Choose ALUNBRIG^® (brigatinib): Download Helpful Resources for Patients

Dr. Albino:

Hello, I am Dr. Miguel Albino, an oncologist at Texas Oncology. Today I will be discussing a first-line treatment option for patients with ALK+ mNSCLC with brain metastases.

For patients with ALK+ mNSCLC, quantity of life is increasing,^1-3 and QoL is also increasingly important. With survival outcomes improving in NSCLC, patients spend more time on therapy.³

It is important to note that more time on therapy increases the importance of treatment efficacy in the brain due to brain metastases,^1,4 long-term tolerability,³ and reduced pill burden.⁵

Because tumor types and treatment approaches can vary, I always perform comprehensive genomic testing to determine whether there is an actionable mutation. This helps guide my treatment recommendations. Next, I will discuss the clinical and safety data for ALUNBRIG^® (brigatinib), a treatment option for ALK+ mNSCLC.

ALUNBRIG is a kinase inhibitor indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Based on clinical data, the National Comprehensive Cancer Network^® (NCCN^®) recommends brigatinib as a Category 1 preferred first-line treatment option for ALK+ mNSCLC.^6,a,b,c Before I discuss the clinical data for ALUNBRIG, I would like to review the Warnings and Precautions.

Voiceover:

WARNINGS AND PRECAUTIONS: Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening respiratory symptoms, particularly during the first week of treatment. Withhold ALUNBRIG for new or worsening respiratory symptoms and promptly evaluate for ILD/pneumonitis. Upon recovery, either dose reduce or permanently discontinue ALUNBRIG. 

Hypertension: Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold ALUNBRIG, then dose reduce or permanently discontinue. 

Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue. 

Visual Disturbance: Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG. 

Creatine Phosphokinase (CPK) Elevation: Monitor CPK levels regularly during treatment. Based on the severity and with muscle pain or weakness, withhold ALUNBRIG, then resume or reduce dose.

Hepatotoxicity: Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels regularly during treatment. Based on severity, withhold dose, then resume at lower level. 

Pancreatic Enzyme Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. 

Hyperglycemia: Assess fasting serum glucose prior to starting ALUNBRIG and regularly during treatment. If not adequately controlled with optimal medical management, withhold ALUNBRIG, then consider dose reduction or permanently discontinue, based on severity. 

Photosensitivity: Advise patients to limit sun exposure. Based on severity withhold ALUNBRIG, then resume at the same dose, reduce the dose, or permanently discontinue. 

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 

Please see more information about each Warning and Precaution, along with additional Important Safety Information later in this presentation.

Dr. Albino:

Now, let’s take a look at the clinical trial that evaluated the efficacy, safety, and tolerability of ALUNBRIG.

ALTA 1L was a phase 3, randomized, open-label, multicenter trial in adult patients with locally advanced or metastatic ALK+ NSCLC who had not previously received an ALK-targeted therapy.^7,8 Eligible patients were allowed to have up to one prior regimen of chemotherapy.⁸ 

A total of 275 patients were randomized 1 to 1 to receive ALUNBRIG 180 mg orally once daily with a 7-day lead-in at 90 mg once daily or crizotinib 250 mg orally twice daily.⁸ 

Patients were stratified by the presence or absence of CNS metastases at baseline and by prior chemotherapy in the locally advanced or metastatic setting.⁸ 
It is important to note that crossover from ALUNBRIG was permitted after disease progression.⁸ 

The major efficacy outcome measure was PFS according to RECIST v1.1. Additional efficacy outcome measures included confirmed ORR, DOR, intracranial ORR, and intracranial DOR.⁸

At the time of the second interim analysis, the data cutoff was 22 months after the last patient was enrolled, with a median follow-up of 24.9 months for ALUNBRIG and 15.2 months for crizotinib.^7,9 The final analysis was conducted at a median follow-up of 40.4 months, and select efficacy data from the final analysis is included in this presentation.¹⁰

Patients in the ALTA 1L trial exhibited characteristics that were common among real-world patients with ALK+ mNSCLC. This included high rates of adenocarcinoma, a presence of brain metastases at baseline, and a median age of 59. Demographics and baseline factors were balanced between the treatment arms.¹¹

ALUNBRIG doubled the median PFS versus crizotinib in the ITT population. In the ALUNBRIG arm, the BIRC-assessed median PFS was 24 months versus 11 months in the crizotinib arm. Additionally, ALUNBRIG exhibited a 51% reduction in the risk of progression or death.⁸ The investigator-assessed median PFS was 29.4 months for ALUNBRIG versus 9.2 months for crizotinib.⁷

