Selpercatinib Continues to Provide Clinically Meaningful Benefit in Advanced RET Fusion–Positive NSCLC

Pipeline Report: April 2022

Selpercatinib continued to provide clinically meaningful benefit to patients with metastatic RET fusion–positive non–small cell lung cancer.

lung cancer

Selpercatinib (Retevmo) continued to provide clinically meaningful benefit to patients with metastatic RET fusion–positive non–small cell lung cancer (NSCLC), according to data from an updated analysis of the phase 1/2 LIBRETTO-001 trial (NCT03157128) presented during the European Lung Cancer 2022 meeting.1

The agent elicited a confirmed objective response rate (ORR) of 61.1% (95% CI, 54.7%-67.2%) among 247 patients who previously received platinum chemotherapy. The confirmed ORR achieved with selpercatinib in 69 patients who were treatment naïve was 84.1% (95% CI, 73.3%-91.8%). Moreover, among 26 patients who had measurable central nervous system (CNS) metastases at baseline, selpercatinib produced a CNS-ORR of 84.6%. Notably, 22 of the 26 patients experienced a complete or partial response as their confirmed best response to treatment.

With a median follow-up of 20.3 months in the treatment-naïve population, the median duration of response (DOR) was estimated to be 20.2 months (55.2% censoring rate). At a median follow-up of 21.2 months in the platinum-pretreated population, the median DOR was estimated to be 28.6 months (60.9%).

The estimated median progression-free survival (PFS) in the treatment-naïve and pretreated populations were 22.0 months (53.6% censoring rate; median follow-up of 21.9 months) and 24.9 months (55.9% censoring rate; median follow-up of 24.7 months), respectively. In those with measurable CNS disease, the median intracranial PFS with selpercatinib was 19.4 months. However, the median estimates remain immature.

“The LIBRETTO trial provides the largest set of clinical data for a RET inhibitor and these results continue to demonstrate evidence of meaningful clinical outcomes for patients with metastatic RET fusion–positive NSCLC treated with [selpercatinib], including those with difficult-to-treat brain metastases,” David Hyman, MD, chief medical officer of oncology at Eli Lilly and Company, stated in a press release.

In May 2020, the FDA granted an accelerated approval to selpercatinib for the treatment of patients with RET alteration–positive NSCLC, medullary thyroid cancer, and other thyroid cancers based on earlier data from LIBRETTO-001.2 The regulatory decision is contingent upon data from a confirmatory trial.

The multicenter phase 1/2 LIBRETTO-001 trial enrolled patients with a diagnosis of advanced or metastatic solid tumors harboring RET alterations.3 Patients needed to have an ECOG performance status ranging from 0 to 2, a QTc of ≤470 msec, and acceptable organ function. Notably, those with asymptomatic CNS metastases were allowed to participate.

A total of 355 patients were eligible for the efficacy analysis; of these patients, 247 patients were previously treated with at least 1 line of platinum chemotherapy and 69 were treatment naïve. Those who received prior treatment had received a median of 2 prior regimens (range, 1-15); 58% of these patients had received anti–PD-1/PD-L1 agents.

The primary end point of the trial was ORR per RECIST v1.1 criteria by independent review, and secondary end points included DOR, PFS, and safety.

The safety findings observed in the cohort proved to be consistent with what is known about selpercatinib. A total of 356 patients who had received at least 1 dose of the agent comprised the safety population. The adverse effects that were experienced by 25% or more of patients included dry mouth, diarrhea, hypertension, increased alanine/aspartate aminotransferase levels, peripheral edema, constipation, rash, headache, and fatigue.

Thirty four percent of patients needed to discontinue treatment with selpercatinib, with 10% doing so because of toxicity. Eleven of these cases were determined to be associated with the study agent.

“We are continuing to build on the robust body of evidence supporting [selpercatinib], including through an ongoing randomized phase 3 confirmatory study, with a planned readout in 2023,” Hyman added.

The phase 3 LIBRETTO-431 (NCT04194944), which is comparing the safety and efficacy of selpercatinib with standard treatment in patients with RET fusion–positive nonsquamous NSCLC that has spread to other parts of the body, is currently recruiting.4


  1. Lilly presents updated data on Retevmo (selpercatinib) in advanced RET fusion-positive non-small-cell lung cancer (NSCLC) at the 2022 European Cancer Congress. News release. Eli Lilly and Company; April 1, 2022. Accessed April 1, 2022.
  2. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. New release. FDA; May 8, 2020. Accessed April 1, 2022.
  3. Besse B, Drilon AE, Solomon BJ, et al. Updated overall efficacy and safety of selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9065. doi:10.1200/JCO.2021.39.15_suppl.9065
  4. A study of selpercatinib (LY3527723) in participants with advanced or metastatic RET fusion-positive non-small cell lung cancer (LIBRETTO-431). Updated March 23, 2022. Accessed April 1, 2022.
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