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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. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


April 28, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208772lbl.pdf

On April 28, 2017, the U.S. Food and Drug Administration granted accelerated approval to brigatinib (ALUNBRIG™ tablets, Takeda Pharmaceutical Company Limited, through its wholly owned subsidiary ARIAD Pharmaceuticals, Inc.) for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Approval was based on a non-comparative, two-arm, open-label, multicenter clinical trial demonstrating a clinically meaningful and durable overall response rate (ORR) in patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib (the ALTA Trial; NCT02094573). All patients had tumors with a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization Probe Kit test. A total of 222 patients were randomized to brigatinib orally either 90 mg once daily (n=112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (n=110).

ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ORR was 48% (95% CI: 39%, 58%) in the 90 mg arm and 53% (95% CI: 43%, 62%) in the 180 mg arm. After a median duration of follow-up of 8 months, median duration of response (DOR) was 13.8 months in both arms. In patients with measurable brain metastases at baseline, intracranial ORR was 42% (95% CI: 23%, 63%) in the 90 mg arm (n=26) and 67% (95% CI: 41%, 87%) in the 180 mg arm (n=18). Median intracranial DOR was not estimable in the 90 mg arm and was 5.6 months in the 180 mg arm. Among patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 180 mg arm maintained an intracranial response for at least 4 months.

Safety was evaluated in 219 patients who received at least one dose of brigatinib in the ALTA trial. The most common adverse reactions, occurring in at least 25% of patients taking brigatinib, were nausea, diarrhea, fatigue, cough, and headache. The most common serious adverse reactions were pneumonia and ILD/pneumonitis. Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each). Visual disturbances also occurred in patients receiving brigatinib. Adverse reactions leading to permanent discontinuation of brigatinib occurred in 2.8% and 8.2% of patients receiving 90 mg and 180 mg, respectively.

Patients receiving brigatinib should be monitored for new or worsening respiratory symptoms, hypertension, bradycardia, visual symptoms, and elevations in amylase, lipase, blood glucose, and creatine phosphokinase.

The recommended dosing regimen of brigatinib is 90 mg orally once daily for the first 7 days then, if tolerated, increase to 180 mg orally once daily.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208772lbl.pdf.

FDA previously granted brigatinib Breakthrough Therapy Designation for the treatment of patients with ALK-positive NSCLC whose tumors are resistant to crizotinib, as well as Orphan Drug Designation for the treatment of ALK+ NSCLC. FDA granted this application priority review. As a condition of the accelerated approval, the company is required to verify the clinical benefit of brigatinib in a confirmatory trial. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

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 by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice - April 28, 2017

Brigatinib (Alunbrig) for the Treatment of Metastatic ALK-Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on Crizotinib

Author: Rebecca Garcia Hunt, PharmD BCOP
Wake Forest University Baptist Medical Center
Winston Salem, NC

What is the potential role for brigatinib in the management of metastatic NSCLC?

  • It is estimated that 2–7% of newly diagnosed NSCLC patients will express the ALK gene rearrangement and are inherently resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI).1
  • Crizotinib is recommended as first-line therapy in patients that are ALK positive and has demonstrated response rates greater than 60%; however, development of resistance is common and often associated with central nervous system (CNS) relapse.1-3 
  • Resistance to crizotinib has led to the development of next-generation ALK inhibitors, including ceritinib, alectinib, and brigatinib, all of which have activity in patients with CNS involvement and are preferred as second-line therapy.1,3
  • Brigatinib approval is based on a phase 2 clinical trial that demonstrated an investigator-assessed objective response rate of 54%, a CNS objective response rate of 67%, median duration of response of 11.1 months, and a median progression-free survival of 12.9 months in patients that received brigatinib 180 mg.4
  • Although no direct comparisons have been made between second-generation ALK inhibitors, clinical trial data have shown better CNS response and median progression-free survival with brigatinib compared to ceritinib and alectinib, as shown in Table 1. The National Comprehensive Cancer Network guidelines do not support the use of one second-generation ALK inhibitor over another, but in vitro data support the efficacy of brigatinib in patients that were resistant to crizotinib, ceritinib, and alectinib.1-3

  Table 1: Comparative Efficacy Between Brigatinib, Ceritinib, Alectinib

 Brigatinib4
(N = 110)
Ceritinib5
(N = 163)
Alectinib6
(N = 138)
Objective response rate (ORR) 54% 56% 45%
Median time to response 1.9 months 6.1 weeks not reported
Median duration of response 11.1 months 8.3 months 11.2 months
Brain metastases at baseline 67% 60% 61%
Intracranial ORR 67% (n = 12)* 36% (n = 28)* 57% (n = 35)*
Median intracranial progression-free survival 15.6 months 6.9 months 10.3 months

