ALK Inhibitors for Non-Small Cell Lung Cancer

Not currently recruiting at 585 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Second-generation ALK inhibitors

Must not be taking: Lorlatinib, Chemotherapy

Disqualifiers: Interstitial lung disease, Cardiovascular abnormalities, Active infection, 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: Up to 6 cycles of 21 days each

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of different ALK inhibitors, alone or with chemotherapy, in treating ALK-positive non-small cell lung cancer. ALK inhibitors, such as lorlatinib and alectinib, aim to stop cancer growth by blocking certain enzymes, while chemotherapy drugs target and kill cancer cells. The trial seeks to determine the most effective treatment combination for this type of lung cancer. Individuals with stage IV ALK-positive non-squamous non-small cell lung cancer who have experienced disease progression after using a second-generation ALK inhibitor may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that may interact with the study drugs, and you must not have taken certain ALK inhibitors shortly before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that each ALK inhibitor tested in this trial has a good safety record.

Alectinib is generally well-tolerated, with mild side effects such as tiredness, constipation, and swelling. Serious issues are rare.

Brigatinib is also considered safe. Some patients have experienced nausea and diarrhea, but these are usually manageable. Rare lung-related problems require close monitoring.

Ceritinib is typically safe, though it can cause stomach issues like diarrhea and nausea. These are usually mild and controllable with medication.

Crizotinib has a good safety profile. Patients sometimes report vision problems and diarrhea, but most side effects are mild and manageable.

Ensartinib is generally well-tolerated in trials, with common side effects including rash and nausea.

Lorlatinib is mostly safe, with common side effects like high cholesterol and swelling. Serious side effects are uncommon.

Lastly, pemetrexed, often used in chemotherapy, can cause side effects like fatigue and low blood counts. These are monitored during treatment.

Each treatment has undergone earlier trials, providing researchers with a good understanding of their safety. Always discuss potential risks and benefits with a doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ALK inhibitors like lorlatinib, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, and others, because these drugs specifically target genetic mutations in non-small cell lung cancer (NSCLC) that standard chemotherapy can't address. While traditional chemotherapy targets rapidly dividing cells in general, ALK inhibitors work by blocking the activity of anaplastic lymphoma kinase (ALK) proteins, which are often responsible for cancer growth in patients with these mutations. This targeted approach can lead to more effective treatment with potentially fewer side effects. Additionally, the variety of ALK inhibitors allows for personalized treatment plans based on specific mutations, making therapy more precise and adaptable to individual needs. This precision medicine approach is a major step forward in treating NSCLC.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Studies have shown that ALK inhibitors, such as lorlatinib, alectinib, brigatinib, ceritinib, crizotinib, and ensartinib, effectively treat ALK-positive non-small cell lung cancer (NSCLC). In this trial, participants with specific ALK mutations will receive different ALK inhibitors. Lorlatinib, for instance, has achieved the longest time without cancer worsening in its category, with half of its patients living without progression for five years. Alectinib also demonstrates strong results, with patients experiencing an average of 25.7 months without cancer progression, compared to 10.4 months for those on crizotinib. Brigatinib has provided better outcomes for patients with ALK-positive NSCLC than crizotinib. Ceritinib remains effective even for patients whose cancer progressed on crizotinib. Crizotinib has shown high efficacy, shrinking tumors in over 90% of patients. Lastly, ensartinib is recognized for its effectiveness and has received FDA approval for treating ALK-positive NSCLC. ^{6 7 8 9 10}

Who Is on the Research Team?

Jessica J Lin

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for stage IV ALK positive non-squamous NSCLC patients who have progressed after one second-generation ALK inhibitor. They must not have had prior lorlatinib or more than one cycle of chemotherapy at diagnosis without progression. Participants need functioning major organs, no significant heart issues, and can't be pregnant or breastfeeding. Eligible individuals should not have other active cancers or serious illnesses that could affect safety.

Inclusion Criteria

I have brain metastases but also have a measurable cancer lesion outside the brain.

I am not on medications that would interfere with the study drug.

I have brain metastases but no symptoms, or they are treated, and I have stable health.