Additionally, high response rates and durable responses were seen with ALUNBRIG in the ITT population. ORR was 74% for ALUNBRIG compared with 62% for crizotinib. Fifteen percent of patients in the ALUNBRIG arm achieved a CR versus 9% in the crizotinib arm.⁸ 

At the final analysis, with 40.4 months of median follow-up, the median DOR was approximately 2.5 times longer with ALUNBRIG (at 33.1 months) than with crizotinib (13.8 months).^8,1

In a post-hoc subgroup analysis of patients with brain metastases at baseline, the median PFS was longer with ALUNBRIG versus crizotinib. The median PFS for patients was 24 months with ALUNBRIG versus 5.6 months with crizotinib. The hazard ratio for disease progression or death in patients with brain metastases at baseline was 0.25. This corresponds to a 75% reduction in risk of progression in patients treated with ALUNBRIG compared with crizotinib.^7,9 ALTA 1L was not powered to detect differences across subgroups.

In the patients with measurable brain metastases at baseline, the intracranial response rate was 3 times higher with ALUNBRIG versus crizotinib. Seventy-eight percent of patients treated with ALUNBRIG had a confirmed intracranial ORR compared with 26% of patients treated with crizotinib. Furthermore, 28% of patients in the ALUNBRIG arm had a CR compared with no patients in the crizotinib arm. ⁸ 

Additionally, 64% of responders achieved an intracranial response duration greater than or equal to 24 months with ALUNBRIG.⁸

In the final analysis of patients in the ITT population, intracranial PFS with ALUNBRIG was 44.1 months vs 21.2 months with crizotinib with a hazard ratio of 0.44. The 3-year intracranial PFS probability in the ITT population was 56% for ALUNBRIG and 38% for crizotinib.¹⁰ 

The secondary endpoint of intracranial PFS was not part of the statistical testing hierarchy. In addition, the clinical relevance of these data is unknown because they do not include disease status in the rest of the body; only brain lesions were reviewed. Patients were counted as having an event if there was radiologic progression, radiotherapy to the brain, or death. ALTA 1L was not powered to detect differences across subgroups; results are presented descriptively.

Intracranial PFS was defined as the time interval from the date of randomization until the first date at which CNS disease progression was objectively documented or death due to any cause, whichever occurred first.¹¹ 

In the final analysis of patients in the brain metastasis population, intracranial PFS with ALUNBRIG was 24.0 months vs 5.5 months with crizotinib with a hazard ratio of 0.29. The 3-year intracranial PFS probability in this population was 31% for ALUNBRIG and 9% for crizotinib.10 The hazard ratio for intracranial PFS in patients who did not have brain metastases at baseline was 0.703.⁹

OS was also assessed in all patients, including those with brain metastases at baseline. In the ITT population, the median OS was not reached for both arms8 —30% of patients in the ALUNBRIG arm expired versus 37% of patients in the crizotinib arm.^8,10 

The 3-year OS rate was 71% with ALUNBRIG and 68% with crizotinib. Forty-seven percent of patients in the crizotinib arm had crossed over to receive ALUNBRIG.¹⁰

In a post-hoc subgroup analysis of patients with measurable brain metastases at baseline, ALUNBRIG reduced the risk of death by 57% versus crizotinib, which corresponds to the hazard ratio of 0.43.¹⁰ As a reminder, this study was not powered to detect differences across subgroups.

Patients taking ALUNBRIG also reported better QoL compared with crizotinib. As a secondary endpoint, ALUNBRIG delayed time to worsening in GHS/QoL compared with crizotinib.⁷ 

Median time to worsening GHS/QoL was 26.7 months in the ALUNBRIG arm compared with 8.3 months in the crizotinib arm.⁷ The time to worsening was assessed by physical, emotional, cognitive, and social functioning scales as well as improvement of disease symptoms.⁹ These patient-reported outcome endpoints were exploratory and not prespecified. The improvement in QoL scores and delay in worsening of GHS/QoL may be an overestimation, because patients were not blinded to treatment assignment. Among responders, the median duration of improvement in QoL had not been reached for ALUNBRIG versus 12 months for crizotinib.⁷

Next, let’s talk about the safety profile for ALUNBRIG. ALUNBRIG has a well-established safety profile.8 Serious ARs occurred in 33% of patients receiving ALUNBRIG. 

