Brain metastases are a common presentation in non-small cell lung cancer (NSCLC), particularly in patients with the anaplastic lymphoma kinase (

) gene rearrangement. In fact, approximately one third of patients with ALK-positive (ALK+) metastatic NSCLC (mNSCLC) will present brain metastases at the time of diagnosis.

The occurrence of brain metastases further complicates the treatment of these patients and puts them at risk for serious side effects and a shorter life expectancy.

 However, the discovery of targeted agents known as ALK inhibitors has dramatically changed the treatment of ALK+ mNSCLC.

 Effective targeted therapies have provided patients with the potential to achieve high overall response rates and remain progression-free for longer periods of time.

 And the landscape has continued to evolve – with a focus on advancing options available for newly diagnosed patients in the first-line setting.

In less than 10 years, several different ALK inhibitors have come to market. Crizotinib, the first approved ALK inhibitor, quickly became the standard of care for patients, but further research uncovered that it had poor penetration in the brain, which posed a problem for the majority of patients who develop brain metastases during the course of their disease.

 Therapies demonstrating intracranial efficacy – in addition to overall efficacy – were needed to effectively address the unique needs of patients in this population. This led to the rise of second-generation ALK inhibitors, which have more effectively delayed progression and achieved higher response rates.

Today, several second-generation ALK inhibitors are available for patients in the first-line setting. While each of the approved ALK inhibitors have shown to be effective, it’s important to have multiple treatment options available to help optimize treatment sequencing. Case in point, treatment resistance is a common occurrence among patients that limits long-term effectiveness of targeted therapies.

 Many patients with ALK+ mNSCLC develop resistance after deriving initial benefit from a targeted therapy through a variety of mechanisms.

 To improve outcomes in the treatment of ALK+ mNSCLC, introducing therapies that may help overcome ALK inhibitor resistance and provide another option for patients and healthcare providers should be a continued priority.

The Role of ALUNBRIG in the ALK+ mNSCLC Treatment Landscape

 (brigatinib) is a second-generation ALK inhibitor that was approved by the U.S. Food & Drug Administration (FDA) in May 2020 for adult patients with ALK+ mNSCLC as detected by an FDA-approved test. The approval was based on results from the international, open-label, multicenter, Phase 3 ALTA 1L trial, which compared the efficacy and safety of ALUNBRIG with crizotinib in 275 adult patients with ALK+ mNSCLC, who had not previously received prior 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 (n=137) or crizotinib at 250 mg orally twice daily (n=138). The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by a blinded independent review committee (BIRC).

Long-term data from the trial showed that ALUNBRIG yielded superior overall and intracranial efficacy outcomes compared to crizotinib. Importantly, newly diagnosed patients treated with ALUNBRIG benefited regardless of the presence or absence of brain metastases at baseline.

In the intent-to-treat (ITT) population, the BIRC-assessed median PFS was 24.0 months (95% CI: 18.5–NE) for ALUNBRIG and 11.0 months (95% CI: 9.2–12.9) for crizotinib.

Confirmed overall response rate (ORR) was 74% (95% CI: 66–81) for ALUNBRIG and 62% (95% CI: 53–70) for crizotinib as assessed by a BIRC.

The median duration of response (DoR) in confirmed responders was not reached (95% CI: 19.4–NE) with ALUNBRIG and was 13.8 months (95% CI: 9.3–20.8) with crizotinib as assessed by a BIRC.

Additionally, ALUNBRIG demonstrated robust and durable responses in the brain, with patients with baseline brain metastases treated with ALUNBRIG yielding superior efficacy compared to crizotinib, as assessed by a BIRC.

Confirmed intracranial ORR for patients with measurable brain metastases at baseline was 78% (95% CI: 52–94) for patients treated with ALUNBRIG (n=14/18) and 26% (95% CI: 10–48) for patients treated with crizotinib (n=6/23).

The proportion of patients who demonstrated an intracranial DoR ≥24 months was 64% in the ALUNBRIG arm and was not reached in the crizotinib arm.

The safety profile of ALUNBRIG in the ALTA 1L trial was generally consistent with previous trials. Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions other than disease progression 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 other than disease progression occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%). The most common adverse reactions in the ALTA 1L trial (≥10%) with ALUNBRIG were diarrhea (53%), rash (40%), cough (35%), hypertension (32%), fatigue (32%), nausea (30%), myalgia (28%), dyspnea (25%), abdominal pain (24%), and headache (22%).

Other Considerations in Making Treatment Decisions

In addition to treatment efficacy and safety considerations, it’s important for healthcare providers to understand how a therapy may affect ALK+ mNSCLC patients’ everyday lives when determining the best treatment option. This is particularly important for patients who may be on treatment for several years.

Unlike the general NSCLC population, ALK+ mNSCLC patients are often younger, with a median age of between 50 and 55 years old.

 For many of these patients, a treatment option that allows them the ability to maintain a sense of normalcy is crucial. ALUNBRIG’s one pill a day administration can have a less significant impact on a patient’s daily routine compared to other regimens. During times like these, the benefits of an oral administration are particularly relevant – given the risk involved with immuno-compromised patients traveling and attending hospital visits due to the COVID-19 pandemic.

In summary, remarkable progress has been made in the treatment of ALK+ mNSCLC patients, and the field continues to grow at a rapid pace. We look forward to working with industry and academic colleagues to spearhead continued progress that will help delay disease progression, so patients can continue on with their lives for as long as possible, with as little disruption as possible.

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 the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), 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 Trial 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 early 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%. Monitor for new or worsening respiratory symptoms (e.g., 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 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.

In the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), hypertension was reported in 32% of patients receiving ALUNBRIG; Grade 3 hypertension occurred in 13% of patients. In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG 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.

In the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG. Grade 3 bradycardia occurred in 1 patient (0.7%). 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. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. 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.

In the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), 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 the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), 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 mg→180 mg group. The incidence of Grade 3‑4 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% 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.

In the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients. 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

 In the ALUNBRIG arm of trial ALTA 1L (180 mg once daily), 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 or permanently discontinuing ALUNBRIG.

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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal 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

In ALTA 1L, serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions other than disease progression 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 other than disease progression occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).

In ALTA, serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) with ALUNBRIG were diarrhea (49%), fatigue (39%), nausea (39%), rash (38%), cough (37%), myalgia (34%), headache (31%), hypertension (31%), vomiting (27%), and dyspnea (26%).

CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If coadministration of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG.

CYP3A Substrates: Coadministration of ALUNBRIG with sensitive CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive CYP3A substrates.

ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG.

Advise females of reproductive potential to use effective non-hormonal 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.

Infertility: ALUNBRIG may cause reduced fertility in males.

The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.

 Of the 359 patients enrolled in the ALTA 1L ALUNBRIG arm and in ALTA, 26.7% were 65 and older and 7.5% were 75 and older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger patients.

No dose adjustment is recommended for patients with mild or moderate hepatic impairment or mild or moderate renal impairment. Reduce the dose of ALUNBRIG for patients with severe hepatic impairment or severe renal impairment.

Please see the full U.S. Prescribing Information for ALUNBRIG at 

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Maione, Paolo et al. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application. 

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