Reference Detail

Ref Type

Journal Article

PMID

(28625637)

Authors

Wehler T, Thomas M, Schumann C, Bosch-Barrera J, Viñolas Segarra N, Dickgreber NJ, Dalhoff K, Sebastian M, Corral Jaime J, Alonso M, Hynes SM, Lin J, Hurt K, Bence Lin A, Calvo E, Paz-Ares L

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Lung cancer (Amsterdam, Netherlands)	108		2017 Jun	212-216	Lung Cancer

URL

Abstract Text

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/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
LY2603618	LY2603618	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LY2603618		LY-2603618\|Rabusertib	CHK1 Inhibitor 17	Rabusertib (LY2603618) is a small molecule that inhibits CHK1, which may lead to disruption of DNA synthesis, early mitosis, and apoptosis, and may increase tumor cell sensitivity to chemotherapeutics (PMID: 24114124, PMID: 28625637).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References