ALK Inhibitors for Non-Small Cell Lung Cancer

Recruiting at 567 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

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This National Cancer Institute (NCI)-NRG ALK Protocol phase II trial studies how well a combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK positive non-squamous non-small cell lung cancer. Lorlatinib, ceritinib, alectinib, brigatinib, ensartinib, and crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether a combination of biomarker/ALK inhibitors or chemotherapy may work better in treating patients with ALK positive non-squamous non-small cell lung cancer.

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.

What data supports the effectiveness of the drug Alectinib for treating ALK-positive non-small cell lung cancer?

Alectinib has been shown to significantly improve progression-free survival (the time during which the cancer does not get worse) compared to crizotinib and chemotherapy in patients with ALK-positive non-small cell lung cancer. It is effective even in patients whose cancer has spread to the brain and is recommended as a preferred first-line therapy. ^{1 2 3 4 5}

Is alectinib safe for humans?

Alectinib has a well-characterized safety profile and is generally considered safe for treating advanced ALK-positive non-small-cell lung cancer. Most side effects can be managed by adjusting the dose, and no new safety concerns have been observed with long-term use. ^{2 5 6 7 8}

What makes ALK inhibitors unique for treating non-small cell lung cancer?

ALK inhibitors like alectinib, brigatinib, and lorlatinib are unique because they target specific genetic changes in non-small cell lung cancer, offering better outcomes and fewer side effects compared to traditional chemotherapy. Lorlatinib, a third-generation ALK inhibitor, is particularly effective in overcoming resistance to earlier treatments and has shown improved results in patients with specific genetic mutations. ^{1 9 10 11 12}

Research Team

Jessica J Lin

Principal Investigator

NRG Oncology

Eligibility Criteria

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacological and clinical properties of lorlatinib in the treatment of ALK-rearranged advanced non-small cell lung cancer. [2022]

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

Profile of alectinib for the treatment of ALK-positive non-small cell lung cancer (NSCLC): patient selection and perspectives. [2020]

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

Alectinib: A Review in Advanced, ALK-Positive NSCLC. [2019]

4. United States 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. [2019]

5. England 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. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer. [2019]

7. England 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Second- and third-generation ALK inhibitors for non-small cell lung cancer. [2022]

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

Ceritinib Bests Chemo for Untreated ALK+ NSCLC. [2018]

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

Crizotinib resistance overcome by ceritinib in an ALK-positive non-small cell lung cancer patient with brain metastases: A case report. [2022]

12. China pubmed.ncbi.nlm.nih.gov

How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC). [2022]