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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

May 8, 2020

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf.

On May 8, 2020, the Food and Drug Administration granted accelerated approval to selpercatinib (RETEVMO, Eli Lilly and Company) for the following indications:

  • Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC);
  • Adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy;
  • Adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001) in patients whose tumors had RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, polymerase chain reaction, or fluorescence in situ hybridization. The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.

Efficacy for RET-fusion-positive NSCLC was evaluated in 105 adult patients, previously treated with platinum chemotherapy. The ORR was 64% (95% CI: 54%, 73%); 81% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 39 patients who never received systemic treatment. The ORR for these patients was 85% (95% CI: 70%, 94%); 58% of responding patients had responses lasting 6 months or longer.

Efficacy for advanced or metastatic RET-mutant MTC was investigated in adults and pediatric patients (≥12 years of age). The trial enrolled patients previously treated with cabozantinib, vandetanib, or both, and patients who had not received these drugs. The ORR for the 55 previously treated patients was 69% (95% CI: 55%, 81%); 76% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 88 patients not previously treated with an approved therapy for MTC. The ORR for these patients was 73% (95% CI: 62%, 82%); 61% of responding patients had responses lasting 6 months or longer.

Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients (≥12 years of age). The trial  enrolled 19 patients who were radioactive iodine-refractory (if appropriate) and had received another prior systemic treatment, and 8 patients who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79% (95% CI: 54%, 94%); 87% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 8 patients who received RAI and no other subsequent therapy. All 8 patients responded (95% CI: 63%, 100%) and 75% had responses lasting 6 months or longer.

The most common adverse reactions, including laboratory abnormalities, (≥ 25%) were increased aspartate aminotransferase, increased alanine aminotransferase, increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

The recommended selpercatinib dose is weight based—120 mg for patients less than 50 kg, and 160 mg for those 50 kg or greater. Selpercatinib is taken orally twice daily with or without food; or with food when co-administered with a proton pump inhibitor.

View full prescribing information for RETEVMO.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was approved 3 months prior to the FDA goal date.

This application was granted accelerated approval based on overall response rate and response duration. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

This application was granted priority review, breakthrough therapy, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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Pharmacist’s Applications to Practice

Selpercatinib for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), and RET fusion-positive thyroid cancer who are radioactive iodine-refractory.

Authors: TJ Schieber, PharmD Candidate 2021, MBA
Pharmacy Student
University of Missouri - Kansas City School of Pharmacy
Kansas City, MO

Diana Tamer, PharmD, BCOP
Clinical Assistant Professor
University of Missouri - Kansas City School of Pharmacy
Kansas City, MO

What is the potential role for selpercatinib in the treatment of RET fusion-positive non-small cell lung cancer (NSCLC), metastatic RET-mutant medullary thyroid cancer (MTC), and RET fusion positive thyroid cancer that is iodine refractory? 1-11

  • On May 8, 2020, the United States Food and Drug Administration (FDA) approved selpercatinib via the accelerated approval process, and it was granted breakthrough designation for the treatment of NSCLC and thyroid cancers with the existence of a rearranged during transfection (RET) gene fusion or specific RET gene mutations.
  • RET fusions occur when the RET receptor tyrosine kinase fuses with a partner molecule, and this fusion has oncogenic capabilities.
  • These RET fusions can coexist with EGFR mutations.
  • Selpercatinib is the first RET inhibitor on the market.
  • The approval was based on results of the global phase I/II LIBRETTO-001 study (NCT03157128). The primary endpoint of the study was objective response rate (ORR) and the secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.
    • RET fusion–positive NSCLC
      • 105 patients who had previously received at least platinum-based chemotherapy
        • ORR was 64% (95% confidence interval [CI], 54 to 73)
        • Median DoR was 17.5 months (95% CI, 12.0 to could not be evaluated)
      • 39 patients previously untreated
        • ORR was 85% (95% CI, 70 to 94)
      • 10 of 11 patients with brain metastasis responded to selpercatinib.
      • The most common grade 3 or higher adverse effects included hypertension (14%), elevated alanine aminotransferase (ALT) (12%), elevated aspartate aminotransferase (AST) (10%), lymphopenia (6%), and hyponatremia (6%). Selpercatinib was discontinued in 2% of patients due to a drug-related adverse event.
    • RET-mutant MTC
      • 55 patients who had previously received cabozantinib, vandetanib, or both
        • ORR was 69% (95% CI, 55 to 81)
        • One-year PFS was 82% (95% CI, 69 to 90)
      • 88 patients who had not previously received cabozantinib or vandetanib
        • ORR was 73% (95% CI, 62 to 82)
        • One-year PFS was 92% (95% CI, 82 to 97)
    • RET fusion-positive thyroid cancer
      • 19 patients previously treated
        • ORR was 79% (95% CI, 54 to 94)
        • One-year PFS was 64% (95% CI, 37-82).
    • The most common grade 3 or higher adverse effects seen in patients with thyroid cancer included hypertension (21%), elevated ALT (11%), elevated AST (9%), hyponatremia (8%), and diarrhea (6%). Similar to the NSCLC patient population, selpercatinib was discontinued in 2% of patients due to a drug-related adverse event.
  • The current NCCN guidelines for treatment of NSCLC prefer selpercatinib or pralsetinib (another RET inhibitor) as first-line therapy for metastatic patients with RET rearrangement discovered prior to first-line systemic therapy. If therapy has already been introduced, then it is recommended to complete the planned systemic therapy including maintenance, or interrupting, followed by preferably selpercatinib or pralsetinib.
    • Pralsetinib was granted FDA approval on September 4, 2020 after the ARROW trial showed an ORR of 57% (95% CI, 46-68) in the 87 patients previously on platinum therapy. Eighty percent of the patients maintained at least a six-month response. In the 27 patients without previous therapy, the ORR was 70% (95% CI, 50 to 86) and 58% of the patients who achieved a response maintained the response for a minimum of 6 months.
  • The current NCCN guidelines for treatment of thyroid carcinoma prefer the use of selpercatinib for locally recurrent, advanced, and/or metastatic thyroid cancer not amenable to RAI therapy and harboring RET mutations and fusions regardless of the histology. Selpercatinib can still be used with bone and CNS metastasis.

