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A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer
Alberto A Chiappori1, Gregory A Otterson2, Afshin Dowlati3
1H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA alberto.chiappori@moffitt.org.
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.
Insights
Linsitinib, an insulin growth factor-1 receptor inhibitor, showed no clinical activity in patients with relapsed small-cell lung cancer (SCLC). While safe, this targeted therapy did not improve progression-free survival compared to topotecan in this phase II trial.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Small-cell lung cancer (SCLC) treatment for relapsed patients is suboptimal.
- Insulin growth factor-1 receptor (IGF-1R) signaling is implicated in SCLC growth, survival, and chemoresistance.
- Linsitinib is an IGF-1R tyrosine kinase inhibitor with potential activity against SCLC.
Purpose of the Study:
- To evaluate the clinical activity and safety of linsitinib in patients with relapsed small-cell lung cancer (SCLC).
- To compare the efficacy of linsitinib against topotecan in a phase II clinical trial setting.
Main Methods:
- A phase II study randomly assigned 8 eligible patients with relapsed SCLC to topotecan or linsitinib.
- The primary endpoint was progression-free survival.
- Patients had relapsed SCLC (platinum sensitive or resistant) with performance status 0-2.
Main Results:
- Median progression-free survival was significantly shorter for linsitinib (1.2 months) compared to topotecan (3.0 months) (p = .0001).
- Linsitinib demonstrated limited clinical activity, with only 1 of 29 patients achieving stable disease.
- Grade 3/4 adverse events were observed for both treatments, with linsitinib showing thrombocytopenia and liver enzyme elevations.
Conclusions:
- Linsitinib was found to be safe in patients with relapsed SCLC.
- The study concluded that linsitinib showed no significant clinical activity in unselected, relapsed SCLC patients.
- The lack of a predictive biomarker may have contributed to the negative outcomes.
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