What Is Lorlatinib (Lorviqua)? FDA Approval, Licensing and Reimbursement in Turkey
In this article
What is lorlatinib (Lorviqua)? Drug profile, efficacy data, licensing and price in Turkey
Lorlatinib is currently the most potent drug available for ALK-positive lung cancer—and "potent" here is a numerical description, not an exaggeration. The first-line CROWN trial comparing it with crizotinib provided 7-year data showing that 55% of patients were still progression-free after seven years . The corresponding rate in the other arm was 3%. A duration like this in metastatic lung cancer would have been unimaginable a decade ago. This article brings together the complete drug profile, current efficacy and toxicity data, dose-reduction schedule, licensing and pricing in Turkey, and the next drug in this field.
| Active ingredient | Lorlatinib |
| Brand name in Turkey | LORVIQUA |
| Brand name in the US | LORBRENA |
| Marketing authorization holder (Turkey) | Pfizer PFE İlaçları Anonim Şirketi |
| Class | Third-generation ALK tyrosine kinase inhibitor; also inhibits ROS1 |
| Administration | Orally, once daily, with or without food |
| Standard dose | 100 mg, 1 dose daily |
| Dose-reduction steps | 100 mg → 75 mg → 50 mg; permanently discontinue if 50 mg is not tolerated |
| Formulations | 100 mg and 25 mg film-coated tablets, packs of 30 |
| Approved use | ALK-positive metastatic non-small cell lung cancer |
| US approvals | November 2, 2018 (previously treated patients) · March 3, 2021 (first-line treatment) |
| European approval | May 6, 2019; last renewal April 5, 2024 |
| Prescription status (Turkey) | Standard (White) Prescription |
A common source of confusion: Lorlatinib blocks both ALK and ROS1 kinases in the laboratory. However, its approved indication is ALK-positive disease only; it is not licensed for ROS1-positive lung cancer. The description "ALK and ROS1 inhibitor" refers to its pharmacologic properties, not its indication.
Mechanism of Action: Why "Third Generation"?
When the ALK gene joins another gene following a chromosomal break (fusion), it produces a growth signal that stays switched on. The cell continually receives the command to divide. ALK inhibitors block this enzyme and interrupt the signal.
The problem is that tumors develop mutations over time that change the shape of the ALK enzyme, so the drug no longer fits its binding site. These mutations are a major cause of resistance to first-generation crizotinib and second-generation drugs. Lorlatinib is a macrocyclic molecule designed specifically to overcome these resistance mutations.
| Mutation | Significance |
|---|---|
| G1202R | Solvent-front mutation; the most common cause of resistance to second-generation ALK inhibitors. Lorlatinib's most notable area of superiority |
| L1196M | Gatekeeper mutation; a classic cause of crizotinib resistance |
| C1156Y, F1174L, R1275Q, I1171 series | Other mutations causing resistance to different generations |
Lorlatinib's second, perhaps more important, feature is its ability to enter the brain. ALK-positive lung cancer spreads to the brain very frequently; many patients have brain metastases at diagnosis or develop them during follow-up. Lorlatinib was designed to cross the blood–brain barrier, and this is the source of CROWN's most striking result. As discussed below, the hazard ratio for intracranial progression is 0.06—meaning that the risk falls to approximately one sixteenth.
The CROWN Trial: 7-Year Data
CROWN is a phase 3 trial comparing lorlatinib with crizotinib in previously untreated ALK-positive metastatic lung cancer (NCT03052608). The latest analysis was presented at ASCO 2026 and published in Annals of Oncology; the data cutoff was October 31, 2025.
were progression-free
crizotinib: 3%
hazard ratio
hazard ratio
were still taking the drug
| Endpoint | 7-year analysis (2026) | 5-year analysis (2024) |
|---|---|---|
| Median follow-up (lorlatinib) | 83.0 months | 60.2 months |
| Median progression-free survival — lorlatinib | Not reached (95% CI 68.5–not reached) | Not reached |
| Median progression-free survival — crizotinib | 9.1 months (7.4–10.9) | 9.1 months |
| Progression-free survival hazard ratio | 0.19 (0.13–0.26) | 0.19 (0.13–0.27) |
| Progression-free patients | At 7 years, 55% (46–63) vs 3% (1–8) | At 5 years, 60% vs 8% |
| Median time to intracranial progression | Not reached vs 16.4 months | Not reached vs 16.4 months |
| Intracranial progression hazard ratio | 0.06 (0.03–0.12) | 0.06 (0.03–0.12) |
| Patients without intracranial progression | At 7 years, 92% vs 16% | At 5 years, 92% vs 21% |
| Overall survival | Still immature. The protocol-specified event count has not been reached; no overall survival hazard ratio has been reported at any data cutoff | |
| Patients continuing treatment | 44% (n=149) vs 3% (n=142) | Median treatment duration 57.0 vs 9.6 months |
Three Details More Meaningful Than the Numbers
No intracranial progression after 30 months
In the lorlatinib arm, after month 30 of treatment, no new intracranial progression events occurred. This suggests that the drug does not merely delay brain disease but can control it within the first two and a half years.
