Written by: Prithviraj Bose, MD, UT MD Anderson Cancer Center

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Description: The purpose of this PQI is to assist in the diagnosis of the advanced systemic mastocytosis patient by providing a diagnostic algorithm.

Background: Systemic mastocytosis (SM) is a myeloid neoplasm driven in ~95% of cases by an activating mutation, D816V, affecting exon 17 of the KIT gene, and characterized by the accumulation of neoplastic mast cells in a variety of extra-cutaneous organs (as opposed to cutaneous mastocytosis (CM), which generally affects children and is limited to the skin).1 The bone marrow is almost always involved, and patients can exhibit an array of symptoms involving multiple organ systems, such as spots, itching, flushing, fatigue, headache, dizziness, “brain fog”, nausea, vomiting, diarrhea and abdominal pain, among many others. Osteopenia and osteoporosis are common. Patients may report a wide range of triggers, stress being the most common, for their symptoms, believed to be a result of mast cell degranulation and mediator release. Anaphylaxis can occur and it is essential that patients have an epinephrine auto-injector in hand. SM is rare, with an annual incidence of 0.89/100,000 in a population study from Denmark.2

The diagnosis of SM is a pathologic one, typically based on examination of the bone marrow.3 Serum tryptase testing and peripheral blood testing for the KIT D816V mutation using a sensitive technique such as digital droplet or allele-specific oligonucleotide polymerase chain reaction (ddPCR or ASO-PCR) can provide extremely helpful clues to the diagnosis in the appropriate setting, and serve as the basis for referral to a hematologist for bone marrow biopsy. Importantly, myeloid mutation panels utilizing next-generation sequencing (NGS) platforms, may miss low (ex. <2-5%) mutant allele frequency KIT mutations.4 Well-differentiated SM, characterized by rounded, instead of spindled, mast cells is very rare but important to recognize because of the usual absence of KIT D816 mutations and hence, responsiveness to imatinib (imatinib is ineffective against the D816V and related mutations).5  A recent, single-institution study from Germany estimated the annual incidence and prevalence of advanced SM (AdvSM, see below) to be 0.8 and 5.2 per million inhabitants in the region, respectively.6 Survival in AdvSM has historically been poor; in a 2019 study by the European Competence Network on Mastocytosis, median survival was 5.7 years for patients with aggressive SM (ASM), 2.9 years for those with SM with an associated hematologic neoplasm (SM-AHN), and 1.9 years for those with mast cell leukemia (MCL).7

PQI Process:

  • Criteria for the diagnosis of systemic mastocytosis: the major criterion and ≥1 minor criteria or ≥3 minor criteria required for diagnosis8
    • Major criterion:
      • Multifocal dense infiltrates of mast cells (≥ 15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)
    • Minor criteria:
      • > 25% of all mast cells are immature or atypical on bone marrow aspirate smears or are spindle-shaped or atypical in mast cell infiltrates detected on biopsy sections of bone marrow or other extra-cutaneous organs
      • Activating c-KIT point mutation at codon 816 in the bone marrow, blood or another extracutaneous organ
      • Mast cells in bone marrow or blood or another extracutaneous organ express CD25 and/or CD2, in addition to normal mast cell markers
      • Serum tryptase concentration > 20 ng/ml in the absence of an associated myeloid neoplasm
    • SM Subclassification:8
      • Indolent SM (ISM): 0-1 B findings and no C findings – life expectancy near-normal (though inferior to that of patients with CM), with a 5-10% risk of progression to more advanced forms
      • Smoldering SM (SSM): ≥2 B findings in the absence of C findings – a condition with relatively high mast cell burden but without organ damage from infiltrating neoplastic mast cells
      • Advanced SM (AdvSM): ≥1 C findings – organ damage attributable to mast cell infiltration AdvSM Subtypes:
        • Aggressive SM (ASM)
        • SM with an associated hematologic neoplasm (SM-AHN) *most common*
          • AHN is usually myeloid, the most frequent ones being myelodysplastic/myeloproliferative (MDS/MPN) “overlap” syndromes such as chronic myelomonocytic leukemia (CMML)
          • Finding of KIT D816V in a patient with another myeloid neoplasm should prompt a search for an occult SM that may have been obscured on histopathology by the AHN9
        • Mast cell leukemia (MCL): presence of ≥20% mast cells on the bone marrow aspirate smear; in contrast, circulating mast cells are usually <10% (“aleukemic” MCL)
          • Rarely a “chronic” variant of MCL, without C findings, may be encountered10
        • B and C Findings8
          • B findings (high mast cell burden but no organ damage)
            • >30% infiltration of bone marrow cellularity by mast cells and serum total tryptase >200 ng/mL
            • Signs of dysplasia or myeloproliferation in non-mast cell lineage(s), but criteria are not met for definitive diagnosis of an associated hematologic neoplasm with normal or only slightly abnormal blood counts
            • Hepatomegaly without impairment of liver function
            • Palpable splenomegaly without hypersplenism
            • Lymphadenopathy on palpation or imaging
          • C findings (organ damage caused by mast cell infiltration)
            • Bone marrow dysfunction caused by neoplastic mast cell infiltration manifested by ≥1 cytopenia: absolute neutrophil count <1.0 × 109/L, hemoglobin level <10 g/dL, and/or platelet count <100 × 109/L
            • Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
            • Skeletal involvement, with large osteolytic lesions with or without pathological fractures (pathological fractures caused by osteoporosis do not qualify as a C finding)
            • Palpable splenomegaly with hypersplenism
            • Malabsorption with weight loss due to gastrointestinal mast cell infiltrates