Exclusion Criteria

I do not have serious heart problems like uncontrolled high blood pressure or recent heart attacks.

I have ongoing or repeated pancreatitis confirmed by tests.

I do not have any serious illness or organ problems that could affect my safety or the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ALK inhibitors or chemotherapy based on their mutation status. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Up to 6 cycles of 21 days each

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Alectinib
• Brigatinib
• Carboplatin
• Ceritinib
• Cisplatin
• Crizotinib
• Ensartinib
• Lorlatinib
• Pemetrexed

Trial Overview The study tests combinations of biomarker/ALK inhibitors (Lorlatinib, Ceritinib, Alectinib, Brigatinib, Ensartinib, Crizotinib) against standard chemotherapy drugs (Pemetrexed, Cisplatin, Carboplatin) in treating advanced lung cancer with specific genetic changes. It aims to determine which treatment method is more effective.

How Is the Trial Designed?

Group I: V1180 Experimental Treatment 3 Interventions

Patients with V1180 mutation receive either lorlatinib PO QD, ceritinib PO QD, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group II: No ALK-resistance mutations Experimental Treatment 8 Interventions

Patients with no ALK-resistant mutations receive either lorlatinib PO QD, ceritinib PO QD, alectinib PO BID, brigatinib PO QD, ensartinib PO QD, or pemetrexed IV over 10 minutes on day 1 with or without either cisplatin IV or carboplatin IV on day 1. ALK inhibitor cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Pemetrexed-based treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Maintenance treatment of pemetrexed may continue until disease progression or unacceptable toxicity.

Group III: MET amplification Experimental Treatment 1 Intervention

Patients with MET amplification receive crizotinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group IV: L1196 (including L1196M) Experimental Treatment 6 Interventions

Patients with L1196 (including L1196M) mutation receive either lorlatinib PO QD, ceritinib PO QD, alectinib PO BID, brigatinib PO QD, or ensartinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group V: I1171 Experimental Treatment 3 Interventions

Patients with I1171 mutation receive either lorlatinib PO QD, ceritinib PO QD, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group VI: G1202 (including G1202del and G1202R) Experimental Treatment 2 Interventions

Patients with G1202 (including G1202del and G1202R) receive either lorlatinib PO QD or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group VII: F1174 Experimental Treatment 3 Interventions

Patients with F1174 receive either lorlatinib PO QD, alectinib PO BID, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group VIII: Compound mutation Experimental Treatment 1 Intervention

Patients with a compound mutation receive lorlatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group IX: C1156Y Experimental Treatment 3 Interventions

Patients with Cy1156Y mutation receive either lorlatinib PO QD, alectinib PO BID, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group X: ALK L1198F mutation (alone or combination with ALK inhibitor) Experimental Treatment 1 Intervention

Patients with ALK L1198F mutation (alone or in combination with another ALK mutation) receive crizotinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Alectinib is already approved in United States, European Union for the following indications:

Approved in United States as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Approved in European Union as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

Alectinib is a second-generation, orally active drug specifically designed to target ALK-positive non-small cell lung cancer (NSCLC) in patients who have developed resistance to the first-line treatment, crizotinib.

The FDA has granted Alectinib several designations, including orphan drug and breakthrough therapy status, highlighting its potential as a significant treatment option for patients with advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized Medicine Tackles Clinical Resistance: Alectinib in ALK-Positive Non-Small Cell Lung Cancer Progressing on First-Generation ALK Inhibitor. Skoulidis, F., Papadimitrakopoulou, VA.[2019]

Alectinib, administered at a dose of 600 mg twice daily, shows a median overall survival of 29.1 months in patients with crizotinib-resistant ALK-positive non-small-cell lung cancer, indicating its robust efficacy.

The study found no significant relationship between drug exposure levels and overall survival or adverse events, confirming that the 600 mg BID dose maintains a well-tolerated safety profile while providing effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer. Morcos, PN., Nueesch, E., Jaminion, F., et al.[2019]

Alectinib is an effective first-line treatment for adults with advanced ALK-positive non-small cell lung cancer (NSCLC), showing significantly improved progression-free survival compared to crizotinib and chemotherapy in clinical trials lasting up to 19 months.

