Brigatinib + Chemotherapy for Lung Cancer

Overseen By Yasir Y Elamin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Brigatinib

Must not be taking: Other TKIs

Disqualifiers: Other malignancies, CNS metastasis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot receive other anti-cancer agents while participating in this study.

What data supports the effectiveness of the drug Brigatinib + Chemotherapy for Lung Cancer?

Brigatinib has been shown to be effective in treating patients with ALK-positive non-small cell lung cancer (NSCLC), especially those who have not responded to another drug called crizotinib. In studies, it improved the time patients lived without their cancer getting worse and worked well even in patients with cancer spread to the brain. ^{1 2 3 4 5}

Is the combination of Brigatinib and chemotherapy safe for humans?

Brigatinib is generally well tolerated in humans, but it can cause early-onset lung issues, which usually appear within two days of starting the treatment and are often reversible. This safety information is based on studies of Brigatinib in patients with a specific type of lung cancer. ^{2 6 7 8 9}

How is the drug brigatinib unique for treating lung cancer?

Brigatinib is unique because it is an oral medication specifically designed to target and inhibit the anaplastic lymphoma kinase (ALK) in non-small cell lung cancer, especially for patients who have developed resistance to other ALK inhibitors like crizotinib. It is effective in treating brain metastases and is well-tolerated, making it a valuable option for patients who have failed previous treatments. ^{2 9 10 11 12}

What is the purpose of this trial?

The goal of this clinical research study is to learn if the combination of brigatinib and either local consolidation therapy (such as radiotherapy or surgery) or chemotherapy (pemetrexed and carboplatin) can help to control the disease compared with brigatinib alone. The safety of these combinations will also be studied.

Research Team

Yasir Y. Elamin

Principal Investigator

MD Anderson Cancer Cetner

Eligibility Criteria

This trial is for individuals with advanced non-small cell lung cancer that tests positive for a change in the ALK gene. Participants should not have received brigatinib previously and must be fit enough for chemotherapy or local treatments like radiotherapy or surgery.

Inclusion Criteria

Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol

My organ functions are within normal ranges.

I will use effective contraception or abstain from sex.

Exclusion Criteria

I have not had major surgery in the last 30 days.

I do not have any current infections requiring IV antibiotics.

I am not taking any other cancer treatments while in this study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive brigatinib alone or in combination with chemotherapy or local consolidation therapy

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Brigatinib
• Carboplatin
• Pemetrexed

Trial Overview The study is testing whether taking brigatinib along with either local consolidation therapy (like radiation or surgery) or chemotherapy drugs pemetrexed and carboplatin can better control lung cancer than just brigatinib alone.

Participant Groups

Group I: Brigatinib Monotherapy Experimental Treatment 1 Intervention

Given by mouth

Group II: Brigatinib + Local Consolidation Therapy (LCT) Experimental Treatment 1 Intervention

Given by vein

Group III: Brigatinib + Carboplatin + Pemetrexed Experimental Treatment 3 Interventions

Given by vein

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a multinational phase III study (ALTA-1L), brigatinib significantly improved progression-free survival and response rates compared to crizotinib in adults with advanced ALK-positive non-small-cell lung cancer, indicating its efficacy as a first-line treatment.

Brigatinib was found to have a manageable tolerability profile with no new safety concerns, making it a viable option for patients, including those with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brigatinib: A Review in ALK-Inhibitor Naïve Advanced ALK-Positive NSCLC. Hoy, SM.[2021]

A population pharmacokinetic analysis of brigatinib, involving 442 participants (337 cancer patients and 105 healthy volunteers), revealed that its plasma concentrations are best described by a three-compartment model, indicating a complex absorption and distribution process.

The study found that factors like age, sex, and mild to moderate renal impairment do not significantly affect the drug's clearance, suggesting that no dose adjustments are necessary for these patient characteristics, which enhances the safety and ease of use of brigatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer. Gupta, N., Wang, X., Offman, E., et al.[2021]

The B-DASH study is a phase II clinical trial designed to evaluate the efficacy of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged non-small cell lung cancer (NSCLC), with a target sample size of 110 participants.

This study aims to determine if the combination therapy can improve progression-free survival (PFS) compared to brigatinib monotherapy, building on previous findings that showed brigatinib alone had a median PFS of 24 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, open-label phase II study of brigatinib and carboplatin plus pemetrexed and brigatinib alone for chemotherapy-naive patients with ALK-rearranged non-squamous non-small cell lung cancer: treatment rationale and protocol design of the B-DASH study (WJOG 14720 L). Wakuda, K., Kenmotsu, H., Sato, Y., et al.[2023]

Brigatinib is a highly effective second-generation ALK tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC) with ALK translocations, showing strong activity against various ALK resistance mutations.

It has demonstrated durable responses in patients who are resistant to crizotinib, including effectiveness in treating both lung and brain metastases, leading to its FDA approval for ALK-positive metastatic NSCLC patients who have progressed on or are intolerant to crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients. Passaro, A., Prelaj, A., Pochesci, A., et al.[2019]

In a phase 2 study of 222 patients with crizotinib-refractory ALK-positive NSCLC, brigatinib at 180 mg once daily showed a significantly higher median progression-free survival (PFS) of 16.7 months compared to 9.2 months for the 90 mg dose, indicating better efficacy at the higher dose.

