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Selpercatinib: Precision Medicine for RET Fusion–Positive NSCLC


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Selpercatinib (LOXO-292), a RET kinase inhibitor, demonstrated antitumor activity in the lungs and brain and durable responses with acceptable tolerability in patients with RET fusion–positive non–small cell lung cancer (NSCLC), according to an updated analysis of the LIBRETTO-001 registration trial.1

Selpercatinib was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) in 2018, based on initial reports from the LIBRETTO-001 trial. At the 2019 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC), Alexander Drilon, MD, of Memorial Sloan-Kettering Cancer Center, New York, presented updated results of LIBRETTO-001 based on 105 patients with NSCLC who received selpercatinib.1


We are encouraged by these data, as there is currently an unmet need to provide genomically tailored therapy to patients with RET fusion–positive NSCLC.
— Alexander Drilon, MD

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“No targeted therapy is currently approved for patients with RET fusion–positive NSCLC. According to data from the LIBRETTO-001 trial, selpercatinib could represent a major advance in filling this unmet need for the proportion of patients with RET-positive NSCLC,” Dr. Drilon stated.

“In this large cohort, selpercatinib’s response rate, durability, robust intracranial activity, and safety show promise. Furthermore, this confirms that RET fusions are clinically targetable alterations, placing them in the company of activating EGFR/ALK/ROS1 alterations. We are encouraged by these data, as there is currently an unmet need to provide genomically tailored therapy to patients with RET fusion–positive NSCLC,” Dr. Drilon stated.

“Older multikinase inhibitors studied in patients with RET fusion–positive NSCLC were ‘dirtier’ drugs, with more toxicity because of multiple targets. Selpercatinib is a ‘cleaner’ drug that does not hit unintended targets and thus has a more favorable safety profile,” he emphasized.

Approximately 1% to 2% of all NSCLC cases harbor RET fusions. This group of patients comprises up to 5,000 of all new cases of lung cancer diagnosed in 2019. Multikinase inhibitors also target RET, but with far less specificity. The hope is that a highly selective RET inhibitor such as selpercatinib can improve outcomes in RET fusion–positive NSCLC and other tumor types that harbor this alteration.

Study Details

LIBRETTO-001 is a global phase I/II trial conducted at 87 sites in 15 countries. The study enrolled patients with advanced RET-altered solid tumors, including RET fusion–positive NSCLC. Patients received oral selpercatinib in 28-day cycles. Phase I established the maximal tolerated dose of 160 mg twice daily moving forward. In phase II, patients were enrolled in one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was objective response rate. Secondary endpoints included antitumor response, duration of response in the lungs and brain, progression-free survival, overall survival, safety, and pharmacokinetics.

As of June 2019, 247 patients with RET fusion–positive NSCLC were treated. The prespecified sample size for the primary analysis for registration of the drug included the first 105 consecutively enrolled patients treated with prior platinum-based chemotherapy; 54% of patients also received prior immune checkpoint inhibitors.

The median age of patients was 61 years, and 59% were female. The median number or previous treatments was 3; 55% received checkpoint inhibitors and 48% received one or more multikinase inhibitors.

Key Findings and Toxicity

The majority of patients in the primary analysis set have been followed for at least 6 months from first response. At the data cutoff, more than two-thirds (68%) achieved a response, the median duration of response was 20.3 months, and the median progression-free survival was 18.4 months. The intracranial objective response rate was 91% (10 of 11 patients with target lesions in the brain at baseline).

“This means that not only can you use this drug for patients who have existing disease intracranially, but also you can use selpercatinib to potentially prevent that acquisition of brain metastases,” noted Dr. Drilon at a press conference.

LIBRETTO-001: RET-Fusion Inhibitor

  • The highly selective RET-fusion inhibitor selpercatinib achieved high response rates, durable responses, robust intracranial activity, and acceptable safety in patients with RET fusion–positive advanced NSCLC in the LIBRETTO-001 registration trial.
  • The drug is poised to be an option for the 1% to 2% of patients with NSCLC whose cancers harbor this genetic alteration.

Dr. Drilon also presented data on 34 patients with treatment-naive disease. The objective response rate was 85%, including one complete response. “This is higher than in previously treated patients,” he said.

In a safety analysis of all 531 patients enrolled in the trial, treatment-related adverse events of any grade occurred in at least 15% of patients. Most of the adverse events were grade 1 or 2 and were manageable, Dr. Drilon said. Grade 3 and 4 treatment-emergent adverse events included diarrhea, hypertension, increased liver enzyme levels and fatigue. The rate of treatment discontinuation related to adverse events was 1.7%.

A randomized global phase III trial will evaluate selpercatinib vs platinum-based chemotherapy with or without immune checkpoint inhibitors as first-line treatment for RET fusion–positive NSCLC.

Future for Selpercatinib

Experts at the press conference pointed out that genetic testing will be required to identify patients who may benefit from selpercatinib. “Unfortunately, the testing question also comes with an economic question,” noted Dr. Drilon. “We have shown that the best possible test is comprehensive next-generation sequencing that has both DNA and RNA, making it most likely to pick up RET fusions as well as other clinically actionable alterations that have targeted drugs. Fluorescence in situ hybridization or real-time polymerase chain reaction could be used in settings where next-generation sequencing is not available, but these methods are not as sensitive for all RET fusions in comparison to next-generation sequencing.”

Dr. Drilon continued: “Similar to other targeted therapies, should selpercatinib be approved, it is almost certainly going to be used as a single agent. The most ideal situation would be to get the drug approved for treatment-naive RET fusion–positive lung cancers, although a preliminary approval in the postplatinum doublet setting would represent an important initial step and would likewise be a win for patients.”

Selpercatinib may also find a role in treating other RET fusion/mutation–positive cancer types. “The trial is interrogating the activity of the drug in other tumors. We’ve already presented data showing that the drug can work in RET fusion–positive pancreatic cancers, papillary thyroid cancers, and other tumors such as congenital fibrosarcoma. In addition, we’ve also shown that the drug is active in RET-mutant medullary thyroid cancers, for which the drug already has an FDA Breakthrough Therapy designation,” Dr. Drilon explained. 

DISCLOSURE: LIBRETTO-001 was funded by Loxo Oncology, Inc. Dr. Drilon has received honoraria and served on advisory boards for AbbVie, Ariad, AstraZeneca, Bayer, BeiGene, BergenBio, Blueprint Medicines, Exelixis, Genentech, Helsinn, Hengrui Therapeutics, Ignyta, Loxo, Lilly, Millennium, MORE Health, Pfizer, Roche, Takeda, TP Therapeutics, Tyra Biosciences, and Verastem; has received institutional research funding from Exelixis, GlaxoSmithKline, Pfizer, PharmaMar, Taiho, and Teva; has received royalties from Wolters Kluwer; and has financial relationships with AstraZeneca, AbbVie, Exelixis, Bayer, Lilly, Loxo Oncology, Pfizer, Genentech/Roche, and Takeda.

REFERENCE

1. Drilon A, et al: 2019 World Conference on Lung Cancer. Abstract PL02.08. Presented September 9, 2019.


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