The most common serious ARs in ALTA 1L were pneumonia (at 4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Fatal ARs occurred in 2.9% of patients and included pneumonia (at 1.5%), cerebrovascular accident (at 0.7%), and multiple organ dysfunction syndrome (also at 0.7%).⁸

The table here shows ARs in greater than or equal to 10% for all grades or greater than or equal to 2% for grades 3 to 4 of patients by arm in ALTA 1L.⁸ 

ALUNBRIG was also well tolerated long-term, based on the median follow-up of 40.4 months in the ALUNBRIG arm of ALTA 1L.10 The median duration of treatment with ALUNBRIG was 24.3 months, with a median relative dose intensity of 97%.⁸ 

Dose reductions occurred in 38% of patients receiving ALUNBRIG. The most common ARs in ALTA 1L that led to dose reduction were increased creatinine phosphokinase (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), ILD/pneumonitis (2.2%), and hypertension (at 2.2%).⁸

Permanent discontinuation due to ARs occurred in 13% of patients receiving ALUNBRIG.The most frequent ARs in ALTA 1L that led to discontinuation were ILD/pneumonitis (3.7%) and pneumonia (at 2.2%).⁸

This table shows the laboratory abnormalities greater than or equal to 20% (all grades) in patients by arm in ALTA 1L, with increased CPK and lipase being the most common grades 3 to 4 abnormalities.⁸

As I touched on earlier, high pill burden can negatively impact adherence and may contribute to poor quality of life.

The dosing for ALUNBRIG is 1 tablet once daily, with or without food. Once-daily dosing can substantially reduce a patient’s pill burden.⁸ For more detailed dosing information, please refer to the Prescribing Information for ALUNBRIG, available above this video.

In summary, consider ALUNBRIG as a first-line treatment option for patients with ALK+ metastatic NSCLC, as it offers systemic and brain mets efficacy, long-term tolerability, and once-daily dosing.⁸ 

Now please listen to the Important Safety Information.

Voiceover:

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.

Dr. Albino:
Thank you for joining me.

Voiceover:

This program is sponsored by Takeda Pharmaceuticals U.S.A., Inc., and has been brought to you by PeerDirect Publishing. Thank you for your participation.

Acronyms:
ALK=anaplastic lymphoma kinase; AR=adverse reaction; BIRC=blinded independent review committee; CNS=central nervous system; CPK=creatine phosphokinase; CR=complete response; CTCAE=Common Terminology Criteria for Adverse Events; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group performance status; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; FDA=US Food and Drug Administration; GHS=global health status; HR=hazard ratio; ICR=intracranial response; ITT=intention to treat; KRAS=Kirsten RAt Sarcoma virus; mNSCLC=metastatic non-small cell lung cancer; NCCN=National Comprehensive Cancer Network^® (NCCN^®); NSCLC=non-small cell lung cancer; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PR=partial response; QLQ-LC13=Quality of Life Questionnaire Lung Cancer 13; QoL=quality of life; RECIST=Response Evaluation Criteria in Solid Tumors.

Slide/Video References:

1. O’Kane GM, Su J, Tse BC, et al. The impact of brain metastases and associated neurocognitive aspects on health utility scores in EGFR mutated and ALK rearranged NSCLC: a real world evidence analysis. Oncologist. 2019;24(7):e501-e509. 
2. Pérez-Larraya JG, Hildebrand J. Brain metastases. Handb Clin Neurol. 2014;121:1143-1157. 
3. Pacheco JM, Gao D, Smith D, et al. Natural history and factors associated with overall survival in stage IV ALK-rearranged non-small cell lung cancer. J Thorac Oncol. 2018;14(4):691-700. 
4. Eton DT, Ridgeway JL, Egginton JS, et al. Finalizing a measurement framework for the burden of treatment in complex patients with chronic conditions. Patient Relat Outcome Meas. 2015;6:117-126. 
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer v3.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed May 1, 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. 
6. ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022. 
7. 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. 
8. Takeda Pharmaceuticals U.S.A., Inc. Data on file. 
9. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor–naïve advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol. 2021;16(12):2091-2108. 
10. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. 
11. Tang W, Lei Y, Su J, et al. TNM stages inversely correlate with the age at diagnosis in ALK-positive lung cancer. Transl Lung Cancer Res. 2019;8(2):144-154.

