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Choose ALUNBRIG^® (brigatinib) for Proven First-Line CNS Efficacy¹

In an ALTA 1L study post hoc subgroup analysis of patients with brain mets at baseline, ALUNBRIG demonstrated durable intracranial responses and extended mPFS vs crizotinib.^1,2

ALUNBRIG delivered durable intracranial response^1,2

Confirmed Intracranial Overall Response Rates:
Patients with Measurable^a Brain Metastases at Baseline^1,2

Visualization of intracranial overall response rates, including PR and CR with ALUNBRIG® and PR with crizotinib.

In patients with any brain metastases at baseline, ALUNBRIG demonstrated 45% complete intracranial response (n=21/47) vs 4% (n=2/49) with crizotinib²

Study Limitation: ALTA 1L was not powered to detect differences across subgroups.

Brain metastases population^a (post hoc subgroup analysis)

75% Reduction in Risk of Progression or Death vs Crizotinib^2,3

Systemic BIRC-assessed PFS in patients with any brain metastases at baseline^2,3

Graph of PFS in patients with any brain metastases at baseline. The median PFS with ALUNBRIG® was 24 months, the median PFS with crizotinib was 5.6 months.

The INV-assessed median PFS was not reached with ALUNBRIG (95% CI: 18.4, NR) vs 5.9 months (95% CI: 3.7, 7.5) with crizotinib²

Study Limitation: ALTA 1L was not powered to detect differences across subgroups.

ITT population (final analysis with 40.4 months of median follow-up)

ALUNBRIG demonstrated durable intracranial PFS of ~4 years⁴

Intracranial PFS in the ITT population

Intracranial PFS in the ITT population. Median intracranial PFS with ALUNBRIG® was 44.1 months vs 21.2 months with crizotinib.

3-year intracranial PFS probability in the ITT population (BIRC-assessed): 56% for ALUNBRIG (n=137) vs 38% for crizotinib (n=138)⁴
In patients with any brain metastases at baseline, the median intracranial PFS was 24.0 months (95% CI: 12.9, 30.8) with ALUNBRIG vs 5.5 months (95% CI: 3.7, 7.5) with crizotinib⁴

Intracranial PFS was not part of the statistical testing hierarchy. The clinical relevance of these data is unknown, as only brain lesions were reviewed. Patients were counted as having an event if there was radiologic progression, radiotherapy to the brain, or death.⁴

Study Limitation: ALTA 1L was not powered to detect differences across subgroups; results are presented descriptively.

Brain metastases population^a (post hoc subgroup analysis)

57% Reduction in the Risk of Death vs Crizotinib⁴

OS in Patients with Measurable Brain Metastases at Baseline⁴

Graph of OS in patients with any brain metastases at baseline, comparing ALUNBRIG® and crizotinib.

Study Limitation: ALTA 1L was not powered to detect differences across subgroups.

The 4-year KM-estimated OS rate was 71% (95% CI: 53%, 84%) with ALUNBRIG vs 44% (95% CI: 28%, 59%) with crizotinib⁴

Discover how first-line ALUNBRIG could treat a hypothetical ALK+ patient with brain mets at baseline

Dr. Vijay K. Gunuganti, an Oncologist at Texas Oncology, discusses patient evaluation, the significance of biomarkers and brain mets, and using ALUNBRIG as a 1L treatment option for ALK+ mNSCLC.

ViewHide Transcript

Dr. Vijay K. Gunuganti:

Hi, I’m Dr. Vijay Gunuganti, a practicing medical oncologist, in San Antonio, Texas part of Texas Oncology.

Cindy is a 43-year-old white female preschool teacher, never-smoker, without significant medical history or family history of cancer. She was diagnosed with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer with asymptomatic brain metastases. ALUNBRIG was initiated at 90 mg once daily tablet for 7 days with or without food, and increased to 180 mg tablet once daily per the recommended/approved dosing. After 2 months of treatment, she had partial systemic and intracranial responses, based on the CT scans of the chest, abdomen; and pelvis and MRI of the brain. She experienced a few manageable adverse events that included grade 1 rash on the lower face that was treated with topical steroid cream. She also experienced light hair thinning and a mild increase in creatine phosphokinase. Otherwise, her treatment was well-tolerated. After completion of 24 cycles, almost 2 years after initiation of ALUNBRIG 180 mg tablets, Cindy remained on treatment with good tolerability. She had a sustained systemic response with further decrease in the tumors in the chest and a complete intracranial response.

