# First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer

Source: https://onco.cc/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/  
OnCo record `paper-shaw-crown-lorlatinib-crizotinib-nejm-2020` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

CROWN's third-generation ALK drug kept 78 percent of patients free of progression at a year against 39 percent on crizotinib, and controlled disease inside the brain far better.

## Summary

The CROWN trial investigators, reported by Shaw, Bauer, de Marinis and colleagues with Solomon as senior author, randomised 296 patients with advanced ALK-positive non-small-cell lung cancer and no previous systemic treatment for metastatic disease between lorlatinib and crizotinib. The primary endpoint was blinded independent central review progression-free survival; intracranial response was a secondary endpoint.

The cost is a distinctive toxicity profile: hyperlipidaemia and central nervous system effects on mood, speed and memory. Lorlatinib is the first lung cancer drug whose main side effect is cognitive, which makes the choice between it and alectinib a quality-of-life question rather than a purely efficacy one.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: New England Journal of Medicine
- Year: 2020
- DOI: 10.1056/NEJMoa2027187
- Authors: Shaw AT, Bauer TM, de Marinis F, et al.
- Findings: 78 percent of patients on lorlatinib were alive without disease progression at 12 months (95 percent confidence interval 70 to 84) against 39 percent on crizotinib (30 to 48).; Hazard ratio for disease progression or death 0.28 (0.19 to 0.41).; A higher frequency of intracranial response with lorlatinib than with crizotinib.; Grade 3 or 4 adverse events were more frequent with lorlatinib, because of the frequent occurrence of altered lipid levels.
- What it means: The current first choice for ALK-positive lung cancer in most guidelines, and the strongest evidence in solid tumour oncology that a drug can be designed to work inside the brain. Five-year follow-up has since shown the majority of patients still progression-free.
- Caveats: An interim analysis at 12 months, and the comparator is crizotinib rather than alectinib, which is what lorlatinib actually competes with.; Lipid abnormalities and central nervous system effects on mood, cognition and speech are common and not fully captured by grade 3 or 4 counts.; No overall survival benefit has been demonstrated against a next-generation comparator.

## Sources

- N Engl J Med 2020: https://doi.org/10.1056/NEJMoa2027187
- PubMed: https://pubmed.ncbi.nlm.nih.gov/33207094/
- ClinicalTrials.gov NCT03052608: https://clinicaltrials.gov/study/NCT03052608

## Connected records

- key papers: [Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/), [Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer](https://onco.cc/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/)
- ideas: [Measure brain metastasis prevention as a primary endpoint, not as a secondary one](https://onco.cc/ideas/idea-lung-brain-metastasis-prevention-as-a-primary-endpoint/), [Prevention trials aimed only at brain metastasis](https://onco.cc/ideas/idea-bio2-brain-met-prevention-trials/)
- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [ALK](https://onco.cc/targets/alk/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Crizotinib](https://onco.cc/drugs/crizotinib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/)
- companies: [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/)
- trials: [CROWN](https://onco.cc/trials/crown/)
- people: [Alice T. Shaw](https://onco.cc/people/alice-shaw/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The brain: barrier and sanctuary](https://onco.cc/bottlenecks/b-brain-delivery/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- roadmaps: [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)

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