Patient Centered Activities:

  • Discuss the importance of testing for KIT and other mutations in the context of other diagnostic criteria
  • Ensure patient has prescription for epinephrine auto-injector and proper knowledge of how to use
  • Ensure bone health is not ignored/overlooked and patients are treated for osteopenia/osteoporosis
  • Discuss diagnostic findings and counsel patients regarding treatment options (symptom-directed therapies for non-advanced SM, KIT-targeted and other cytoreductive therapies for advanced SM)

References:

  1. Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future. Cancer Res. 2017 Mar 15;77(6):1261-70.
  2. Cohen SS, Skovbo S, Vestergaard H, Kristensen T, Moller M, Bindslev-Jensen C, et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014 Aug;166(4):521-8.
  3. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001 Jul;25(7):603-25.
  4. Gotlib J, Gerds AT, Bose P, Castells MC, Deininger MW, Gojo I, et al. Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018 Dec;16(12):1500-37.
  5. Alvarez-Twose I, Matito A, Morgado JM, Sanchez-Munoz L, Jara-Acevedo M, Garcia-Montero A, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget. 2016 Jul 19;8(40):68950-63.
  6. Schwaab J, Cabral do O Hartmann N, Naumann N, Jawhar M, Weiss C, Metzgeroth G, et al. Importance of Adequate Diagnostic Workup for Correct Diagnosis of Advanced Systemic Mastocytosis. J Allergy Clin Immunol Pract. 2020 Oct;8(9):3121,3127.e1.
  7. Sperr WR, Kundi M, Alvarez-Twose I, van Anrooij B, Oude Elberink JNG, Gorska A, et al. International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 2019 Dec;6(12):e638-49.
  8. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53.
  9. Craig JW, Hasserjian RP, Kim AS, Aster JC, Pinkus GS, Hornick JL, et al. Detection of the KIT(D816V) mutation in myelodysplastic and/or myeloproliferative neoplasms and acute myeloid leukemia with myelodysplasia-related changes predicts concurrent systemic mastocytosis. Mod Pathol. 2020 Jun;33(6):1135-45.
  10. Valent P, Sotlar K, Sperr WR, Reiter A, Arock M, Horny HP. Chronic mast cell leukemia: a novel leukemia-variant with distinct morphological and clinical features. Leuk Res. 2015 Jan;39(1):1-5
Important notice: 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. Updated 10.13.21
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Written by: Danny Nguyen, MD, Nishan Tchekmedyian, MD, André K.D. Liem, MD, City of Hope National Medical Center

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Description: Mobocertinib (Exkivity™) is an oral EGFR tyrosine kinase inhibitor (TKI) designed to specifically target EGFR ex20ins mutations.1 This PQI will discuss effective strategies for side effect management.