I'd like to highlight that not all patients are alike and other patients sometimes may experience other side effects. In the ALTA 1L clinical trial, serious adverse reactions occurred in 33% of patients receiving Alunbrig. The most common adverse reactions were pneumonia, ILD/pneumonitis, pyrexia, dyspnea, pulmonary embolism, and asthenia. Fatal ARs occurred in 2.9% of patients and included pneumonia, cerebrovascular accident, and multiple organ dysfunction syndrome.

Please see additional safety information of ALUNBRIG at the end of this video.

Initially when I see a patient with lung cancer, I conduct testing for the mutations recommended by the National Comprehensive Cancer Network (NCCN), including analysis for mutations or alterations in EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, ERBB2 (HER2) and PD-L1.^1†‡ I know that it may be difficult to conduct biomarker testing due to a paucity of tissue, but I try hard to get at least these targetable mutations. I conduct next-generation sequencing that encompasses all of these. In the meantime, I also perform a liquid biopsy if I do not have sufficient tissue to make sure that we do not miss anything.

It is very important to conduct biomarker testing.^1†‡In 2022, the oral segment accounted for about 60% of the cancer biological therapy market and many of these oral agents are targeted therapies.²Now that efficacious oncologic treatments that target specific tumor mutations or biomarkers are available, biomarker testing results help guide my treatment selection. However, physicians who are not testing for all of the NCCN recommended biomarkers may not be aware of such guideposts. Identification of Cindy’s ALK+ status for her metastatic non-small cell lung cancer tumor indicated that she could benefit from an ALK inhibitor.^1†‡

In my experience, ALUNBRIG is well-tolerated and has good intracranial response, which I have seen in many of my patients and will discuss later. In ALTA-1L, the median duration of treatment with ALUNBRIG was 24.3 months with a median relative dose intensity of 97%, supporting that it’s well tolerated.³ That's why I feel ALUNBRIG was the choice for her.

Intracranial disease is very important to control in addition to systemic disease. Patients who had baseline brain mets achieved better responses with ALUNBRIG vs crizotinib. If you look at the intracranial responses that were seen in the ALTA-1L trial that compared ALUNBRIG with crizotinib. 78% of patients that is, 14 out of 18, treated with ALUNBRIG had a confirmed intracranial response compared with 26% of patients or 6 out of 23 treated with crizotinib, demonstrating an intracranial response rate three times higher with ALUNBRIG. In the ALUNBRIG group, 28% of patients or, 5 out of 18, had a complete response compared with no patients in the crizotinib group. And 64% of responders or, 9 out of 14, in the ALUNBRIG group had a confirmed intracranial response of 24 months or longer, while the duration of intracranial response was not estimable for crizotinib.³ In addition, the median progression free survival for patients with brain metastases at baseline was longer with ALUNBRIG at 24 months compared with 5.6 months for crizotinib.⁴

In my opinion, Cindy is a strong candidate for ALUNBRIG as she has ALK+ mNSCLC disease, which means we should be using a targeted approach. Second, she has asymptomatic brain metastases, so we want an ALK TKI with good intracranial efficacy, which narrows options down. ALUNBRIG is one of those options.

Annotations:
^†The NCCN Guidelines^® for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques, but do not endorse any specific commercially available biomarker assays or commercial laboratories.^‡See the NCCN Guidelines for detailed recommendations, including other preferred treatment options.

Reference List:

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer V.3. 2023. © National Comprehensive Cancer Network, Inc. All rights reserved. Accessed March 13, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Precedence Research. Cancer biological therapy market size to reach USD 213.6 bn by 2032. March 01, 2023. Accessed March 09, 2023. https://www.globenewswire.com/en/newsrelease/2023/03/01/2618622/0/en/CancerBiological-Therapy-Market-Size-to-Reach-USD-2136-BN-by-2032.html
ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022.
Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naïve ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J Clin Oncol. 2020;38(31):3592-3603.
Takeda Pharmaceuticals U.S.A., Inc. Data on file.

