grade ≥3 TEAEs, and serious TEAEs occurred in 78.6%, 35.7% and 21.4% of pts. The most common TEAEs (≥20%) including AST increased (39.3%), upper respiratory tract infection (32.1%), ALT increased (25%), GGT increased (21.4%). Grades ≥3 TEAEs (≥5%) including pneumonia (10.7%, n=3) and hypertension (7.1%, n=2). In dose levels ≥20 mg, several serum enzyme elevations were observed, predominantly grade 1 and characterized by a slowly accumulative increase before reaching stable. These elevations were not associated with liver or other end-organ injuries and typically required no intervention. The pattern of these elevations is consistent with other CSF-1R inhibitors, suggesting a liver macrophage-mediated clearance of these enzymes.

The PK profile in cGVHD pts was similar to that of other indications. Significant PD changes including decrease in non-classical monocytes and increase in plasma CSF-1 levels were observed after Pimi Tx.

Conclusions

The efficacy and safety results are in favor of Pimi as a promising Tx option for cGvHD, addressing significant unmet medical needs, especially in heavily pre-treated pts. Further explorations are warranted to confirm these findings with long-term outcomes.

Disclosures

No relevant conflicts of interest to declare.

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2024
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