Bottom Line: Selpercatinib (also known as LOXO-292) is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastasis. Phase 1/2 data from the LIBRETTO-001 trial presented at the IASLC 2019 World Conference on Lung Cancer demonstrates selpercatinib’s marked antitumor activity in RET fusion-position non-small cell lung cancer (NSCLC) patients. These findings, presented by Alexander Drilon, MD, principal investigator and Research Director of Early Drug Development at Memorial Sloan Kettering Cancer Center, will form the basis of an US Food and Drug Administration new drug application submission.
Background: Selpercatinib is an oral and highly selective investigational drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the Rearranged During Transfection gene (RET). Genomic alterations involving RET, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. Patients with RET fusion-positive NSCLC comprise up to two percent of all NSCLC cases, but there are currently no targeted therapies approved for this patient population.
Selpercatinib was granted Breakthrough Therapy Designation by the FDA in 2018 based on initial data from the LIBRETTO-001 trial.
Findings: As of June 17, 2019, 253 RET fusion-positive NSCLC patients were treated at 87 sites in 16 countries. The primary analysis set (PAS) consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients also received prior anti-PD-1/PD-L1 agents. The majority of PAS responders have been followed for more than six months from first response. In addition, a separate cohort of 34 patients with treatment-naïve disease was analyzed.
Among PAS patients, the overall response rate was 68 percent. Responses did not differ by fusion partner, or the type or number of prior therapies, including chemotherapy, anti-PD-1/PD-L1 agents, and multikinase inhibitors with anti-RET activity. The median duration of response was 20.3 months with a median follow-up of eight months. The intracranial overall response rate was 91 percent for patients with measurable brain metastases at baseline. The overall response rate in efficacy evaluable treatment naïve RET fusion-positive NSCLC was 85 percent.
Expert Comment: “This promising data offers hope to a patient population who currently have no targeted treatment options available,” explained Dr. Drilon. “As precision medicine advances, we’re seeing a shift in how we treat certain cancers and that is certainly what we are seeing here with selpercatinib. The drug’s response rate, durability, robust CNS activity, and safety are likely to revolutionize therapy options for these patients.”