Abstract
WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.
Highlights
Crizotinib, a tyrosine kinase inhibitor (TKI) targeting anaplastic lymphoma kinase (ALK), receptor tyrosine kinase 1 (ROS1) as well as MET, was the first drug approved by the Food and Drug Administration (FDA) for patients with advanced ALK-rearranged or
Of all the 153 patients in full analysis set (FAS), 140 (91.5%) patients were with adenocarcinoma while 4 (2.6%) patients were with squamous cell carcinoma
A total of 150 patients were tested for ALK rearrangement status and 80 patients were tested for ROS1 rearrangement status
Summary
Gene fusions that lead to overexpression of anaplastic lymphoma kinase (ALK) protein, originally identified in anaplastic large cell lymphoma, occurred in 3–7% of unselected non-small cell lung cancer (NSCLC) patients.[1,2] Chromosomal rearrangements involving ROS proto-oncogene, receptor tyrosine kinase 1 (ROS1), another therapeutically tractable oncogenic driver, have been found in 1–2% of patients with NSCLC.[3,4] Both ALK and ROS1 rearrangements can led to expression of oncogenic fusion proteins with constitutive kinase activity, with each defining a specific molecular subset of NSCLC which displays high sensitivity to ALK or ROS1 inhibition. In cell-line models, WX-0593 had superior inhibitory activity against the ALK- resistant mutants (including ALK-G1202R mutants), ROS1 wild-type and mutants resistant to crizotinib (except for ROS1-G2032R and ROS1-L1951R mutants) at therapeutic concentration when administered 180 mg, once daily (Supplementary Material). These preclinical results indicated that WX-0593 might be a potentially potent therapeutic agent for patients with ALK- or ROS1-rearranged NSCLC. We report the results of the first-in-human (FIH) phase 1 study of WX-0593, which was conducted to explore the maximum tolerated dose (MTD), safety, antitumor activity, and pharmacokinetics (PK) of WX-0593 in advanced NSCLC patients with ALK or ROS1 rearrangement
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