Brigatinib approval yields additional treatment options for crizotinib-resistant, ALK-positive NSCLC patients

The accelerated approval by the United States Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, marked the fourth approved drug in this class.¹ The most recent approval expands the available treatment options for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib. The FDA based its decision on the results of the phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage.²

The pivotal trial was a noncomparative, 2-arm, open-label, multicenter study that was carried out during June 2014-September 2015 at 71 centers across 18 countries. Eligible patients were 18 years or older, with locally advanced or metastatic ALK-positive NSCLC, disease progression while taking crizotinib, at least 1 measurable lesion, adequate organ and hematologic function, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (range, 0-5, where 0 means the patient is fully active, and 2, ambulatory and capable of all self-care but not able to carry out any work activities).

Patients were excluded from the trial if they had received previous ALK inhibitor therapy, other than crizotinib, or had received crizotinib within 3 days of the first dose of brigatinib, or they had received chemotherapy, radiation therapy, or investigational drugs within 14 days or monoclonal antibody therapy within 30 days of the first dose of the study drug. Anyone with a history or the presence of pulmonary interstitial disease or drug-related pneumonitis or symptomatic central nervous system (CNS) metastases that were neurologically unstable or required an increasing dose of corticosteroids was also ineligible.

A total of 222 patients were randomized to receive one of two brigatinib doses, either 90 mg daily or 180 mg daily after a 7-day lead-in at 90 mg (the latter to help mitigate pulmonary adverse events observed in previous studies). Randomization was stratified according to baseline brain metastases (present or absent) and best investigator-assessed response to crizotinib (complete response [CR] or partial response [PR] vs other or unknown)

Chest and abdomen imaging by computed-tomography (CT) or magnetic resonance imaging (MRI) with contrast were performed to assess disease at screening and every 8 weeks through cycle 15, and then every 12 weeks until disease progression. Contrast-enhanced brain MRI was carried out at screening and repeated after baseline for the 68% of patients who had CNS metastases at the time of enrollment.

The primary endpoint was confirmed investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and secondary endpoints included CNS response, duration of response (DoR), progression-free and overall survival (PFS and OS, respectively). ORRs for the 90-mg and 180-mg doses were 48% and 53%, respectively. Responses occurred quickly and were durable in both arms; after a median follow-up of 8 months, median DoR was 13.8 months for both doses. Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively, notable because of the poor ability of crizotinib to penetrate the blood-brain barrier.

Other secondary outcomes also favored the 180-mg dose. Investigator-assessed PFS for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year OS was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose. There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

The safety of brigatinib was evaluated in 219 patients who received at least 1 dose of brigatinib. Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events (AEs). The most common AEs were nausea, diarrhea, fatigue, cough, and headache, and visual disturbances also occurred. The most common serious AEs were pneumonia and interstitial lung disease/pneumonitis.

The prescribing information details warnings and precautions about these and other potential toxicities, including hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.³ Patients should be monitored for new or worsening respiratory symptoms, especially during the first week of initiating brigatinib treatment; blood pressure should be controlled before treatment initiation and monitored after 2 weeks and at least monthly thereafter; heart rate and blood pressure should be monitored frequently; patients should be advised to report any visual symptoms, or any unexplained muscle pain, tenderness or weakness; CPK, lipase, and amylase levels should be monitored during treatment, and fasting glucose tested before starting treatment and periodically thereafter.

Brigatinib should be withheld in any patient with new or worsening respiratory symptoms, for grade 3 hypertension despite optimal antihypertensive therapy, for symptomatic bradycardia, for patients with new or worsening visual symptoms of grade 2 or above, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved. Treatment should be permanently discontinued for grade 3 or 4 or recurrent interstitial lung disease/pneumonitis, grade 4 or recurrent grade 3 hypertension, life-threatening bradycardia, and grade 4 visual disturbance.

Based on its mechanism of action, brigatinib can cause fetal harm and patients of reproductive potential should be advised of the risks and necessary precautions. Brigatinib is marketed as Alunbrig. It was discovered by Ariad Pharmaceuticals Inc, which was acquired by Takeda in February 2017.