Voiceover References:

1. O’Kane GM, Su J, Tse BC, et al. The impact of brain metastases and associated neurocognitive aspects on health utility scores in EGFR mutated and ALK rearranged NSCLC: a real world evidence analysis. Oncologist. 2019;24(7):e501-e509. 
2. Chia PL, Mitchell P, Dobrovic A, John T. Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol. 2014;6:423-432. 
3. Pacheco JM, Gao D, Smith D, et al. Natural history and factors associated with overall survival in stage IV ALK-rearranged non-small cell lung cancer. J Thorac Oncol. 2018;14(4):691-700. 
4. Pérez-Larraya JG, Hildebrand J. Brain metastases. Handb Clin Neurol. 2014;121:1143-1157. 
5. Eton DT, Ridgeway JL, Egginton JS, et al. Finalizing a measurement framework for the burden of treatment in complex patients with chronic conditions. Patient Relat Outcome Meas. 2015;6:117-126. 
6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer v3.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed May 1, 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. 
7. 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. 
8. ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022. 
9. Takeda Pharmaceuticals U.S.A., Inc. Data on file. 
10. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor–naïve advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol. 2021;16(12):2091-2108. 
11. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039.
     

Kayla Haines, MSN, APRN, FNP-C:

Hi, I’m Kayla Haines, and I work at Florida Cancer Specialists & Research Institute. Today, I’d like to discuss the treatment of metastatic non-small cell lung cancer. 

Non-small cell lung cancer, or NSCLC, is the most common type of lung cancer.

Lung cancer is the leading cause of cancer death worldwide, and the 5-year relative survival rate for metastatic NSCLC is as low as 9%. NSCLC also has a broad molecular profile with several known genetic mutations, also called oncogenic biomarkers, known to cause the disease. Rearrangements in the anaplastic lymphoma kinase, or ALK gene are found in 3%-5% of patients with NSCLC.

ALK-positive NSCLC is more commonly seen in women and younger patients, never or light smokers, and patients with adenocarcinoma histology. 

Patients also tend to be younger, as the median age of diagnosis for ALK-positive NSCLC is 51 years.

ALK rearrangements are usually mutually exclusive with other common biomarkers in NSCLC, such as EGFR and KRAS. 

As with most cases of NSCLC, 5-year survival rates for metastatic disease remain low for ALK-positive patients. ALK-positive metastatic NSCLC can be treated with tyrosine kinase inhibitors, or TKIs, a class of therapy that can deliver positive outcomes to many patients.

Patients with ALK-positive metastatic NSCLC are likely to experience metastases in the brain. Brain metastases affect up to 35% of patients with ALK-positive metastatic NSCLC at the time of diagnosis. These pose many issues for patients, including psychological problems, like depression, anxiety, and cognitive issues as well as symptoms such as headaches and seizures.

Additionally, brain metastases may introduce a financial burden on patients and caregivers, with the average monthly cost per patient almost quadrupling after a diagnosis of brain metastases.

In my experience, I’ve seen that brain metastases can impact patients in a multitude of ways. Frequently I see patients with brain metastases suffer from edema, which often requires treatment with corticosteroids. Dizziness and lack of coordination are also common. More severe symptoms like seizures may also occur, and management often requires an interdisciplinary approach involving neuro-oncologists, neurologists, and neurosurgeons.

Brain metastases may affect a patient’s ability to perform fundamental tasks—how they think, how they walk, and how they take in sensory information. Due to the severity of these symptoms, there’s also a taxing psychological component that comes with a diagnosis of brain metastases. 

Patients become anxious about how brain metastases will impact them in the future, and often question whether they’ll still be able to walk and talk, or if they will experience mood changes over time. The prospect of having a seizure is also extremely daunting for patients and their care teams. This diagnosis alone brings a significant amount of anxiety and fear.

Ultimately, if a treatment option can deliver intracranial efficacy, you may avoid the need to administer additional therapy, like radiation, which can cause cognitive impairment, fatigue, and hair loss. Additionally, by offering an option with intracranial efficacy, you may be able to provide some benefit to patients if their metastases go into remission.

One of the most important things you can do for your patients is to give them the ability to participate in major life milestones, whether that means attending their daughter’s wedding or their grandson’s graduation. Intracranial efficacy may make that possible.

Therefore, given the affinity for ALK-positive metastatic NSCLC to metastasize to the brain, intracranial efficacy is a crucial consideration when determining a treatment. With the advent of ALK TKIs, patient outcomes have improved in recent years. With patients spending more time on therapy, pill burden also becomes an increasingly important consideration when determining a therapy.

