Selpercatinib Improves PFS Vs Chemotherapy in RET+ Advanced NSCLC

The randomized phase 3 LIBRETTO-431 trial (NCT04194944) included an enrollment of 261 patients with advanced or metastatic RET fusion–positive disease who did not receive any previous systemic therapy.

Selpercatinib (Retevmo) improved progression-free survival (PFS) over platinum-based chemotherapy plus pemetrexed with or without pembrolizumab (Keytruda) in the initial treatment of patients with RET fusion–positive, advanced or metastatic non-small cell lung cancer (NSCLC), according to a press release from Eli Lilly and Company on topline results from the phase 3 LIBRETTO-431 study (NCT04194944).¹

Data from a prespecified interim efficacy analysis indicated that the PFS improvement was statistically significant and clinically meaningful, according to an independent data monitoring committee. These data met the primary end point of the study.

Moreover, the adverse effect (AE) profile resembled what has been seen in prior trials. According to the agent’s labeling, selpercatinib may cause hepatotoxicity, interstitial lung disease (ILD) or pneumonitis, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, risk of impaired wound healing, hypothyroidism, or embryo-fetal toxicity.

Detailed findings are planned for presentation at a future medical conference and for submission 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 a first-line standard of care,” David Hyman, MD, chief medical officer at Loxo@Lilly, said in the 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. We look forward to sharing these data in more detail with the oncology community.”

Selpercatinib is a RET kinase inhibitor with central nervous system activity, and it can affect both tumor cells and healthy cells. The FDA-approved oral dosages are 120 mg for those under 50 kg in body weight or 160 mg for those who weigh 50 kg or higher; the agent is administered twice daily until progression or unacceptable toxicity.

The agent had previously yielded long-term outcomes in the phase 1/2 LIBRETTO-001 basket study (NCT03157128), which included patients with a variety of solid tumors.2 Treatment with selpercatinib in this trial resulted in a median PFS of 13.2 months (95% CI, 7.4-26.2) by independent review committee. Additionally, the median overall survival (OS) by investigator assessment was 18.0 months (95% CI, 10.7-not estimable). The overall response rate (ORR) by investigator assessment was 44% (95% CI, 29%-60%) in the efficacy evaluable population (n = 41).

The randomized LIBRETTO-431 trial included an enrollment of 261 patients with advanced or metastatic RET fusion–positive disease who did not receive any previous systemic therapy. Patients were randomly assigned 2:1 to receive an initial treatment of either selpercatinib or platinum-based chemotherapy consisting of either carboplatin or cisplatin, as well as pemetrexed with or without pembrolizumab. RET fusions could be identified with local testing.

The primary end point of the trial was PFS, and secondary end points included OS, ORR, intracranial ORR, and duration of response. Crossover was allowed at progression for patients who received the control regimen.

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 7, 2023. https://bit.ly/47orIgY
2. Subbiah V, Wolf J, Konda B, et al. Tumor agnostic efficacy of selpercatinib in patients with RET fusion+ solid tumors: a global, multicenter, registrational trial update (LIBRETTO-001). J Clin Oncol. 2022;40(suppl 16):3094. doi:10.1200/JCO.2022.40.16_suppl.3094