title: 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: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States. Electronic address: cathy.pietanza@merck.com.
authors: M Catherine
authors: MC
authors: Pietanza
authors: Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
authors: Anya M
authors: AM
authors: Litvak
authors: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Anna M
authors: AM
authors: Varghese
authors: Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
authors: Lee M
authors: LM
authors: Krug
authors: Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Martin
authors: M
authors: Fleisher
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Jerrold B
authors: JB
authors: Teitcher
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Andrei I
authors: AI
authors: Holodny
authors: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Cami S
authors: CS
authors: Sima
authors: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Kaitlin M
authors: KM
authors: Woo
authors: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
authors: Kenneth K
authors: KK
authors: Ng
authors: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Helen H
authors: HH
authors: Won
authors: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors: Michael F
authors: MF
authors: Berger
authors: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
authors: Mark G
authors: MG
authors: Kris
authors: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
authors: Charles M
authors: CM
authors: Rudin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; C561435:sonidegib; D005047:Etoposide; D002945:Cisplatin
keywords: Circulating tumor cells; Hedgehog inhibitor; Hedgehog pathway; LDE225; SOX2 amplification; Small cell lung cancer