Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial

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.

Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, first-in-human phase 1 study

“…The safety profile of conteltinib was similar but not identical to other ALK TKIs. The incidence of grade ≥ 3 TRAEs was 14.1% in patients who received conteltinib in this study, while 24% in crizotinib [4], 49% in ceritinib [27], 36% in brigatinib [28], 23% in ensartinib [16], 26% in alectinib [29], and 35% in iruplinalkib [17]. In terms of drug-related gastrointestinal toxicities which are some of the most frequently reported AEs in ALK TKIs, diarrhea, nausea, and vomiting occurred in 35.9-71.9% patients in this study of conteltinib, mostly were grade 1-2 and in early stages of treatments, while 39-56% in crizotinib [4], 65-82% in ceritinib [27], 11-36% in ensartinib [16], 21-53% in brigatinib [28], < 10% in alectinib [29], and 14-34% in iruplinalkib [17].…”

“…Several second-generation ALK TKIs, such as ceritinib, alectinib, brigatinib, ensartinib, and iruplinalkib, and third-generation ALK TKIs, such as lorlatinib, have been developed to overcome crizotinib resistance. These ALK TKIs have achieved clinical benefits in crizotinib-refractory patients, with a median PFS of 6.9-12.9 months [13][14][15][16][17][18]. Moreover, in ALK TKI-naïve, ALK-positive advanced NSCLC patients, these ALK TKIs are more efficacious, with a median PFS of 18.4-34.8 months [13,16,17,19,20].…”

“…These ALK TKIs have achieved clinical benefits in crizotinib-refractory patients, with a median PFS of 6.9-12.9 months [13][14][15][16][17][18]. Moreover, in ALK TKI-naïve, ALK-positive advanced NSCLC patients, these ALK TKIs are more efficacious, with a median PFS of 18.4-34.8 months [13,16,17,19,20]. Central nervous system (CNS) metastases are highly prevalent in patients with ALK-positive advanced NSCLC and the most common metastasis types in patients receiving crizotinib treatment [21].…”

“…Central nervous system (CNS) metastases are highly prevalent in patients with ALK-positive advanced NSCLC and the most common metastasis types in patients receiving crizotinib treatment [21]. Of note, the next-generation ALK TKIs have better CNS penetration, showing efficacy in controlling brain metastases [13,17,22,23].…”

Targeting ALK Rearrangements in NSCLC: Current State of the Art

“…Other novel ALK TKIs include TQ-B3139 ( 88 ), WX-0593 ( 89 ), PLB-1003 ( 90 ), SAF-189s ( 91 ), and CT-707 ( 92 ). Several other ALK TKIs are under preclinical investigation, such as gilteritinib ( 93 ) and XMU-MP-5 ( 94 ).…”