The accelerated approval by the United States Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, marked the fourth approved drug in this class.¹ The most recent approval expands the available treatment options for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib. The FDA based its decision on the results of the phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage.²

The pivotal trial was a noncomparative, 2-arm, open-label, multicenter study that was carried out during June 2014-September 2015 at 71 centers across 18 countries. Eligible patients were 18 years or older, with locally advanced or metastatic ALK-positive NSCLC, disease progression while taking crizotinib, at least 1 measurable lesion, adequate organ and hematologic function, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (range, 0-5, where 0 means the patient is fully active, and 2, ambulatory and capable of all self-care but not able to carry out any work activities).

Patients were excluded from the trial if they had received previous ALK inhibitor therapy, other than crizotinib, or had received crizotinib within 3 days of the first dose of brigatinib, or they had received chemotherapy, radiation therapy, or investigational drugs within 14 days or monoclonal antibody therapy within 30 days of the first dose of the study drug. Anyone with a history or the presence of pulmonary interstitial disease or drug-related pneumonitis or symptomatic central nervous system (CNS) metastases that were neurologically unstable or required an increasing dose of corticosteroids was also ineligible.

A total of 222 patients were randomized to receive one of two brigatinib doses, either 90 mg daily or 180 mg daily after a 7-day lead-in at 90 mg (the latter to help mitigate pulmonary adverse events observed in previous studies). Randomization was stratified according to baseline brain metastases (present or absent) and best investigator-assessed response to crizotinib (complete response [CR] or partial response [PR] vs other or unknown)

Chest and abdomen imaging by computed-tomography (CT) or magnetic resonance imaging (MRI) with contrast were performed to assess disease at screening and every 8 weeks through cycle 15, and then every 12 weeks until disease progression. Contrast-enhanced brain MRI was carried out at screening and repeated after baseline for the 68% of patients who had CNS metastases at the time of enrollment.

The primary endpoint was confirmed investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and secondary endpoints included CNS response, duration of response (DoR), progression-free and overall survival (PFS and OS, respectively). ORRs for the 90-mg and 180-mg doses were 48% and 53%, respectively. Responses occurred quickly and were durable in both arms; after a median follow-up of 8 months, median DoR was 13.8 months for both doses. Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively, notable because of the poor ability of crizotinib to penetrate the blood-brain barrier.

Other secondary outcomes also favored the 180-mg dose. Investigator-assessed PFS for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year OS was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose. There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

The safety of brigatinib was evaluated in 219 patients who received at least 1 dose of brigatinib. Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events (AEs). The most common AEs were nausea, diarrhea, fatigue, cough, and headache, and visual disturbances also occurred. The most common serious AEs were pneumonia and interstitial lung disease/pneumonitis.

The prescribing information details warnings and precautions about these and other potential toxicities, including hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.³ Patients should be monitored for new or worsening respiratory symptoms, especially during the first week of initiating brigatinib treatment; blood pressure should be controlled before treatment initiation and monitored after 2 weeks and at least monthly thereafter; heart rate and blood pressure should be monitored frequently; patients should be advised to report any visual symptoms, or any unexplained muscle pain, tenderness or weakness; CPK, lipase, and amylase levels should be monitored during treatment, and fasting glucose tested before starting treatment and periodically thereafter.

Brigatinib should be withheld in any patient with new or worsening respiratory symptoms, for grade 3 hypertension despite optimal antihypertensive therapy, for symptomatic bradycardia, for patients with new or worsening visual symptoms of grade 2 or above, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved. Treatment should be permanently discontinued for grade 3 or 4 or recurrent interstitial lung disease/pneumonitis, grade 4 or recurrent grade 3 hypertension, life-threatening bradycardia, and grade 4 visual disturbance.

Based on its mechanism of action, brigatinib can cause fetal harm and patients of reproductive potential should be advised of the risks and necessary precautions. Brigatinib is marketed as Alunbrig. It was discovered by Ariad Pharmaceuticals Inc, which was acquired by Takeda in February 2017.