Background: Mobocertinib is indicated in locally advanced or metastatic non-small cell lung cancer (NSCLC). Mobocertinib demonstrated meaningful clinical benefit in 114 platinum-pretreated patients (PPP) with EGFR ex20ins+ NSCLC in a phase 1/2 study (NCT02716116), with confirmed objective responses by independent assessment reported in 28% of patients and median duration of response of 17.5 months.2

PQI Process:  By far, the most common side effect associated with mobocertinib is diarrhea (92%), followed by rash (78%), stomatitis (46%), vomiting (40%) and nausea (37%). Mobocertinib also includes a boxed warning for QTc prolongation and Torsades de Pointes. Below are tips that may improve patient quality of life on mobocertinib thereby maximizing the benefit patients may receive from mobocertinib:

  • Monitoring:4
    • Monitor QTc and electrolytes at baseline and periodically during treatment
    • Monitor for new or worsening pulmonary symptoms indicative of Interstitial Lung Disease (ILD)/pneumonitis and immediately withhold in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed
    • Monitor cardiac function, including left ventricular ejection fraction, at baseline and during treatment. Withhold, then resume at reduced dose or permanently discontinue based on severity
    • Monitor electrolytes and advise patients to start an antidiarrheal agent at first episode of diarrhea and to increase fluid and electrolyte intake. Withhold, reduce, or permanently discontinue based on severity
  • Drug-Drug Interactions: 4
    • Mobocertinib is a CYP3A substrate
      • Avoid concomitant use of mobocertinib with strong or moderate CYP3A inhibitor. If concomitant use is unavoidable, reduce the dose and monitor the QTc interval more frequently with ECGs
      • Avoid concomitant use with strong/moderate CYP3A inducers, may reduce anti-tumor activity
      • Avoid concomitant use of hormonal contraceptives
      • Avoid concomitant use of other medications known to prolong the QTc interval. If concomitant use is unavoidable, monitor the QTc interval more frequently with ECGs
Diarrhea Severity (CTCAE Grade)Intervention
Grade 0 or on Cycle 1, Day 1Consider prophylaxis when prescribing mobocertinib:

a) Loperamide 2 mg PO daily to BID (titrate to 1-2 BM per day)

Grade 1Loperamide 4 mg, followed by 2 mg after each loose stool (max: 16 mg/day)
Grade 2Interventions listed in Grade 1 and:

a) Diphenoxylate/atropine 5 mg QID until control achieved (max: 20 mg/day)

b) Consider cholestyramine 4 g orally BID (30 minute prior to meals)

c)  Consider budesonide 9 mg daily for 4 weeks

d) Assess the need for IV hydration (saline) frequently

Grade 3Interventions listed in Grade 1 and 2 and:

a) Consider holding mobocertinib until resolution of diarrhea to Grade ≤ 1

b) Opium tincture (morphine 10 mg/mL) 6 mg of undiluted opium tincture QID

c)  Octreotide 100 to 150 mcg sq TID

d) Strongly consider IV hydration unless contraindicated

Rash Severity
(CTCAE Grade)
Intervention
Grade 0 or on Cycle 1, Day 1Consider prophylaxis with:

a) Doxycycline 100 mg PO BID or Minocycline 100 mg PO BID

b) Daily moisturizing lotion, bland emollient

Grade 1Interventions listed in Grade 0 and:

a) Face: hydrocortisone 1.0% to 2.5% BID to affected area

Body: triamcinolone 0.1% BID to affected area

b) Derma-Smoothe* 0.01% (or similar) apply topical TID to affected area copiously

Grade 2Interventions listed in Grade 0 and 1 and:

a)     Add clindamycin 1.0% cream BID to affected area

Grade 3Interventions listed in Grade 0 and:

a) Hold mobocertinib until resolution of rash to Grade ≤ 1

b) Increase clindamycin 1.0% to 2.0% cream BID to affected area

c)  Start on oral prednisone 5 to 10 mg PO daily.  Increase by 5 to 10 mg PO weekly depending on improvement.  Alternatively, can start on a Medrol DosePak

Grade 4Interventions listed in Grade 3

*Special consideration for folliculitis/rash involving the scalp

 

Stomatitis Severity
(CTCAE Grade)
Intervention
Grade 0 or on Cycle 1, Day 1Consider prophylaxis with:

a) Dexamethasone 0.5 mg/5mL oral solution: 10 mL swish and spit QID 1 hour NPO afterwards

b) Biotѐne mouthwash

c)  Doxycycline 100 mg PO BID or minocycline 100 mg PO BID

Grade 1Interventions listed in Grade 0
Grade 2Interventions listed in Grade 0 and:

a) Magic mouthwash1

Grade 3Interventions listed in Grade 2 and:

a) Hold mobocertinib until resolution of mucositis to Grade ≤ 1

b) Start on oral prednisone 5 to 10 mg PO daily.  Increase by 5 to 10 mg PO weekly depending on improvement.  Alternatively, can start on a Medrol DosePak

 