Brigatinib demonstrated a high intracranial objective response rate of 67% in patients with brain lesions, along with a median duration of intracranial response of 16.6 months, suggesting it is effective for treating brain metastases in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial. Huber, RM., Hansen, KH., Paz-Ares Rodríguez, L., et al.[2022]

Brigatinib, an ALK tyrosine kinase inhibitor approved in China for treating advanced non-small cell lung cancer (NSCLC) with ALK rearrangements, has shown significant improvements in survival and quality of life compared to Crizotinib in clinical trials.

While Brigatinib is generally well tolerated, it can cause early-onset pulmonary toxicity, which occurs within a median of 2 days and is characterized by rapid tolerance and reversibility, highlighting the need for clinicians to monitor for these symptoms closely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Early Onset Pulmonary Events and Management Strategies during the Treatment of ALK Positive NSCLC Patients with Brigatinib]. Yang, M., Luo, W., Zhou, Q.[2023]

Brigatinib is an effective treatment for patients with ALK-positive non-small cell lung cancer (NSCLC), showing a pooled objective response rate of 64% and a disease control rate of 88%, with particularly strong results in patients receiving it as a first-line treatment (mPFS of 24 months).

The treatment also demonstrates significant efficacy in patients with brain metastases, with an intracranial objective response rate of 54% and an intracranial progression-free survival of 19.26 months, while the most common adverse events, such as increased creatine phosphokinase and gastrointestinal issues, are manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis. Xing, P., Hao, X., Zhang, X., et al.[2022]

In clinical trials of brigatinib for advanced ALK+ non-small cell lung cancer (NSCLC), early-onset pulmonary adverse events (EOPEs) occurred in 8% of patients in phase 1/2, 6% in phase 2, and 3% in phase 3 studies, with a higher frequency linked to increased starting dosages.

A total of 3% of patients experienced severe (grade 3 or higher) EOPEs leading to treatment discontinuation, while 1.5% had milder events that allowed them to continue treatment, indicating that while EOPEs are a concern, many patients can manage them with appropriate interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early-Onset Pulmonary Events Associated With Brigatinib Use in Advanced NSCLC. Ng, TL., Narasimhan, N., Gupta, N., et al.[2022]

Brigatinib is an effective treatment for patients with metastatic ALK+ non-small-cell lung cancer (NSCLC) who have either progressed on or are intolerant to crizotinib, showing the ability to overcome crizotinib-resistant mutations and improve survival by about one year.

The drug is administered in a two-step dosage regimen, starting at 90 mg daily for the first week and then increasing to 180 mg daily, but it can cause side effects such as nausea, fatigue, and serious pulmonary-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brigatinib: Novel ALK Inhibitor for Non-Small-Cell Lung Cancer. Spencer, SA., Riley, AC., Matthew, A., et al.[2020]

Brigatinib demonstrated significant efficacy in treating ALK-positive advanced non-small cell lung cancer (NSCLC) in a heavily pretreated population, with a median progression-free survival (PFS) of 6.6 months and a disease control rate of 78.2% among 104 patients studied.

The median overall survival (OS) after starting brigatinib was 17.2 months, indicating that it can provide meaningful benefits even after multiple lines of prior treatment, including at least two ALK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study). Descourt, R., Perol, M., Rousseau-Bussac, G., et al.[2020]

Brigatinib, an ALK inhibitor for metastatic non-small cell lung cancer, shows significantly increased brain accumulation when the multidrug transporters ABCB1 and ABCG2 are genetically knocked out, indicating these transporters play a crucial role in limiting its central nervous system exposure and potential toxicity.

Coadministration of ABCB1/ABCG2 inhibitors can dramatically increase brigatinib's brain-to-plasma ratios, but this also raises concerns about unexpected toxicities, highlighting the need for careful monitoring in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

P-glycoprotein and breast cancer resistance protein restrict brigatinib brain accumulation and toxicity, and, alongside CYP3A, limit its oral availability. Li, W., Sparidans, RW., Wang, Y., et al.[2019]

Brigatinib, a second-generation ALK tyrosine kinase inhibitor, showed significant efficacy in patients with EML4-ALK-rearranged lung cancer who had developed resistance to previous treatments, achieving a 75.8% partial response rate and a median progression-free survival of 9.9 months across 35 patients.

The treatment was particularly effective in patients with brain metastases, with 54% showing a response, and brigatinib was well tolerated, indicating a favorable safety profile for patients transitioning from crizotinib or ceritinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution. Hochmair, M., Weinlinger, C., Schwab, S., et al.[2020]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Brigatinib: A Review in ALK-Inhibitor Naïve Advanced ALK-Positive NSCLC. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Randomized, open-label phase II study of brigatinib and carboplatin plus pemetrexed and brigatinib alone for chemotherapy-naive patients with ALK-rearranged non-squamous non-small cell lung cancer: treatment rationale and protocol design of the B-DASH study (WJOG 14720 L). [2023]

4. Spain pubmed.ncbi.nlm.nih.gov

Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Early Onset Pulmonary Events and Management Strategies during the Treatment of ALK Positive NSCLC Patients with Brigatinib]. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Early-Onset Pulmonary Events Associated With Brigatinib Use in Advanced NSCLC. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Brigatinib: Novel ALK Inhibitor for Non-Small-Cell Lung Cancer. [2020]

10. Ireland pubmed.ncbi.nlm.nih.gov

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study). [2020]

11. Netherlands pubmed.ncbi.nlm.nih.gov

P-glycoprotein and breast cancer resistance protein restrict brigatinib brain accumulation and toxicity, and, alongside CYP3A, limit its oral availability. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution. [2020]