Quality of Life

Explore how ALUNBRIG may impact a patient's quality of life

REVIEW QUALITY OF LIFE

^aPatients with brain metastases ≥10 mm in longest diameter at baseline.
^bDuration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥20% from nadir, or unequivocal progression of intracranial nontarget lesions) or death.

BIRC, blinded independent review committee; CI, confidence interval; CNS, central nervous system; CR, complete response; DOR, duration of response; HR, hazard ratio; INV, investigator; ITT, intent-to-treat; KM, Kaplan- Meier; mPFS, median PFS; NE, not estimable; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.

IMPORTANT SAFETY INFORMATION, INDICATION, AND USAGE

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WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis
Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving ALUNBRIG. ILD/pneumonitis occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with Grade 3 to 4 reactions occurring in 2.2% of patients. In ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred within 9 days of initiation of ALUNBRIG (median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7% of patients. Monitor for new or worsening respiratory symptoms (dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table 1 of the full Prescribing Information after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension
In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; 13% of patients experienced Grade 3 hypertension. In ALTA, hypertension was reported in 11% of patients in the 90 mg group and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1, resume ALUNBRIG at the same dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia
In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG; one patient (0.7 %) experienced Grade 3 bradycardia. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. One patient (0.9%) in the 90 mg group experienced Grade 2 bradycardia. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance
In ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance, including blurred vision, photophobia, photopsia, and reduced visual acuity, were reported in 7.4% of patients receiving ALUNBRIG. In ALTA, adverse reactions leading to visual disturbance, including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation
In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was 24%. Dose reduction for CPK elevation occurred in 15% of patients. In ALTA, CPK elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90→180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% of patients in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation with Grade 2 or higher muscle pain or weakness. Upon resolution or recovery to Grade 1 CPK elevation or baseline, resume ALUNBRIG at the same dose or at a reduced dose per Table 2 of the full Prescribing Information.

Pancreatic Enzyme Elevation
In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients who received ALUNBRIG. Lipase elevations occurred in 59% of patients and Grade 3 or 4 lipase elevation occurred in 17% of patients. In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hepatotoxicity
In ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of patients and Grade 3 or 4 AST elevations occurred in 4.5% of patients who received ALUNBRIG. Alanine aminotransferase (ALT) elevations occurred in 52% of patients and Grade 3 or 4 ALT elevations occurred in 5.2% of patients. One patient (0.7%) had a serious adverse reaction of hepatocellular injury. In ALTA, AST elevations occurred in 38% of patients in the 90 mg group and 65% of patients in the 90→180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. Grade 3 or 4 AST elevations occurred in 0.9% of patients in the 90 mg group and did not occur in any patients in the 90→180 mg group. Grade 3 or 4 ALT elevations did not occur in any patients in the 90 mg group and in 2.7% of patients in the 90→180 mg group. Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during the first 3 months. Withhold ALUNBRIG for Grade 3 or 4 hepatic enzyme elevation with bilirubin less than or equal to 2 × ULN. Upon resolution or recovery to Grade 1 or less (less than or equal to 3 × ULN) or to baseline, resume ALUNBRIG at a next lower dose per Table 2 of the full Prescribing Information. Permanently discontinue ALUNBRIG for Grade 2 to 4 hepatic enzyme elevation with concurrent total bilirubin elevation greater than 2 times the ULN in the absence of cholestasis or hemolysis.

Hyperglycemia
In ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 7.5% of patients. In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG dosage per Table 1 of the full Prescribing Information or permanently discontinuing ALUNBRIG.

Photosensitivity
In ALTA 1L, 3.7% of patients who received ALUNBRIG experienced photosensitivity, with 0.7% of patients experiencing Grade 3 to 4 reactions. In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group and 0.9% of patients in the 90→180 mg group experienced photosensitivity. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90→180 mg group. Advise patients to limit sun exposure while taking ALUNBRIG, and for at least 5 days after discontinuation of treatment. Advise patients, when outdoors, to wear a hat and protective clothing, and use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Based on the severity, withhold ALUNBRIG, then resume at the same dose, or reduce the dose, or permanently discontinue.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

The most common adverse reactions (≥25%) with ALUNBRIG were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

DRUG INTERACTIONS
CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose. ALUNBRIG may cause reduced fertility in males.