The drug has a manageable safety profile, with most side effects being mild to moderate, making it a recommended option in treatment guidelines for patients with advanced ALK-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib: A Review in Advanced, ALK-Positive NSCLC. Paik, J., Dhillon, S.[2019]

Alectinib has been shown to significantly improve progression-free survival and overall survival compared to crizotinib in patients with advanced ALK-positive non-small-cell lung cancer, as demonstrated in the phase III ALEX study and confirmed in subsequent studies in Japanese and Asian populations.

The safety profile of alectinib is manageable, with most adverse events being treatable through dose reduction, and no new safety concerns have emerged during long-term follow-up, reinforcing its recommendation as a preferred first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib. Dziadziuszko, R., Peters, S., Ruf, T., et al.[2023]

Alectinib significantly improves overall survival compared to crizotinib in patients with metastatic or locally advanced ALK-positive non-small cell lung cancer (NSCLC), based on a systematic review of 13 randomized controlled trials.

In terms of progression-free survival, alectinib also outperformed crizotinib and ceritinib, demonstrating a favorable safety profile compared to other ALK inhibitors, particularly in patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis. Samacá-Samacá, D., Prieto-Pinto, L., Peréz, AY., et al.[2023]

Alectinib is an effective first-line treatment for patients with metastatic ALK+ non-small cell lung cancer (NSCLC), showing significant improvements in survival rates, even for those with brain metastases.

The review highlights alectinib's ability to target ALK gene rearrangements specifically, positioning it as a crucial therapy in the treatment course for ALK+ NSCLC patients, especially after prior treatment with crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of alectinib for the treatment of ALK-positive non-small cell lung cancer (NSCLC): patient selection and perspectives. Karachaliou, N., Fernandez Bruno, M., Bracht, JWP., et al.[2020]

In a phase III trial involving 107 patients with advanced ALK-positive non-small-cell lung cancer, alectinib demonstrated a significantly longer median progression-free survival (PFS) of 9.6 months compared to just 1.4 months for standard chemotherapy, indicating its superior efficacy.

Alectinib also showed a higher objective response rate in patients with central nervous system disease (54.2% vs. 0% for chemotherapy) and had a more favorable safety profile, with fewer grade ≥3 adverse events (27.1% for alectinib vs. 41.2% for chemotherapy).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Novello, S., Mazières, J., Oh, IJ., et al.[2022]

Citations

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Real-world usage and clinical outcomes of alectinib among ... Prognosis is poor for patients with metastatic disease, with the median survival <1 year because of delays in diagnosis.

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Survival results for ALECENSA® (alectinib) PFS by IRC: In the ITT population, mPFS was 25.7 months for ALECENSA (95% CI: 19.9, NE) compared with 10.4 months with crizotinib (95% CI: 7.7, ...

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Real-world comparative outcomes of alectinib and ... In this real-world study, both alectinib and brigatinib provided favorable survival outcomes in patients with ALK-positive NSCLC.

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Advanced-stage ALK-positive non–small-cell lung cancer ... Among 382 patients receiving 1L alectinib overall survival (OS) rate was 88.7 % and 73.3 % at 24 and 60 months, respectively. Median progression ...

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final overall survival analysis of the phase III ALEX study Final mature OS results are from the updated data cut-off of 28 April 2025. Overall, 149 patients died: 76/152 (50.0%) in the alectinib arm and ...

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Pooled overall survival and safety data from the pivotal ... Alectinib demonstrated a median OS of 29.1 months (95% CI 21.3-39.0). No new or unexpected safety findings were observed. The most common all-grade AEs included ...

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ALECENSA® (alectinib) Fact Sheet NP28673 is a Phase II global, single-arm, open-label, multicenter trial evaluating the safety and efficacy of ALECENSA (600 mg orally twice daily) in 138 people ...

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Clinical experience and management of adverse events in ... Here, we review the safety and tolerability of long-term alectinib treatment in patients with advanced ALK-positive NSCLC and provide guidance for physicians, ...