On April 28, 2017, brigatinib (Alunbrig) was granted accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) who have had disease progression on or are intolerant to crizotinib (Xalkori).^1,2

Supporting Efficacy Data

Approval was based on durable responses observed in the 2-arm ALTA trial, in which 222 patients were randomized to oral brigatinib at 90 mg once daily (n = 112) or 180 mg once daily after a 7-day lead-in at 90 mg once daily (n = 110). Randomization was stratified by the presence of brain metastases and best response to prior crizotinib. ALK rearrangement was documented with a U.S. Food and Drug Administration (FDA)-approved test or a different test with adequate archival tissue to confirm ALK rearrangement by the Vysis ALK Break Apart FISH Probe Kit test. 

Overall, patients had a median age of 54 years (range = 18–82 years; 23% ≥ 65 years), 67% were white and 31% Asian, 57% were female, 93% had Eastern Cooperative Oncology Group performance status of 0 or 1, 95% were never or former smokers, 98% had stage IV disease, 97% had adenocarcinoma histology, 74% had prior systemic chemotherapy, 69% had brain metastases, 61% had received prior radiation to the brain, 39% had bone metastases and 26% had liver metastases, and 64% had an objective response to prior crizotinib.

Median duration of follow-up was 8 months. Objective response rates as assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were 48% (95% confidence interval [CI] = 39%–58%), including a complete response in 3.6%, in the 90-mg group and 53% (95% CI = 43%–62%), including complete response in 4.5%, in the 180-mg group. Median duration of response was 13.8 months in both groups. 

Among the 26 patients in the 90-mg group and 18 in the 180-mg group with measurable brain metastases at baseline, intracranial objective response rates were 42% (95% CI = 23%–63%) in the 90-mg group, including a complete response in 7.7%; and 67% (95% CI = 41%–87%) in the 180-mg group. Median intracranial duration of response was not estimable in the 90-mg group and was 5.6 months in the 180-mg group; among responders, 78% in the 90-mg group and 68% in the 180-mg group maintained response for ≥ 4 months.

How It Works

Brigatinib is an inhibitor of multiple tyrosine kinases including ALK, ROS1, IGF-1R, and FLT3, as well as epidermal growth factor receptor (EGFR) deletion and point mutations. Brigatinib inhibits autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. The agent also inhibits the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and showed dose-dependent inhibition of growth of EML4-ALK–positive NSCLC xenografts in mice. 

Brigatinib inhibits the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as cells with EGFR E746-A750 deletion, ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Antitumor activity has been demonstrated in vivo against four mutant forms of EML4-ALK, including G1202R and L1196M mutants found in NSCLC tumors in patients who have had disease progression on crizotinib. Treatment with the agent also reduced tumor burden and prolonged survival in mice with intracranial implants of an ALK-driven tumor cell line.

How It Is Used

The recommended dose of brigatinib is 90 mg once daily for the first 7 days with an increase to 180 mg once daily if 90 mg is tolerated. Treatment should be continued until disease progression or unacceptable toxicity. If treatment is interrupted for ≥ 14 days for reasons other than adverse reactions, it should be resumed at 90 mg once daily for 7 days before an increase to the previously tolerated dose. 

Sequential reductions in daily dose for adverse events are to 60 mg in patients receiving 90 mg once daily and to 120 mg, 90 mg, and 60 mg in those receiving 180 mg; treatment should be discontinued if the 60-mg dose is not tolerated. The dose should not be increased after it has been reduced for adverse reactions. 

As specified in product labeling, dose modifications including withholding treatment and dose reduction are recommended for the first occurrence of grade 1 or 2 interstitial lung disease or pneumonitis, grade 3 or 4 hypertension, symptomatic bradycardia and bradycardia with life-threatening consequences if a contributing concomitant medication is identified, grade 2 or 3 visual disturbance, grade 3 or 4 creatine phosphokinase elevation, grade 3 or 4 lipase or amylase elevation, grade 3 hyperglycemia, and other grade 3 or 4 adverse events. 

Permanent treatment discontinuation is recommended for recurrent grade 1 or 2 interstitial lung disease or pneumonitis, initial grade 3 or 4 interstitial lung disease or pneumonitis, recurrent grade 4 hypertension, initial bradycardia with life-threatening consequences if no contributing concomitant medication is identified and recurrent bradycardia with life-threatening consequences, grade 4 visual disturbance, and other recurrent grade 4 reactions. Treatment discontinuation is also to be considered as an option for recurrent grade 3 hypertension and initial grade 4 hypertension, grade 3 hyperglycemia, other recurrent grade 3 adverse events, and first occurrence of other grade 4 adverse events.

Concomitant use with strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin, and St. John’s wort) should be avoided. Concomitant use with strong CYP3A inhibitors (eg, boceprevir [Victrelis], cobicistat, indinavir [Crixivan], nelfinavir [Viracept], ritonavir, clarithromycin, itraconazole, ketoconazole, conivaptan [Vaprisol], and grapefruit/grapefruit juice) should be avoided; if use is unavoidable, the brigatinib dose should be reduced by approximately 50%. Coadministration with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates. 

Safety Profile

In the ALTA trial, the most common adverse events of any grade were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) in the 90-mg group and nausea (40%), diarrhea (38%), fatigue (36%), and cough (34%) in the 180-mg group. The most common grade 3 or 4 adverse events were hypertension (5.5%), dyspnea (2.8%), and pneumonia (2.8%) in the 90-mg group and hypertension (6.4%), pneumonia (5.5%), rash (3.6%), interstitial lung disease/pneumonitis (2.7%), and hypoxia (2.7%) in the 180-mg group. The most common grade 3 or 4 laboratory abnormalities were increased lipase (4.6%), increased amylase (3.7%), and hyperglycemia (3.7%) in the 90-mg group and increased lipase (5.5%), lymphopenia (4.5%), hyperglycemia (3.6%), and decreased phosphorus (3.6%) in the 180-mg group.

Serious adverse events occurred in 38% of the 90-mg group and 40% of the 180-mg group, with the most common being pneumonia (3.7% and 7.3%) and interstitial lung disease or pneumonitis (1.8% and 7.3%). Adverse events led to dose reduction in 7.3% and 20% of patients, with the most common cause being increased creatine phosphokinase (1.8% and 4.5%). 

Adverse events led to permanent treatment discontinuation in 2.8% and 8.2% of patients, with the most common causes being interstitial lung disease or pneumonitis (0.9% and 1.8%) and pneumonia (1.8% in the 180-mg group). Fatal adverse events occurred in 3.7% of patients, consisting of pneumonia (two patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, and urosepsis (one patient each).

Brigatinib carries warnings/precautions for interstitial lung disease/pneumonitis, hypertension, bradycardia, visual disturbance, creatine phosphokinase elevation, pancreatic enzyme elevation, hyperglycemia, and embryofetal toxicity. Patients should be monitored for new or worsening respiratory symptoms, particularly during the first week of treatment. Blood pressure, heart rate, creatine phosphokinase level, lipase and amylase levels, fasting glucose level, and visual symptoms should be monitored regularly during treatment. Women of reproductive potential should be advised of risk to a fetus and to use a nonhormonal method of effective contraception. ■

REFERENCES

1. U.S. Food and Drug Administration: Brigatinib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555841.htm. Accessed November 8, 2017.

2. Alunbrig (brigatinib) tablets prescribing information, Ariad Pharmaceuticals, April 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/208772lbl.pdf. Accessed November 8, 2017.