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 75mg/m(2) cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m(2) pemetrexed on Day 1 (both arms) and 275mg 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.
- Wehler, T.
- Thomas, M.
- Schumann, C.
- Bosch-Barrera, J.
- Vinolas Segarra, N.
- Dickgreber, N. J.
- Dalhoff, K.
- Sebastian, M.
- Corral Jaime, J.
- Alonso, M.
- Hynes, S. M.
- Lin, J.
- Hurt, K.
- Bence Lin, A.
- Calvo, E.
- Paz-Ares, L.
Keywords
- Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
- Carcinoma, Non-Small-Cell Lung/*drug therapy/mortality/*pathology
- Checkpoint Kinase 1/antagonists & inhibitors
- Cisplatin/administration & dosage
- Disease Progression
- Female
- Humans
- Induction Chemotherapy
- Kaplan-Meier Estimate
- Lung Neoplasms/*drug therapy/mortality/*pathology
- Maintenance Chemotherapy
- Male
- Pemetrexed/administration & dosage
- Phenylurea Compounds/administration & dosage
- Pyrazines/administration & dosage
- Treatment Outcome
- *Checkpoint kinase 1
- *Cisplatin
- *ly2603618
- *Non-small cell lung cancer
- *Pemetrexed