Lorlatinib vs Crizotinib for Non-Small Cell Lung Cancer

Not currently recruiting at 201 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Pfizer

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Cardiovascular disease, Active infection, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, lorlatinib (Lorbrena) and crizotinib (Xalkori), to determine which more effectively slows the progression of advanced ALK-positive non-small cell lung cancer (NSCLC). Researchers aim to discover if lorlatinib can help patients live longer without their cancer worsening compared to crizotinib. Suitable participants have advanced ALK-positive NSCLC that hasn't been treated before and at least one cancer spot outside the brain that hasn't received radiation. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Previous studies have shown that lorlatinib is well-tolerated in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). Common side effects include weight gain, swelling, and mood changes, but these are generally manageable. Serious side effects are rare.

Research has indicated that crizotinib is also generally well-tolerated. Common side effects can include vision problems, nausea, and diarrhea, with serious side effects being uncommon.

Both lorlatinib and crizotinib have approval for treating certain types of lung cancer, supporting their safety profiles. Participants in clinical trials for these treatments have demonstrated that side effects are usually mild and manageable. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for non-small cell lung cancer?

Lorlatinib is unique because it targets a specific genetic mutation in non-small cell lung cancer (NSCLC) called ALK, which isn't addressed by all other treatments. Unlike most treatments that may not penetrate the blood-brain barrier efficiently, Lorlatinib is designed to do so, offering potential benefits for patients with brain metastases. Researchers are excited about Lorlatinib's ability to provide a more tailored approach to treating NSCLC, potentially improving outcomes for patients with this specific mutation.

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

This trial will compare Lorlatinib and Crizotinib for treating advanced ALK-positive non-small cell lung cancer (NSCLC). Research has shown that Lorlatinib is promising, with studies finding that many patients on Lorlatinib lived longer without their cancer worsening, as they had not yet reached a median progression-free survival (PFS). About 60% of these patients were alive without their disease worsening after five years. Additionally, 76% of patients who started treatment with Lorlatinib were still alive after five years. Crizotinib has been a standard treatment, but research suggests that Lorlatinib might provide better long-term results for patients. Participants in this trial will receive either Lorlatinib or Crizotinib to evaluate their effectiveness. ^{4 6 7 8 9}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38819031/

5-Year Outcomes From the Phase III CROWN Study Conclusion: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported ...

2. jto.org jto.org/article/S1556-0864(24)02484-5/fulltext

Final Overall Survival and Long-Term Safety of Lorlatinib in ... At a median follow-up of 72.7 months, the median OS was NR with lorlatinib with a five-year OS probability of 76% in patients with treatment-naïve, advanced, ...

3. cancer.gov cancer.gov/news-events/cancer-currents-blog/2024/lorlatinib-alk-positive-lung-cancer-initial-treatment

Lorlatinib Slows Growth of ALK-Positive Lung Cancers ... After 5 years of follow-up data, the investigators found, 60% of the participants in the lorlatinib group were alive without the disease having ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0169500225006543

Advanced-stage ALK-positive non–small-cell lung cancer ... The overall survival rates were 88.4 % and 74.8 % at 24 and 60 months, respectively. Liver involvement and ECOG PS emerged as the only reliable ...

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1577607/full

Real-world analysis of the efficacy and safety of lorlatinib in ... Lorlatinib demonstrates strong efficacy and manageable safety, especially in first-line treatment of advanced ALK-positive NSCLC, supporting its role as an ...

6. lorbrena.pfizerpro.com lorbrena.pfizerpro.com/api/vc/en/content/material/20c16739-773d-4500-875f-f45d70872ff3/Efficacy%20and%20Safety%20Brochure%20%28Digital%20PDF%29%20-%20June%20Update_CLEAN.pdf?download=true

OVERVIEW OF EFFICACY AND SAFETY DATA EFFICACY AND SAFETY DATA. INDICATION. LORBRENA® (lorlatinib) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer. (NSCLC) ...

7. lorbrena.pfizerpro.com lorbrena.pfizerpro.com/

LORBRENA® (lorlatinib) Official HCP Website | Safety Info Learn more about LORBRENA®, an Rx option for patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). See risks and benefits.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38879393/

Updated Efficacy and Safety of Lorlatinib in a Phase 2 ... Updated Efficacy and Safety of Lorlatinib in a Phase 2 Study in Chinese Patients With Previously Treated Advanced ALK-Positive Non-small Cell Lung Cancer.

9. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.e20659

Real-life efficacy and safety data of lorlatinib treatment in ... Lorlatinib has shown clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with ...