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An ALK inhibitor with the longest disease control ever recorded for a targeted lung cancer pill: 60% progression-free at five years.
Lorlatinib is a macrocyclic third-generation ALK and ROS1 inhibitor designed to cover resistance mutations including G1202R and to cross the blood-brain barrier, taken as 100 mg once daily. In CROWN it achieved a 5-year progression-free survival of 60% versus 8% for crizotinib, with near-complete protection against brain progression. It was approved in 2018 after prior ALK inhibitors and in 2021 for first-line ALK-positive NSCLC. Its distinctive toxicities are metabolic and neurological: raised cholesterol and triglycerides, weight gain, oedema, neuropathy and cognitive or mood effects, which need active management. Its position against alectinib and newer agents such as neladalkib remains open. For a newcomer: the ALK pill with the most durable results, balanced against side effects that touch thinking and mood.
Macrocyclic third-generation ALK/ROS1 TKI covering G1202R. Connects to ALK.
1.Oral drug is absorbed and reaches the tumour
Background: ADC sequencing, Antigen escape (antigen loss, lineage switch), BCG-unresponsive, Castration-resistant prostate cancer (CRPC), Circulating tumour DNA (ctDNA). Also on OnCo: Resistance: how tumours escape each drug class · Lines of therapy.
Source: www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications. Doses are for orientation; the current label governs.
Oral, self-administered, so it is a Part D drug: covered through a stand-alone Part D plan or Medicare Advantage drug benefit, usually on the specialty tier with 25 to 33% coinsurance until the annual cap ($2,000 in 2025, $2,100 in 2026).
Covered for FDA-labelled and NCCN-listed uses, but almost always behind prior authorisation confirming diagnosis, biomarker and line of therapy; dispensed through a specialty pharmacy.
Part D out-of-pocket capped at $2,000 (2025) / $2,100 (2026). Medicare patients cannot use manufacturer co-pay cards; charity funds (PAN, HealthWell, CancerCare) and the Extra Help subsidy are the routes.
Sources: Medicare.gov: Drug coverage (Part D) · Medicare.gov: Costs for Medicare drug coverage (annual out-of-pocket cap). Not medical or financial advice; verify with your plan.
Sources: NICE TA628 · NHS England Cancer Drugs Fund list · SMC advice: lorlatinib. Funding decisions are indication-specific and change monthly; verify with NICE and your treating team.
ALK-positive metastatic NSCLC that has progressed on: • Crizotinib and at least one other ALK inhibitor for metastatic disease; or • Alectinib as the first ALK inhibitor therapy for metastatic disease; or • Ceritinib as the first ALK inhibitor therapy for metastatic disease
ALK+ NSCLC after prior ALK TKIs (accelerated) source
ALK-positive metastatic NSCLC that has progressed on: • Crizotinib and at least one other ALK inhibitor for metastatic disease; or • Alectinib as the first ALK inhibitor therapy for metastatic disease; or • Ceritinib as the first ALK inhibitor therapy for metastatic disease
First-line ALK+ NSCLC (CROWN); full approval source
| Region | Year | Indication |
|---|---|---|
| US | 2018 | ALK+ NSCLC after prior ALK TKI |
| US | 2021 | First-line ALK+ NSCLC |
| England (NICE) | 2020 | ALK-positive advanced non-small-cell lung cancer progressing after alectinib or ceritinib as the first ALK inhibitor, or after crizotinib and at least one other ALK inhibitor · TA628, published 13 May 2020, subject to the commercial arrangement. |
| England (NICE) | 2025 | ALK-positive advanced non-small-cell lung cancer not previously treated with an ALK inhibitor · TA1103, published 21 October 2025 (CROWN); must be funded in England within 90 days of publication. |
| Adverse event |
|---|
| Hypercholesterolaemia |
| Hypertriglyceridaemia |
| Oedema |
| Weight gain |
| Peripheral neuropathy |
| Cognitive and mood effects |
| Hypertension |
CROWN: ~70% any grade, ~20% grade 3-4. Events listed without rates were not read from a primary source; see the label. Blank cells mean the figure was not sourced, not that it is zero.
| Country | Reimbursement | List price | Assistance |
|---|---|---|---|
| United States | Medicare Part D (oral); commercial plans per formulary, often with prior authorisation | not disclosed | pfizeroncologytogether.com |
| United Kingdom | NICE: recommended first-line for ALK+ NSCLC (TA909) | not disclosed | - |
List prices are manufacturer or Medicare figures where publicly disclosed; net prices after rebates are usually lower. Reimbursement changes; check the payer.
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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.
It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.
It made repeat biopsy and genotyping at progression the standard in ALK-positive lung cancer, because after a second-generation inhibitor the presence or absence of an ALK mutation is what separates patients who should receive a third-generation inhibitor from those who should not.
It is the cleanest demonstration in oncology that resistance is a property of a particular drug bound to a particular protein rather than a property of the tumour, and that genotyping at every progression can reopen an option that looked closed.
Query for this drug: (TITLE:"Lorlatinib" OR ABSTRACT:"Lorlatinib" OR TITLE:"Lorbrena" OR ABSTRACT:"Lorbrena") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Lorlatinib, not a curated reading list.
Shares Neladalkib, Prevention trials aimed only at brain metastasis, Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer, ALK fusion (ALK-positive).
Shares Dong-Wan Kim, Sequence: targeted therapy before immunotherapy in driver-positive NSCLC, University of Colorado Cancer Center, ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer.
Shares Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F, University of Colorado Cancer Center, ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer, Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.
Shares Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F, ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer, Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer, ALK fusion (ALK-positive).
Shares Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer, ALK fusion (ALK-positive), Lung cancer drugs in England: what NICE has recommended, Inflammatory myofibroblastic tumour (IMT).
Shares Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer, ALK fusion (ALK-positive), Lung cancer drugs in England: what NICE has recommended, Non-small cell lung cancer (KEGG map).
Shares ALK fusion (ALK-positive), Non-small cell lung cancer (KEGG map), ALK-positive non-small-cell lung cancer, ALK.
Shares Dong-Wan Kim, D. Ross Camidge, ALK-positive non-small-cell lung cancer, ALK.