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: 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.

Exosomal Sonic Hedgehog derived from cancer‐associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma

“…In light of significance of TGFβ1, SHH, EGFR, and LEF‐1 in the proliferation and migration of cancer cells, we examined the differential expression of those proteins in the cell lysis solution of NFs and CAFs and paid our attention to the different expression of SHH. As previously reported, abnormal activation of Hedgehog signaling pathway was positively correlated with the clinical manifestations, lymph node metastasis, and overall survival rate of many cancers . Strikingly, SHH signaling pathway is not merely a cell‐intrinsic pathway that regulates the activity of the cancer cell, but is also modulated by the extrinsic microenvironment .…”

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

“…Patients received up to six, 21-day cycles of etoposide/cisplatin with 400 or 800 mg daily sonidegib. A total of 800 mg was determined to be the MTD, with 79% of patients showing partial response 55. Interestingly, a high efficacy is observed when a higher dose of sonidegib is used.…”

The clinical utility of circulating tumour cells in patients with small cell lung cancer

“…A promising utility of CTC enumeration in early phase trials is for serial monitoring as a surrogate for response. Pietanza et al (49) incorporated CTC enumeration into a phase 1 trial of sonidegib (a hedgehog pathway inhibitor) in combination with cisplatin and etoposide in a cohort of 15 patients with extensive SCLC. CTCs were enumerated at baseline, at each cycle of chemotherapy, every 3 months on maintenance therapy and at disease progression.…”