Written by: Tammy McClellan, PharmD
Description: The purpose of this PQI is to expand on therapy management of ibrutinib when used in combination with obinutuzumab.
Background: This FDA has extended the indications for ibrutinib; already approved as a single agent OR in combination with bendamustine and rituximab. Ibrutinib is indicated for Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) at doses of 560 mg daily. Ibrutinib is also indicated for Waldenstrom’s Macroglobulinemia (WM), chronic Graft versus Host disease (cGVHD) and Chronic Lymphocytic Lymphoma/Small Lymphocytic Lymphoma (CLL/SLL) at doses of 420 mg daily.
Ibrutinib in combination with obinutuzumab has been approved for adult patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This indication is a non-chemotherapy option for treatment naïve patients diagnosed with CLL/SLL, which may further help reduce the need for chemotherapy. As an oral and IV combination therapy, coordination of the medically integrated pharmacy team is critical. The Illuminate trial4 found ibrutinib and obinutuzumab to show to be efficacious as first-line, non-chemotherapy regimen in CLL/SLL patients regardless of age or disease status. The median follow-up was 31.3 months and the most common grade 3 or 4 adverse effect was neutropenia and thrombocytopenia. After a median follow-up of 31.3 months (IQR 29.4–33.2), median progression-free survival was significantly longer in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33.6–non-estimable]) than in the chlorambucil plus obinutuzumab group (19.0 months [15.1–22.1]; hazard ratio 0.23; 95% CI 0.15–0.37; p<0.0001). Estimated 30-month progression-free survival was 79% (95% CI 70–85) in the ibrutinib plus obinutuzumab group and 31% (23–40) in the chlorambucil plus obinutuzumab group.
PQI Process: Upon receiving a new prescription for ibrutinib for specific use in combination with obinutuzumab:
- Verify an established CLL/SLL diagnosis (independent of patient’s del(17p) status, comorbidities and age) in the treatment naive patient and relevant dosing
- Assess risk for Tumor Lysis Syndrome (laboratory abnormalities of potassium, uric acid, phosphate, serum creatinine) which commonly occurs during the first cycle
- Ibrutinib 420 mg by mouth once daily with:
- Obinutuzumab 100 mg IV on Day 1
- then Obinutuzumab 900 mg IV on Day 2
- then Obinutuzumab 1000 mg IV on Day 8 and Day 15 every 28 days for 1 Cycle
- Followed by Ibrutinib 420 mg by mouth once daily with:
- Obinutuzumab 1000 mg IV on Day 1 every 28 Days for 5 Cycles
- Consider administering ibrutinib prior to obinutuzumab when given on the same day
- Consider modification for ibrutinib if warranted due to hypertension, dermatologic toxicities, risk of bleeding, hepatic impairment, fluid retention, cardiac arrhythmias or abnormalities
- Verify scheduling of premeditations for obinutuzumab:
- Acetaminophen 650 mg – 1000 mg at least 30 minutes prior
- Antihistamine (ex: diphenhydramine 50 mg) at least 30 minutes prior
- IV glucocorticoid (ex: dexamethasone 20 mg) at least 60 minutes prior
- Review CBC, CMP, hepatitis, LDH, and quantitative immunoglobulins monthly and as indicated
- Verify recommended antiviral (herpes and varicella virus) and pneumocystis prophylaxis are initiated
- Review Ibrutinib (Imbruvica®) Management PQI
- Confirm baseline EKG has been obtained
Patient Centered Activities:
- Provide ibrutinib Oncology Chemotherapy Education (OCE) sheet
- Counsel patient on disease state, treatment regimen, what to expect and verify patient understanding
- Ibrutinib should be taken at the same time each day, swallowed whole, with a glass of water and prior to obinutuzumab
- Avoid grapefruit products and Seville oranges.
- Advise patient to take a missed dose as soon as possible on the same day and to resume normal dosing schedule for the next day
Ibrutinib is approved in first-line therapy for CLL/SLL patients but is also considered as an option for the following populations as well:
- Patients with and without del(17p)/TP53 mutation who are:
- 64 years old and younger without significant comorbidities
- 65 years old and older with significant comorbidities
- IMBRUVICA® (Package Insert). Pharmacyclics LLC in conjunction with Janssen Biotech INC, Sunnyvale, CA.
- Gazyva® (Package Insert). Genetech, South San Fransico, CA.
- Micromedex Online, Ann Arbor, MI: IBM Watson Health, Inc.; updated 6/18/19. https://www.micromedexsolutions.com/micromedex2/librarian/.
- Moreno C, Greil R, Demirkan F, et al: Ibrutunib plus Obintuzumab versus Chlorambucil plus Obintuzumab in first-line treatment of chronic lymphocytic leukemia (ILLUMINATE): A multicenter, randomized, open-label, phase 3 trial. Lancet Oncol 20:43-56,2019.
- U.S National Library of Medicine (clinicaltrials.gov). Ibrutunib in Treating patients with Relapsed Hairy Cell Leukemia. Assessed at: https://clinicaltrials.gov/ct2/show/NCT01841723. 6-28-19.
