Stylized lung with glowing ALK gene against a cityscape at dawn, symbolizing progress in cancer treatment.

Lorlatinib vs. Crizotinib: A New Hope for ALK-Positive Lung Cancer?

Mira Elwood monogram
Mira Elwood in Health & Wellness October 2026 • 4 min read.

"A groundbreaking study explores lorlatinib as a potential first-line treatment, offering new possibilities for patients with advanced ALK-positive non-small cell lung cancer."


Lung cancer remains a significant global health challenge, with non-small cell lung cancer (NSCLC) accounting for a substantial proportion of cases. Among NSCLC patients, a subset harbors alterations in the anaplastic lymphoma kinase (ALK) gene, making them candidates for targeted therapies.

Crizotinib, an oral tyrosine kinase inhibitor, has been a standard treatment for advanced ALK-positive NSCLC. However, resistance to crizotinib often develops, and the central nervous system (CNS) can be a common site of disease relapse. This limitation has spurred the development of newer ALK inhibitors with improved CNS penetration and activity against resistance mutations.

Lorlatinib is a CNS-penetrant ALK inhibitor that has demonstrated promising activity against both de novo ALK fusions and resistance mutations. This article delves into a randomized, open-label phase 3 study comparing lorlatinib to crizotinib as a first-line treatment for patients with advanced ALK-positive NSCLC, shedding light on its potential to improve patient outcomes.

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Five-Year Disease Control in CROWN

The phase 3 CROWN trial (NCT03036488), sponsored by Pfizer, is described in a 2026 update as providing long-term evidence for lorlatinib in treatment-naive ALK-positive NSCLC. A separate report of the trial’s five-year results says 60% of patients receiving lorlatinib had no progression of advanced ALK-positive lung cancer at five years. A 2026 population-level model notes that lorlatinib and alectinib have shown better efficacy than crizotinib, while also stating that no head-to-head trials have compared lorlatinib with alectinib.

Guidance and Shared Treatment Decisions

NICE published technology appraisal guidance TA909 for lorlatinib in untreated ALK-positive advanced non-small-cell lung cancer on July 12, 2023. NICE’s October 2025 guidance, TA1103, updates and replaces TA909 and notes a commercial access agreement for lorlatinib. A practical guide developed with patients living with advanced ALK-positive NSCLC and experienced healthcare professionals aims to help patients understand what to expect and take an informed, active role in their care.

Approval and CROWN Milestone

Lorlatinib, marketed as Lorbrena by Pfizer, was first approved by the FDA on November 2, 2018. The phase III CROWN study later established lorlatinib as a standard first-line therapy for advanced ALK-positive NSCLC. A 2024 report presented overall survival and long-term safety results from the final analyses of a pivotal phase 2 study in patients with advanced ALK-positive NSCLC.

Why Lorlatinib Could Be a Game-Changer

Stylized lung with glowing ALK gene against a cityscape at dawn, symbolizing progress in cancer treatment.

The study, titled "A randomized, open-label comparison of lorlatinib versus crizotinib as first-line treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer," aimed to determine if lorlatinib is superior to crizotinib in prolonging progression-free survival (PFS) in treatment-naïve patients with advanced ALK-positive NSCLC. Additionally, the study sought to identify potential biomarkers predictive of clinical efficacy or treatment resistance.

The trial design was a global, multicenter, open-label phase 3 study that enrolled approximately 280 treatment-naïve patients. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had at least one measurable extracranial target lesion that had not been previously treated with radiotherapy. Patients with asymptomatic brain metastases were also eligible.

  • Study Design: Global, multicenter, open-label phase 3.
  • Participants: Approximately 280 treatment-naïve patients with advanced ALK-positive NSCLC.
  • Eligibility Criteria: Aged ≥ 18 years, ECOG performance status 0-2, measurable extracranial target lesion, and no prior radiotherapy.
  • Randomization: 1:1 to lorlatinib 100 mg once daily or crizotinib 250 mg twice daily.
  • Stratification: Presence of brain metastases (yes/no) and ethnicity (Asian/non-Asian).
  • Primary Endpoint: Progression-free survival (PFS) based on blinded independent central review (BICR).
  • Secondary Endpoints: PFS based on investigator assessment (IA), overall survival, objective response (OR) by BICR and IA, intracranial (IC) OR, IC time to progression.
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Adverse Events Require Attention

Lorlatinib is an oral treatment for advanced ALK-positive NSCLC, and five-year CROWN follow-up showed effective long-term disease control. Its distinct side-effect profile means treatment also involves potential adverse events. An expert consensus article emphasizes adequate monitoring and management of adverse events in patients receiving ALK tyrosine kinase inhibitors such as lorlatinib.