*Includes only the patients with measurable baseline brain metastases

 

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

  • Brigatinib is initially dosed at 90 mg daily for the first 7 days and if tolerated is increased to 180 mg daily to decrease the risk of early pulmonary toxicity, such as interstitial lung disease or pneumonitis with reported incidence rates of 9.1%. Pharmacists can ensure that providers and patients understand the reason for this dose increase.4,7
  • Pharmacists should monitor for adverse events associated with brigatinib and be aware of the appropriate dose adjustments, as shown in Table 2. Dose modifications are recommended for interstitial lung disease or pneumonitis (9.1%), hypertension (21%), symptomatic bradycardia (7.6%), visual disturbances (10%), creatine phosphokinase (CPK) increases (48%), lipase/amylase increases (39%), and hyperglycemia (43%), which are among the most common adverse reactions reported with brigatinib.1,7

Table 2: Dose Reductions for Brigatinib



Dose

Dose-Reduction Levels

First

Second

Third

90 mg daily

60 mg daily

Permanently discontinue

N/A

180 mg daily

120 mg daily

90 mg daily

60 mg daily

 

  • Hypertension should be controlled before therapy is begun. Antihypertensives that cause bradycardia, such as beta-blockers, should be used with caution because of the increased risk of bradycardia with brigatinib.7
  • Clinical trial data indicate that brigatinib is associated with a moderate emetogenic risk (33%). Premedication with an antiemetic, such as a 5HT3 antagonist, should be used.4,7

 

Clinical Pearls

  • Takeda Oncology’s ALUNBRIG 1Point program is dedicated to helping patients gain access to brigatinib and ensures affordability. The program offers assistance options for patients who have commercial insurance or government insurance and to those who are underinsured.  More information about this program is available at www.ariadpass.com/hcp_alunbrig.html.
  • Although brigatinib is not included on the 2016 National Institute of Occupational Safety and Health List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, it does meet criteria to be classified as a hazardous drug. Patients and healthcare providers should use caution (including the wearing of single-use gloves during administration) when handling this medication.8
  • If patients require treatment delays longer than 14 days for reasons other than the occurrence of drug-related adverse events, brigatinib should be resumed at 90 mg for 7 days before increasing back to 180 mg. Patients who require a dose adjustment because of adverse events should not be rechallenged on a higher dose.7
  • Severe, life-threatening pulmonary toxicity has been reported in 9.1% of patients who received brigatinib 180 mg and can occur as early as 1 week within the start of therapy, with a median onset of 2 days.3,4
  • Brigatinib is a substrate of CYP3A4. Concomitant use with strong CYP3A4 inhibitors should be avoided if possible. If the interaction cannot be avoided, brigatinib doses should be reduced by approximately 50%. Strong CYP3A4 inducers should also be avoided if possible; however, no recommendations regarding dose modifications are provided if the interaction cannot be avoided.2,7
  • Brigatinib is a CYP3A4 inducer and can interact with hormonal birth controls. Patients taking brigatinib should be advised to use alternative methods for contraception.7
  • The Kim et al. study is a phase 2 study that supported FDA approval and determined that the therapeutic dose of 180 mg brigatinib be further explored in phase 3 studies. Clinicians should stay up-to-date on the studies being conducted and the resulting data as they become available.4  

References

  1. Non-small cell lung cancer. Version 6.2017. National Comprehensive Cancer Network. Available at: www.nccn.org. Accessed June 3, 2017.
  2. Markham A. Brigatinib: first global approval. Drugs. 2017; 77:1131-35.
  3. Gadgeel SM. Sequencing of ALK inhibitors in ALK+ non-small cell lung cancer. Curr Treat Options in Oncol. 2017; 18:36.
  4. Kim DW, Tiseo M, AhnMj et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol, 2017 May 5. Available at www.jco.org. Accessed June 3, 2017.
  5. Kim, DW, Mehra, R, Tan DSW, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicenter, open-label, phase 1 trial. Lancet Oncol. 2016; 17(4):452-63.
  6. Our SI, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol; 34:661-68.
  7. ALUNBRIGTM (brigatinib) [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; April 2017.
  8. Brigatinib (ALUNBRIGTM). Lexi-Drugs OnlineTM. Hudson, Ohio: Lexi-Comp, Inc. Accessed June 26, 2017.
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