High pill burden can negatively impact adherence, and may contribute to poor quality of life. Patients with cancer frequently have comorbid conditions and must often balance multiple complex dosing schedules, resulting in a high pill burden. Additionally, patients may find it challenging to integrate multiple dosing schedules and accommodate the dietary requirements of other treatments, such as with food or on an empty stomach.

From my experience, I’ve seen how important pill burden is, especially for my elderly patients. These patients may have difficulty swallowing or may be on other therapies, so having a low pill burden is important to them. This is also important when it comes to adherence. With an increasing number of required daily pills comes an increasing likelihood of a missed dose. Therefore, prioritizing treatment options with a lower pill burden may help optimize your patient’s treatment journey.

ALK-positive metastatic NSCLC is a unique type of lung cancer affecting a smaller group of patients, and its treatment involves some unique challenges. When making a treatment decision, it’s important to consider clinical aspects like systemic and intracranial efficacy, as well as practical considerations like treatment burden and patient adherence.

I would now like to highlight a treatment option for ALK-positive metastatic NSCLC that may be appropriate for your next eligible patient.

Today, I’d like to discuss ALUNBRIG for the first-line treatment of ALK-positive metastatic NSCLC.

ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. 

ALUNBRIG can offer the following key benefits for patients with ALK-positive metastatic NSCLC. Let’s discuss the results of the first-line trial, ALTA 1L. 

ALTA 1L was a Phase 3 trial designed to assess the efficacy, safety, and tolerability of ALUNBRIG for patients with ALK-positive metastatic NSCLC who had not previously received treatment with an ALK inhibitor. Patients were randomized to receive ALUNBRIG 180 mg orally once daily with a 7‐day lead‐in at 90 mg once daily or crizotinib 250 mg orally twice daily. The primary endpoint was PFS according to RECIST v1.1 as evaluated by a Blinded Independent Review Committee, or BIRC. Additional endpoints included BIRC-assessed ORR, DOR, intracranial ORR, and intracranial DOR. Patients with a history of interstitial lung disease, drug‐related pneumonitis, or radiation pneumonitis were excluded from the trial.

ALTA 1L reflected real-world ALK-positive metastatic NSCLC, as patients in the trial exhibited common, real-world characteristics like high rates of adenocarcinoma, presence of brain metastases at baseline, and a preponderance of patients in their 50s. 

Now, let’s take a look at how patients did while receiving ALUNBRIG. 

ALUNBRIG met the primary endpoint of ALTA 1L, doubling the median PFS vs crizotinib in the ITT population. ALUNBRIG lowered the risk of progression or death by 51% vs crizotinib and delivered a median PFS of 24 months vs 11 months with crizotinib. In the ITT population, the median OS was not reached for either arm. Additional OS data are presented here.

ALUNBRIG also demonstrated intracranial efficacy in ALTA 1L. 

In a post hoc subgroup analysis of patients with any brain metastases at baseline, the median PFS was longer with ALUNBRIG vs crizotinib, and the risk of progression or death was reduced by 75%. A post hoc subgroup survival analysis was also conducted in patients with measurable brain metastases at baseline. In these patients, ALUNBRIG reduced the risk of death vs crizotinib by 57%. 

I’ve seen first-hand how intracranial efficacy can impact patients’ lives. For example, when a patient learns that their brain metastases are in remission, it can be like a weight lifted off their shoulders, as they may no longer need to worry about the symptoms associated with brain metastases.

Additionally, in ALTA 1L, ALUNBRIG demonstrated a well-established safety profile. Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions in ALTA 1L were pneumonia (4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (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%).

Please take a moment to review key laboratory abnormalities seen in the ALTA 1L trial.

ALUNBRIG also demonstrated long-term tolerability in ALTA 1L, which is an important consideration in a treatment setting where patients frequently receive long-term therapy. 

The median duration of treatment with ALUNBRIG was 24.3 months and the median relative dose intensity was 97%. Permanent discontinuation due to adverse reactions occurred in 13% of patients receiving ALUNBRIG. Furthermore, patients who took ALUNBRIG reported better quality of life as measured by delayed median time to worsening in the Global Health Score/Quality of Life scale. There were several study limitations. These patient-reported outcome endpoints were exploratory and not prespecified. The improvement in QoL scores and delay in worsening of GHS/QoL may be an overestimation, because patients were not blinded to treatment assignment. These differences in global QoL could reflect differences in efficacy on disease-related symptoms and in treatment-related adverse events.

