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A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer

LESSONS LEARNED: Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Desp...

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Autores principales: Chiappori, Alberto A., Otterson, Gregory A., Dowlati, Afshin, Traynor, Anne M., Horn, Leora, Owonikoko, Taofeek K., Ross, Helen J., Hann, Christine L., Abu Hejleh, Taher, Nieva, Jorge, Zhao, Xiuhua, Schell, Michael, Sullivan, Daniel M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AlphaMed Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061534/
https://www.ncbi.nlm.nih.gov/pubmed/27694157
http://dx.doi.org/10.1634/theoncologist.2016-0220
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author Chiappori, Alberto A.
Otterson, Gregory A.
Dowlati, Afshin
Traynor, Anne M.
Horn, Leora
Owonikoko, Taofeek K.
Ross, Helen J.
Hann, Christine L.
Abu Hejleh, Taher
Nieva, Jorge
Zhao, Xiuhua
Schell, Michael
Sullivan, Daniel M.
author_facet Chiappori, Alberto A.
Otterson, Gregory A.
Dowlati, Afshin
Traynor, Anne M.
Horn, Leora
Owonikoko, Taofeek K.
Ross, Helen J.
Hann, Christine L.
Abu Hejleh, Taher
Nieva, Jorge
Zhao, Xiuhua
Schell, Michael
Sullivan, Daniel M.
author_sort Chiappori, Alberto A.
collection PubMed
description LESSONS LEARNED: Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. BACKGROUND. Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. METHODS. In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m(2) intravenously or 2.3 mg/m(2) orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0–2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. RESULTS. Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5–3.6) and 1.2 (95% CI, 1.1–1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2–7.6) and 3.4 (95% CI, 1.8–5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib. CONCLUSION. Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.
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spelling pubmed-50615342016-10-13 A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer Chiappori, Alberto A. Otterson, Gregory A. Dowlati, Afshin Traynor, Anne M. Horn, Leora Owonikoko, Taofeek K. Ross, Helen J. Hann, Christine L. Abu Hejleh, Taher Nieva, Jorge Zhao, Xiuhua Schell, Michael Sullivan, Daniel M. Oncologist Clinical Trial Results LESSONS LEARNED: Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. BACKGROUND. Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. METHODS. In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m(2) intravenously or 2.3 mg/m(2) orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0–2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. RESULTS. Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5–3.6) and 1.2 (95% CI, 1.1–1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2–7.6) and 3.4 (95% CI, 1.8–5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib. CONCLUSION. Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients. AlphaMed Press 2016-10 2016-09-30 /pmc/articles/PMC5061534/ /pubmed/27694157 http://dx.doi.org/10.1634/theoncologist.2016-0220 Text en ©AlphaMed Press; the data published online to support this summary is the property of the authors.
spellingShingle Clinical Trial Results
Chiappori, Alberto A.
Otterson, Gregory A.
Dowlati, Afshin
Traynor, Anne M.
Horn, Leora
Owonikoko, Taofeek K.
Ross, Helen J.
Hann, Christine L.
Abu Hejleh, Taher
Nieva, Jorge
Zhao, Xiuhua
Schell, Michael
Sullivan, Daniel M.
A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
title A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
title_full A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
title_fullStr A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
title_full_unstemmed A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
title_short A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
title_sort randomized phase ii study of linsitinib (osi-906) versus topotecan in patients with relapsed small-cell lung cancer
topic Clinical Trial Results
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061534/
https://www.ncbi.nlm.nih.gov/pubmed/27694157
http://dx.doi.org/10.1634/theoncologist.2016-0220
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