Lorlatinib Compared With Crizotinib

The phase 3 trial report describes lorlatinib as a third-generation ALK inhibitor with antitumor activity in previously treated ALK-positive NSCLC. A 2024 comparative review states that next-generation ALK inhibitors, including lorlatinib, alectinib, and brigatinib, are preferred first-line therapies and have established superiority over crizotinib, a first-generation ALK inhibitor. A separate systematic review and network meta-analysis evaluates lorlatinib against other ALK inhibitors as first-line treatment, but the provided source material does not give its comparative effect estimates.

Patients were randomized 1:1 to receive either lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. Treatment continued until disease progression, patient refusal, or unacceptable toxicity. Crossover between treatment arms was not permitted. The primary endpoint was progression-free survival (PFS) based on blinded independent central review (BICR) using RECIST v1.1.

The Future of ALK-Positive NSCLC Treatment

This study has the potential to change the treatment landscape for patients with advanced ALK-positive NSCLC. By comparing lorlatinib to crizotinib as a first-line treatment, researchers aim to provide valuable insights into the efficacy and safety of lorlatinib, as well as identify potential biomarkers predictive of clinical outcomes. The results of this study could pave the way for lorlatinib to become a new standard of care, offering hope for improved outcomes and a better quality of life for patients with this challenging disease.

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Long-Term Activity Across Patient Groups

Final analyses after five years of follow-up from a phase 2 study supported substantial activity and prolonged overall survival with lorlatinib in treatment-naive and previously treated patients with ALK-positive advanced NSCLC. The report says these findings held across biomarker subgroups. It also identifies resistance mechanisms as part of the study’s analysis, but the supplied source summary does not specify the mechanisms or their frequency.

Progression-Free and Intracranial Benefit

In the phase III CROWN study, lorlatinib improved progression-free survival compared with crizotinib in previously untreated patients with advanced ALK-positive NSCLC. The report also describes improved intracranial activity versus crizotinib. These findings concern trial outcomes; the supplied source summary does not provide patient-reported experiences or broader real-world outcome data.

PFS estimates across different comparisons

  • 8.67 monthsIn RMST models through 27 months, lorlatinib’s PFS advantage over crizotinib was estimated at 8.67 months.[1]
  • 6.86 monthsAmong patients with brain metastases at baseline, the estimated PFS advantage for lorlatinib over crizotinib during 16 months of follow-up was 6.86 months.[1]
  • 0.61 and 0.57 hazard ratioA network meta-analysis reported hazard ratios for independent-review PFS of 0.61 for lorlatinib versus alectinib and 0.57 versus brigatinib.[2]
  • 25.8 and 12.7 monthsIn a separate comparison, median PFS was 25.8 months with ensartinib and 12.7 months with crizotinib.[3]

What these comparisons add-and what they cannot settle

The RMST estimates express the modeled time without progression gained relative to crizotinib over specified follow-up periods. They suggest that the estimated advantage also appeared in the subgroup with brain metastases at baseline, but do not establish how every individual patient fared.[1]

The network estimates compare lorlatinib with other inhibitors, while the ensartinib result is a distinct comparison with crizotinib. These results address different comparisons and should not be read as a single ranking of treatments.[2] [3]

How modeled comparisons fit beside trial evidence

A review notes that randomized trials have not directly compared lorlatinib with second-generation ALK inhibitors. The network meta-analysis likewise cautions that its results are a platform for future trials, not direct evidence for promoting a particular first-line agent.[4] [5]

Preclinical findings describe lorlatinib activity against several ALK mutant forms, including mutations detected in tumors after progression on ALK inhibitors. These laboratory and mouse findings provide biological context, rather than clinical outcome evidence in patients.[6]

