Selpercatinib (LOXO-292) shows durable activity in RET fusion-positive lung cancer

Recent data from the LIBRETTO-001 trial shows that selpercatinib has durable activity in patients with Rearranged During Transfection gene (RET)-fusion positive NSCLC. Not only are the effects on response rate, durability, intracranial activity, and safety promising, it also shows that RET fusions are clinically targetable alterations.

Approximately 1-2% of unselected NSCLC patients harbour RET rearrangements. Multitarget tyrosine kinase inhibitors (TKI) have been investigated in this setting but show disappointing results and concerning toxicity. Novel selective RET inhibitors have been investigated recently in early phase trials with promising efficacy. Selpercatinib, formerly known as LOXO-292, is a potent and highly selective RET inhibitor. It is being investigated for the treatment of patients with cancers harbouring RET abnormalities (gene fusions and point mutations) leading to overactive RET signalling and uncontrolled cell growth. In 2018, selpercatinib was granted breakthrough therapy designation by the FDA based on the LIBRETTO-001 study, which included 87 sites in 16 countries. It was shown that selpercatinib demonstrated robust anti-tumour activity in a group of RET fusion-positive NSCLC patients, alongside strong evidence of durability.

Dr Alexander Drilon (Memorial Sloan Kettering Cancer Center, USA) presented a primary analysis set from the LIBRETTO-001 trial, featuring 105 NSCLC patients who received treatment with selpercatinib [1]. Of these NSCLC patients who were previously treated with platinum-based chemotherapy, 68% achieved responses and median duration of response was 20.3 months. The intracranial objective response rate was 91% for patients with target lesions in the brain at baseline. Data from the safety data set (n=531; this included all enrolled patients in the trial) further showed 5 treatment-related adverse events occurring in ≥15% of patients. These were dry mouth, diarrhoea, hypertension, increased aspartate aminotransferase (AST) and increased alanine aminotransferase (ALT). Most adverse events were grade 1-2; discontinuation rate was only 1.7%.

1. Drilon A, et al. PL02.08. WCLC 2019.

Posted on 8 November, 20195 March, 2021