(P 164) PRELIMINARY PHASE 1B RESULTS OF ABSK021 FOR ADVANCED TENOSYNOVIAL GIANT CELL TUMOR: SIGNIFICANT ANTITUMOR ACTIVITY AND FAVOURABLE SAFETY PROFILE

Objective: Tenosynovial giant cell tumor (TGCT) is a rare type of locally aggressive neoplasm that occurs in the joint synovia, bursa, and tendon sheath, which is mainly caused by overexpression of colony-stimulating factor 1 (CSF1). Neoplastic clones with overexpression of CSF1 recruits the CSF-1R-positive inflammatory cells into the lesion and induce local inflammation and joint destruction. Surgical resection has been the treatment cornerstone for decades, however, the high rate of recurrences in diffuse type indicated the high unmet clinical need for additional on-target treatment options. ABSK021 is an oral, highly potent and selective small-molecule antagonist of CSF-1R with minimum inhibition of c-Kit and PDGFR. Preclinical studies have demonstrated its strong in vivo efficacy in tumor models and superior selectivity against other kinases in vitro to limit off-target toxicities. Here, we report the preliminary efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) results of ABSK021 in treating Chinese advanced TGCT patients for which surgical resection would be associated with potentially worsening functional outcomes or severe morbidity.

Methods: This is an open-label, first-in-human Phase 1 study currently ongoing in China and the US (NCT04192344), which consists of a dose-escalation part (phase 1a) in patients with advanced solid tumor and an expansion part (phase 1b) to further evaluate the preliminary antitumor activity among selected tumor types, including advanced TGCT. A total of 4 doses were evaluated in phase 1a and 50mg QD was selected as the current RDE for TGCT patients in phase 1b. The primary endpoint is the objective response rate (ORR, per RECIST1.1). The secondary endpoints include overall tolerability, range of motion improvement and patient report outcome of pain and stiffness. As of June 01, 2022, twenty-seven Chinese advanced TGCT patients were enrolled in phase 1b and treated with continuous oral dosing of 50mg QD ABSK021.

Results: The patients’ median age was 44 years (range, 24-76) and 44% of them were male. The tumor location was mainly in knee (12 patients, 44%), and 18 patients (67%) had received at least one prior surgery. The overall median treatment duration was 105 days (n=20, range: 49-164), and 96.3% (26/27) of the patients remained on treatment except one consent withdrawal, while 74.0% (20/27) of them have been on-treatment ≥3 months. Most treatment-emergent adverse events (TEAEs) were Grade 1 or 2. Only 1 Grade 3 TEAE (pyrexia) was reported in 1 patient (probably irrelevant) and no other ≥Grade 3 TEAEs were reported. Most commonly reported TEAEs (≥20%) were creatine phosphokinase (CPK) increase (82%), LDH increase (74%), α-HBDH increase (63%), AST increase (56%), amylase increase (33%), ALT increase (30%), somnolence (26%) and dizziness (22%). No hair color changes or serious liver injury cases were reported. CPK and transaminase elevations were asymptomatic, on-target and quickly recovered after drug interruptions. No dose modification due to adverse event happened by the data cut-off. A total of 20 patients completed the first tumor response assessment by the investigators at week 13. Tumor regression was observed in almost all evaluated patients. The ORR was 35% (7/20 partial response; 95%CI: 15.4%-59.2%) at week 13. The median duration of response was not reached. Flexion range of knee at week 13 was assessed in 9 patients with an average improvement of 27 degrees (range: 5-58) from baseline along with a similar trend of stiffness and pain alleviation. Preliminary PK results showed that ABSK021 has a rapid absorption and relatively long elimination t1/2, which supports the QD dosing regimen. ABSK021 treatment led to notable PD marker changes, including induction of CSF1 and reduction of non-classical monocytes and C-terminal telopeptide.

Conclusion: ABSK021 has demonstrated significant antitumor activity and favourable safety profile with no apparent hepatotoxicity associated with CSF-1R inhibitors. This is the first result of an oral CSF-1R inhibitor with encouraging preliminary efficacy and safety results in Chinese advanced TGCT patients, which supports the further evaluation of ABSK021 as a promising treatment option for this disease.