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Sponsored by Takeda Oncology

Reimagining What's Possible: What Targeted Treatments Have Done for Patients with ALK+ mNSCLC

Author: Mike Humphries, Senior Scientific Director, Head of Lung, Global Medical Affairs Oncology, Takeda

Over the last decade, the lung cancer treatment landscape has experienced tremendous progress toward better patient outcomes, which has, in part, been due to the introduction of targeted therapies. According to a study published in the New England Journal of Medicine (NEJM) in 2020, the discovery and availability of targeted therapies has caused marked improvements in survival rates for people with non-small cell lung cancer (NSCLC) – including an improvement in the five-year survival rate for the first time in history.1-2

Despite advancements, disease progression remains a challenge
Even with substantial improvements in treatment options, lung cancer was still responsible for nearly 20% of cancer-related deaths worldwide in 2020.2-3 This can be partially attributed to the fact that, despite deriving initial benefit from treatment, the majority of patients will eventually experience acquired resistance and subsequent disease progression.4

Anaplastic lymphoma kinase-positive (ALK+) NSCLC is a rare and particularly aggressive form of lung cancer caused by a mutation in the ALK gene, which frequently develops acquired resistance.4-6 Approximately 35% of people with ALK+ NSCLC will have brain metastases at diagnosis and up to 75% will ultimately develop brain metastases at some point during the course of their disease.7-8,10-13

While ALK+ NSCLC only makes up 3-5% of the NSCLC population,9-10 there have been five tyrosine kinase inhibitors (TKIs) approved by the U.S. Food and Drug Administration (FDA) in the last decade to treat ALK+ NSCLC.14-18

First-generation TKIs for ALK+ NSCLC revolutionized the treatment experience by targeting the driver behind the disease, resulting in response rates superior to systemic chemotherapy, which was the previous standard of care.16 Next-generation TKIs have built on the improved response rates demonstrated by first- generation TKIs by addressing the spread of disease to the brain – something first-generation TKIs were not able to effectively treat.14-15,17-18

As a result, patients are living longer, but they remain at high risk for disease progression and development of brain metastases.14,19 With several next-generation TKIs to choose from, it's critical healthcare providers (HCPs) select a first-line therapy that has the best chance of delaying spread to the brain and treating existing brain metastases for an extended period of time.

Long-term data from ALUNBRIG demonstrated durability in patients with ALK+ mNSCLC
ALUNBRIG is an FDA-approved treatment for adult patients with ALK+ metastatic NSCLC (mNSCLC).14

The Phase 3 ALTA 1L trial – the basis of the ALUNBRIG's FDA approval in the first line – investigated ALUNBRIG versus crizotinib – a first-generation TKI – in patients with ALK+ mNSCLC who have not received prior treatment with an ALK inhibitor. Initial results of the study demonstrated clinically and statistically meaningful benefits for patients in the intent-to-treat (ITT) population, as well as a manageable safety profile. These findings were relatively consistent in subsequent analyses of the trial, reinforcing the durability of ALUNBRIG's efficacy and safety profile.

Further demonstrating the durability of long-term treatment as assessed by a blinded independent review committee (BIRC), at a median follow-up of 40.4 months, the final results of the ALTA 1L trial showed:

- Overall, ALUNBRIG reduced the risk of disease progression or death by greater than 50% compared with crizotinib (progression-free survival hazard ratio [PFS HR] = 0.48, 95% confidence interval [CI]:0.35-0.66, p value <.0001) with a median PFS of 24.0 months versus 11.1 months for crizotinib.20

-In patients with baseline brain metastases, ALUNBRIG demonstrated a median intracranial PFS of 24.0 months versus 5.5 months with crizotinib.20

-Overall, ALUNBRIG demonstrated a median duration of response (DoR) of 33.2 months versus 13.8 months for crizotinib.20

-In patients with measurable baseline brain metastases, ALUNBRIG demonstrated a median intracranial DoR (iDoR) of 27.9 months versus 9.2 months with crizotinib.20

-Overall, the three-year overall survival (OS) rate was 71% for ALUNBRIG versus 68% for crizotinib (HR=0.81).20

-In patients with measurable baseline brain metastases, the three-year OS rate was 74% for ALUNBRIG versus 55% for crizotinib (HR=0.43).20

ALUNBRIG has shown durable intracranial and overall efficacy for patients with or without brain metastases in multiple treatment lines. 20

Importantly, the safety profile of ALUNBRIG also remained consistent and manageable despite extended treatment duration. Grade 3-4 adverse events (AEs) occurred in 70% of patients. AEs (Grade 5) leading to death occurred in 8% of patients, none of which were treatment-related. AEs leading to treatment discontinuation occurred in 13% of patients, AEs leading to dose reductions occurred in 44% of patients and AEs leading to dose interruption occurred in 72% of patients. 20

Selecting the right first-line therapy is critical
Evidenced by these data, ALUNBRIG provides patients a targeted treatment option that has demonstrated long-term, durable responses in patients with ALK+ mNSCLC with or without brain metastases.

It has been my distinct pleasure to oversee the investigation of ALUNBRIG and witness its continued progress over the past several years. In the face of an aggressive and relentless cancer, it is gratifying to meet patients who have been able to benefit from this treatment.

Takeda looks forward to continuing its ongoing development of ALUNBRIG, with the goal of improving the lives of people living with ALK+ mNSCLC around the globe. Learn more about ALK+ mNSCLC and ALUNBRIG by visiting ALUNBRIG.com.
 


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.

All trademarks are property of their respective owners

@2022 Takeda Pharmaceuticals U.S.A. Inc., All rights reserved. USO-BRG-0448 – 4/22


References
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13 Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018; 19(12): 1654-1667.
14 ALUNBRIG (brigatinib) Prescribing Information. Takeda Pharmaceutical Company Limited.; 3/2022
15 LORBRENA (lorlatinib) Prescribing Information. Pfizer Inc.; 3/2021
16 XALKORI (crizotinib) Prescribing Information. Pfizer Inc.; 9/2021
17 ALECENSA (alectinib) Prescribing Information. Genentech.; 2021
18 ZYKADIA (ceritinib) Prescribing Information. Novartis.; 2021
19 National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. Version 3. 3/2022
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