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Brigatinib for ALK-Positive Metastatic Non–Small Cell Lung Cancer


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On May 22, 2020, brigatinib was approved for the treatment of adult patients with ALK-positive, metastatic non–small cell lung cancer (NSCLC), as detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 The FDA also approved the Vysis ALK Break Apart FISH Probe Kit as a companion diagnostic for brigatinib.

Supporting Efficacy Data

Approval was based on findings in the multicenter, open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier NCT02737501).3 In the trial, 275 patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy were randomly assigned to receive brigatinib at 180 mg once daily, with a 7-day lead-in at 90 mg once daily (n = 137), or crizotinib at 250 mg twice daily (n = 138). Patients with a history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis were excluded from the trial. The trial required patients to have an ALK rearrangement based on local standard-of-care testing. Clinical samples from 259 patients were centrally tested retrospectively with the Vysis ALK Break Apart FISH Probe Kit; 239 patients had positive results, and 20 had negative results.

OF NOTE

Brigatinib has warnings/precautions for interstitial lung disease/pneumonitis, hypertension, bradycardia, visual disturbance, CPK elevation, pancreatic enzyme elevation, hyperglycemia, and embryofetal toxicity.

The major efficacy outcome was progression-free survival, as assessed by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. The confirmed overall response rate was an additional efficacy outcome measure.

Median patient age was 59 years (range = 27–89, 32% ≥ 65 years). Overall, 59% were white and 39% were Asian, 55% were female, and the Eastern Cooperative Oncology Group performance status was 0 in 39% and 1 in 56%. In addition, 58% were never smokers, 93% had stage IV disease, 27% received chemotherapy in the locally advanced or metastatic setting, 14% had received central nervous system (CNS) radiation, 31% had bone metastases and 20% had liver metastases, and 35% had CNS metastases, with 43% (n = 41) having  measurable lesions.

Median progression-free survival was 24 months (95% confidence interval [CI] = 18.5 months to not estimable) in the brigatinib group vs 11 months (95% CI = 9.2–12.9 months) in the crizotinib group (hazard ratio [HR] = 0.49, 95% CI = 0.35–0.68, P < .0001). The confirmed overall response rate was 74% vs 62% (P = .0342), with a complete response in 15% vs 9%. Median duration of response was not reached (95% CI = 19.4 months to not estimable) vs 13.8 months (95% CI = 9.3–20.8 months), with 51% vs 30% having a response duration of at least 24 months.

Among 18 vs 23 patients with measurable intracranial metastases, the confirmed intracranial overall response rate was 78% vs 26%, with a complete response in 28% vs 0%. Response duration was at least 24 months in 64% of patients who responded to brigatinib treatment.

How It Works

Brigatinib is an inhibitor of multiple tyrosine kinases including ALK, ROS1, IGF-1R, and FLT3, as well as 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 EGFR-Del (E746-A750), 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. Brigatinib also reduced the tumor burden and prolonged survival in mice with intracranial implants of an ALK-driven tumor cell line.

How It Is Used

Patients must be selected for brigatinib treatment on the basis of an FDA-approved test. The recommended dosage is 90 mg once daily for the first 7 days followed by an increase to 180 mg once daily, with treatment continuing until disease progression or unacceptable toxicity. If treatment is interrupted for more than 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.

Recommended dose reductions for adverse reactions 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.

KEY POINTS

  • Brigatinib was approved for treatment of adult patients with ALK-positive, metastatic NSCLC, as detected by an FDA-approved test.
  • The recommended dosage is 90 mg once daily for the first 7 days followed by an increase to 180 mg once daily, with treatment continuing until disease progression or unacceptable toxicity.

Product labeling provides instructions on dosage modification, including treatment discontinuation for adverse reactions including interstitial lung disease/pneumonitis, hypertension, bradycardia, visual disturbance, creatine phosphokinase (CPK) elevation, lipase/amylase elevation, hyperglycemia, and any grade 3 or 4 adverse reactions.

Concomitant use with strong or moderate CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin) and moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided. Prescribing information provides instructions on brigatinib dose reductions in patients receiving strong or moderate CYP3A inhibitors and dose increases in patients receiving moderate CYP3A inducers if concomitant use cannot be avoided.

The brigatinib dose should be reduced by approximately 40% in patients with severe hepatic impairment and by approximately 50% in patients with severe renal impairment.

Safety Profile

The most common adverse events of any grade (at least 25% of patients) with brigatinib treatment in clinical trials have been diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

In the ALTA-1L trial, the median duration of brigatinib treatment was 24.3 months, with 78% of patients having exposure for at least 6 months and 68% for more than 1 year. The most common adverse events of any grade (at least 25% of patients) in study participants receiving brigatinib were diarrhea (53% vs 57% with crizotinib), rash (40% vs 17%), cough (35% vs 20%), hypertension (32% vs 8%), fatigue (32% vs 40%), nausea (30% vs 58%), myalgia (28% vs 23%), and dyspnea (25% vs 22%).

The most common grade 3 or 4 adverse events included hypertension (13% vs 3%), pneumonia (5% vs 3%), rash (3% vs 0%), dyspnea (3% vs 4%), and interstitial lung disease/pneumonitis (3% vs 1%). The most common grade 3 or 4 laboratory abnormalities were increased CPK (24% vs 5%), increased lipase (17% vs 10%), decreased lymphocytes (9% vs 5%), and hyperglycemia (8% vs 4%).

Serious adverse events occurred in 33% of patients receiving brigatinib, with the most common being pneumonia (4.4%), interstitial lung disease/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Adverse events led to dose reduction in 38%, with the most common causes being increased CPK (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), interstitial lung disease/pneumonitis (2.2%), and hypertension (2.2%).

Permanent treatment discontinuation due to adverse events occurred in 13% of patients, with the most common causes being interstitial lung disease/pneumonitis (3.7%) and pneumonia (2.2%). Fatal adverse reactions occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).

Brigatinib has warnings/precautions for interstitial lung disease/pneumonitis, hypertension, bradycardia, visual disturbance, CPK 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 should be monitored after 2 weeks and then at least
monthly during treatment. Heart rate, CPK level, lipase and amylase levels, and fasting glucose levels should be monitored regularly.

Patients should be advised to report visual symptoms. Women of reproductive potential should be advised to use an effective nonhormonal method of contraception during treatment. Patients should be advised not to breastfeed while taking brigatinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves brigatinib for ALK-positive metastatic NSCLC. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-brigatinib-alk-positive-metastatic-nsclc. Accessed June 2, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Alunbrig (brigatinib) tablets, for oral use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208772s008lbl.pdf. Accessed June 2, 2020.

3. Camidge DR, Kim HR, Ahn MJ, et al: Brigatinib vs crizotinib in ALK-positive non–small-cell lung cancer. N Engl J Med 379:2027-2039, 2018.

 


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