A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer

This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY + Pem + Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status <= 1. Patients were randomized (2:1) to LY + Pem + Cis or pemetrexed and cisplatin (Pem + Cis). Induction therapy comprised four 21-day cycles of 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin on Day 1 (both arms) and 275 mg LY2603618 on Day 2 (LY + Pem + Cis arm). Maintenance therapy comprised 500 mg/m(2) pemetrexed on Day 1 (both arms) and 275 mg LY2603618 on Day 2 (LY + Pem + Cis arm) until disease progression. The primary endpoint was progression-free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY + Pem + Cis arm. Sixty-two patients were enrolled (LY + Pem + Cis, n = 39; Pem + Cis, n =23). Bayesian and frequentist analysis demonstrated superior PFS in the LY + Pem + Cis arm vs the Pem + Cis arm (median [90% confidence interval]: LY + Pem + Cis, 4.7 months [4.-7.1]; Pem + Cis, 1.5 months [1.3-2.9]; P = 0.022). Seven patients in the LY+ Pem + Cis arm (vs 0 in the Pem + Cis arm) experienced serious thromboembolic events: pulmonary embolism (n = 5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618 + Pem + Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials. gov Identifier: NCT01139775. (C) 2017 Published by Elsevier Ireland Ltd.