In line with previous reports, with additional follow-up, selpercatinib showed substantial and durable antitumour activity in patients with RET fusion-positive non-small cell lung cancer (NSCLC), who received selpercatinib as first-line treatment, in those who had received previous platinum-based chemotherapy, and in those with central nervous system (CNS) metastases at baseline. With 3.5 years of follow-up, median overall survival (OS) was 47.6 months in pretreated patients and not reached in treatment-naïve patients.
The data from a registrational phase I/II, single-arm, open-label LIBRETTO-001 study constitute the first mature estimation of median OS for selpercatinib and provide insights into OS maturation in phase III LIBRETTO-431 study according to Dr. Alexander Drilon of the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center in New York, NY, US and colleagues, who published the findings on 21 February 2025 in the JCO.
Selpercatinib, a highly selective RET kinase inhibitor with CNS penetration, was approved for the treatment of RET fusion-positive NSCLC on the basis of the results of the single-arm phase I/II LIBRETTO-001 study. These results were confirmed in the recent randomised phase III LIBRETTO-431 study; at an interim analysis, selpercatinib demonstrated superior progression-free survival (PFS) over platinum-based chemotherapy with or without pembrolizumab in first-line treatment.
In the latest article, published in the JCO, the authors report long-term efficacy and safety from the final analysis of selpercatinib in patients with RET fusion-positive NSCLC in the LIBRETTO-001 study, providing 3-year response outcomes, PFS and OS, including the first reports of median OS in pretreated patients and median PFS in patients with measurable CNS metastasis at baseline.
With 19 months of additional follow-up, the study team reported the final efficacy and safety results of selpercatinib in patients with RET fusion-positive NSCLC of whom 247 had previously received platinum-based chemotherapy and 69 were treatment-naïve. The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-naïve patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatment-naïve patients with median follow-up of approximately 38 months.
Median PFS was 26.2 months for pretreated and 22.0 months for treatment-naïve patients with median follow-up approximately 40 months. Median OS was 47.6 months in pretreated patients and was not reached in the treatment-naïve group with median follow-up of approximately 43 months. At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-naïve patients were alive.
Among 26 patients with measurable CNS metastases at baseline, the CNS ORR was 85% with a CNS DoR of 9.4 months and CNS PFS of 11.0 months, marking the first report for RET fusion-positive NSCLC and showing comparable PFS benefit to other selective agents targeting driver alterations.
The safety profile of selpercatinib was consistent with previous reports. It continues to be characterised by toxicities that are manageable by dose modifications and standard clinical care. Although dose reductions were seen in 49% of patients to manage adverse events, only 4% discontinued due to selpercatinib-related toxicity, suggesting dose reduction effectively allows patients to continue treatment.
The authors concluded that with substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety profile in patients with RET fusion-positive NSCLC. Recently, the randomised phase III LIBRETTO-431 study confirmed the clinical benefit of selpercatinib, with median OS not yet reached. The data from LIBRETTO-001 constitute the first mature estimation of median OS for selpercatinib and provide insights into OS maturation in LIBRETTO-431 study. Furthermore, the results reinforce the importance of testing for RET fusions in NSCLC to identify patients who may benefit from first-line treatment with selpercatinib.
The findings were previously presented at the European Lung Cancer Congress (Prague, Czech Republic; 20-23 March 2024).
The study was supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company.
Reference
Gautschi O, Park K, Solomon BJ, et al. Selpercatinib in RET Fusion–Positive Non–Small Cell Lung Cancer: Final Safety and Efficacy, Including Overall Survival, From the LIBRETTO-001 Phase I/II Trial. JCO; Published online 21 February 2025. DOI: https://doi.org/10.1200/JCO-24-02076