Patient Centered Activities:3

  • Provide Oral Chemotherapy Education (OCE) Sheet
  • Counsel patient on how to take mobocertinib and the common side effects
  • Some patients may find that certain foods or may worsen symptoms and should be avoided
  • Patients should be encouraged to maintain hydration, especially if they are experiencing diarrhea
  • Taking mobocertinib at different times in the day may improve symptoms. Instituting a brief dose hold on mobocertinib may be required to improve symptoms, but should be minimized as they may impact overall effectiveness of mobocertinib3 

References:

  1. Riely GJ, Neal JW, Camidge DR, et al. Activity and safety of mobocertinib (TAK-788) in previously treated non–small cell lung cancer with EGFR exon 20 insertion mutations from a phase 1/2 trial. Cancer Discov. 2021;11(7):1688-1699.
  2. Zhou C, Ramalingam SS, Kim TM, et al. Mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: phase 1/2 open-label study. JAMA Oncol. 2021. In press.
  3. Nguyen D,Ramalingam SS, Spira AI, et al. (2021, Oct). Characterization of GI Toxicities and Their Impact on Efficacy in Patients With EGFR Exon 20 Insertion+ (ex20ins+) Non–Small Cell Lung Cancer (NSCLC) Treated With Mobocertinib (TAK-788) Who Previously Received Platinum Chemotherapy. European Society for Medical Oncology (Virtual).
  4. EXKIVITY (mobocertinib) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America.
Important notice: 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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Written By: Joshua Nubla, PharmD, NCODA

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Description: This PQI is developed to provide guidance for management of patients treated with selpercatinib.

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

A multicohort study was conducted in patients with RET fusion-positive metastatic NSCLC, advanced or metastatic MTC, and RET point-mutation advanced or metastatic MTC. The major efficacy outcome, objective response rate (ORR) to selpercatinib was 64% in previously treated NSCLC. 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

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

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 Oral Chemotherapy Education (OCE) sheet
  • Counsel patient to swallow the capsules whole with or without food and to not crush/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.
  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: 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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Written by Isabel Houlzet, PharmD, BCPS, BCOP, Miami Cancer Institute
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Description: This PQI will review patient identification and clinical considerations for this treatment option for gastric cancer.

Background: Trifluridine and Tipiracil is approved for use in patients with gastric or gastroesophageal junction (GEJ) cancer who have failed at least two prior lines of chemotherapy including a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. This approval is based on results from the TAGS trial, a Phase III, multinational, randomized, double-blind trial that compared trifluridine/tipiracil plus best supportive care vs. placebo plus best supportive care in metastatic GEJ/gastric cancer patients previously treated with at least 2 prior regimens.  Median overall survival was 5.7 months (95% CI 4.8–6.2) in the trifluridine/tipiracil group and 3.6 months (3.1–4.1) in the placebo group.1 Sequencing of treatment in advanced gastric cancer is still not well defined, but trifluridine/tipiracil serves as a viable option for 3rd and subsequent lines of treatment and is currently NCCN category 1 recommended for 3rd line (or later) therapy.2

PQI Process:

  • Identify patients with metastatic gastric or GEJ cancer who have failed at least two prior lines of chemotherapy (including a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy)
  • Consider conversation with care team with trifluridine/tipiracil as potential oral oncolytic option

Upon receiving a prescription for trifluridine and tipiracil:

  • Verify appropriateness of treatment (indication, prior lines of treatment)
  • Verify correct dose: rounded to nearest 5mg (see dosing in Supplemental Information)
  • Check complete blood counts prior to Day 1 and on Day 15 of each cycle
    • Do not initiate cycle until ANC ≥ 1,500/mm3 and platelets ≥ 75,000/mm3
    • Hold treatment for ANC < 500/mm3, febrile neutropenia, or platelets < 50,000 mm3
  • Kidney function
    • CrCl 15-29 mL/min – Dose adjust to 20 mg/m2 BID with food on days 1-5 and 8-12 of 28 day cycle
      • Consider dose reduction to 15 mg/m2 BID if unable to tolerate 20 mg/m2
    • Liver function
      • Do not initiate therapy in patients with moderate to severe hepatic impairment (bilirubin >1.5 ULN and any AST elevation)
    • The most common grade 3 or worse adverse effect is neutropenia (38%)
      • In the TAGS trial, the majority of episodes were managed by delaying the next dose
      • 16% of subjects in that trial were managed with granulocyte colony-stimulating factor
    • Consider antiemetic and antidiarrheal medications to manage potential patient adverse effects

Patient Centered Activities:

