April 17, 2020

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf

On April 17, 2020, the Food and Drug Administration approved (TUKYSA, Seattle Genetics, Inc.) in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The U.S. FDA, the Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority (Singapore), and Swissmedic (Switzerland) collaborated on this review. 
While the FDA approved tucatinib today, the application is still under review at the
other agencies.

Efficacy was demonstrated in the HER2CLIMB trial (NCT02614794) enrolling 612 patients with HER2-positive metastatic breast cancer who had prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine. Patients received either tucatinib 300 mg twice daily plus trastuzumab and capecitabine (tucatinib arm, n=410) or placebo plus trastuzumab and capecitabine (control arm, n=202).

The primary endpoint was progression-free survival (PFS), assessed by a blinded independent central review, evaluated in the initial 480 randomized patients. The median PFS in patients receiving tucatinib was 7.8 months (95% CI: 7.5, 9.6) compared to 5.6 months (95% CI: 4.2, 7.1) for patients enrolled on the control arm (HR 0.54; 95% CI: 0.42, 0.71; p<0.00001).

Additional efficacy outcome measures were evaluated in all randomized patients and included overall survival (OS), PFS among patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).

The median OS in patients on the tucatinib arm was 21.9 months (95% CI: 18.3, 31.0) compared to 17.4 months (95% CI: 13.6, 19.9) for patients on the control arm (HR: 0.66; 95% CI: 0.50, 0.87; p=0.00480). The median PFS for patients with baseline brain metastases on the tucatinib arm was 7.6 months (95% CI: 6.2, 9.5) compared to 5.4 months (95% CI: 4.1, 5.7) for those on the control arm (HR: 0.48; 0.34, 0.69; p<0.00001).

The confirmed ORR for patients with measurable disease was 40.6% (95% CI: 35.3, 46.0) and 22.8% (95% CI: 16.7, 29.8) for patients in the tucatinib and control arms, respectively (p=0.00008).

The most common adverse reactions (≥ 20% of patients) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Tucatinib can also cause severe diarrhea and hepatotoxicity.

The recommended tucatinib dose is 300 mg taken orally twice a day in combination with trastuzumab (at standard dosage) and capecitabine (1000 mg/m2 given orally twice daily on days 1-14 of a 21-day cycle) until disease progression or unacceptable toxicity.

View full prescribing information for TUKYSA.

This review used the Real-Time Oncology Review (RTOR) pilot program and Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. The FDA approved this application 4 months ahead of the FDA goal date.

FDA granted tucatinib orphan drug, fast track, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

For information on the COVID-19 pandemic, see the following resources:

• FDA: Coronavirus Disease 2019 (COVID-19)
• NCI: Coronavirus: What People With Cancer Should Know
• CDC: Coronavirus (COVID-19)

Follow the Oncology Center of Excellence on Twitter @FDAOncology

Pharmacist’s Applications to Practice

Tucatinib in combination with trastuzumab and capecitabine for advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting

Author: Stephanie A. Collins, PharmD, BCOP
Specialty Practice Pharmacist – Breast Medical Oncology
The Ohio State University Wexner Medical Center/The James Cancer Hospital and Solove Research Institute
Columbus, OH

What is the potential role for tucatinib in the treatment of breast cancer?