Quality of life is crucial, especially for younger patients with metastatic disease who require long-term therapy. Quality of life is important because metastatic NSCLC is a life-long disease. We want to make sure patients are living the best life that they can. Additionally, many of our patients want to avoid the psychological component of feeling sick and having to go to the clinic for IV infusions. The ability to offer patients as few pills a day as possible can make a positive difference in their lives. This offers a fitting transition in our discussion to the dosing and administration of ALUNBRIG.

Dosing with ALUNBRIG is simple, and can be worked into your patients’ schedules with ease. The recommended dosage of ALUNBRIG is 1 tablet, once daily. It can be taken at any time of the day either with or without food.

Once-daily dosing can substantially reduce a patient’s pill burden. Consider, for example, the yearly number of pills a patient may take under more complex dosing schedules, such as those involving 2 or 4 pills daily. The dosage of ALUNBRIG is 90 mg once daily for the first 7 days. This dosage is then increased to 180 mg once daily and administered until disease progression or unacceptable toxicity occurs.

In my experience of treating ALK-positive metastatic NSCLC, I’ve seen that 1-tablet, once-daily dosing provides patients with a convenient option. The 90-mg and 180-mg doses each involve just 1 pill per day, making it easier to change the dosage if we need to, and for patients to adhere to their prescribed dosing schedule. 

Patients can start treatment with the help of the ALUNBRIG Initiation Pack, which conveniently provides the first month’s tablets. The instructions are clear and detailed, helping to reinforce a patient’s knowledge on how to properly start therapy.

As we’ve seen, when you choose ALUNBRIG for first-line ALK-positive metastatic NSCLC, you can offer systemic efficacy, efficacy in patients with brain metastases at baseline, tolerability over long-term treatment, and simple, once-daily dosing, which can help alleviate pill burden. 

In the ALK-positive setting, the ability to offer an option with strong intracranial efficacy can make a real impact on patients’ lives.

As an experienced clinician, I know how brain metastases can take a toll on patients. I’ve seen the pain they cause, as well as the effects on behavior and mood. I also know what intracranial efficacy can mean for patients. Remission of brain metastases can offer cathartic relief, giving cause for celebration. You may offer your next patient that same chance for systemic and intracranial efficacy, and it’s available as a once-daily oral therapy that is easy for patients to take, and tolerable over the long term.

I hope that you will consider first-line ALUNBRIG for your next patient with ALK-positive metastatic NSCLC.
 

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.² Now 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:

1. 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. 
2. 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 
3. ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022. 
4. 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. 
5. Takeda Pharmaceuticals U.S.A., Inc. Data on file.
    

Dr. Vijay K. Gunuganti:

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

Jim is a 49-year-old Asian male construction worker, never-smoker, without significant medical history or family history of cancer. He was diagnosed with stage IV metastatic non-small cell lung cancer. PD-L1 expression was 50%. MRI of the brain showed no evidence of brain metastases. The patient was found to have anaplastic lymphoma kinase (ALK)-positive disease. The rest of the oncogenic driver mutations, such as EGFR, KRAS and ROS1, were negative. Jim’s Asian ethnicity is well-represented in the ALTA-1L trial, since more than 40% of the participants treated with ALUNBRIG were of Asian descent, as were 36% of patients treated with crizotinib.¹ 

After his diagnosis, Jim began first-line therapy with ALUNBRIG 90 mg once daily tablet for 7 days with or without food, then increased to 180 mg tablet once daily. Just 2 months after starting treatment, he had a good reduction in the size of the pulmonary and liver masses. After 2 years of treatment and 24 cycles of ALUNBRIG, Jim had a sustained pulmonary response. At 28 months, there was minimal CT evidence of any previous mass. 

One of the adverse events he had was grade 1 elevation of aspartate aminotransferase (AST) at 2 months of treatment that was resolved after 4 months of treatment without any dose reduction. He experienced some mild fatigue and nausea and a little bit of photosensitivity with occupational sun exposure since he's a construction worker. Otherwise, he tolerated the treatment well. 

In the ALTA 1L clinical trial, serious adverse reactions occurred in 33% of patients receiving Alunbrig. The most common serious ARs 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.

While results vary among patients, Jim just completed 30 cycles of ALUNBRIG 180 mg, and he currently has a complete pulmonary response based on CT scans that are performed every 4 months. Annual MRI follow-up studies have not revealed intracranial metastatic disease.

