Selpercatinib Meets PFS End Point in Newly Diagnosed Advanced or Metastatic RET+ NSCLC

David Hyman, MD

Selpercatinib (Retevmo) significantly improved progression-free survival (PFS) vs platinum-based chemotherapy plus pemetrexed and pembrolizumab (Keytruda) in patients with advanced or metastatic non–small cell lung cancer (NSCLC) harboring RET fusions, meeting the primary end point of the phase 3 LIBRETTO-431 (NCT04194944).¹

This is the first targeted therapy to demonstrate this finding vs a PD-1 inhibitor plus chemotherapy in this patient population, according to Eli Lilly and Company. The result was based on a prespecified interim efficacy analysis that was performed by an independent data monitoring committee.

Regarding safety, toxicities observed with selpercatinib proved to be in line with what has been observed in other trials examining its use, including LIBRETTO-001 (NCT03157128), LIBRETTO-121 (NCT03899792), and LIBRETTO-321 (NCT04280081).

Full findings from LIBRETTO-431 will be shared at an upcoming medical meeting and discussed with health authorities. The data will also be submitted to a peer-reviewed journal.

“The LIBRETTO-431 trial aims to answer an important question about the selection of initial treatment for people with advanced RET fusion–positive NSCLC and these results suggest [selpercatinib] should be considered as first-line standard of care,” David Hyman, MD, chief medical officer of Loxo Oncology and Lilly Oncology, stated in a press release. “Additionally, this clinically meaningful achievement of improved outcomes underscores the importance of timely and comprehensive genomic testing to inform initial treatment decisions for all patients with NSCLC. The results of this study provide further confirmation that RET status – like EGFR, ALK, and others in the family of lung cancer oncogenic drivers – should be known prior to initiating therapy.”

The global, open-label, randomized, controlled phase 3 trial enrolled patients who were at least 18 years of age with histologically or cytologically confirmed stage IIB to IIIC or stage IV NSCLC that is not suitable for radical surgery or radiation and a RET gene fusion in the tumor.² Patients needed to have a histology that was predominantly nonsquamous, measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 to 2, a life expectancy of at least 3 months, and acceptable organ function.

Patients could not have additional known oncogenic drivers in NSCLC, symptomatic central nervous system involvement, carcinomatous meningitis, or untreated spinal cord compression. They also could not have a history of or active cardiovascular disease; active, uncontrolled, systemic bacterial, viral, or fungal infection in need of treatment; and serious ongoing intercurrent illness that is not controlled, even with treatment.

Moreover, if patients previously received systemic therapy, underwent a major surgical procedure within 3 weeks before study treatment initiation, palliative radiation within 1 week of the first study dose or any radiation within 6 months before the first study dose, they were excluded.

Study participants were randomly assigned 2:1 to receive selpercatinib at 160 mg twice daily or pemetrexed at 500 mg/m2 every 3 weeks plus physician’s choice of chemotherapy in the form of carboplatin area under the curve 5 every 3 weeks for 4 cycles or cisplatin at 75 mg/m2 every 3 weeks for 4 cycles with or without pembrolizumab at 200 mg every 3 weeks.

Notably, those on the control arm who experience disease progression are permitted to cross over to the investigative arm.

PFS by blinded independent central review for selpercatinib vs chemotherapy and pembrolizumab served as the primary end point.1 Secondary end points included overall survival, overall response rate (ORR), duration of response, and intracranial ORR.

References

1. Lilly’s Retevmo (selpercatinib) is the first targeted therapy to demonstrate superior progression-free survival compared to a PD-1 inhibitor plus chemotherapy for adults with newly-diagnosed advanced or metastatic RET fusion-positive non-small cell lung cancer. News release. Eli Lilly and Company. August 4, 2023. Accessed August 4, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-retevmor-selpercatinib-first-targeted-therapy-demonstrate
2. Loong HHF, Goto K, Elamin YY, et al. LIBRETTO-431: selpercatinib in treatment (Tx)-naïve patients with RET fusion-positive (RET) non-small cell lung cancer (NSCLC). Ann Oncol. 2020;31(suppl 4):S893. doi:10.1016/j.annonc.2020.08.1727