- Younes A, Sehn LH, Johnson P, et al. Randomized phase III trial of Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma [published online March 22, 2019]. J Clin Oncol. Doi:10.1200/jco.18.02403.
- Cancer Therapy Advisor Online, New York, NY: Haymarket Media, Inc.; Revised 11/2016. https://www.cancertherapyadvisor.com/home/cancer-topics/hematologic-cancers/chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-cll-sll/?utm_source=newsletter&utm_medium=email&utm_campaign=cta-spotlight-.
- Cancer Therapy Advisor Online, New York, NY: Haymarket Media, Inc.; Published August 6, 2019. Use of MRD status following Obinutuzumab/Ibrutinib therapy to Guide in Subsequent Therapy Selection in CLL. https://www.cancertherapyadvisor.com/home/cancer-topics/chronic-lymphocytic-leukemia/chronic-leukemia-cll-obinutuzumab-ibrutinib-mrd-status-guide-treatment.
- Targeted Oncology. Ibrutinib Plus Obinutuzumab Approved by FDA as Frontline CLL/SLL Treatment. Assessed at: https://www.targetedonc.com/news/ibrutinib-plus-obinutuzumab-approved-by-fda-as-frontline-cllsll-treatment.
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.
Written by: Brandy Persson, PharmD, BCPS, BCOP and Rebecca Fanning, PharmD, BCPS, Cone Health
Description: Fam-trastuzumab deruxtecan-nxki is indicated for the treatment of:
- Adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer previously treated with two or more anti-HER2-based regimens.1,2 This indication is under accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- Adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.1,6
The purpose of this PQI is to provide guidance for management of fam-trastuzumab deruxtecan-nxki.
Background: Fam-trastuzumab deruxtecan-nxki is a HER2 directed antibody-drug conjugate (ADC). Fam-trastuzumab deruxtecan-nxki was FDA approved for metastatic breast cancer in December 2019 based on results from the DESTINY-Breast01 trial that established its efficacy and safety in patients previously treated with trastuzumab emtansine. The overall response (complete response and partial response) was 60.9%. Secondary endpoints included a median progression free survival of 16.4 months in all patients and 18.1 months in 24 patients enrolled with asymptomatic brain metastases.2 Fam-trastuzumab deruxtecan-nxki was FDA approved in January 2021 for patients with gastric and gastroesophageal junction adenocarcinoma based on the results of the DESTINY-Gastric01 trial. This study evaluated the safety and efficacy versus physician’s choice chemotherapy (irinotecan or paclitaxel monotherapy) in patients who had progressed on at least two prior regimens which included trastuzumab, a fluoropyrimidine and a platinum agent. The study demonstrated a statistically significant improvement in the major efficacy outcomes of median overall survival (12.5 vs 8.4 mo) and confirmed objective response rate (43% vs 12%). Additional efficacy outcomes of median progression free survival (5.6 vs 3.5 mo) and median duration of response (11.3 vs 3.9 mo) were also improved.6
- Review the medical record:
- Ensure patient is an appropriate candidate for fam-trastuzumab deruxtecan-nxki
- Confirm no history of interstitial lung disease (ILD), pneumonitis, or other lung condition
- These patients were excluded from the DESTINY-Breast01 and DESTINY-Gastric01 studies
- Although not a contraindication, ILD/pneumonitis is a boxed warning
- Assess Left Ventricular Ejection Fraction (LVEF) prior to initiation
- Patients with LVEF < 50% were not studied2,6
- Evaluate CBC prior to initiation, as well as prior to each dose, and as clinically indicated
- Review treatment plan:
- Verify premedication orders:
- Antiemetics – Moderately emetogenic3– 5-HT3 antagonist + dexamethasone prior to treatment and consideration for days 2 and 3; PRN antiemetic available for home use
- Acetaminophen + H1 blocker may be included to prevent infusion related reactions per institutional policy or provider preference
- Verify dosing of fam-trastuzumab deruxtecan-nxki1
- Breast cancer dosing is 5.4 mg/kg intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity
- Gastric cancer dosing is 6.4 mg/kg intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity
- First infusion is administered over 90 minutes
- If patient tolerates the first infusion, subsequent infusions may be given over 30 minutes
- Slow or interrupt infusion rate if patient develops infusion-related symptoms
- No dose adjustments required for mild or moderate renal or hepatic impairment
- Patients with severe renal or hepatic impairment were not studied
- CBC: baseline, then before each treatment cycle
- Fam-trastuzumab deruxtecan-nxki treatment should be interrupted for patients with a neutrophil count < 1,000 cells/mm3 or a platelet count < 50,000/microliter
- Growth factor support may be used to maintain counts when appropriate2,5,6
- LVEF: baseline and at regular intervals during treatment as clinically indicated
- Discontinue treatment if LVEF < 40%, if an absolute LVEF decrease of > 20% from baseline LVEF or symptomatic congestive heart failure
- ILD and pneumonitis: Monitor, consider imaging, and promptly investigate signs and symptoms including cough, dyspnea, fever, and new or worsening respiratory symptoms
