Download Tagrisso®: The First Agent Approved for the Treatment of Metastatic

Tagrisso®: The First Agent Approved for the Treatment of Metastatic Epidermal Growth Factor
Receptor T790M Mutation-Positive Non-Small Cell Lung Cancer
Lauren Schmidt, PharmD Candidate 2017
Mandee Noval, PharmD Candidate 2018
Jennifer Andres, PharmD, BCPS
Temple University School of Pharmacy
The U.S. Food and Drug Administration (FDA) recently approved Tagrisso (osimertinib)
for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with treatmentresistant epidermal growth factor receptor (EGFR) mutation T790M. Although lung cancer
remains the leading cause of cancer-related death in men and women in the United States, the
overall rate and incidence has decreased in the past 50 years due to declining tobacco use.
Existing in 80% of the lung cancer population, NSCLC is the predominant form of lung cancer
diagnosed today. NSCLC exhibits a slower growth rate and doubling time compared to small
cell lung cancer (SCLC), however, the overall 5-year survival rate remains at a discouraging
15%. Associated with an overexpression of EGFR, initial NSCLC treatment consists of tyrosine
kinase inhibitors (TKI), such as erlotinib and gefinitib. Although these agents have been
successful in treating NSCLC, acquired resistance after 1 to 2 years of therapy has been known
to occur. While inherent resistance to conventional EGFR inhibitors rarely exists upon
diagnosis, commonly, the T790M EGFR mutation is acquired after EGFR therapy, resulting in
low response rates. Seen in two thirds of cases, the most common mechanism of acquired drug
resistance has been associated with the mutant form EGFR T790M. Osimertinib is the first
medication to be FDA approved to target lung cancer patients who test positive for this specific
EGFR mutation.
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Formulated as a 40 mg or 80 mg once daily tablet, osimertinib acts as an irreversible
EGFR kinase inhibitor, specifically targeting the T790M mutation prevalent in a majority of
NSCLC patients. In order to use osimertinib, patients must test positive for the EGFR T790M
mutation using the recently approved cobas EGFR Mutation Test v2. In partnership,
AstraZeneca and Roche developed the cobas EGFR Mutation Test v2, serving as a diagnostic
tool to detect a variety of EGFR mutations, including T790M. The test assesses up to 42
mutations using a real-time PCR, valuable in the fact that the sample can be obtained via tissue
biopsy or plasma. Results can be obtained in as little as four hours, showing how useful the test
can be in determining which patients may benefit from osimertinib treatment.
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Established by two Phase II clinical trials, AURA extension and AURA2, osimertinib was
granted fast track, breakthrough therapy, priority review and accelerated approval status by the
FDA. Based on a multicenter, open-label, single arm design, the two studies included a total of
411 patients with confirmed EGFR mutation-positive T790M via the cobas EGFR Mutation Test
v2. Baseline characteristics showed a median age of 63 years, female gender (68%), Asian
origin (60%), and metastatic (96%) patient population. Sixty-nine percent of patients received
two or more lines of previous therapy. Excluded patients had a past history of radiation
pneumonitis or interstitial lung disease (ILD) requiring steroid therapy, serious arrhythmias, a
baseline QTc level of 470 msec or greater, or received cytotoxic chemotherapy, investigational
agents, or other anticancer drugs within 14 days of the first dose of the study. An overall
response rate, assessed by an objective complete or partial reduction in tumor size, was seen in
57% of AURA extension and 61% of AURA2 patients. The majority (96%) of confirmed
objective response patients had ongoing responses ranging from 1.1 to 5.6 months with a
median duration of follow-up of 4.2 months in AURA extension and 4.0 in AURA2. The most
common side effects were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity
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(25%). Serious side effects included the potential for lung inflammation, including ILD and
pneumonitis, QTc prolongation, embryofetal toxicity (animal models), and cardiomyopathy.
Additionally, osimertinib should be avoided with concomitant administration of strong CYP3A4
inhibitors and inducers.
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While the safety and efficacy of osimertinib is continuously being monitored through
post-marketing surveillance, this appears to be a breakthrough and evolution to patients
suffering with NSCLC. The first of its kind, osimertinib may now provide hope for patients who
possess tumors with the T790M mutation, once untreatable. Osimertinib is currently available
as a once daily tablet, sold at select specialty pharmacies for a monthly price of about $16,770
(Avella Specialty Pharmacy. December 28, 2015. Telephone). The recommended dose of
osimertinib is 80 mg once daily until unacceptable toxicity or disease progression. Osimertinib
is currently being studied in an open label, randomized, phase III study, AURA3, designed to
assess the efficacy and safety of osimertinib versus platinum-based doublet chemotherapy in
patients with EGFR T790M positive, locally advanced, or metastatic NSCLC who have
progressed following prior therapy with an EGFR-TKI. Osimertinib is additionally being
investigated as an adjuvant, in combination with other pharmacologic agents, for metastatic
first-line treatment, including in patients with brain metastases.
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References
1. Adams VR, Arnold SM. Chapter 106. Lung Cancer. In: DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach,
9e. New York, NY: McGraw-Hill; 2014.
http://accesspharmacy.mhmedical.com.libproxy.temple.edu/content.aspx?bookid=689%
Sectionid=48811501. Accessed November 26, 2015.
2. Janne P, et al. AZD9291 in EGFR Inhibitor-Resistant Non-Small-Cell Lung Cancer. New
England Journal of Medicine 2015; 372 (18): 1689-1699.
3. U.S. Food and Drug Administration. FDA approves new pill to treat certain patients with
non-small cell lung cancer.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472525.htm
Published November 13, 2015. Accessed December 23, 2015.
4. Roche. Cobas® EGFR Test for Lung Cancer Patients.
http://egfrmutationtestv2.roche.com/ Updated September 24, 2015. Accessed December
23, 2015.
5. Tagrisso [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP: 2015.