Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer

Abstract

Background: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.

Conclusions: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Figure 1.. Efficacy.

Shown are waterfall plots of the maximum change in tumor size in all target lesions, according to investigator assessment (Panel A), in intracranial target lesions in patients who had previously received platinum-based chemotherapy, according to independent review (Panel B), and in all target lesions in previously untreated patients, according to investigator assessment (Panel C). Data for five patients who had previously received platinum-based chemotherapy are not shown, since one had nontarget lesions only and four did not undergo measurement of the target lesion after the baseline measurement. Data for one patient in the untreated group are not shown because the patient discontinued treatment before any imaging after baseline was performed. The dashed lines at 20% and −30% indicate growth and shrinkage of target lesions, respectively. Anti–PD-1 denotes anti–programmed cell death protein 1 (PD-1), and anti–PD-L1 anti–programmed cell death ligand 1.

Figure 2.. Kaplan–Meier Plots of the Duration of Response and Progression-free Survival.

Shown are data (according to investigator assessment) for patients who had previously received platinum-based chemotherapy. Panel A shows the duration of response among 73 patients with a confirmed response, and Panel B shows progression-free survival among all 105 patients. Tick marks indicate censored data.