- Permanently discontinue in all patients with ≥ grade 2 ILD/ pneumonitis, promptly initiate systemic corticosteroid treatment (ex. ≥1 mg/kg/day prednisone) and continue upon improvement for at least 14 days followed by gradual taper (ex. at least 4 weeks)
- Evaluate the need for dose modifications. Do not re-escalate dose after dose reduction is made
- Dose modifications for breast cancer:
- First dose reduction: 4.4 mg/kg
- Second dose reduction: 3.2 mg/kg
- Further required dose reductions: Discontinue treatment
- Dose modifications for gastric cancer:
- First dose reduction: 5.4 mg/kg
- Second dose reduction: 4.4 mg/kg
- Further required dose reductions: Discontinue treatment
- See package insert for additional dose modifications and management information
- Reconstitute fam-trastuzumab deruxtecan-nxki 100 mg vials with 5 mL of Sterile Water for Injection, USP for a final concentration of 20 mg/mL
- Inject dose into a 100 mL bag of 5% Dextrose Injection, USP. Do not use sodium chloride
- Fam-trastuzumab deruxtecan-nxki is compatible with an infusion bag made of polyvinylchloride, or polyolefin (copolymer of ethylene and polypropylene)
- IV over 30 – 90 minutes with an infusion set made of polyolefin or polybutadiene and a 0.2- or 0.22-micron in-line polyethersulfone or polysulfone filter
- 5% dextrose is recommended for priming and flushing the administrative line
- Cover the infusion bag to protect from light
Patient Centered Activities:
- Patient Education:1,5
- Provide written medication information to patient
- Instruct patient to report any new/worsening shortness of breath, dry cough, wheezing, or fever
- Caution patient regarding increased risk of infection and infection prevention methods
- Review the possibility this drug could weaken the pumping action of the heart muscle and to promptly report any chest pain or tightness, rapid weight gain, significant swelling in ankles or trouble breathing
- Remind patient that this drug may cause significant hair loss
- Instruct patient to report adverse events including fever, diarrhea, nausea/vomiting or fatigue
- Ensure patient has access to supportive medications
- Anti-nausea: 5-HT3 receptor antagonist, metoclopramide, or prochlorperazine
- Anti-diarrheal: loperamide
- Patient assistance: ENHERTU4U4
- Patient Savings Program: Assists eligible commercial patients with their out-of-pocket costs
- Patient Assistance Program: Assists qualifying uninsured, underinsured or Medicare patients who are having difficulty affording their medications
- Assistance may also be available through independent charitable patient assistance foundations
- EnhertuÒ (fam-trastuzumab deruxtecan-nxki) [prescribing information]. Basking Ridge, NJ: Daiichi Sankyo, Inc.
- Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020;382(7):610-621.
- National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2020.
- ENHERTU4U: Patent Access to Treatment. https://www.enhertu4u.com/patient/affording-your-medicine.html.
- Fam-trastuzumab Derutecan-nxki (EnhertuÒ). JNCCN Spotlights: https://jnccn360.org/breast/jnccn-spotlights/fam-trastuzumab-deruxtecan-nxki.
- Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020; 382:2419-2430.
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.
Exelixis Announces U.S. FDA Approval of CABOMETYX® (cabozantinib) for Patients with Previously Treated Radioactive Iodine-Refractory Differentiated Thyroid Cancer
– FDA approval based on phase 3 COSMIC-311 pivotal trial, which demonstrated significant improvement in progression-free survival with CABOMETYX versus placebo –
– Exelixis is prepared to fully support expanded indication immediately –
– Application approved well ahead of Prescription Drug User Fee Act target action date of December 4, 2021 –
ALAMEDA, Calif.–(BUSINESS WIRE)–Sep. 17, 2021– Exelixis, Inc. (Nasdaq: EXEL) today announced that the U.S. Food and Drug Administration (FDA) approved CABOMETYX® (cabozantinib) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible. The FDA granted Breakthrough Therapy designation and Priority Review to CABOMETYX and its approval comes more than two months ahead of the Prescription Drug User Fee Act (PDUFA) target action date of December 4, 2021. DTC is the most common type of thyroid cancer in the U.S., and patients who are resistant to radioactive iodine treatment face a poor prognosis.1,2,3,4
“Before today, patients with radioactive iodine-refractory differentiated thyroid cancer who have progressed following prior VEGFR-targeted therapy were facing aggressive disease and no standard treatment option,” said Marcia S. Brose, M.D., Ph.D., Chief, Cancer Center Operation Sidney Kimmel Cancer Center at Jefferson Torresdale Hospital, Co-Director, Community Based Clinical Trials, Sidney Kimmel Cancer Center at Thomas Jefferson University, and principal investigator of COSMIC-311. “In the COSMIC-311 pivotal phase 3 trial, CABOMETYX extended the time patients live without progression of their cancer. The FDA approval of CABOMETYX is an important advancement for these patients who are badly in need of new treatment options.”
Read complete release HERE.