  • Provide Oncology Chemotherapy Education (OCE) sheet and counsel on potential side effects
  • Counsel patient on dosing schedule and administration (see Supplemental Information)
  • Consider starting on a Monday to complete days 1-5 from Monday to Friday, break on the weekend (days 6-7), and resume Monday to Friday for days 8-12. Patient does not take therapy for days 13-28
  • Notify the patient that dose delays may be beneficial when managing adverse effects, and should not interfere with their ability to receive treatment or achieve benefit
  • Provide medication and clinic appointments calendar (dosage calculator and calendar creator at http://www.lonsurfhcp.com/dosing/dosage-calculator)
  • Ensure patient has access to at home antiemetic and antidiarrheal medications
  • Counsel patient on safe storage, handling, and disposal of cytotoxic drugs (instruct caregiver to wear gloves)
  • Provide support kit – Lonsurf® Starter Kits contain patient and caregiver brochures, pillboxes, and thermometer

References:

  1. Shitara K. et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1437-1448. doi: 10.1016/S1470-2045(18)30739-3.
  2. NCCN Guidelines Gastric Cancer.
  3. Lonsurf® (trifluridine/tipiracil) [package insert]. Princeton, NY: Taiho Oncology, Inc.

Supplemental Information

Dosing and Administration:

  • 35 mg/m2 (based on trifluridine) twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle
  • Round to the nearest 5 mg (available in 15 mg and 20 mg tablets)
  • Maximum dose 80 mg trifluridine/dose (160 mg/day)
  • Administer with food and swallow tablets whole, within 1 hour after completion of morning and evening meals
  • If treatment held for neutropenia, thrombocytopenia, or other Grade 3/4 adverse effect, after recovery, reduce dose by 5 mg/m2/dose if:
    • Patient had febrile neutropenia, uncomplicated Grade 4 neutropenia or thrombocytopenia that resulted in > 1 week delay in start of next cycle
    • Nonhematologic grade 3 or 4 adverse reaction, except for grade 3 or 4 nausea/vomiting controlled by antiemetics or grade 3 diarrhea responsive to antidiarrheal medication
    • Maximum of 3 dose reductions. Permanently discontinue if unable to tolerate 20 mg/m2/dose.
    • Do not escalate dose after it has been reduced

Copay Support

Important notice: 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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Written By: Joshua Nubla, PharmD, NCODA
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Description: The purpose of this PQI is to discuss the option of using bortezomib for multiple myeloma (MM) and mantle cell lymphoma (MCL) patients.

Background: Bortezomib is a reversible proteasome inhibitor of the chymotrypsin-like activity of the 26S proteasome and is approved for treatment of adult patients with multiple myeloma (MM) or mantle cell lymphoma (MCL). In a randomized, open-label study in patients with previously untreated MM, patients who received bortezomib, melphalan, and prednisone (Vc-MP) had a median time to progression of 20.7 months versus 15 months with melphalan and prednisone (MP) (HR=0.54); at a median follow-up of 60.1 months, the median overall survival (OS) was 56.4 months versus 43.1 months (HR 0.695). The bortezomib arm had complete and partial response rates of 30% and 40% respectively whereas the MP arm reported 4% and 30% complete and partial response rates.2,3 For newly diagnosed MCL, a phase 3, randomized, open-label study reported a median PFS of 25 months in the VcR-CAP regimen arm (bortezomib with rituximab, cyclophosphamide, doxorubicin, and prednisone) vs 14 months in the R-CHOP arm (HR=0.63); the median OS was 91 months versus 56 months at a median follow-up of 78.5 months (HR=0.66).4 In an integrated safety analysis of single agent bortezomib in 1163 patients with relapsed MM or relapsed MCL, the most commonly reported (>20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ³ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

PQI Process:  Upon order of bortezomib:

  • Verify dosing of bortezomib is 1.3 mg/m2 with a concentration of 1 mg/mL intravenously or at a concentration of 2.5 mg/mL subcutaneously
    • Bortezomib is for intravenous or subcutaneous use only
    • When administered intravenously, administer as a 3 to 5 second bolus intravenous injection
    • Retreatment may be considered for patients with MM who had previously responded to treatment with bortezomib and who have relapsed at least six months after completing prior bortezomib treatment. Treatment may be started at the last tolerated dose
  • Bortezomib is available in single-dose vials containing 3.5 mg of lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose
  • Preparation: Bortezomib should only be reconstituted with 0.9% sodium chloride and should be a clear/colorless solution
Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration1
Route of AdministrationBortezomib (mg/vial)Diluent (0.9% Sodium Chloride)Final Bortezomib Concentration (mg/mL)
Intravenous3.5 mg3.5 mL1 mg/mL
Subcutaneous3.5 mg1.4 mL2.5 mg/mL