No discontinuation for toxicity after 26 months
All patients who stopped because of side effects did so within the first 26 months. In other words, this drug's toxicity is not cumulative ; patients who tolerate the first two years can generally continue for a long time.
Among patients reaching 24 months, 79% remained progression-free at year 7
Conditional analysis: For a patient who was progression-free at month 24, the probability of remaining so in the seventh year was 79%. This is among the most concrete statements that can be communicated to a patient.
Why Are Overall Survival Data Still Unavailable? Even after seven years, immature overall survival data may initially seem a shortcoming. They are not; on the contrary, too few patients have died for the analysis to be performed. Still, we must be candid: randomized evidence has not shown that lorlatinib extends life. What has been demonstrated is prolonged prevention of progression and substantial prevention of spread to the brain. In addition, patients in the crizotinib arm most likely received more potent ALK inhibitors after progression, which would diminish a survival difference. This is a structural limitation, not a flaw in the study.
Side Effects and Their Rates
Lorlatinib's side-effect profile is qualitatively different from that of other ALK inhibitors. Elevated blood lipids and central nervous system effects stand out, rather than nausea and elevated liver enzymes. This is the most important point to understand before using it.
| Adverse event | Any grade 7-year analysis |
Grade 3–4 5-year analysis |
Crizotinib any grade |
|---|---|---|---|
| Elevated cholesterol | 73% | 21% | 4% |
| Elevated triglycerides | 71% | 25% | 6% |
| Edema | 58% | — | 43% |
| Peripheral nerve effects | 46% | — | 16% |
| Weight gain | 45% | 23% (grade 3) | 13% |
| Central nervous system effects (total) | 42% (5-year) | 9% | — |
| — Cognitive effects | 30% | 5% | 7% |
| — Mood effects | 21% | 1.7% | — |
| — Speech effects | 6% | — | — |
| — Psychotic symptoms | 5% | — | — |
| High blood pressure | 18% (product information) | 12% | — |
| High blood sugar | 9% (product information) | 3.2% | — |
| Lung inflammation (ILD / pneumonitis) | 1.9% (pooled) | 0.6% | — |
| AV block | 1.9% (pooled) | 0.2% (pacemaker required) | — |
| Any grade ≥3 adverse event | 77% | 57% | |
| Serious adverse event | 44% | 32% | |
How to read the table: The columns come from different data cutoffs . Any-grade rates come from the 7-year analysis, most grade 3–4 rates from the 5-year analysis, and lung inflammation and AV block rates from the product information's pooled safety population rather than CROWN alone. An adverse-event-specific grade 3–4 breakdown has not been published for the 7-year analysis. CROWN also did not report a separate elevated liver enzyme rate for the lorlatinib arm.
Timing and Management of Side Effects — The Information That Matters Most
| Adverse event | Median time to onset | Management |
|---|---|---|
| Elevated blood lipids | 0.5 months (5.6–6.4 months for grade ≥3) | 71% were managed with lipid-lowering medication. According to the product information, 83% of patients need lipid-lowering treatment. Dose reduction is not the first option |
| Central nervous system effects | 3.8 months (7.4 months for grade ≥3) | 60% resolved. 58% were managed without any medical intervention. For grade 2–3 events, interrupt treatment and resume at the next lower dose |
| Edema | 1.8 months | Salt restriction, leg elevation and a diuretic if needed |
| Peripheral nerve effects | 3.7 months | Dose reduction; symptomatic treatment |
| Weight gain | — | No dose modification was needed in 95% of grade 2–3 weight gain events |
The two most important figures in this table concern central nervous system effects: 60% resolve and 58% can be managed without intervention . Cognitive and mood effects are among the most feared aspects of this drug and worry many patients. In fact, they are mostly mild, generally arise in the first months, respond well to dose reduction and are largely reversible. The rate of grade 3 or higher cognitive effects is 5%of patients.
But patients must be told one thing: The person who notices these effects is often not the patient but a family member or someone close to them. Difficulty finding words, forgetfulness, unusual irritability or elation, and insomnia may be dismissed as "getting older" or "being tired." At the start of treatment, someone close to the patient should also be informed , and these issues should be asked about explicitly at every visit. An early-recognized cognitive effect is readily managed by dose reduction; an unrecognized one can make life difficult.
Dose Reduction and Treatment Interruption: How Common Are They?
| 7-year analysis | 5-year analysis | |
|---|---|---|
| Dose reduction | 34% (17% once, 17% twice) | 23% |
| Treatment interruption | — | 62% |
| Discontinuation because of adverse effects | 5% (crizotinib 6%) | 5% |
| Median time to first dose reduction | 25 weeks | — |
These rows should be read together: one third have a dose reduction and two thirds interrupt treatment at some point, but only 5% stop the drug permanently , all within the first 26 months. This drug can therefore be managed through dose adjustments, and reducing the dose does not mean treatment failure. Efficacy has also been reported to be maintained at 75 mg and 50 mg.
