A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer. (September 2016)

• Record Type: Journal Article
• Authors: Pietanza, M. Catherine; Litvak, Anya M.; Varghese, Anna M.; Krug, Lee M.; Fleisher, Martin; Teitcher, Jerrold B.; Holodny, Andrei I.; Sima, Cami S.; Woo, Kaitlin M.; Ng, Kenneth K.; Won, Helen H.; Berger, Michael F.; Kris, Mark G.; Rudin, Charles M.
• Is Part Of: Lung cancer. Volume 99(2016)
• Page Start: 23
• Page End: 30
• Publication Date: 2016-09
• Subjects: Small cell lung cancer -- LDE225 -- Hedgehog pathway -- Hedgehog inhibitor -- Circulating tumor cells -- SOX2 amplification; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2016.04.014
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Sonidegib with etoposide/cisplatin in newly diagnosed SCLC patients is safe and effective. Creatine kinase elevations were noted, similar to other studies evaluating sonidegib. Genomic characterization of an exceptional responder reveals SOX2 amplification on 3q26. Abstract: Objectives: The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC. Materials and methods: Patients received 4–6 21-day cycles of etoposide/cisplatin with daily sonidegib. Patients with response or stable disease were continued on sonidegib until disease progression or unacceptable toxicity. Two dose levels of sonidegib were planned: 400 mg and 800 mg daily, with 200 mg daily de-escalation if necessary. Next generation sequencing was performed on available specimens. Circulating tumor cells (CTCs) were quantified at baseline and with disease evaluation. Results: Fifteen patients were enrolled. 800 mg was established as the recommended phase II dose of sonidegib in combination with etoposide/cisplatin. Grade 3 or greater toxicities included: anemia (n = 5), neutropenia (n = 8), CPK elevation (n = 2), fatigue (n = 2), and nausea (n = 2). Toxicity led to removal of one patient from study. Partial responses were confirmed in 79% (11/14; 95% CI: 49–95%). One patient with SOX2 amplification remains progression-free on maintenance sonidegib after 27 months. CTC count, at baseline, was associated with the presence of liver metastases and after 1 cycle of therapy, with overall survival. Conclusions: Sonidegib 800 mg daily was the MTD when administered with EP. Further genomic characterization of exceptional responders may reveal clinically relevant predictive biomarkers that could tailor use in patients most likely to benefit.