ALUNBRIG^® (brigatinib) Exhibits Broad Mutational Coverage and Activity in the CNS¹

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.