Lorlatinib vs Crizotinib for Non-Small Cell Lung Cancer

Recruiting at 164 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Pfizer

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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 33 months

296 Participants Needed

Trial Summary

What is the purpose of this trial?

A phase 3 study to demonstrate whether lorlatinib given as monotherapy is superior to crizotinib alone in prolonging the progression-free survival in advanced ALK-positive NSCLC patients who are treatment naïve and to compare lorlatinib to crizotinib with respect to overall survival in the same population

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong CYP3A inhibitors, strong CYP3A inducers, and P gp substrates with a narrow therapeutic index, at least 12 days before starting the study drugs. If you are on any of these, you will need to stop them before participating.

What data supports the effectiveness of the drugs Lorlatinib and Crizotinib for treating ALK-positive non-small cell lung cancer?

Lorlatinib has shown better effectiveness than Crizotinib in treating advanced ALK-positive non-small cell lung cancer, especially in patients who have not been treated before, as demonstrated in the CROWN study. Crizotinib has also been effective, with significant response rates in patients with this type of lung cancer. ^{1 2 3 4 5}

What is known about the safety of Lorlatinib and Crizotinib for treating non-small cell lung cancer?

Lorlatinib is generally safe, with most side effects being mild to moderate and manageable, though it can cause issues like high cholesterol, weight gain, and nerve problems. Crizotinib has been linked to serious lung problems in some cases. Both drugs require careful monitoring for side effects. ^{5 6 7 8 9}

How does the drug lorlatinib differ from crizotinib for treating non-small cell lung cancer?

Lorlatinib is a third-generation drug that works better than crizotinib for treating advanced ALK-positive non-small cell lung cancer, especially in preventing the cancer from spreading to the brain. It is more effective in keeping patients alive without the disease getting worse compared to crizotinib. ^{5 10 11 12 13}

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility Criteria

This trial is for adults over 18 with advanced ALK-positive NSCLC who haven't had treatment before. They need good organ function and a negative pregnancy test if applicable. People with serious infections, lung fibrosis, uncontrolled heart conditions, recent major surgery or certain mental health risks can't join.

Inclusion Criteria

I have not received any systemic treatment for NSCLC.

My bone marrow, liver, kidneys, and pancreas are functioning well.

There is a stored tissue sample available for the study.

Exclusion Criteria

I do not have any ongoing infections.

I haven't taken certain strong medications or specific foods that affect drug metabolism in the last 12 days.

I have spinal cord compression but my pain is well managed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either lorlatinib or crizotinib continuously to assess progression-free survival and overall survival

Up to 33 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Crizotinib
• Lorlatinib

Trial Overview The study compares two drugs: Lorlatinib and Crizotinib as first-line treatments for NSCLC. It aims to see if Lorlatinib is better at delaying cancer progression without the disease getting worse and will also look at overall survival rates compared to Crizotinib.

Participant Groups

Group I: Lorlatinib Experimental Treatment 1 Intervention

Lorlatinib single agent, 100 mg (4 x 25 mg) oral tables, QD, continuously

Group II: Crizotinib Active Control 1 Intervention

Crizotinib single agent, 250 mg (1 x 250) oral capsules, BID, continuously

Crizotinib is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in European Union as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Japan as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Canada as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

Lorlatinib shows significant brain penetration and demonstrates autoinduction after multiple doses, which means its clearance increases with continued use, potentially affecting dosing strategies.

In a study involving 329 patients (54 in phase I and 275 in phase II), lorlatinib's plasma exposure increased proportionally with single doses and slightly less so with multiple doses, indicating consistent efficacy in treating ALK-positive non-small cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study. Chen, J., O'Gorman, MT., James, LP., et al.[2022]

Crizotinib (Xalkori) has shown excellent efficacy in treating advanced ALK-positive non-small cell lung cancer (NSCLC), with objective response rates of 61% in phase I and 51% in phase II studies, significantly outperforming standard therapies that have response rates below 10%.

The treatment is well tolerated, with common side effects being mild gastrointestinal issues and visual disturbances, and it has led to improvements in patients' quality of life, including reduced fatigue and cough.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ALK-positive non-small cell lung cancer. Bang, YJ.[2018]

Lorlatinib is a highly effective oral treatment for advanced ALK-positive non-small cell lung cancer (NSCLC), showing superior systemic and intracranial efficacy compared to crizotinib in treatment-naïve patients, as demonstrated in the phase 3 CROWN trial.

Lorlatinib remains effective against certain ALK resistance mutations after patients have progressed on earlier ALK inhibitors, making it a valuable option in the treatment landscape for advanced ALK-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC. Yun, KM., Bazhenova, LA.[2022]

Lorlatinib is a promising third-generation ALK tyrosine kinase inhibitor that effectively penetrates the blood-brain barrier and targets most resistance mutations associated with earlier ALK inhibitors, making it a strong option for treating ALK-positive non-small-cell lung cancer.

The safety profile of lorlatinib is generally favorable, with most adverse events being mild to moderate and manageable, allowing for continued treatment without significant interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consensus Recommendations for Management and Counseling of Adverse Events Associated With Lorlatinib: A Guide for Healthcare Practitioners. Reed, M., Rosales, AS., Chioda, MD., et al.[2021]

A study of 130 treatment courses in 111 patients revealed that safety monitoring activities (SMAs) for EGFR and ALK inhibitors were inconsistently conducted, with prevalence ranging from 10.0% to 84.6%, and 31.5% of courses had no SMAs performed.

EGFR inhibitors were associated with a higher likelihood of SMAs being conducted compared to ALK inhibitors, highlighting the need for clinicians to closely follow FDA guidelines to ensure patient safety and monitor for serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. Singh, AM., Rubiera-Pebe, R., Ahmad, Y., et al.[2023]

In a study of 29 patients treated with crizotinib, 6 cases of interstitial lung disease (ILD) were identified, highlighting a significant risk of severe lung complications associated with this medication.

The less severe form of ILD, which developed gradually and was associated with better progression-free survival (19.9 months), suggests that while crizotinib can lead to serious lung issues, some patients can be safely retreated after experiencing milder symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib Associated with Ground-Glass Opacity Predominant Pattern Interstitial Lung Disease: A Retrospective Observational Cohort Study with a Systematic Literature Review. Créquit, P., Wislez, M., Fleury Feith, J., et al.[2018]

References

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

Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors. [2020]

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

First-Line Lorlatinib Versus Crizotinib in ALK-Positive NSCLC: Japanese Subgroup Analysis of CROWN. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study. [2022]

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

Treatment of ALK-positive non-small cell lung cancer. [2018]

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

Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Comparison of Efficacy and Safety of Brigatinib in First-Line Treatments for Patients with Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Systematic Review and Indirect Treatment Comparison. [2022]

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

Consensus Recommendations for Management and Counseling of Adverse Events Associated With Lorlatinib: A Guide for Healthcare Practitioners. [2021]

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

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. [2023]

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

Crizotinib Associated with Ground-Glass Opacity Predominant Pattern Interstitial Lung Disease: A Retrospective Observational Cohort Study with a Systematic Literature Review. [2018]

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

Lorlatinib Outperforms Crizotinib in NSCLC. [2021]

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

Lorlatinib in ALK-Rearranged Lung Cancer. [2021]

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

Comparative efficacy of first-line ceritinib and crizotinib in advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer: an adjusted indirect comparison with external controls. [2020]

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

First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. [2023]