Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial.

Abstract

9516 Background: Patients with RET fusion-positive NSCLC have an ~50% lifetime prevalence of developing central nervous system (CNS) metastases. Selpercatinib is a highly selective oral RET inhibitor with CNS penetration. Its intracranial antitumor activity was previously demonstrated in an orthotopic RET fusion-positive preclinical model. The activity of selpercatinib in RET fusion-positive NSCLC patients with CNS metastases was evaluated as a prespecified subgroup analysis in LIBRETTO-001, a registrational phase 1/2 trial (NCT03157128). Methods: This global (89 sites, 16 countries) trial enrolled patients with advanced RET-altered solid tumors, including patients with RET fusion-positive advanced NSCLC with baseline CNS metastases. The selpercatinib recommended phase 2 dose was 160 mg twice daily, dosed orally in 28-day cycles. CNS metastases were assessed by MRI/CT scan at baseline, then every 8 weeks for 1 year, and every 12 weeks thereafter. The primary endpoint for this analysis was intracranial objective response rate (ORR, confirmed; RECIST v1.1) as assessed by independent review committee (IRC). Secondary endpoints included intracranial duration of response (DoR) by IRC. To be included in the efficacy analysis, patients were required to have adequate follow-up time (opportunity for ≥6 months follow-up from the first dose). Analyses were based on 17Jun2019 data cutoff date. Results: 79 patients with RET fusion-positive NSCLC and baseline CNS metastases were enrolled. Per IRC, 22 of 79 patients had measurable (≥10 mm) CNS disease; 14 of the 22 patients had adequate follow-up time for analysis. This efficacy-evaluable population had a median age of 64 yrs (range 43-80), ECOG PS 0/1 = 21% / 79%, and all had prior systemic therapy. 5 of the 14 patients received prior intracranial radiotherapy; all radiotherapy was completed > 2 months prior to selpercatinib. The intracranial ORR in the 14 patients was 93% (n = 13; 95% CI = 66.1 – 99.8), including 2 complete responses (14%) and 11 partial responses (79%). The median intracranial DoR was 10.1 months (95% CI = 6.7 – NE), with CNS progression events (n = 5) or death (n = 1) reported in 6 of 13 responders. The remaining responders (n = 7) were ongoing and censored. Presentation will include updated IRC data as of 16Dec2019. Conclusions: Selpercatinib had marked intracranial anti-tumor activity in RET fusion-positive NSCLC patients with CNS metastases. Tumor responses were durable, independently-confirmed, and observed in patients with prior systemic chemotherapy. Clinical trial information: NCT03157128 .