Investigators Seek New Standard in RET Fusion–Positive NSCLC

Rachel Narozniak, MA
Published: Tuesday, Feb 04, 2020
Geoffrey R.
Oxnard, MD

Geoffrey R. Oxnard, MD
Investigators hope selpercatinib (LOXO-292), a highly selective RET inhibitor, will demonstrate potential as a new standard of care (SOC) for patients with advanced or metastatic treatment-naïve RET fusion–positive non–small cell lung cancer (NSCLC) in the phase III LIBRETTO-431 (NCT04194944) trial.1

Developed to inhibit native RET signaling with minimal off-target effects, selpercatinib can potentially induce “a dramatic effect” on tumor activity without excess toxicity, Oxnard said. “Selpercatinib is like other smart designer drugs that we use, such as osimertinib (Tagrisso) for EGFR and alectinib (Alecensa) and brigatinib (Alunbrig) for ALK, agents that precisely inhibit the protein of interest without off-target toxicity, thereby leading to efficacy with minimal adverse events [AEs],” Oxnard said.

Figure. Selpercatinib in Metastatic RET Fusion–Positive NSCLC (Click to Enlarge)

Due to the modest activity of the available treatment options, it is essential to expand the armamentarium for RET-positive NSCLC, Oxnard said. Chemotherapy has some efficacy in RET fusion–positive NSCLC and, although data are limited, immunotherapy “doesn’t tend to work in these genotype-driven cancers,” he added. Moreover, multikinase inhibitors used off label, such as cabozantinib (Cabometyx) and vandetanib (Caprelsa), come with toxicity and work only occasionally. “There are no good, reliable, approved RET inhibitors for these patients,” he added.

LIBRETTO-431 is not yet recruiting but will accrue patients across 158 sites globally. To be eligible to participate in LIBRETTO-431, patients must have histologically confirmed stage IIIb to stage IIIc or stage IV nonsquamous, RET fusion–positive NSCLC that is not suitable for radical surgery or radiation therapy (Figure). The primary end point is progression-free survival (PFS). Secondary end points include overall survival, overall response rate (ORR), duration of response (DOR), and intracranial ORR. Crossover will be permitted for patients randomized to the control arm.

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