Jim is a good candidate for ALUNBRIG for the following reasons: he has been diagnosed with ALK+ disease but he is also young with an active lifestyle. Patients, like Jim, with an active lifestyle and desire to continue working, need effective treatment with a dosing regimen that fits their lifestyle. When looking at medications, we always look at efficacy, safety and tolerability. For me, efficacy is an important factor. ALUNBRIG is efficacious, for both systemic and intracranial disease.² ALTA-1L showed that ALUNBRIG was associated with a doubled median progression-free survival of about 24 months vs. 11 months, a higher confirmed overall response rate and about 2.5 times longer median duration of response vs. crizotinib.²

Quality of life is important for patients with stage IV non-small cell lung cancer. Treatment with next-generation ALK inhibitors is often prolonged, especially for younger patients,³ so the effects of treatment on health-related quality of life may be particularly important. These patient-reported outcome endpoints in ALTA-1L trial were exploratory and not prespecified. The improvement in QoL scores and delay in worsening of GHS/ quality of life may be an overestimation, because patients were not blinded to treatment assignment. And ALTA-1L showed that patients taking ALUNBRIG reported better quality of life compared to crizotinib across multiple functional and symptom scales.^4,5

Hepatotoxicity can occur with ALUNBRIG.² That's why we keep monitoring the liver enzymes in these patients, especially for the first several months, as well as throughout treatment. If you see an increase in terms of grade 3 or grade 4 toxicity without significant elevation of bilirubin, then we must hold the drug. If the patient experiences grade 4 toxicity and the bilirubin is elevated in the absence of cholestasis or hemolysis, then we must discontinue it.²

Reference List:

1. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. 
2. ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022.
3. Pacheco JM, Gao D, Smith D, et al. Natural history and factors associated with overall survival in Stage IV ALK-rearranged non-small cell lung cancer. J Thorac Oncol. 2019;14(4):691-700. 
4. 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. 
5. Takeda Pharmaceuticals U.S.A., Inc. Data on file.

Dr. Vijay K. Gunuganti:

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

Carl is a 50-year-old Hispanic male, factory sales representative, never-smoker, with a history of diabetes, hypertension and obesity. He recently developed a pleural effusion associated with a 6-cm left lower lobe mass and analysis of the fluid showed non-small cell lung cancer. MRI of the brain identified multiple small focal lesions consistent with metastatic lung cancer, although he was asymptomatic. Molecular biomarker testing revealed positive results for anaplastic lymphoma kinase (ALK) rearrangement. The rest of the biomarker testing was negative. PD-L1 expression was 70%. Carl was diagnosed with stage IV ALK-positive non-small cell lung cancer and started on first-line therapy with ALUNBRIG 90 mg once daily tablet for 7 days with or without food, then the dose was increased to 180 mg tablet once daily.

After two cycles of treatment, Carl had a reduction in the size of the pulmonary mass. At cycle 4, he had a considerable reduction in the pulmonary mass with a complete intracranial response based on an MRI scan. Overall, he tolerated the treatment well. However, he did have an episode of grade 3 hypertension at week 2 while taking the 180 mg dose of ALUNBRIG, despite coadministration of two antihypertensive agents. ALUNBRIG was temporarily withheld, dietary changes were suggested, and home monitoring of blood pressure was arranged. Blood pressure normalized and ALUNBRIG was resumed at the usual dose without incident. Currently, after six cycles of treatment, Carl remains on ALUNBRIG 180 mg with stable partial systemic response, complete intracranial response, and a good blood pressure control. 

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.

Carl's treatment plan with ALUNBRIG needs to include appropriate monitoring of his comorbid conditions of diabetes, obesity, and hypertension. In ALTA-1L, grade 3 episodes of hypertension occurred in 13% of participants and grade 3 hyperglycemia in 7.5% of participants.¹ Periodic assessment of blood pressure and fasting glucose are recommended with ALUNBRIG therapy.¹

Drug-drug interactions are important to consider. We need to look at all the medications patients are taking to assess for potential interactions that can impact ALUNBRIG efficacy and manage patients accordingly. Some medications, such as CYP3A inducers, can decrease the efficacy or concentration of ALUNBRIG.¹ Alternatively, CYP3A inhibitors can increase the concentration of ALUNBRIG.¹ Usually, I defer to my pharmacist to ensure that we go through each drug-drug interaction before I prescribe ALUNBRIG.