• The current treatment algorithm for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is first-line treatment with trastuzumab, pertuzumab and a taxane (based on the CLEOPATRA trial) followed by second-line trastuzumab emtansine (based on the EMELIA trial). Several options exist for third-line treatment, with no consensus on which is preferred.¹
• Tucatinib is a tyrosine kinase inhibitor (TKI) of HER2. Tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream signaling and cell proliferation.²
• On April 17, 2020 tucatinib was approved by the U.S. Food and Drug Administration (FDA) to be used in combination with trastuzumab and capecitabine as a treatment option for patients with advanced unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens in the metastatic setting.²
• Tucatinib is the third oral TKI of the HER2 receptor approved by the FDA for treatment of HER2-postive breast cancer. The others are lapatinib and neratinib.^2-4
• The HER2CLIMB trial compared the efficacy and safety of tucatinib or placebo, in combination with trastuzumab and capecitabine in patients with HER2-positive breast cancer who had previously received two or more lines of anti-HER2-based regimens, including previous treatment with trastuzumab, pertuzumab, and trastuzumab emtansine in the metastatic setting. This randomized, double-blind phase 3 clinical trial demonstrated improved progression-free survival (PFS) with the tucatinib combination versus the placebo combination evaluated in the initial 480 randomized patients, the planned primary endpoint. The median PFS in patients receiving tucatinib was 7.8 months compared to 5.6 months for patients receiving placebo (hazard ratio [HR] 0.54; 95% confidence interval [CI]: 0.42-0.71; p<0.00001). In the total population (n = 612), the median overall survival (OS) was 21.9 months compared to 17.4 months, respectively (HR: 0.66; 95% CI: 0.50-0.87; p=0.00480). Diarrhea was the most common adverse effect in the tucatinib arm, and most events were grade 1 (43.3% of patients) or grade 2 (24.8%). Diarrhea of grade 3 or higher occurred in 12.9% of patients in the tucatinib arm. Other common adverse effects (>20%) included palmer-plantar erythrodysesthesia syndrome (hand–foot syndrome), nausea, fatigue, vomiting, stomatitis, decreased appetite, headache, increased aspartate aminotransferase increased (AST) and increased alanine aminotransferase (ALT).⁵
  • Up to 50% of patients with HER2-postive breast cancer develop brain metastases, however patients with untreated or symptomatic brain metastases are frequently excluded from clinical trials. The HER2CLIMB trial included patients with brain metastases unless they were in need of immediate local intervention. In the total population, 47.5% of patients had brain metastases at baseline. The median PFS for patients with baseline brain metastases was 7.6 months for the tucatinib combination compared to 5.4 months for the placebo combination (HR: 0.48; 0.34-0.69; p<0.00001), and the median OS was 18.1 months (95% CI, 15.5 to not evaluable) compared to 12 months (95% CI, 11.2-15.2), respectively.⁶
• The National Comprehensive Cancer Network (NCCN) recognizes tucatinib in combination with trastuzumab and capecitabine as a category 1 recommended regimen for patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more lines of prior HER2-targed therapy in the metastatic setting.¹
  • Even though patients in the clinical trial received tucatinib as third-line treatment, the FDA indication and NCCN recommendation support use as second-line treatment. Because of this, current second-line treatment options include trastuzumab emtansine and tucatinib. The presence of brain metastases will likely influence a provider’s decision to choose tucatinib as second-line treatment based on control of CNS disease seen in the HER2CLIMB therapy.^1,2,6
• Currently, there are no randomized trials comparing tucatinib to other oral HER2-targeting TKIs. NCCN recognizes tucatinib as a category 1 recommendation, while recognizing neratinib and lapatinib as category 2A recommendations. The FDA approved tucatinib as second-line therapy, while the others are approved as third-line therapy. Some other factors to consider when selecting an agent include presence of brain metastases, adverse effect profiles, cost, administration schedule and patient and/or clinician preference.^1-5
  • NCCN recognizes lapatinib in combination with trastuzumab or capecitabine as category 2A recommendations for unresectable or metastatic HER2-positive breast cancer. NCCN recognizes lapatinib in combination with an aromatase inhibitor with or without trastuzumab as a category 2A recommendation for unresectable or metastatic hormone receptor-positive, HER2-postive breast cancer.¹
  • NCCN recognizes neratinib in combination with capecitabine as category 2A recommendations for unresectable or metastatic HER2-positive breast cancer.¹
• There is no compelling data to support use of an anti-HER2 TKI after prior progression on another medication in the same class. In HER2CLIMB, only 5.6% of patients received prior therapy with lapatinib.⁵

What role can the pharmacist play in the management of patients on tucatinib?