What role can the pharmacist play in the management of patients on selpercatinib? 2,12,14

  • Dosing of selpercatinib is weight-based:
    • >50 kg: 160 mg twice daily
    • <50 kg: 120 mg twice daily
    • Selpercatinib is available as 40 and 80 mg capsules
  • Dosage interruption while on therapy occurred in 42% of patients on selpercatinib.
  • Counsel patients on the importance of adherence and how to appropriately administer the drug.
    • Selpercatinib can be taken with or without food and should be taken at the same time each day.
    • Selpercatinib should be taken whole and not crushed, cut, or dissolved.
    • If a dose is missed, the patient should not take the missed dose unless it is more than 6 hours until their next scheduled dose. Recommend taking the next dose at the regularly scheduled time.
    • Avoid concomitant use of a proton pump inhibitor (PPI), a histamine-2 (H2) receptor antagonist, or a locally-acting antacid. If concomitant use cannot be avoided, administer selpercatinib with food when co-administered with a PPI, 2 hours before or 10 hours after administration of an H2 receptor antagonist, and2 hours before or 2 hours after administration of a locally-acting antacid.
  • Monitor for drug-drug interactions and drug-food interactions
    • Counsel patients on avoiding eating or drinking grapefruit or grapefruit juice as it may interact with selpercatinib.
    • Dose reduce selpercatinib by 40 mg per dose for concomitant use with moderate CYP3A inhibitors and 80 mg per dose for strong CYP3A inhibitors.
  • Pharmacists should monitor and counsel patients on selpercatinib for serious adverse effects, including:
    • ALT and AST should be monitored at baseline, every two weeks for three months, and monthly thereafter.
    • Blood pressure should be optimized at or before initiation and monitored at baseline, one week after initiation, and monthly or as clinically indicated thereafter.
    • QTc prolongation should be monitored in high risk patients along with TSH and electrolytes at baseline and periodically during treatment.
    • Hemorrhagic events while on therapy should lead to permanent discontinuation.
    • Patients should be counseled to monitor for impaired wound healing.
    • Selpercatinib should be held for all hypersensitivity reactions and treated with high dose corticosteroids (at a dose of 1 mg/kg). Selpercatinib may be resumed at a reduced dose by 3 dose levels while continuing corticosteroids and may be increased by 1 dose level each week until the dose taken prior to hypersensitivity onset is reached. At this point, the corticosteroids may be tapered.
      • Selpercatinib-induced hypersensitivity recurred in some patients within 3 to 6 hours following administration of the drug.
        • If recurrence is severe, may need to repeat management as previously stated, however target dose should be adjusted to 1 dose level before that at which recurrence occurred. If the recurrence is clinically significant at the initial re-exposure dose, selpercatinib should be permanently discontinued
        • In the absence of a clinically significant recurrent hypersensitivity, after a minimum of 7 days on re-exposure dose, the dose may be escalated sequentially. If the patient tolerates treatment for at least 7 days at the final dose, steroids may be tapered slowly.
        • In the event of a mild recurrence, patients can cautiously continue selpercatinib with supportive care, such as topical treatments or ibuprofen.
    • Use of selpercatinib during pregnancy can cause fetal harm. A pregnancy test should be performed prior to the initiation of therapy. Males with female partners of reproductive potential should use effective contraception during treatment and for 1 week after their last selpercatinib dose.
  • Other common adverse effects include increased blood glucose, decreased leukocytes, fatigue, dry mouth, decreased albumin, diarrhea, edema, increased cholesterol, decreased platelets, rash, constipation, decreased serum sodium, and increased alkaline phosphatase.
  • Dosing adjustment may be required for the following toxicities:
    • Grade 3 or 4 hepatotoxicity: Withhold selpercatinib and monitor AST and/or ALT weekly until resolution to baseline or grade 1. Resume at a reduced dose two dose levels below and may increase one dose level every two weeks up to prior dose.
    • Grade 3 hypertension: Withhold if hypertension perseveres through optimum blood pressure therapy and resume once blood pressure is controlled.
    • Grade 3 QT prolongation: Withhold until recovery to grade one or baseline.
    • Dose-reduction algorithms for use following resolution of adverse reactions are outlined in the package insert.
  • Discontinue selpercatinib for Grade 4 adverse events.
  • Do not administer selpercatinib for 7 days before surgery or and continue to hold for 14 days following surgery. Resumeonce adequate wound healing has commenced.
  • No dose adjustment has been provided by the manufacturer for CrCl<30 mL/minute.
  • Patient assistance program: Retevmo savings card is available for eligible commercially insured patients. Patients may pay as little as $0 a month up for up to $25,000 per year. An interim access program is also available that can provide a 15-day supply for eligible patients.