When considering dosage adjustments, it is important to note that in ALTA-1L, 13% of patients permanently discontinued ALUNBRIG for adverse reactions, and 38% of patients required a dose reduction due to adverse reactions.¹ Dose adjustments of ALUNBRIG are recommended in the case of systolic blood pressure ≥160 mm HG or diastolic blood pressure ≥100 mm Hg, or blood sugar >250 mg/dL.¹

Reference List:

1. ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022. 
2. Drugs.com. Drug interactions between ALUNBRIG and atorvastatin. Updated January 2023. Accessed January 15, 2023. https://www.drugs.com/interactionscheck.php?drug_list=380618473,276- 0&types%5B%5D=major&types%5B%5D=minor&types%5B%5D=moderate&types%5B%5D=food &types%5B%5D=therapeutic_duplication 
3. Takeda Pharmaceuticals U.S.A., Inc. Data on file; 20USO-BRG-0647 5/23

Dr. Vijay K. Gunuganti:

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

Liz is a 62-year-old woman who recently underwent evaluation after presenting with bloody sputum and productive cough. Other comorbid conditions were anxiety, depression and hypertension, and current medications include an SSRI, beta blocker and thiazide diuretic. A CT scan showed pulmonary nodules and a biopsy revealed non-small cell lung cancer adenocarcinoma. MRI of the brain showed evidence of intracranial metastases. Molecular biomarker testing revealed positive results for anaplastic lymphoma kinase (ALK) rearrangement. Once the diagnosis of stage IV ALK-positive metastatic non-small cell lung cancer was established, Liz was started on first-line therapy with ALUNBRIG 90 mg once daily tablet for 7 days with or without food, then increased to 180 mg tablet once daily. 

After 2 months, CT scans performed to evaluate response to treatment showed stable pulmonary disease. The patient tolerated the treatment well but developed mild to moderate blurred vision. ALUNBRIG was withheld for 5 days with complete resolution of symptoms and then was resumed at a slight dose reduction of 120 mg. She had constipation that was managed with dietary fiber and hydration. Currently Liz has completed a second cycle, tolerating ALUNBRIG 120 mg well with no recurrence of visual symptoms and stable pulmonary and intracranial disease without evidence of progression.

I have treated many patients on ALUNBRIG. I have seen that patients tolerate the treatment well. The results of ALTA 1L demonstrated a median duration of treatment with ALUNBRIG of 24.3 months and a median relative dose intensity of 97%, underscoring the long-term tolerability of ALUNBRIG.¹ In addition, for patients receiving ALUNBRIG in ALTA 1L, dose reductions occurred in 38% and permanent discontinuation due to adverse reactions occurred in 13%.¹

Because Liz has a medical history of anxiety and depression as well as baseline brain metastases, central nervous system efficacy and minimizing central nervous system effects are an important treatment consideration.²

ALTA-1L was a randomized, open-label, multicenter phase 3 trial designed to assess the efficacy, safety and tolerability of ALUNBRIG compared with crizotinib.^1,4 The primary endpoint result of ALTA-1L demonstrated significantly longer median progression-free survival (PFS) of 24.0 months with ALUNBRIG treatment compared with 11.0 months with crizotinib.¹ In addition, ALUNBRIG treatment was associated with a significantly higher confirmed overall response rate compared with crizotinib.1 And the ALUNBRIG responses were durable, with a median duration of response that was about 2.5 times longer with ALUNBRIG vs. crizotinib through 40.4 months of median follow-up at the final analysis.^1,3

In a post hoc subgroup analysis of patients in ALTA-1L with any brain metastases at baseline, the median PFS was longer with ALUNBRIG treatment vs. crizotinib, with PFS of 24 months for ALUNBRIG vs. 5.6 months for crizotinib.⁴ Also, the intracranial response rate was three times higher with ALUNBRIG at 78% (14 of 18 patients) vs. 26% (6 of 23 patients) for crizotinib, among patients with measurable brain metastases at baseline in the ALTA-1L study.¹ And 64% of responders (9 of 14) achieved an intracranial response duration of 24 or more months with ALUNBRIG treatment in the brain metastases population of the ALTA-1L study; the duration of intracranial response was not estimable for crizotinib.⁴

Reference List:

1. ALUNBRIG. Prescribing information. Takeda Pharmaceuticals America, Inc; 2022. 
2. Guérin A, Sasane M, Zhang J, et al. Brain metastases in patients with ALK+ non-small cell lung cancer: clinical symptoms, treatment patterns and economic burden. J Med Econ. 2015;18(4):312-322. 
3. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor–naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol. 2021;16(12):20912108. 
4. 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.