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

M. Catherine Pietanza, Anya M. Litvak, Anna M. Varghese, Lee M. Krug, Martin Fleisher, Jerrold B. Teitcher, Andrei I. Holodny, Cami S. Sima, Kaitlin M. Woo, Kenneth K. Ng, Helen H. Won, Michael F. Berger, Mark G. Kris, Charles M. Rudin

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)23-30
Number of pages8
JournalLung Cancer
Volume99
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Small Cell Lung Carcinoma
Etoposide
Cisplatin
Circulating Neoplastic Cells
Maximum Tolerated Dose
Therapeutics
LDE225
Neutropenia
Nausea
Fatigue
Disease Progression
Anemia
Cell Count
Biomarkers
Maintenance
Neoplasm Metastasis
Survival
Liver

Keywords

  • Circulating tumor cells
  • Hedgehog inhibitor
  • Hedgehog pathway
  • LDE225
  • Small cell lung cancer
  • SOX2 amplification

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

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. / 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.

In: Lung Cancer, Vol. 99, 01.09.2016, p. 23-30.

Research output: Contribution to journalArticle

Pietanza, MC, Litvak, AM, Varghese, AM, Krug, LM, Fleisher, M, Teitcher, JB, Holodny, AI, Sima, CS, Woo, KM, Ng, KK, Won, HH, Berger, MF, Kris, MG & Rudin, CM 2016, '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', Lung Cancer, vol. 99, pp. 23-30. https://doi.org/10.1016/j.lungcan.2016.04.014
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. / 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. In: Lung Cancer. 2016 ; Vol. 99. pp. 23-30.
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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.",
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AU - Pietanza, M. Catherine

AU - Litvak, Anya M.

AU - Varghese, Anna M.

AU - Krug, Lee M.

AU - Fleisher, Martin

AU - Teitcher, Jerrold B.

AU - Holodny, Andrei I.

AU - Sima, Cami S.

AU - Woo, Kaitlin M.

AU - Ng, Kenneth K.

AU - Won, Helen H.

AU - Berger, Michael F.

AU - Kris, Mark G.

AU - Rudin, Charles M.

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N2 - 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.

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KW - Hedgehog inhibitor

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KW - Small cell lung cancer

KW - SOX2 amplification

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