Selpercatinib efficacy from the LIBRETTO-001 and LIBRETTO-431 trials

The efficacy of selpercatinib was initially investigated in the phase I/II LIBRETTO-001 study and later confirmed in the phase III LIBRETTO-431 study in patients with advanced RET+ non-small cell lung cancer (NSCLC). At WCLC 2024, an analysis of the relationship between selpercatinib and RET fusion partner in a combined cohort from both LIBRETTO studies was presented.

Selpercatinib is a highly selective and potent central nervous system (CNS) active RET inhibitor approved for treating advanced RET+ NSCLC. Previous studies in NSCLC patients have suggested that the efficacy of RET-selective inhibitory drugs may depend on a specific RET fusion partner.

Study design

This analysis assessed data from 415 selpercatinib-treated NSCLC patients with a known RET fusion partner. This cohort comprised of 325 patients with or without prior treatment from LIBRETTO-001 who had initiated selpercatinib treatment 6 months prior to the data cutoff, and 90 treatment-naïve patients from LIBRETTO-431 who also began selpercatinib treatment 6 months prior to data cutoff. A multivariate analysis was conducted in a combined cohort of 383 patients of selpercatinib-treated patients from both trials with KIF5B-RET (n=296) or CCDC6-RET (n=87). A separate controlled analysis was performed for treatment-naïve patients from LIBRETTO-001 and LIBRETTO-431 who received selpercatinib, compared to patients from LIBRETOO-431 who receive chemotherapy with/without pembrolizumab. This analysis was limited to patients with KIF5B-RET due to low numbers of patients with other fusion partners.

Results

Patients across all RET fusion groups were more likely to be younger than 65 years of age, never smokers, with an ECOG performance status of <2. RET fusion partners were identified by NGS in 99.5% of patients, the most commonly identified RET fusion partners were KIF5B-RET (71.6% and CCDC6-RET (21.2%). RET fusion (KIF5B-RET vs. CCDC6-RET) was the strongest prognostic factor for PFS (Cox multivariate model) and ORR (logistic regression model) in selpercatinib-treated patients from LIBRETTO-001 and LIBRETTO-431. Median progression-free survival (PFS) had not been reached in the CCDC6-RET group vs. 19.4 months and 16.9 months in the KIF5B-RET and other-RET groups, respectively. Median duration of response was not reached in the CCDC6-RET group compared to 20.3 months for KIF5B-RET and 17.6 months for other-RET. The PFS was similar between treatment-naïve patients with KIF5B-RET from both studies. PFS was longer for selpercatinib-treated patients from either study compared to chemotherapy with/without pembrolizumab. Overall response rates were 83%, 65%, and 53% in patients with CCDC6-RET, KIF5B-RET, and other-RET, respectively.

Conclusion

Robust and durable efficacy was seen in selpercatinib-treated patients with RET+ NSCLC from LIBRETTO-001 and LIBRETTO-431, regardless of fusion partner. PFS for patients with KIF5B-RET from the LIBRETTO-431 control arm was consistent with poor prognosis previously reported in this patient group. However, clinical outcomes were improved with selpercatinib vs. chemotherapy with/without pembrolizumab. These results further support early and comprehensive genomic testing to identify RET fusions and the use of selpercatinib as the first-line therapy for patients with advanced RET+ NSCLC.

Reference

Solomon BJ, et al. Efficacy of selpercatinib by RET fusion partner in RET+ NSCLC: results from the LIBRETTO-001 and LIBRETTO-431 trials. Presented at WCLC 2024; Poster P1.12B.09.