Dose adjustments and exposure-response associated with selpercatinib in patients with advanced NSCLC

Given the potent and selective nature of the RET inhibitor selpercatinib, an analysis investigating whether a lower dose of the drug could still provide the same clinical benefit for patients with advanced non-small cell lung cancer (NSCLC) was performed. At WCLC 2024, the results of this analysis were presented. 

Treatment with selpercatinib has resulted in consistent clinical benefit for patients with advanced NSCLC, with a median progression-free survival (PFS) of approximately 2 years. For these patients, dose adjustments are used to manage selpercatinib-associated toxicity and to allow patients to continue treatment. Dose reductions due to treatment-emergent adverse events (TEAEs) were required in 48.9% and 51.3% of patients in LIBRETTO-001 and LIBRETTO-431, respectively, highlighting the importance of dose reduction in the management of adverse events. However, whether selpercatinib is as effective at a lower dose has not been extensively studied.

Study design

A population pharmacokinetic model averaging selpercatinib dose over 10 doses prior to a safety or efficacy event followed by exposure response analysis that related selpercatinib exposures to the probability or magnitude of an efficacy outcome was performed. Data from 504 patients from both LIBRETTO studies was used for this analysis. Patients were started at 160mg twice daily, with dose reductions to 120mg, 80mg, and 40mg twice daily being permitted. Once the adverse event had resolved, patients were allowed to re-escalate to their original dose.

Results

Of the 504 patients in this analysis, 52.8% had at least one dose reduction with a median time to first dose reduction of 2 months. These patients tended to be older, with lower body weight, and longer time on therapy. The most common adverse events leading to dose reduction were alanine and aspartate aminotransferase elevation, QT prolongation, and hypertension. Furthermore, exposure-response analysis for pooled data from LIBRETTO-001 and LIBRETTO-431 suggested increased exposure (as a consequence of higher doses) appears to be associated with better response rate. Exploratory analysis of PFS in 504 patients (254 events) by exposure parameters showed no significant relationship with PFS. Therefore, no further modelling was pursued.

Conclusion

In both LIBRETTO studies, dose reductions were implemented effectively to manage adverse events. The pharmacokinetic model did not find any correlation between drug exposure and PFS, but did suggest that higher exposure was associated with better response rates. Therefore, for patients experiencing toxicity on selpercatinib, temporary dose adjustment to reduce exposure may allow ongoing clinical benefit without a decremental impact on PFS.  As such, all patients receiving selpercatinib should be carefully monitored for toxicity, with dose adjustments as needed, with a goal of maximizing adherence to maintain benefit from selpercatinib.

Reference

Park K, Dose adjustments and exposure-response associated with selpercatinib in patients with advanced NSCLC. Presented at WCLC 2024; P1.12B.10.