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

Abstract

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/m2 intravenously or 2.3 mg/m2 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.

• Authors: Alberto A Chiappori, Gregory A Otterson, Afshin Dowlati, Anne M Traynor, Leora Horn, Taofeek K Owonikoko, Helen J Ross, Christine L Hann, Taher Abu Hejleh, Jorge Nieva, Xiuhua Zhao, Michael Schell, Daniel M Sullivan
• Journal: The oncologist (Oncologist) Vol. 21 Issue 10 Pg. 1163-1164 (10 2016) ISSN: 1549-490X [Electronic] England
• PMID: 27694157 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• Imidazoles
• Pyrazines
• Topotecan
• Receptor, IGF Type 1

Topics

• Adult
• Aged
• Aged, 80 and over
• Female
• Humans
• Imidazoles (adverse effects, therapeutic use)
• Lung Neoplasms (drug therapy, mortality)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• Pyrazines (adverse effects, therapeutic use)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Small Cell Lung Carcinoma (drug therapy, mortality)
• Topotecan (adverse effects, therapeutic use)