The cited review describes poor CNS penetration by crizotinib and reports that newer inhibitors showed stronger intracranial responses than crizotinib. It also identifies the brain as a common site of metastasis and relapse and discusses drug efflux as a proposed explanation for crizotinib’s limited CNS penetration.[4]

Sources

  1. Identifying optimal ALK inhibitors in first- and second-line treatment of patients with advanced ALK-positive non-small-cell lung cancer: a systematic review and network meta-analysis (pmc.ncbi.nlm.nih.gov)
  2. Systematic review and network meta-analysis of lorlatinib with comparison to other anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) as first-line treatment for ALK-positive advanced (pubmed.ncbi.nlm.nih.gov)
  3. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with oncogene-addicted metastatic non-small-cell lung cancer (pmc.ncbi.nlm.nih.gov)
  4. Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC (pmc.ncbi.nlm.nih.gov)
  5. Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer (pmc.ncbi.nlm.nih.gov)
  6. LORBRENA® (lorlatinib) tablets (www.accessdata.fda.gov)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

Everything You Need To Know

1

What is lorlatinib and what role does it play in treating ALK-positive non-small cell lung cancer?

Lorlatinib is a medication that is being studied as a potential treatment for ALK-positive non-small cell lung cancer (NSCLC). It is a type of ALK inhibitor, designed to target the ALK gene. The study discussed compares lorlatinib to crizotinib, another ALK inhibitor that has been a standard treatment for this type of cancer. The significance of lorlatinib lies in its potential to offer improved outcomes for patients, particularly because it demonstrates activity against resistance mutations and penetrates the central nervous system (CNS) more effectively. This is important because resistance to treatments like crizotinib and CNS involvement are common challenges in treating ALK-positive NSCLC.

2

How does crizotinib relate to the use of lorlatinib?

Crizotinib is an oral tyrosine kinase inhibitor that has been a standard treatment for advanced ALK-positive NSCLC. However, a common issue with crizotinib is that patients often develop resistance to it over time, and the cancer can also spread to the central nervous system (CNS). The study is comparing lorlatinib to crizotinib to see if lorlatinib can overcome some of these limitations. This means that lorlatinib might be more effective in preventing the cancer from progressing, especially in the brain, and could offer a longer period of time before the disease worsens. This comparison is critical because it aims to establish whether lorlatinib can improve patient outcomes where crizotinib has limitations.

3

What does it mean for a patient to have ALK-positive non-small cell lung cancer (NSCLC), and why is it important?

ALK-positive non-small cell lung cancer (NSCLC) is a subtype of NSCLC where the cancer cells have alterations in the anaplastic lymphoma kinase (ALK) gene. These alterations make the cancer cells grow and spread. This is significant because these genetic changes make the cancer susceptible to targeted therapies, like lorlatinib and crizotinib, that are designed to block the ALK protein and stop the cancer from growing. Knowing that a patient has ALK-positive NSCLC is crucial, because it guides the use of specific medications that are likely to be more effective than standard chemotherapy in these cases.

4

What is progression-free survival (PFS), and why is it important in this study?

Progression-free survival (PFS) is a key measure in the study and refers to the length of time during and after the treatment that a patient lives without their cancer getting worse. In this study, PFS is measured using a method called blinded independent central review (BICR). The study also looks at overall survival, which is the total time a patient lives after starting treatment. The significance of PFS is that it helps assess the effectiveness of a treatment, such as lorlatinib versus crizotinib, in controlling the disease. A longer PFS indicates the treatment is successful in delaying cancer progression, improving a patient's quality of life and potentially extending their overall survival.

5

What does the study entail and what is the significance of this research?

The study design is a global, multicenter, open-label phase 3 trial. Approximately 280 treatment-naïve patients with advanced ALK-positive NSCLC are participating in the trial. Patients are randomly assigned to receive either lorlatinib or crizotinib. The trial's open-label design means that both the patients and the researchers know which treatment the patients are receiving. Phase 3 studies are a critical part of the drug development process because they involve a large number of patients and are designed to confirm the benefits of a new treatment, compared to an existing one, and assess potential side effects. The results of this study will help determine whether lorlatinib is more effective and safer than crizotinib and could potentially establish lorlatinib as a new standard of care.

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