No Survival Benefit of IGF-1R/Insulin Receptor Inhibitor Linsitinib in Advanced Adrenocortical Carcinoma
In a phase III trial reported in The Lancet Oncology, Fassnacht et al found that linsitinib, an insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor inhibitor, did not improve overall survival vs placebo in patients with previously treated locally advanced or metastatic adrenocortical carcinoma.
Study Details
In this double-blind study, 139 adult patients from nine countries who had previously received chemotherapy, including mitotane, were randomly assigned 2:1 between December 2009 and July 2011 to receive oral linsitinib 150 mg twice daily (n = 90) or placebo (n = 49). The primary endpoint was overall survival in the intention-to-treat population.
The linsitinib and placebo groups were generally balanced for age (median 50 and 48 years), sex (67% and 61% female), ethnicity (90% white in both), Eastern Cooperative Oncology Group performance status (0 for 44% and 45%, 1 for 50% and 53%, 2 for 6% and 2%), prior surgery (92% and 88%), prior mitotane (1% and 2% neoadjuvant, 37% and 43% adjuvant, 90% and 88% advanced/metastatic setting), median mitotane level (4.8 and 3.6 mg/L), prior radiotherapy (32% and 29%), and prior chemotherapy (eg, cisplatin-based in 52% and 61%, streptozotocin in 13% and 12%, other cytotoxic drugs in 11% and 8%). Median time from diagnosis was longer in the linsitinib group (26.5 vs 14.9 months).
No Survival Difference
The trial was unblinded in March 2012 due to the failure of linsitinib to increase progression-free or overall survival. At database lock, median overall survival was 323 days (95% confidence interval [CI] = 256–507 days) in the linsitinib group vs 356 days (95% CI = 249–556 days) in the placebo group (hazard ratio [HR] = 0.94, P = .77). Median progression-free survival was 44 days vs 46 days (HR = 0.83, P = .30). Partial response occurred in 3% vs 0%. Disease control rates were 16% vs 8% at week 12 and 7% vs 0% at week 24.
Subgroup analyses showed no evidence of differences in overall or progression-free survival between linsitinib and placebo groups according to sex, age, performance status, smoking history, previous systemic and cytotoxic chemotherapy, or use of noninsulinotropic antihyperglycemic drugs.
Adverse Events
The most common treatment-related adverse events of any grade in the linsitinib group were fatigue (16% vs 6% in the placebo group), nausea (11% vs 8%), and QTc prolongation (10% vs 2%). The most common treatment-related adverse events of grade ≥ 3 were fatigue (3% vs 0%), nausea (2% vs 0%), and hyperglycemia (2% vs 0%).
The investigators concluded: “Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma.”
Gary D. Hammer, MD, of the University of Michigan, Ann Arbor, is the corresponding author of The Lancet Oncology article.
The study was funded by Astellas. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
