No Survival Advantage for Linsitinib in Advanced Adrenocortical Carcinoma

IGF-IR and insulin receptor inhibition does not extend overall or progression-free survival in most adrenocortical carcinoma patients, although a few may benefit

medwireNews: Linsitinib does not improve survival outcomes in patients with adrenocortical carcinoma and thus “cannot be recommended” for this group of patients, a placebo-controlled trial finds, but may benefit select individuals.

“[A]lthough dysregulation of the IGF-2 [Insulin-like growth factor 2] locusand the resultant increase in IGF-2 expression is a major contributor to the development of adrenocortical carcinoma, pharmacological inhibition of IGF-2 signalling through IGF-1R [insulin-like growth factor 1 Receptor] and the insulin receptor in patients with adrenocortical carcinoma does not appear sufficient to substantially affect disease progression, except in a few patients”, writes the team in The Lancet Oncology.

Median overall survival was 323 days for the 90 individuals with locally advanced or metastatic unresectable disease who received the dual IGF-1R and insulin receptor inhibitor at a dose of 150 mg twice a day over a 21-day cycle. This did not differ significantly from the 356 days observed in the 49 patients given placebo.

The secondary endpoint of progression-free survival was also comparable between the linsitinib and placebo groups, at a median of 44 versus 46 days.

However, three patients in the linsitinib treatment arm showed a “long-lasting” partial response with reduced tumour burden, continuing treatment with the study drug even after the study was unblinded following the recommendation of the data monitoring committee, report Gary Hammer, from the University of Michigan in Ann Arbor, USA, and colleagues.

They add that two of these patients have since been enrolled in another linsitinib trial after remaining on the study drug for 45 months and 38 months, while the third patient discontinued the linsitinib at 37 months as a result of a non-treatment-related adverse event.

First author Martin Fassnacht, from University of Würzburg in Germany, added in a press release: “One of our patients is still controlling her disease with a remarkable partial response by taking linsitinib now for more than 4 1/2 years – which is really amazing in advanced adrenal cancer, which has usually a median survival of less than 15 months.”

The researchers have not yet established the factors that may predict response, but suggest that “[o]ngoing genomic characterisation of tumour samples of treatment responders versus non-responders might reveal the basis for the observed sensitivity to linsitinib and aid in future identification of patients most likely to respond to targeted anticancer drugs that inhibit IGF-1R signalling.”

Linsitinib treatment was “well tolerated” with adverse events of any grade and those of grade 3 or higher observed in 56% and 19% of linsitinib-treated participants, respectively. This compared with a respective 44% and 2% of patients in the placebo arm.

In a linked commentary, Lawrence Kirschner, from the Ohio State University in Columbus, USA, notes that the drug “might still have a role in combination therapy” as a result of the “favourable” toxicity profile.

Commending the authors on their “carefully designed and well done study”, he concludes: “Although results were negative, the information gained from these patients can hopefully be used to understand why linsitinib failed. If so, these data can then be used to develop new therapies for the next trial in adrenocortical carcinoma.”

References

Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study.Lancet Oncol2015; Advance online publication 17 March. doi:10.1016/S1470-2045(15)70081-1

Kirschner LS. Inhibition of IGF-1R in adrenocortical carcinoma. Lancet Oncol2015; Advance online publication 17 March. doi:10.1016/S1470-2045(15)70130-0

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