LIBRETTO-001: Selpercatinib achieves high ORRs in RET fusion-positive NSCLC
medwireNews: Selpercatinib elicits deep antitumor responses and is well tolerated by patients with advanced non-small-cell lung cancer (NSCLC) harboring RET fusions, show updated trial data presented at the IASLC World Conference on Lung Cancer 2019.
Speaking at a press conference in Barcelona, Spain, Alexander Drilon (Memorial Sloan Kettering Cancer Center, New York, USA) explained that RET fusions are the oncogenic driver in about 2% of NSCLC cases, but thus far there have not been many treatment options for this “underserved population.”
“We have really tried hard to develop older, dirtier drugs – these are the multikinase inhibitors – but those clinical trials have been fraught with issues related to low response rates and really substantial toxicity,” he added.
By contrast, selpercatinib – previously known as LOXO-292 – is a selective RET inhibitor that was designed to be active against resistance mutations and cross the blood–brain barrier, Drilon stated.
The researchers previously reported findings from 82 participants of the LIBRETTO-001 trial with different tumors harboring a range of RET alterations, but the current presentation was focused on the primary analysis set comprising 105 previously treated patients with RET fusion-positive NSCLC.
Treatment with selpercatinib at a twice-daily dose of 160 mg led to an objective response rate (ORR) of 68%, with complete responses in 2% and partial responses in 66%. The median duration of response was 20.3 months.
The drug also demonstrated “meaningful clinical intracranial activity,” noted Drilon, with a central nervous system ORR of 91% for the 11 participants with brain metastases at baseline.
At the time of analysis, median progression-free survival (PFS) was 18.4 months.
Drilon also reported on a further 34 trial participants who had not received prior systemic therapy. In this group, the ORR was 85%, with complete responses in 3% and partial responses in 82%.
Selpercatinib has “a favorable safety profile,” said the presenter, with most adverse events (AEs) tending to be of grade 1 or 2 and unrelated to treatment.
The most common treatment-related AE of grade 3–4 was hypertension, occurring at a rate of around 8%, followed by elevations in alanine aminotransferase and aspartate transaminase, at 7% and 5%, respectively.
Of note, just 1.7% of patients discontinued treatment due to AEs attributable to selpercatinib.
Drilon said that these data will form the basis of a New Drug Application to the US FDA later in the year, and that a phase III trial comparing selpercatinib with platinum–pemetrexed, either with or without pembrolizumab, in treatment-naïve patients with RET fusion-positive NSCLC is due to be initiated in the coming months.
Noting that multikinase inhibitors achieved ORRs of around 25% and median PFS durations of approximately 2.3 months in these patients, discussant Robert Doebele (University of Colorado, Aurora, USA) commented that “selpercatinib succeeds where multikinase inhibitors failed.”
He said, however, that certain questions remain to be answered, such as whether the activity of the drug differs between KIF5B and non-KIF5B fusions, and additional data on intracranial activity and resistance are awaited.
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