Linsitinib (OSI-906) is an investigational drug developed to treat various types of cancer. It represents a targeted therapy, a class of medications designed to interfere with specific molecules involved in tumor growth, progression, and spread. This orally available small molecule has been studied in clinical trials.
Mechanism of Action
Linsitinib functions as a dual inhibitor, blocking the activity of two related protein receptors: the insulin-like growth factor 1 receptor (IGF-1R) and the insulin receptor (IR). The IGF-1 signaling pathway regulates cell growth, development, and survival. Cancer cells can hijack this pathway, overactivating IGF-1R to promote uncontrolled proliferation, prevent programmed cell death (apoptosis), and enable their transformation into malignant forms.
Linsitinib selectively inhibits IGF-1R and also affects the insulin receptor. By blocking these receptors, linsitinib aims to disrupt the signaling pathways that support tumor growth and survival. It inhibits IGF-1R autophosphorylation and the subsequent activation of downstream proteins such as Akt, ERK1/2, and S6 kinase. This interference is designed to slow or stop the uncontrolled growth of cancer cells and encourage their demise.
Clinical Applications and Investigations
Linsitinib has been investigated in clinical trials for several cancer types. A primary focus of its clinical evaluation has been adrenocortical carcinoma (ACC), a rare and aggressive cancer with limited treatment options. A phase 3 study specifically compared linsitinib against a placebo in patients with locally advanced or metastatic ACC.
Beyond ACC, linsitinib has also been explored for its activity in other malignancies, including:
Thyroid cancer, where it has shown some activity against the IGF-1R target
Non-small cell lung cancer (NSCLC)
Breast cancer
Multiple myeloma
Ovarian cancer
Hepatocellular carcinoma
It is important to note that the use of linsitinib in these contexts was strictly within the framework of clinical trials, signifying its investigational status rather than approved medical use.
Reported Side Effects and Safety Profile
Patients receiving linsitinib experienced various adverse effects. Common side effects included fatigue, nausea, and diarrhea. Musculoskeletal complaints, such as muscle cramps, myalgias, and back pain, were also observed. Liver function test abnormalities, including elevated liver enzymes, were frequent adverse events.
Hyperglycemia (high blood sugar) is a predictable side effect given linsitinib’s mechanism of inhibiting the insulin receptor. This interference affects the body’s ability to regulate blood glucose levels. While typically manageable, grade 2-3 hyperglycemia was noted. More serious but less common side effects included neutropenia (a reduction in white blood cells). Overall, the drug was generally well-tolerated.
Current Status and Development
Linsitinib (OSI-906) is not an FDA-approved drug and is not commercially available. Its development for oncology indications has largely been discontinued due to clinical trial outcomes. For instance, the phase 3 study in adrenocortical carcinoma, which enrolled 139 patients, was unblinded early because linsitinib did not demonstrate an increase in progression-free survival or overall survival compared to placebo.
While some studies showed preliminary anti-tumor activity and an acceptable tolerability profile, linsitinib often did not meet the primary efficacy endpoints required for regulatory approval in many of the cancers it was tested for. Research for indications like multiple myeloma, ovarian cancer, hepatocellular carcinoma, and non-small cell lung cancer was discontinued due to unsatisfactory results. As of 2017, no new oncology clinical trials for linsitinib were in progress. However, linsitinib is currently being developed for Thyroid Eye Disease (TED), where it has shown positive topline results in a Phase 2b/3 trial by inhibiting the IGF-1R target, and a confirmatory Phase 3 trial is anticipated to begin in 2025.