RET fusions are driver alterations found in several solid tumour types, including thyroid cancer subsets (5–10%), non-small-cell lung cancer (NSCLC; 1–2%) and other solid tumour types (<1%). In the phase I/II LIBRETTO-001 trial, the RET kinase inhibitor selpercatinib showed activity in selected RET fusion-positive cancers, leading to an FDA Accelerated Approval of this drug for patients aged ≥12 years with RET fusion-positive thyroid cancer or NSCLC. Now, updated data from this trial confirm the efficacy of selpercatinib in NSCLC and show promising activity in other types of RET fusion-positive solid tumours.

LIBRETTO-001 involved 806 patients with RET fusion-positive solid tumours. Objective response rate (ORR) was the primary end point.

The NSCLC population of LIBRETTO-001 included patients with treatment-naive (n = 69) or previously treated (n = 247) disease. At a median follow-up duration of at least 20.2 months, the ORR was 84% and 61% in the previously untreated and treated cohorts, respectively, and the complete response (CR) rates were 6% and 7%. The median progression-free survival (PFS) durations were 22.0 months and 24.9 months. At a median follow-up duration of at least 25.2 months, median overall survival (OS) duration was non-estimable in both groups. In 106 patients with brain metastases at baseline, intracranial ORR was 85%, with intracranial CRs in 27% of patients.

The histology-agnostic population involved 45 previously treated patients with any of 14 tumour types, the most common of which were pancreatic (n = 12) and colon (n = 10) cancer. The median follow-up duration was 16.4 months; 41 patients were included in efficacy analyses. The ORR was 43.9%, with a CR in 2 patients. The median PFS and OS durations were 13.2 months and 18.0 months, respectively.

Grade ≥3 treatment-related adverse events occurred in ~38% patients, both in the histology-agnostic and overall populations. No new safety signals were detected.

“Selpercatinib was granted Accelerated Approval … becoming a new histology-agnostic indication”

In September 2022, these results supported an FDA upgrade of the existing approval for selpercatinib in NSCLC to regular approval. In addition, selpercatinib was granted Accelerated Approval for adult patients with advanced-stage RET fusion-positive solid tumours, becoming a new histology-agnostic indication.