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Positive Quality Intervention: Selpercatinib Genomic Testing Management

Description:

This PQI is developed to provide guidance to genomic testing with respect to selpercatinib (Retevmo®).

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 testAssociated tumor type(s)
RET-fusionNSCLC, Thyroid
RET-mutationMTC

PQI Process:

  • 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
      • FISH
        • High rate of false positive/false negative
        • Should only be considered in rare circumstances (eg. if NGS or RT-PCR are not available)
      • Provide testing schedule to patient

Patient Centered Activities:

  • Provide education to patients regarding genetic testing and what to expect
  • Prepare care team for timely turnaround time of testing results

Supplementary Information:

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 response.15

References:

  1. 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
  2. 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
  3. 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
  4. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173-186. https://doi.org/10.1038/nrc3680
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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.
  13. 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
  14. 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
  15. RETEVMO [package insert]. Lilly USA, LLC, Indianapolis, IN; January 2021

Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

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Positive Quality Intervention: Selpercatinib Management

Description:

This PQI is developed to provide guidance for management of patients treated with selpercatinib (Retevmo®).

Background:

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 response.1

An efficacy study was conducted with patients with RET fusion-positive NSCLC who had received at least platinum-based chemotherapy; the objective response to selpercatinib of 64%. Median duration of response was 17.5 months and 63% of the responses were ongoing at a median follow-up of 12.1 months. For those who were previously untreated, ORR was measured at 85% (n=39).2 Efficacy in patients with RET-mutant MTC who were previously treated with cabozantinib and/or vandetanib was studied and ORR was 69% (n=55) and median duration of response was not reached despite a median follow-up of 14.8 months. In this same study, cabozantinib or vandetanib-naive patients had an ORR of 73% (n=88). RET fusion-positive thyroid cancer patients who were radioactive iodine (RAI)-refractory and were systemic therapy naïve had an ORR of 100% (CR 12.5%, PR 74%, n=8). Those thyroid patients previously treated with sorafenib, lenvatinib, or both had an ORR of 79% (CR 5.3%, PR 74%, n=19)3. Permanent discontinuation due to adverse reactions occurred in 5% of patients who have received selpercatinib. Dosage reductions due to an adverse reaction occurred in 31% of patients and the reactions where at least 2% or more of patients required reduction included ALT increased, AST increased, QT prolongation and fatigue.

PQI Process:

  • Determine if a patient is eligible for selpercatinib
    • Review potential patients for presence of a RET gene fusion in NSCLC or thyroid cancer or presence of a RET gene mutation in MTC
    • Review the Selpercatinib Genomic Testing Management PQI for additional information

Upon prescription of selpercatinib

  • Confirm Correct Dosing
    • Recommended dosage in adults and pediatric patients 12 years of age or older is based on weight
      • Less than 50 kg: 120 mg orally twice daily
      • 50 kg or greater: 160 mg orally twice daily
    • Dosing considerations for Adverse Reactions
o   Recommended Selpercatinib Dose Reductions for Adverse Reactions1
Dose ReductionPatients Weighing Less Than 50 kgPatients Weighing 50 kg or Greater
First80 mg orally twice daily120 mg orally twice daily
Second40 mg orally twice daily80 mg orally twice daily
Third40 mg orally once daily40 mg orally twice daily
  • Permanently discontinue if patient is unable to tolerate three dose reductions
  • Recommended Selpercatinib Dose Reductions for Adverse Reactions1
Adverse ReactionSeverityDosage Modification
HepatotoxicityGrade 3
or
Grade 4
· Withhold selpercatinib and monitor AST/ALT once weekly until resolution to Grade 1 or baseline.

· Resume at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT.

· Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence.

HypertensionGrade 3· Withhold selpercatinib for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled.
Grade 4· Discontinue selpercatinib.
QT Interval ProlongationGrade 3· Withhold selpercatinib until recovery to baseline or Grade 0 or 1.

· Resume at a reduced dose.

Grade 4· Discontinue selpercatinib.
Hemorrhagic EventsGrade 3
or
Grade 4
· Withhold selpercatinib until recovery to baseline or Grade 0 or 1.

· Discontinue selpercatinib for severe or life-threatening hemorrhagic events.

Hypersensitivity ReactionsAll Grades· Withhold selpercatinib until resolution of the event. Initiate corticosteroids.

· Resume at a reduced dose by 3 dose levels while continuing corticosteroids.

· Increase dose by 1 dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids.

Other Adverse ReactionsGrade 3
or
Grade 4
· Withhold selpercatinib until recovery to baseline or Grade 0 or 1.

· Resume at a reduced dose.

·       Recommended Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors
Current DosageRecommended Dosage
Moderate CYP3A InhibitorStrong CYP3A Inhibitor
120 mg orally twice daily80 mg orally twice daily40 mg orally twice daily
160 mg orally twice daily120 mg orally twice daily80 mg orally twice daily

 

·       Recommended Dosage for Severe Hepatic Impairment
Current DosageRecommended Dosage
120 mg orally twice daily80 mg orally twice daily
160 mg orally twice daily80 mg orally twice daily

Patient Centered Activities:

  • Provide Oncology Chemotherapy Education (OCE) Sheet
  • Counsel patient to swallow the capsules whole with or without food and to not crush or chew the capsules
  • Review patient medication list to avoid concomitant use of strong and moderate CYP3A inhibitors
  • Counsel patient to report adverse events related to high blood pressure, liver problems, heart rhythm changes, signs of bleeding, allergic reactions, and lack of wound healing
  • Tumor lysis syndrome (TLS) occurred in 1% of patients with medullary thyroid carcinoma receiving selpercatinib
    • Counsel patient to contact care team to report signs and symptoms of TLS4
      • Nausea
      • Vomiting
      • Lack of appetite
      • Fatigue
      • Dark urine/flank pain
      • Reduced urine output
      • Numbness, seizures, hallucinations
      • Muscle cramps
      • Heart palpitations

References:

  1. RETEVMO [package insert]. Lilly USA, LLC, Indianapolis, IN; Jan 2021
  2. Drilon A, Oxnard GR, et al. Efficacy of Selpercatinib in RETFusion–Positive Non–Small-Cell Lung Cancer. N Engl J Med. 2020; 383:813-824
  3. Shah MH, Sherman EJ, et al. Selpercatinib (LOXO-292) in patients with RET-mutant medullary thyroid cancer. J Clin Oncol. 2020; 38 (15)
  4. Gupta A, Moore JA. Tumor Lysis Syndrome. JAMA Oncol. 2018;4(6):895.

Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

Read More