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

• Published in: The oncologist (Dayton, Ohio) Ohio), 2016-10, Vol.21 (10), p.1163-1164e
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Clinical Trial Results; Female; Humans; Imidazoles - adverse effects; Imidazoles - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Male; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Pyrazines - adverse effects; Pyrazines - therapeutic use; Receptor, IGF Type 1 - antagonists & inhibitors; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - mortality; Topotecan - adverse effects; Topotecan - therapeutic use
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2016-0220

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. 作者总结 经验 • 小细胞肺癌(SCLC)患者靶向治疗的选择非常有限, 迄今尚无一种制剂被看好有充足的潜力进入III期临床试验。 • Linsitinib是强效的胰岛素生长因子1受体酪氨酸激酶抑制剂, 可能对SCLC具有治疗活性。 • 本文的阴性结果在一定程