Episode 8: The LIBRETTO-431 trial demonstrates the efficacy of selpercatinib in RET fusion-positive NSCLC

In this episode of WND, Professor Johan Vansteenkiste from University Hospitals Leuven and Professor Mariana Brandao, a medical oncologist at Institut Jules Bordet in Brussels, introduce the LIBRETTO-431 trial examining the efficacy of selpercatinib in patients with RET fusion-positive NSCLC.

Since RET fusions are a rare subgroup, comprising less than 5% of NSCLC patients, this is a global phase 3 trial comparing the RET-specific TKI selpercatinib in the first line to the standard of care, initially chemotherapy and evolving to chemoimmunotherapy with pembrolizumab.

Selpercatinib has demonstrated efficacy in the second line and beyond, for which it is approved in Belgium. The LIBRETTO-431 trial reveals its benefit in the first line as well. The median PFS doubled from 11 to 24 months, and notably, this was also observed in patients with untreated asymptomatic brain metastases. Remarkably, the ORR of selpercatinib exceeded 80%. Selpercatinib demonstrated an intracranial response rate also surpassing 80% and prolonged the time to CNS progression, offering clear benefits to these patients. OS data are not yet available and will most likely be impacted by patient cross over but given this PFS difference, they are expected to be positive.

Selpercatinib exhibits manageable liver toxicity, but other inconvenient toxicities can occur such as diarrhoea and hypertension, with cardiovascular disease being a significant comorbidity in lung cancer patients. Rare adverse effects include neuropathy and alterations in creatinine.

This trial firmly establishes the role of TKIs in the first line. Both experts agree ample data supports the immediate use of these agents rather than chemotherapy, considering the clear benefits of increased PFS, better quality of life, and fewer side effects.

The compelling data in the metastatic setting predicts efficacy in other stages, including the curative setting. Regulatory authorities play a vital role in this matter by facilitating patient access to these treatments, even in cases of rare subtypes like EGFR-mutated NSCLC tumours, where conducting clinical trials may not be feasible. This trial also demonstrates the importance of comprehensive NGS before initiating treatment.