Safety, efficacy and pharmacokinetics of VC004, a highly selective next-generation pan-TRK inhibitor, in patients with locally advanced/metastatic solid tumors.
Authors: Zhou Shengyu , Wang Guowen , Qian Jun , Li Xian-an , Wang Jiaqiang , Luo Suxia , Li Zhendong , Wei Ting , Li Yongsheng , Zhang Qingyuan , Chen Yu , Liu Yongqiang , Gong Yanchun , Wu Yong , Lai Xiaojuan , Shi Yuankai 
Published: June 2024

3101 Background: VC004 is a next-generation TRK tyrosine kinase inhibitor (TKI) developed to overcome acquired resistance to first-generation TRK TKIs in NTRK fusion-positive cancers for more durable response. It potently inhibited wildtype TRK A/B/C and mutants in tumor models. NCT04614740 is a first-in-human, multi-center, open-label, phase 1/2 clinical trial evaluating VC004 in locally advanced/metastatic solid tumors. Methods: The phase 1 study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, 4 dose levels (25, 50, 100, and 200 mg BID) of VC004 were tested using a "3+3" design in patients (pts) having failed or ineligible for standard therapy. In Part 2, NTRK fusion-positive pts were treated at 25, 50 and 75 mg BID. The primary endpoints were to evaluate safety and determine MTD/RP2D of VC004. Preliminary efficacy and PK were also assessed. Results: From Dec 4, 2020 to Dec 31, 2023, 51 pts were treated, 16 in Part 1 and 35 in Part 2. The mean (SD) age was 45.5 (16.4) years for Part 1 and 52.6 (13.6) years for Part 2. ECOG PS was 1 for all pts in Part 1 and 0-1 for 97.1% (34/35) of the pts in Part 2. Twelve (34.3%) of the pts in Part 2 had received ≥ 3 prior lines of therapy and 7 were TRK TKI-pretreated. Treatment-related adverse events (TRAEs) occurred in 98.0% (50/51) of the pts and most were grade 1-2. No fatal TRAEs occurred. Four (7.8%) pts reported treatment-related severe adverse events which were all recovered/resolved. TRAEs leading to dose reduction, interruption and permanent discontinuation occurred in 1 (2.0%), 12 (23.5%) and 1 (2.0%) pts, respectively. The most common TRAEs (≥20%) included dizziness, weight increased, hypertriglyceridemia, anemia, alanine aminotransferase increased, aspartate aminotransferase increased, hypercholesterolemia, and hyperuricemia, consistent with the safety profile of first-generation TRK TKIs. At 50 mg BID, the selected RP2D, confirmed and confirmed + unconfirmed overall response rates were 65.4% (95% CI, 44.3 to 82.8) and 80.8% (95% CI, 60.6 to 93.4) in the TRK TKI-naïve pts (n=26) per RECIST v1.1. Target lesions disappeared in 1 pt. Two of the 3 pts who had progressed on TRK TKIs previously had tumor reduction, 1 of which achieved partial response (39.6%). Of the 8 pts with brain metastasis at baseline, intracranial lesions shrank by 48.4% and 25% for 2 pts, respectively, and non-target lesions disappeared in 2 pts after 4 months of treatment. Median duration of response (DoR) or progression-free survival has not been reached but 23.8% of the TRK TKI-naïve pts had maintained response for ≥ 12 months (DoR up to 27.6 months). The plasma exposure to VC004 increased in a dose proportional manner over the dose range examined in both parts. Conclusions: VC004 showed a manageable safety profile and promising efficacy against NTRK fusion-positive tumors. The phase 2 study has recently been initiated. Clinical trial information: NCT04614740 .