RET Inhibition Shows Significant Intracranial Responses in RET-Altered NSCLC

Selpercatinib (Retevmo) demonstrated durable intracranial responses in patients with RET fusion–positive non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases, according to findings from a subset of patients in the LIBRETTO-001 trial.¹

The objective response rate (ORR) among 22 patients with measurable CNS disease was 81% (95% CI, 59.7%-94.8%) by independent review committee. With a median follow-up of 9.5 months, the median duration of response (DOR) seen was 9.4 months (95% CI, 7.4 to not evaluable [NE]).

“Selpercatinib had marked intracranial anti-tumor activity in RET fusion–positive patients with [NSCLC and] CNS metastases. Tumor responses were durable, independently confirmed, and observed in patients with prior systemic chemotherapy,” the study authors, led by Vivek Subbiah, MD, wrote in their poster presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. Subbiah is an associate professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

RET inhibition with selpercatinib has demonstrated significant activity in patients with RET fusion–positive solid tumors. Last month the FDA approved selpercatinib for the treatment of patients with lung cancer or thyroid cancer harboring RET alterations, based on findings from the LIBRETTO-001 trial.² And updated data presented through the ASCO Virtual Scientific Program maintained the benefit in these patient populations.

Among patients with RET fusion–positive NSCLC who have previously received platinum-based chemotherapy, the ORR was 64% (95% CI, 54%-73%) by independent review with a median DOR of 18 months (95% CI, 12-NE). Treatment-naïve patients had an ORR of 85% (95% CI, 70%-94%) by independent review, and the median DOR was not yet reached.3

By investigator review, the ORR was 70% (95% CI, 60%-78%) in patients who had previously received platinum doublet chemotherapy and was 90% (95% CI, 76%-97%) in patients who were not previously exposed to treatment.

The agent also demonstrated a manageable safety profile with most adverse events being low grade and not related to treatment with selpercatinib. Only 2% of patients discontinued treatment due to treatment-related adverse events.

However, about 50% of patients with RET fusion–positive NSCLC will develop CNS metastases in the course of their disease.

Investigators reviewed intracranial responses (CNS ORR) among patients with CNS metastasis at baseline (n = 80), 22 of whom had measurable CNS disease. The secondary end point was CNS DOR by independent review committee.¹

Patients had a median age of 64.0 years (range, 36-80) and 81.8% were female. A majority of the patients (72.7%) had an ECOG performance status of 1, were white (63.6%), and never smokers (81.8%). The most common RET fusion partner was KIF5B in 72.7% followed by CCDC6 in 13.6%. Twenty of the patients (90.2%) had received prior systemic therapy, including platinum chemotherapy in 72.7%, anti–PD-1/PD-L1 in 54.5%, and a multikinase inhibitor in 50.0%. More than a third of patients (36.4%) received brain radiotherapy for their CNS metastasis.

The best overall CNS response included complete responses (CRs) in 5 patients, partial responses in 13, and stable disease in 4.

The CNS ORR among patients who received prior radiotherapy for CNS metastases (n = 8) was 75.0% (95% CI, 34.9%-96.8%) compared with 85.7% (95% CI, 57.2%-98.2%) in patients without prior CNS radiotherapy (n = 14).

In the prior CNS radiotherapy group, the median duration of CNS follow-up was 9.5 months, and the median CNS DOR was not evaluable. Among the patients who did not receive prior CNS radiotherapy, the median duration of follow-up was 15.7 months and the median CNS DOR was 9.4 months.

The authors noted that a randomized, global phase 3 trial is ongoing exploring the efficacy of selpercatinib versus platinum-pemetrexed with or without pembrolizumab (Keytruda) in patients with treatment-naïve RET fusion–positive NSCLC, including those who have asymptomatic brain metastases (LIBRETTO-431; NCT04194944).

_References:

_{1. Subbiah V, Gainor JF, Oxnard GR, et al. Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial. J Clin Oncol. 2020;38(suppl):9516. doi:10.1200/JCO.2020.38.15_suppl.9516}

_{2. FDA Approves First Therapy for Patients with Lung and Thyroid Cancers with a Certain Genetic Mutation or Fusion. News release. FDA. May 8, 2020. https://bit.ly/3dsLuuO. Accessed June 4, 2020.}

_{3. Goto K, Oxnard GR, Tan DSW, et al. Selpercatinib (LOXO-292) in patients with RET-fusion+ non-small cell lung cancer. J Clin Oncol. 2020;38(suppl):3584. doi:10.1200/JCO.2020.38.15_suppl.3584}