By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the third drug in the class of second-generation, orally active, anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-positive non-small cell lung cancer (NSCLC), joining alectinib and ceritinib. The FDA granted brigatinib breakthrough therapy, orphan drug designation, priority review, and accelerated approval. An accelerated approval is based on tumor response rate and duration of response. Continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.1 It is marketed as Alunbrig.
INDICATIONS
Brigatinib is indicated for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.1
DOSAGE
The recommended dose is 90 mg daily for the first seven days, and if tolerated, increase to 180 mg once daily.1 It may be taken without regard to meals. Patients take brigatinib until there is disease progression or unacceptable toxicity.
Dose modification due to the nature and severity of adverse events is detailed in the prescribing information.1 Brigatinib is available as 30 mg and 90 mg tablets.
POTENTIAL ADVANTAGES
Brigatinib is more potent than crizotinib and provides another option in targeting crizotinib-resistant mutations.2,3 It appears to target the most common resistant mutation, G1202R, found in patients progressing on second-generation ALK-tyrosine kinase inhibitors (TKI).2-4
POTENTIAL DISADVANTAGES
Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease have occurred with a frequency of 4-9%, depending on the dosage regimen.1 Other adverse events can include hypertension (11-21%), bradycardia (6-8%), visual disturbance (7-10%), creatine phosphokinase elevation (27-48%), pancreatic enzyme elevation (27-39%), and new or worsening hyperglycemia (43%). Adverse events resulted in a discontinuation rate of 8.2% with the recommended dose. Coadministration with strong CYP3A inhibitors or inducers should be avoided.
COMMENTS
The accelerated approval for brigatinib was based on a randomized, Phase II trial in subjects with locally advanced or metastatic ALK-positive NSCLC that progressed on crizotinib and documented ALK rearrangement.1,5 Ninety-eight percent had stage IV disease, 69% had brain metastases, and 64% had objective response to crizotinib. Subjects were randomized to two arms: brigatinib 90 mg once daily (n = 112) or 180 mg once daily with a seven-day lead-in period (n =110) and stratified by the presence of brain metastases. Primary efficacy endpoint was confirmed overall response rate (ORR) as evaluated by an Independent Review Committee based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional outcomes included duration of response (DOR) and intracranial ORR and DOR. Endpoints also were measured based on investigator assessment. After a median follow-up of eight months, ORRs were 48% for the lower dose and 53% for the higher dose. Responses were mainly partial, 45% vs. 48%, and DOR was 13.8 months for both arms. Results from investigator assessments were similar. For those stratified with measurable brain metastases, intracranial ORRs were 42% vs. 67% and partial response rates, 35% vs. 67%, respectively.
CLINICAL IMPLICATIONS
Lung cancer is the second most common cancer worldwide, with 85-90% classified as NSCLC. Approximately 3-7% of NSCLC showed ALK rearrangement.6 Currently, the National Comprehensive Cancer Network recommends crizotinib or ceritinib as first-line therapy.7 For those who progress, ceritinib or alectinib are recommended as subsequent therapy. Resistance to AKL-TKIs may result from ALK gene mutation or activation of alternative signaling pathways bypassing ALK. Brigatinib is the newest addition to the second-generation ALK-TKIs. These agents generally are more potent than crizotinib and active against brain metastasis.4 There may be differences in adverse reaction profiles as the frequency of gastrointestinal adverse events and elevation of AST/ALT are lower for alectinib and brigatinib compared to ceritinib.4 Brigatinib may have the benefit of the ability to overcome a common resistant mutation of the second-generation agents. Its ultimate role in therapy remains to be determined. A Phase III comparison trial to crizotinib is in progress in ALK-positive (ALK inhibitor-naïve) NSCLC subjects, with results expected in 2021.8 The cost for brigatinib is $17,100 for a 30-day supply of 180 mg per day.
REFERENCES
- Alunbrig Prescribing Information. ARIAD Pharmaceutical, Inc. April 2017.
- Drizou M, et al. Treating patients with ALK-rearranged non-small-cell lung cancer: Mechanisms of resistance and strategies to overcome it. Clin Transl Oncol 2017;19:658-666.
- Gainor JF, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 2016;6:1118-1133.
- Metro G, et al. Optimal management of ALK-positive NSCLC progressing on crizotinib. Lung Cancer 2017;106:58-66.
- Kim DW, 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: JCO2016715904. doi: 10.1200/JCO.2016.71.5904. [Epub ahead of print].
- Qian M, et al. Drug resistance in ALK-positive non-small cell lung cancer patients. Semin Cell Dev Biol 2017;64:150-157.
- National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, May 12, 2017. Available at: http://bit.ly/2egeM4u. Accessed May 22, 2017.
- ClinicalTrials.gov. ALTA-1L Study: A Phase 3 Study of Brigatinib Versus Crizotinib in ALK-positive Advanced Non-Small Cell Lung Cancer Patients (ALTA-1L). Available at: http://bit.ly/2rua3Dm. Accessed May 22, 2017.
Brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib.
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