Written By: Joshua Nubla, PharmD, NCODA
Description: This PQI is developed to provide guidance to genomic testing with respect to selpercatinib.
Background: RET-altered cancers include both RET fusions and RET mutations. Both alterations involve activating RET signaling pathways that promote unwanted cell proliferation in cancers. NCCN guidelines for NSCLC include a Category 2A recommendation for RET testing as part of broad molecular profiling in routine clinical practice. In multiple guidelines, RET testing is considered as part of a larger initial panel or secondary single analyte test following negative results for other genetic variants such as EGFR, ALK, and ROS1. Molecular testing within RET-mutated medullary thyroid cancer (MTC) is applicable as approximately 50% of patients with sporadic MTC have somatic RET mutations. In American Thyroid Association, NCCN, and ESMO guidelines, RET testing should be considered within the MTC space. Next generation sequencing (NGS) analyzes DNA and/or RNA when detecting RET. This method requires a small amount of tissue for multiplex testing for many common and rare cancer-related biomarkers. Tissue testing is often considered as RET alteration may not be found in the blood through liquid biopsy and up to 30% of RET alterations can be missed if only ctDNA is tested. There are multiple testing methods for RET that will help determine patient eligibility for selpercatinib, noting that indicated tumor types are associated with specific alterations (Review Supplemental Information section for approved indications).
|RET alteration to test||Associated tumor type(s)|
- Consider the following preferred testing methods when planning for RET genomic testing:
- Next generation sequencing (NGS) when applicable
- Account for 2-4 weeks for test completion
- Both DNA and RNA-based NGS testing methods are appropriate and care team should discuss the general advantages and disadvantages of both
- RNA-based NGS is able to reveal unbiased fusion information and there are no intron coverage issues 5,10
- Reverse Transcription-PCR
- Quick and relatively inexpensive; test completion with 1-2 days
- PCR testing is designed predominantly for fusions and RET fusion frequency is underestimated
- High rate of false positive/false negative
- Should only be considered in rare circumstances (ex. if NGS or RT-PCR are not available)
- Provide testing schedule to patient
- Next generation sequencing (NGS) when applicable
Patient Centered Activities:
- Provide education to patients regarding genetic testing and what to expect
- Prepare care team for timely turnaround time of testing results
- Refer to Selpercatinib (Retevmo® Management PQI and Oral Chemotherapy Education (OCE) sheet
Selpercatinib is a kinase inhibitor indicated for the treatment of:
- Adult patients with metastatic RETfusion-positive non-small cell lung cancer (NSCLC)*
- Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy*
- Adult and pediatric patients 12 years of age and older with advanced or metastatic RETfusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)*
*This indication is approved under accelerated approval based on overall response rate and duration of response15
- Normanno N, Denis MG, Thress KS, et al. Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer. 2017;8(7):12501-12516. https://doi.org/10.18632/oncotarget.13915.
- Meric-Bernstam F, Johnson A, Holla V, et al. A decision support framework for genomically Informed investigational cancer therapy. 2015;107(7). https://doi.org/10.1093/jnci/djv098
- Drilon A, Hu ZI, Lai GG, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. https://doi.org/10.1038/nrclinonc.2017.175.
- Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173-186. https://doi.org/10.1038/nrc3680.
- Garinet S, Laurent-Puig P, Blons H, Oudart JB. Current and future molecular testing in NSCLC, what can we expect from new sequencing technologies? J Clin Med. 2018;7(6):144. https://doi.org/10.3390/jcm7060144.
- Lee SE, Lee B, Hong M, et al. Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma. Mod Pathol. 2015;28(4):468-479. https://doi.org/10.1038/modpathol.2014.107.
- Chen F, Clark DP, Hawkins AL, et al. A break-apart fluorescence in situ hybridization assay for detecting RET translocations in papillary thyroid carcinoma. Cancer Genet Cytogenet. 2007;178(2):128-134. https://doi.org/10.1016/j.cancergencyto.2007.07.006.
- Musholt TJ, Staubitz JI, Cámara RJ, et al. Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques – a molecular and clinical analysis. Eur J Surg Oncol. 2019;45(6):1018-1024. https://doi.org/10.1016/j.ejso.2018.11.009.
- Go H, Jung YJ, Kang HW, et al. Diagnostic method for the detection of KIF5B-RET transformation in lung adenocarcinoma. Lung Cancer. 2013;82(1):44-50. https://doi.org/10.1016/j.lungcan.2013.07.009.
- Drilon A, Wang L, Arcila ME, et al. Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res. 2015;21(16):3631-3639. https://doi.org/10.1158/1078-0432.CCR-14-2683
- Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv192-iv237. http://dx.doi.org/10.1093/annonc/mdy275. Published correction appears in Ann Oncol. 2019;30(5):863-870. http://dx.doi.org/10.1093/annonc/mdy474
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline for Thyroid Carcinoma V.1.2020. © National Comprehensive Cancer Network, Inc 2020. Accessed June 19, 2020. To view the most recent and complete version of the guideline, go online to org.
- Wells SA Jr., Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. http://dx.doi.org/10.1089/thy.2014.0335.
- Pacini F, Castagna MG, Brilli L, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl 7):110-119. https://doi.org/10.1093/annonc/mds230.
- RETEVMO® [package insert]. Lilly USA, LLC, Indianapolis, IN.