• Tucatinib is given in combination with capecitabine and trastuzumab until progression or unacceptable toxicity.
  • Tucatinib 300 mg (two 150 mg tablets) is taken orally twice a day, 12 hours apart with or without food.
  • Capecitabine 1000 mg/m² is taken orally twice a day, 12 hours apart within 30 minutes of a meal on days 1 through 14 of a 21-day cycle.
  • Tucatinib and capecitabine may be taken at the same time. Both oral medications should be taken whole, not crushed or chewed.
  • If a dose is missed or vomited, administer the next dose at its usual time.
  • Trastuzumab is given intravenously (IV) as an 8 mg/kg loading dose on day 1 and then 6 mg/kg every 21 days or as a 600 mg subcutaneous injection every 21 days.²
• Tucatinib is not recommended for use in patients with severe renal impairment (CrCl < 30 mL/min estimated by Cockcroft-Gault Equation).²
• The initial dose of tucatinib should be reduced to 200 mg twice daily in patients with pre-existing severe hepatic impairment (Child-Pugh Class C).²
• Dose interruptions or modifications are recommended for increases in AST/ALT and bilirubin, diarrhea, and other grade 3 or 4 toxicities.²
• Tucatinib can cause severe diarrhea. In HER2CLIMB, 81% of patients who received tucatinib experienced diarrhea, including 12.9% with Grade 3 or higher diarrhea. The median time to onset of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea prophylaxis was not required in the clinical trial and is not recommended in the package labeling, but patients should be educated on the use of antidiarrheals.²
• Tucatinib can increase AST/ALT and bilirubin and can cause severe hepatotoxicity. Monitor AST, ALT, and bilirubin prior to starting tucatinib, every 3 weeks during treatment, and as clinically indicated.²
• Tucatinib inhibits renal tubular transport of creatinine without an effect on glomerular function, leading to increased serum creatinine (SCr). The mean increase in SCr was 32% within the first 21 days of treatment. The increases persisted throughout treatment and were reversible upon discontinuation of tucatintib.²
• Tucatinib is associated with several drug interactions. A thorough review of the patient’s medication list for drug interactions should be conducted prior to starting tucatinib. Pharmacists can play an important role in educating patients and providers on potential drug interactions.
  • Tucatinib is a major substrate of CYP2C8 and CYP3A4. Avoid concomitant use of tucatinib with strong CYP3A inducers or moderate CYP2C8 inducers (i.e. rifampin). Avoid concomitant use of tucatinib with strong CYP2C8 inhibitors (i.e. gemfibrozil), and increase monitoring for tucatinib toxicity with moderate CYP2C8 inhibitors.
  • Tucatinib is a strong inducer of CYP3A4 and P-glycoprotein (P-gp). Avoid concomitant use of tucatinib with CYP3A4 substrates with a small therapeutic index (i.e. buspirone, fentanyl). If concomitant use is unavoidable, decrease the CYP3A4 substrate dosage in accordance with product labeling. Also, consider reducing the dosage of P-gp substrates with a small therapeutic index (i.e. digoxin).²
• A patient education sheet on tucatinib produced by the Association of Community Cancer Centers, HOPA, the National Community Oncology Dispensing Association, and the Oncology Nursing Society can be found at http://oralchemoedsheets.com/sheets/Tucatinib_Patient_Education.pdf.

Clinical Pearls

• Tucatinib is available as 50 mg and 150 mg film-coated tablets.²
• Tablets should be dispensed to the patient in original container only. The tablets should be store at room temperature in the original container to protect from moisture. The cap should be securely replaced on the bottle each time after opening and the desiccant should not be discarded. Once opened, the tablets should be used within 3 months. Any unused tablets should be discarded 3 months after opening the bottle.²
• Seattle Genetics offers a commercial out-of-pocket assistance program with a low out-of-pocket cost and an annual maximum assistance threshold high enough to assist the majority of eligible patients throughout the year. Criteria include commercially-insured, not enrolled in government insurance, and a diagnosis within the FDA-approved label. They also offer a free drug program after completion of an insurance and eligibility check. Criteria include uninsured or underinsured and a diagnosis within the FDA-approved label.

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 6.2020 (September 16, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
2. Tukysa (tucatinib) [package insert]. Bothell, WA: Seattle Genetics; 2020.
3. Tykerb (lapatinib) [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2018.
4. Nerlynx (neratinib) [package insert]. Los Angeles, CA: Puma Biotechnology, Inc; 2020.
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Eng J Med. 2020;382:597-609.
6. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial. J Clin Oncol. 2020;38:2610-2619.