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

doi:10.1016/j.lungcan.2016.04.014

Lung Cancer

Volume 99, September 2016, Pages 23-30

https://doi.org/10.1016/j.lungcan.2016.04.014 Get rights and content

Highlights

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Sonidegib with etoposide/cisplatin in newly diagnosed SCLC patients is safe and effective.
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Creatine kinase elevations were noted, similar to other studies evaluating sonidegib.
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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.

Introduction

Aberrant activation of the Hedgehog (Hh) pathway has been implicated in the initiation, maintenance and proliferation of SCLC. Hh signaling is essential in early stromal development and branching morphogenesis of the embryonic airways [1]. SCLC appears to be a relatively undifferentiated airway epithelial tumor that may recapitulate aspects of early lung development [2]. Expression of the ligand, Sonic Hh, and transcriptional factor, Gli-1, are upregulated relative to normal airway epithelium in SCLC [3]. Analogous to its role in early lung formation, Hh signaling has been implicated in SCLC initiation [4]. Constitutive activation of the pathway promotes tumor progression, and deletion of Smo, the seven-transmembrane receptor, suppresses initiation and progression in murine models of SCLC [3], [4]. Pharmacologic blockade of Smo inhibits the growth of both mouse and human SCLC [3], [4]. Following chemotherapy, Hh pathway inhibition may delay or prevent recurrence of residual disease in multiple murine SCLC models [4], [5].

Hh signaling has a role in regulating stem cell maintenance and differentiation, which has been suggested to parallel its role in tumorigenesis. Inhibition of Hh signaling in both in vitro and in vivo models has been associated with a loss of tumorigenic potential and improved survival across multiple tumor models [6], [7], [8], [9], [10]. In SCLC cell lines, Hh inhibition reportedly decreases cell growth primarily via a progenitor population [11]. These data support a model in which clonogenic recurrence of SCLC is dependent on a subset of chemotherapy-resistant progenitor cells and which may depend on the Hh developmental pathway.

The addition of a Hh inhibitor to cisplatin and etoposide (EP) may promote a more sustained treatment response and ultimately improve clinical outcomes in SCLC. As a test of this hypothesis, we undertook this phase I study to evaluate sonidegib [LDE225, N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)-1,1′-[biphenyl]-3-carboxamide diphosphate], an oral Smo antagonist, and to determine its maximum tolerated dose (MTD) in combination with EP in newly diagnosed extensive stage SCLC (ES-SCLC) patients.

Section snippets

Materials and methods

This was a single institution, open label Phase I study [NCT01579929], reviewed and approved by the Institutional Review Board. All patients provided written informed consent.

Patient characteristics

Between March 2012 and September 2014, 15 patients with untreated ES-SCLC were enrolled on this phase I study. Baseline characteristics are listed in Table 1.

Dose escalation and maximum tolerated dose

The dose escalation scheme is summarized in Fig. 1. At the first dose level, two patients experienced a DLT, including one of grade 3 nausea and one of grade 3 febrile neutropenia. This led to a dose de-escalation to 200 mg daily of sonidegib, as pre-specified in the protocol, with no further DLTs observed in the two patients enrolled in

Discussion

The primary goal of this Phase I study was to establish the safety profile and recommended phase II dose of the Hh inhibitor sonidegib when given with standard of care first-line cisplatin and etoposide in patients with newly diagnosed ES-SCLC, which proved to be cisplatin 60 mg/m² on day 1 with etoposide 120 mg/m² daily on days 1–3, and sonidegib 800 mg daily on days 1–21 of a 21-day cycle. Pharmacokinetic analyses did not suggest that EP had a substantial effect on sonidegib exposure. Based on

Conflict of interest

M. Catherine Pietanza—Dr. Pietanza reports employment from Merck. Previously reports personal fees from Genentech, personal fees from CelGene Corp, personal fees from Abbvie, personal fees from Clovis Oncology, grants and personal fees from Novartis, grants and personal fees from Bristol Myers Squibb, grants from Stemcentrx, Inc, grants from OncoMed Pharmaceuticals, Inc.

Lee M. Krug—Dr. Krug reports employment from Bristol-Myers Squibb.

Cami S. Sima—Dr. Sima reports employment from

Funding

This research was funded, in part, through Novartis and the National Institute of Health(NIH)/National Cancer Institute (NCI) Cancer Center Support Grant (P30CA008748).

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This conformational change subsequently removes SMO inhibition, which further leads to the activation of transcription factor GLI and its entry to the cell nucleus, which regulates cell growth, proliferation, and differentiation (Robbins et al., 2012). Abnormal activation of the hedgehog signaling pathway has been found in various human cancers (McMillan and Matsui, 2012; Pietanza et al., 2016; Villegas et al., 2016; Xu et al., 2014). Hedgehog signaling plays a crucial role in tumor development, tumor growth, and controlling residual cancer cells after treatment (Dierks et al., 2008; Zhao et al., 2009).
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¹: Present affiliation: Merck Research Laboratories, Rahway, NJ, United States.

View full text

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

Highlights

Abstract

Objectives

Materials and methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Patient characteristics

Dose escalation and maximum tolerated dose

Discussion

Conflict of interest

Funding

Curr. Biol.

Cancer Cell

Eur. J. Cancer

J. Mol. Diagn.

Lancet Oncol.

Cancer Cell

Am. J. Pathol.

J. Thorac. Oncol.

Ann. Oncol.

Predicting survival within the lung cancer histopathological hierarchy using a multi-scale genomic model of development

PLoS Med.

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer

Nature

A crucial requirement for Hedgehog signaling in small cell lung cancer

Nat. Med.

A novel HH pathway inhibitor, IPI-926, delays recurrence post-chemotherapy in a primary human SCLC xenograft model

Hedgehog signaling: progenitor phenotype in small-cell lung cancer

Cell Cycle

Targeting Hedgehog—a cancer stem cell pathway

Clin. Cancer Res.

Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia

Nature