Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial

Abstract

We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the US for RET fusion-positive non-small cell lung cancers (NSCLCs). Methods:In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RETaltered solid tumors, selpercatinib was dosed orally (160mg twice/day) in 28-day cycles.Patients with baseline intracranial metastases had MRI/CT scans every 8-weeks for 1 year (12-weeks thereafter). In this pre-planned analysis of RET fusion-positive NSCLC patients with baseline intracranial metastases, the primary endpoint was independently-assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.Results: Eighty NSCLC patients had brain metastases at baseline. Patients were heavily pretreated (median=2 systemic therapies, range=0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% (95%CI=60-95), including 23% with complete responses. Among all intracranial responders (measurable and non-measurable, n=38), median duration of intracranial response was not reached (95%CI=9.3-NE) at a median duration of follow-up of 9.5 months (IQR=5.7,12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95%CI=10.9-NE) at a median duration of follow-up of 11.0 months (IQR=7.4,16.5). No new safety signals were revealed in patients with brain metastases compared to the full NSCLC trial population. Conclusion:Selpercatinib has robust and durable intracranial efficacy in RET fusion-positive NSCLC patients.Research.

Precision therapy for RET-altered cancers with RET inhibitors

“…Both selective RET inhibitors cross the blood–brain barrier and demonstrate clinical intracranial responses. In the LIBRETTO-001 trial, intracranial ORR was 82% [95% confidence interval (CI), 60–95], including 23% with complete responses among 22 patients with measurable intracranial efficacy evaluable disease at baseline [ 97 ]. In the ARROW trial with pralsetinib, shrinkage of intracranial metastases was seen in all patients with measurable intracranial metastases at baseline and at least one post-baseline intracranial response assessment.…”

Molecular Testing and Treatment Strategies in RET-Rearranged NSCLC Patients: Stay on Target to Look Forward

“…Interestingly, the major benefit was observed in the cohort of 39 treatmentnaive patients: the ORR was 85% (95% CI: 70%-94%) and, to date, the median duration of response and PFS have not been reached yet [32]. Among 11 patients with measurable intracranial disease at baseline, intracranial ORR was 91% (95% CI: 60-95) [55]. The safety profile was relatively favorable with most low grade adverse events and a treatment discontinuation rate of 1.7%.…”

RET receptor signaling: Function in development, metabolic disease, and cancer

“… 110 ) Notably, both inhibitors also exhibited anti-tumor activity in patients with brain metastasis. 111 , 112 ) Selpercatinib has been approved (September, 2021) and implemented (December 2021) for RET -rearranged NSCLC in Japan.…”