 

  • Dose Adjustment
    • No starting dosage adjustment of bortezomib is recommended for patients with mild hepatic impairment (tbili ≤1x ULN and AST > ULN, or tbili >1 to 1.5x ULN and any AST)
    • Consider reducing the starting dose in patients with moderate (tbili >1.5 to 3x ULN and any AST) or severe (tbili >3x ULN and any AST) hepatic impairment to 0.7 mg/m2 in the first cycle
      • Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability
    • No starting dose adjustment of bortezomib for patients with renal impairment
      • In patients requiring dialysis, bortezomib should be given after dialysis procedure
  • For Previously Untreated MM, bortezomib is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1
  • Prior to initiating any cycle of therapy with bortezomib in combination with melphalan and prednisone:
    • Platelet count should be at least 70 x 109/L and absolute neutrophil count (ANC) ³ 1 x 109/L
    • Nonhematological toxicities should have resolved to Grade 1 or baseline
    • If any of these requirements are not met, review prescribing information for dose modifications
Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma1
Twice Weekly Bortezomib (Cycles 1 to 4)
Week123456
Bortezomib

(1.3 mg/m2)

Day

1

Day

4

Day

8

Day

11

Rest

period

Day

22

Day

25

Day

29

Day

32

Rest

period

Melphalan (9 mg/m2)

Prednisone (60 mg/m2)

Day

1

Day

2

Day

3

Day

4

Rest

period

Rest

period

Once Weekly Bortezomib (Cycles 5 to 9 when used in combination with Melphalan and Prednisone)
Week123456
Bortezomib

(1.3 mg/m2)

Day

1

Day

8

Rest

period

Day

22

Day

29

Rest

period

Melphalan (9 mg/m2)

Prednisone (60 mg/m2)

Day

1

Day

2

Day

3

Day

4

Rest

period

Rest

period

  • For previously untreated MCL, bortezomib is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in Table 2
    • Bortezomib is administered first followed by rituximab
    • If response first documented at cycle 6, two additional VcR-CAP cycles are recommended
    • At least 72 hours should elapse between consecutive doses of bortezomib
  • Prior to the first day of each cycle (other than Cycle 1):
    • Platelet count should be at least 100 x 109/L and ANC should be at least 1.5 x 109/L
    • Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L)
    • Nonhematologic toxicity should have recovered to Grade 1 or baseline
    • If any of these requirements are not met, review prescribing information for dose modifications
    • Hold at the onset of Grade 3 toxicities, excluding neuropathy managed without holding
Table 2: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma1
Twice Weekly Bortezomib (6, Three-Week Cycles)*
Week123
Bortezomib (1.3 mg/m2)Day 1Day 4Day 8Day 11Rest period
Rituximab (375 mg/m2)

Cyclophosphamide (750 mg/m2)

Doxorubicin (50 mg/m2)

Day 1 

 

 

 

Rest period
Prednisone (100 mg/m2)Day 1Day 2Day 3Day 4Day 5Rest period

*Dosing may continue for two more cycles (8 cycles total) if response is seen at cycle 6

  • Administration
    • When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site
    • If local injection site reactions occur following subcutaneous administration, a less concentrated solution (1 mg/mL) may be administered subcutaneously. Intravenous route can be considered

Patient Centered Activities:

  • Patient Education
    • Counsel patient on common side effects including peripheral neuropathy, headache, diarrhea, constipation, nausea/vomiting, and appropriate management of side effects
      • See Chemotherapy Induced Peripheral Neuropathy PQI
      • See Chemotherapy Induced Nausea and Vomiting PQI
      • See Chemotherapy, Oncolytic, Antiemetic Induced Constipation PQI
      • See Oncolytic Induced Diarrhea PQI
    • Velcade Reimbursement Assistance Program (VRAP) – https://www.velcade.com/paying-for-treatment
      • Takeda Oncology Here2Assist
      • View online at www.Here2Assist.com or by calling 1-844-817-6468, Option 2
      • Provide Velcade starter kit

References:

  1. Velcade (bortezomib) [prescribing information]. Cambridge, MA: Millennium Pharmaceuticals, Inc.
  2. San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med 2008; 359:906-917.
  3. San Miguel JF, Schlag R, Khuageva NK et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 2013; 31(4):448-55.
  4. Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. The Lancet. Oncology. 2018;19(11):1449–1458.
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