Response to Selective RET Inhibition With LOXO-292 in a Patient With RET Fusion-Positive Lung Cancer With Leptomeningeal Metastases.

Abstract

The development of leptomeningeal metastases is a poor prognostic factor in patients with advanced cancers.1–3 In non–small-cell lung cancers (NSCLCs), median overall survival of patients from the diagnosis of leptomeningeal disease is 1 to 2 months without treatment and up to 8 months with systemic therapy.4–6 Furthermore, patients with leptomeningeal disease have historically had limited access to novel therapies in clinical trials. Recent efforts from many groups, including the European Society for Medical Oncology and the US Food and Drug Administration (FDA), have encouraged the inclusion of patients with leptomeningeal metastases in clinical trials, in addition to promoting standardization of intracranial response assessments.7–9 These efforts are crucial given that many investigational agents have substantial CNS activity and may improve outcomes in driver-positive cancers with leptomeningeal involvement.5,10 RET fusions are actionable oncogenic drivers that are identified in 1% to 2% of NSCLCs.11,12 To date,chemotherapy and/or immunotherapy remain the only approved systemic therapies for these cancers. Multikinase inhibitors with activity against RET (eg, cabozantinib or vandetanib) were repurposed to treat patients with RET fusion-positive lung cancers. Although these agents were found to be active in a subset of these patients, outcomes are modest compared with targeted therapies in other driver-positive lung cancers, and intracranial activity is poor.13,14 Selective RET inhibitors currently in development, such as LOXO-292 and BLU-667, have improved outcomes for patients with RET fusion-positive cancers because of increased potency and less offtarget toxicity.15,16 In September of 2018, LOXO-292 received Breakthrough Therapy designation from the FDA for treatment of patients with metastatic RET fusion-positive NSCLCs (as well as RET fusion-positive thyroid cancers and RET-mutant medullary thyroid cancer). In addition, confirmed intracranial responses and durable disease control have been achieved in patients with brain metastases in an ongoing phase I/II trial of LOXO-292 for patients with RET fusion-positive cancers.15 Its activity in leptomeningeal disease, however, has not previously been characterized. In this article, we describe a patient with a RET fusion-positive lung cancer with brain and leptomeningeal metastases who had an impactful intracranial response to selective RET inhibition with LOXO-292.