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

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: 400mg and 800mg daily, with 200mg 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. 800mg 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 800mg 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.

Keywords: Circulating tumor cells; Hedgehog inhibitor; Hedgehog pathway; LDE225; SOX2 amplification; Small cell lung cancer.

Fig. 1

Dose Escalation Scheme and Dose Limiting Toxicities (DLT). Diagram describes the dose escalation with associated toxicities in each cohort, if any. Sonidegib was administered orally once daily with etoposide/cisplatin administered every 3 weeks. A study oversight committee reviewed the data and febrile neutropenia was determined to be secondary to etoposide/cisplatin and not sonidegib, leading to exclusion of this adverse event from the DLT definition. The maximum tolerated dose was determined to be 800 mg after treating 6 patients.

Fig. 2

Spider Diagram. Treatment course of all 15 patients documented (identified as numbers 1–15 along the y-axis) including dose reductions. One patient remains on study at the time of the manuscript preparation.

Fig. 3

Waterfall plot. Only 14 patients are evaluable (one patient died of an unrelated cause one week after cycle 2). The individual patient identification number, along the x-axis, labels its respective bar and corresponds to patients 1–15 in Fig. 2. The response rate was 79% (11 out of 14, 95% CI: 49–95%).

Fig. 4

Mean sonidegib plasma concentration-time curve for each patient on study. Steady state was reached by cycle 7 with a concentration trough of 1080 ng/ML. Two patients treated at the 800 mg dose had the highest sonidegib plasma concentrations; neither required dose reductions.