Clinical Pearls 2,13

  • Selpercatinib has been evaluated in pediatric patients >12 years of age.
  • No difference in efficacy or safety was seen in the geriatric patients <75 years old (67 of 702 patients studied).
  • Selpercatinib can be stored at room temperature in a dry location away from light. Store at 20-25°C/(68°F–77°F), but excursions between 15-30°C are allowed.
  • Mouth irritation and sores can occur on selpercatinib. To prevent this, patients may rinse their mouth four times daily with 1/4 teaspoon of baking soda and 1/8 teaspoon of salt in 8 ounce of warm water (not hot), use a soft tooth brush, and avoid alcohol (including in mouthwash) and tobacco products.
  • Fatigue can occur while on selpercatinib. To help prevent this patients should be encouraged to stay active and plan activities in times where they are not tired.
  • Diarrhea can occur while on treatment with selpercatinib. Patients should be counseled to notify theirontact prescriber with 4 or more loose stools in one day. Over the counter loperamide can be recommended and patients should be instructed to eat small bland meals and drink 8 to 10 glasses of water a day unless their prescriber has instructed them to limit fluid intake.
  • Selpercatinib is a first in class drug approval. There are other diseases in which RET-fusions may occur, and off-label use may occur in genomics clinics and precision-guided therapeutics clinics, or when next-generation sequencing has been performed and these mutations have been identified.

References

  1. US Food & Drug Administration. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. May 11, 2020. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions. Accessed September 11, 2020.
  2. Retvemo (selpercatinib) capsules, for oral use [package insert]. Indianapolis, IN: Eli Lilly & Company; 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf.
  3. O’Leary C, Xu W, Pavlakis N, et al. Rearranged during transfection fusions in non–small-cell lung cancer. Cancers (Basel). 2019;11:620.
  4. Gainor JF, Shaw AT. Novel targets in non–small-cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18:865-875.
  5. Kato S, Subbiah V, Marchlik E, et al. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23:1988-1997.
  6. Takeuchi K. Discovery stories of RET fusions in lung cancer: mini-review. Front Physiol. 2019;10:216.
  7. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Aug 27;383(9):813-824.
  8. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. 2020 Aug 27;383(9):825-835.
  9. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. Version 7.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 11, 2020.
  10. US Food & Drug Administration. FDA approves pralsetinib for lung cancer with RET gene fusions. September 8, 2020. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions#:~:text=On%20September%204%2C%202020%2C%20the,by%20an%20FDA%20approved%20test. Accessed September 11, 2020.
  11. National Comprehensive Cancer Network. Thyroid Carcinoma. Version 2.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed September 11, 2020.
  12. Lilly USA. Retevmo Savings & Support. https://www.retevmo.com/hcp/savings-support#savings-card. Accessed September 25, 2020.
  13. Oral Chemotherapy Education Selpercatinib. May 27, 2020. http://oralchemoedsheets.com/sheets/Selpercatinib_Patient_Education.pdf. Accessed September 25, 2020.
  14. McCoach C, Tan DSW, Besse B, et al. Hypersensitivity reactions to selpercatinib in patients with RETfusion-positive non-small cell.
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