LIBRETTO-431: Selpercatinib as 1L SoC for RET fusion–positive NSCLC

Selpercatinib, a selective RET kinase inhibitor, showed superior efficacy vs chemotherapy and pembrolizumab as first-line (1L) treatment in patients with stage IIIB–IV nonsquamous non-small-cell lung cancer (NSCLC) with RET gene fusions, according to results of the open-label phase III LIBRETTO-431 study presented at the European Society for Medical Oncology Congress 2023 (ESMO 2023).

The prevailing standard of care (SoC) in 1L treatment of RET fusion–positive NSCLC is a platinum-based compound plus pemetrexed and pembrolizumab, which has a reported response rate of 48 percent and a median progression-free survival (mPFS) of 9 months. [N Engl J Med 2018;378:2078-2092] The corresponding values reported for selpercatinib in the single-arm phase I/II LIBRETTO-001 study were 84 percent and 22 months. [J Clin Oncol 2023;41:385-394]

“The randomized phase III LIBRETTO-431 study was designed to define the optimal 1L regimen for patients with RET fusion–positive NSCLC,” explained Dr Herbert Loong of the Department of Clinical Oncology, Chinese University of Hong Kong (CUHK). The trial included patients with stage IV or IIIB–IIIC disease not suitable for radical surgery or radiotherapy. Patients with asymptomatic brain metastases were eligible to participate in the trial and comprised approximately 20 percent of the enrolled population.

Patients were randomized 2:1 to receive selpercatinib (n=159) or SoC (n=102) with carboplatin or cisplatin plus pemetrexed with (80 percent of patients; intention-to-treat [ITT]-pembrolizumab population) or without pembrolizumab. Asian patients comprised 59 percent and 52 percent of the selpercatinib and control arms, respectively. [Loong HHF, et al, ESMO 2023, abstract LBA4]

“The trial met its primary endpoint of PFS assessed by blinded independent committee review,” reported Loong. “At a median follow-up of 19 months, the selpercatinib group had a mPFS of 24.8 months vs 11.2 months in the ITT-pembrolizumab group, producing a hazard ratio [HR] of 0.456 [95 percent confidence interval (CI), 0.309–0.699; p<0.001]. This was echoed in the overall population where the HR was 0.482 [95 percent CI, 0.331–0.700; p<0.001].”

Consistent PFS benefit was observed across all prespecified subgroups. In particular, the HRs for Asian and non-Asian patients were 0.422 (95 percent CI, 0.241–0.741) and 0.554 (95 percent CI, 0.314–0.978), respectively, and were 0.478 (95 percent CI, 0.299–0.762) and 0.508 (95 percent CI, 0.234–1.105) for patients with and without brain metastases, respectively. Both patients with positive (HR, 0.460; 95 percent CI, 0.262–0.805) and negative PD-L1 expression (HR, 0.853; 95 percent CI, 0.268–2.716) derived benefit from selpercatinib treatment.

The overall response rate was higher (83.7 percent vs 65.1 percent) and responses were more durable (median duration of response, 24.2 months vs 11.5 months) with selpercatinib vs SoC treatment. Being able to penetrate the central nervous system, selpercatinib also produced higher rates of intracranial overall response (82.4 percent vs 58.3 percent) and complete response (35.5 percent vs 16.7 percent) vs SoC.

“The cumulative incidence of new brain metastases at 12 months among patients who did not have them at baseline was 1.1 percent vs 14.7 percent in the selpercatinib vs control arm, with a cause-specific HR of 0.17 [95 percent CI, 0.04–0.69], which suggests selpercatinib has a preventive effect against brain metastases in patients with RET fusion–positive NSCLC,” highlighted Loong.

The most common adverse events (AEs) with selpercatinib were increases in aspartate aminotransferase (62 percent vs 40 percent with SoC) and alanine transaminase (60 percent vs 40 percent), hypertension (48 percent vs 7 percent), diarrhoea (44 percent vs 25 percent), and oedema (42 percent vs 28 percent).