The accelerated approval by the United States Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, marked the fourth approved drug in this class.¹ The most recent approval expands the available treatment options for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib. The FDA based its decision on the results of the phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage.²

The pivotal trial was a noncomparative, 2-arm, open-label, multicenter study that was carried out during June 2014-September 2015 at 71 centers across 18 countries. Eligible patients were 18 years or older, with locally advanced or metastatic ALK-positive NSCLC, disease progression while taking crizotinib, at least 1 measurable lesion, adequate organ and hematologic function, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (range, 0-5, where 0 means the patient is fully active, and 2, ambulatory and capable of all self-care but not able to carry out any work activities).

Patients were excluded from the trial if they had received previous ALK inhibitor therapy, other than crizotinib, or had received crizotinib within 3 days of the first dose of brigatinib, or they had received chemotherapy, radiation therapy, or investigational drugs within 14 days or monoclonal antibody therapy within 30 days of the first dose of the study drug. Anyone with a history or the presence of pulmonary interstitial disease or drug-related pneumonitis or symptomatic central nervous system (CNS) metastases that were neurologically unstable or required an increasing dose of corticosteroids was also ineligible.

A total of 222 patients were randomized to receive one of two brigatinib doses, either 90 mg daily or 180 mg daily after a 7-day lead-in at 90 mg (the latter to help mitigate pulmonary adverse events observed in previous studies). Randomization was stratified according to baseline brain metastases (present or absent) and best investigator-assessed response to crizotinib (complete response [CR] or partial response [PR] vs other or unknown)

Chest and abdomen imaging by computed-tomography (CT) or magnetic resonance imaging (MRI) with contrast were performed to assess disease at screening and every 8 weeks through cycle 15, and then every 12 weeks until disease progression. Contrast-enhanced brain MRI was carried out at screening and repeated after baseline for the 68% of patients who had CNS metastases at the time of enrollment.

The primary endpoint was confirmed investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and secondary endpoints included CNS response, duration of response (DoR), progression-free and overall survival (PFS and OS, respectively). ORRs for the 90-mg and 180-mg doses were 48% and 53%, respectively. Responses occurred quickly and were durable in both arms; after a median follow-up of 8 months, median DoR was 13.8 months for both doses. Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively, notable because of the poor ability of crizotinib to penetrate the blood-brain barrier.

Other secondary outcomes also favored the 180-mg dose. Investigator-assessed PFS for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year OS was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose. There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

The safety of brigatinib was evaluated in 219 patients who received at least 1 dose of brigatinib. Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events (AEs). The most common AEs were nausea, diarrhea, fatigue, cough, and headache, and visual disturbances also occurred. The most common serious AEs were pneumonia and interstitial lung disease/pneumonitis.

The prescribing information details warnings and precautions about these and other potential toxicities, including hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.³ Patients should be monitored for new or worsening respiratory symptoms, especially during the first week of initiating brigatinib treatment; blood pressure should be controlled before treatment initiation and monitored after 2 weeks and at least monthly thereafter; heart rate and blood pressure should be monitored frequently; patients should be advised to report any visual symptoms, or any unexplained muscle pain, tenderness or weakness; CPK, lipase, and amylase levels should be monitored during treatment, and fasting glucose tested before starting treatment and periodically thereafter.

Brigatinib should be withheld in any patient with new or worsening respiratory symptoms, for grade 3 hypertension despite optimal antihypertensive therapy, for symptomatic bradycardia, for patients with new or worsening visual symptoms of grade 2 or above, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved. Treatment should be permanently discontinued for grade 3 or 4 or recurrent interstitial lung disease/pneumonitis, grade 4 or recurrent grade 3 hypertension, life-threatening bradycardia, and grade 4 visual disturbance.

Based on its mechanism of action, brigatinib can cause fetal harm and patients of reproductive potential should be advised of the risks and necessary precautions. Brigatinib is marketed as Alunbrig. It was discovered by Ariad Pharmaceuticals Inc, which was acquired by Takeda in February 2017.