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Associate Professor, Thoracic Oncology
Director, Thoracic Oncology Program
Department of Medical Oncology
New York University
New York, New York
Vamsidhar Velcheti, MD, has reported that he has received consulting fees from AstraZeneca, Bristol-Myers Squibb, EMD Serono, Foundation Medicine, and Merck.
RET genetic alterations, which can manifest as fusions or mutations, have been shown to drive cancer development. RET fusions are observed in 1% to 2% of non-small-cell lung cancers (NSCLC) and in 10% to 20% of papillary and other thyroid cancers, whereas RET mutations are observed in 40% to 60% of medullary thyroid cancers.
In this commentary, I discuss the clinical implications of the recent approval of the RET inhibitor selpercatinib specifically for advanced RET fusion–positive NSCLC, which represents a practice-changing breakthrough for this group of patients with rare disease.
Approval of Selpercatinib for RET Fusion–Positive NSCLC
Selpercatinib—a RET-targeted kinase inhibitor—was approved by the FDA in May 2020 for the treatment of patients with lung cancer or thyroid cancer harboring RET alterations:
Selpercatinib was approved under the FDA’s Accelerated Approval program based on positive results from the LIBRETTO-001 trial, a single-arm, multicenter phase I/II trial that evaluated the optimal dose, safety, and efficacy of selpercatinib in 702 patients with locally advanced/metastatic solid tumors intolerant or refractory to standard therapy, including patients with advanced NSCLC. In this trial, treatment with selpercatinib achieved an ORR of 68% in the first 105 patients with RET fusion–positive NSCLC who had received previous platinum doublet chemotherapy, with a duration of response of 20.3 months. Significant responses were observed regardless of previous treatment with chemotherapy, immunotherapy, or a multikinase inhibitor. The ORR was even higher for 34 patients with previously untreated, RET fusion–positive NSCLC, at 85%. In the subset of 11 patients with brain metastases, selpercatinib demonstrated a CNS ORR of 91%, which is important considering that up to one half of patients with RET fusion–positive NSCLC can experience brain metastases. Selpercatinib was well tolerated compared with standard-of-care treatment options, and most adverse events were low grade. Indeed, very few patients on the LIBRETTO-001 study discontinued treatment because of adverse events.
Approval of selpercatinib is conditional and contingent upon confirmation of the clinical benefit in phase III trials (LIBRETTO-431 [NCT04194944] in advanced RET fusion–positive NSCLC and LIBRETTO-531 [NCT04211337] in RET-mutant medullary thyroid cancer), which are currently enrolling patients.
Recommendations on Testing for RET Alterations
Most large academic centers, such as the one at which I work, generally use next-generation sequencing (NGS)–based platforms to identify gene fusions arising from oncogenic chromosomal rearrangements. In fact, in addition to testing for genomic alterations in EGFR, ALK, ROS1, and BRAF, current guidelines recommend using NGS testing to detect alterations in NTRK, HER2, RET, MET, and KRAS as part of a broad, panel-based approach, when available. More recently, studies have looked at RNA sequencing–based approaches, which tend to have higher sensitivity for fusions than DNA-based approaches. RET fusions can be detected by a RET FISH test, but the sensitivity and reproducibility are relatively poor.
Clinical Implications: My Thoughts
I think one of the most important takeaways from this trial and the approval of selpercatinib is that it is becoming extremely important to perform comprehensive genomic sequencing for patients with lung cancer. Although some alterations may be rare, such as those in the RET gene, there are now multiple targeted therapies approved in lung cancer that could potentially have a significant clinical impact in select groups. It is imperative that we test for and identify these genetic alterations, because if we don’t, we will be unable to match the right patients to the right treatment.
Although selpercatinib is well tolerated, approximately one half of the patients did have varying degrees of liver enzyme elevations (transaminitis) although most of these increases were mild and clinically insignificant. Nevertheless, this should be closely monitored and would require a dose reduction for grade 3/4 transaminitis.
What questions do you have about the use selpercatinib in your patients with advanced NSCLC? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below.