RET Inhibitor LOXO-292 Shows Promise in Phase I Trial

Alterations in the oncogene RET occur in several solid tumors, including non-small cell lung cancer (NSCLC), thyroid cancer, and pancreatic cancer. Unfortunately, previous attempts to target these alterations with multikinase inhibitors have failed. LOXO-292 is a potent and highly selective RET inhibitor that has demonstrated high activity against RET-altered tumors in both in vitro and in vivo models. At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Alexander Drilon, MD (Memorial Sloan Kettering Cancer Center, New York, New York, United States), presented results from an ongoing, first-in-human, phase I, dose-escalation study (LIBRETTO-001) that evaluates LOXO-292 in 82 patients with locally advanced or metastatic RET-altered solid tumors whose disease was refractory to prior therapy. Patients received doses of LOXO-292, ranging from 20 mg daily to 240 mg twice daily, dosed in 28-day cycles.


In patients with RET fusions, the objective response rate (ORR) was 77%, including a 77% ORR in the 38 patients with RET­-altered NSCLC and a 78% ORR in patients with other RET fusion-positive cancers. At data cutoff, no patients with RET fusions had developed progressive disease. LOXO-292 was active, regardless of RET fusion partner or prior treatment with multikinase inhibitors.


In patients with RET-mutated medullary thyroid cancer, the ORR was 45%, including 1 confirmed complete response. Two patients with medullary thyroid cancer developed progressive disease. Four patients with no known activating RET mutations were included on this trial, and there were no responses in these patients.


Brain metastases occur in more than a quarter of patients with RET-altered cancers. In preclinical studies, LOXO-292 demonstrated high activity against intracranial tumors. A total of 12 patients enrolled in LIBRETTO-001 had brain metastases at baseline, with measurable intracranial disease in 3 patients. Currently, all 12 patients with brain metastases remain on treatment, and all 3 patients with measurable disease responded to treatment.


LOXO-292 was associated with a manageable toxicity profile. Treatment-emergent adverse events (AEs) occurring in ≥10% of patients included fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%). All doses of LOXO-292 were well tolerated, and the maximum tolerated dose has not been identified.


In his conclusion, Dr Drilion commented that the results seen with LOXO-292 thus far are highly promising, with high rates of response in heavily pretreated patient populations, including those with brain metastases. Although follow up is short, almost 90% of patients remain on treatment, supporting the tolerability of this treatment and the durability of responses.


J Clin Oncol. 2018;36(suppl): Abstract 102.

Clinical Opinion Poll

What frontline therapy would you recommend for a 49 y/o woman diagnosed with low tumor burden metastatic ALK+ NSCLC (lung and liver metastases, normal brain MRI, PS0)?