Lactation: Advise patients not to breastfeed.

Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment.

Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis
Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving ALUNBRIG. ILD/pneumonitis occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with Grade 3 to 4 reactions occurring in 2.2% of patients. In ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred within 9 days of initiation of ALUNBRIG (median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7% of patients. Monitor for new or worsening respiratory symptoms (dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table 1 of the full Prescribing Information after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension
In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; 13% of patients experienced Grade 3 hypertension. In ALTA, hypertension was reported in 11% of patients in the 90 mg group and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1, resume ALUNBRIG at the same dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia
In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG; one patient (0.7 %) experienced Grade 3 bradycardia. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. One patient (0.9%) in the 90 mg group experienced Grade 2 bradycardia. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance
In ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance, including blurred vision, photophobia, photopsia, and reduced visual acuity, were reported in 7.4% of patients receiving ALUNBRIG. In ALTA, adverse reactions leading to visual disturbance, including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation
In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was 24%. Dose reduction for CPK elevation occurred in 15% of patients. In ALTA, CPK elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90→180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% of patients in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation with Grade 2 or higher muscle pain or weakness. Upon resolution or recovery to Grade 1 CPK elevation or baseline, resume ALUNBRIG at the same dose or at a reduced dose per Table 2 of the full Prescribing Information.

Pancreatic Enzyme Elevation
In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients who received ALUNBRIG. Lipase elevations occurred in 59% of patients and Grade 3 or 4 lipase elevation occurred in 17% of patients. In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hepatotoxicity
In ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of patients and Grade 3 or 4 AST elevations occurred in 4.5% of patients who received ALUNBRIG. Alanine aminotransferase (ALT) elevations occurred in 52% of patients and Grade 3 or 4 ALT elevations occurred in 5.2% of patients. One patient (0.7%) had a serious adverse reaction of hepatocellular injury. In ALTA, AST elevations occurred in 38% of patients in the 90 mg group and 65% of patients in the 90→180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. Grade 3 or 4 AST elevations occurred in 0.9% of patients in the 90 mg group and did not occur in any patients in the 90→180 mg group. Grade 3 or 4 ALT elevations did not occur in any patients in the 90 mg group and in 2.7% of patients in the 90→180 mg group. Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during the first 3 months. Withhold ALUNBRIG for Grade 3 or 4 hepatic enzyme elevation with bilirubin less than or equal to 2 × ULN. Upon resolution or recovery to Grade 1 or less (less than or equal to 3 × ULN) or to baseline, resume ALUNBRIG at a next lower dose per Table 2 of the full Prescribing Information. Permanently discontinue ALUNBRIG for Grade 2 to 4 hepatic enzyme elevation with concurrent total bilirubin elevation greater than 2 times the ULN in the absence of cholestasis or hemolysis.

Hyperglycemia
In ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 7.5% of patients. In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG dosage per Table 1 of the full Prescribing Information or permanently discontinuing ALUNBRIG.

Photosensitivity
In ALTA 1L, 3.7% of patients who received ALUNBRIG experienced photosensitivity, with 0.7% of patients experiencing Grade 3 to 4 reactions. In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group and 0.9% of patients in the 90→180 mg group experienced photosensitivity. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90→180 mg group. Advise patients to limit sun exposure while taking ALUNBRIG, and for at least 5 days after discontinuation of treatment. Advise patients, when outdoors, to wear a hat and protective clothing, and use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Based on the severity, withhold ALUNBRIG, then resume at the same dose, or reduce the dose, or permanently discontinue.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

The most common adverse reactions (≥25%) with ALUNBRIG were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

DRUG INTERACTIONS
CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose. ALUNBRIG may cause reduced fertility in males.

Lactation: Advise patients not to breastfeed.

Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment.

Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

Show References

REFERENCES: 1. ALUNBRIG. Prescribing Information. Takeda Pharmaceuticals America, Inc.; 2022. 2. Camidge DR, Kim HR, Ahn MJ, et al. J Clin Oncol. 2020;38(31):3592-3603. 3. Takeda Pharmaceuticals U.S.A., Inc. Data on file; 2021. 4. Camidge DR, Kim HR, Ahn MJ, et al. J Thorac Oncol. 2021;16(12):2091-2108.