Dose Reduction and Management Schedule
| Step | Dose |
|---|---|
| Starting dose | 100 mg, 1 dose daily |
| 1st reduction | 75 mg, 1 dose daily |
| 2nd reduction | 50 mg, 1 dose daily |
| If 50 mg is not tolerated | Permanently discontinue |
| Condition | Action |
|---|---|
| Central nervous system effects — grade 2 or 3 | Interrupt treatment; once reduced to grade 1 or below, resume at the next lower dose to continue treatment |
| Central nervous system effects — grade 4 | Permanently discontinue |
| Elevated blood lipids — mild/moderate | No dose change; start lipid-lowering treatment |
| Elevated blood lipids — severe | No dose change; intensify lipid-lowering treatment |
| Elevated blood lipids — life-threatening | Interrupt; once reduced to mild/moderate, resume at the same dose ; if it recurs, reduce to the next lower dose |
| PR prolongation / asymptomatic 1st-degree AV block | Continue without interruption |
| Symptomatic 1st-degree AV block | Interrupt; resume at a lower dose after resolution |
| Asymptomatic 2nd-degree AV block | Interrupt; resume at a lower dose when ECG normalizes |
| Symptomatic 2nd-degree AV block | Interrupt treatment; consider a pacemaker; resume at a lower dose if it resolves |
| Complete (3rd-degree) AV block | Interrupt treatment. May resume at full dose if a pacemaker is implanted; without a pacemaker, resume at a reduced dose only after resolution |
| Lung inflammation — grade 1–2 | Interrupt; resume at a reduced dose on return to baseline; consider corticosteroids |
| Lung inflammation — grade 3–4 | Permanently discontinue |
| Condition | Dose |
|---|---|
| Mild or moderate hepatic impairment | No change needed |
| Severe hepatic impairment | 50 mg, 1 dose daily |
| Creatinine clearance ≥30 ml/min | No change needed |
| Creatinine clearance 15–30 ml/min | 75 mg, 1 dose daily |
| With a strong CYP3A inhibitor or fluconazole | Reduce dose |
Absolute contraindication: strong CYP3A inducers. Drugs such as rifampin, carbamazepine, phenytoin, phenobarbital and St. John's wort not only reduce lorlatinib blood levels but also cause severe liver injury. In healthy volunteers taking it with rifampin, 83% developed grade 3–4 elevated liver enzymes . Strong CYP3A inducers therefore cannot be used with lorlatinib. This is an absolute prohibition, not a routine interaction warning.
Monitoring Schedule
- Blood lipids (cholesterol, triglycerides): At baseline, during the first two months and regularly thereafter. Elevation is almost the rule and begins, on average, within the first two weeks.
- ECG: At baseline and during follow-up, with particular attention to the PR interval.
- Cognitive and mood assessment: At every visit, ask explicitly and, if possible, seek observations from someone close to the patient.
- Weight and edema: At every visit.
- Liver tests and blood glucose: Regularly.
- Lung symptoms: Stop treatment and assess the lungs if new cough, shortness of breath or fever develops.
- Pregnancy and contraception: May harm the unborn baby; effective contraception is required during and after treatment. Lorlatinib may reduce the effectiveness of hormonal contraceptive pills; a nonhormonal method is therefore recommended.
Pharmacokinetics
| Parameter | Value |
|---|---|
| Oral absorption | 81%; not substantially affected by food |
| Time to peak blood level | 1.2–2 hours |
| Plasma protein binding | Approximately 66% |
| Time to steady state | Approximately 15 days |
| Metabolic pathway | CYP3A4 and UGT1A4 |
| Excretion | Feces 41%, urine 48% |
| Half-life | Approximately 24 hours |
A half-life of 24 hours allows once-daily use. Metabolism through CYP3A4 explains the entire interaction profile: drugs that inhibit this enzyme, such as ketoconazole, itraconazole, clarithromycin and grapefruit, increase lorlatinib levels and toxicity, while drugs that induce it reduce efficacy and create the liver injury risk described above.
Licensing, Reimbursement and Pricing in Turkey
Licensing. LORVIQUA is licensed by Turkey's Ministry of Health. The marketing authorization holder is Pfizer PFE İlaçları Anonim Şirketi. The approved indication in Turkey is:
"LORVIQUA is indicated as monotherapy for adults with ALK-positive metastatic NSCLC who have not previously received an ALK inhibitor or who have received one or more ALK tyrosine kinase inhibitors (TKIs)."
Thus, the indication in Turkey covers both first-line and later-line use.
A Warning and Its Reason Third-party SmPC mirrors still circulate the old indication restricting use to patients previously treated with an ALK inhibitor only . That text predates CROWN. The only reliable way to verify the current SmPC is to search for the active ingredient "lorlatinib" at titck.gov.tr/kubkt ; third-party drug websites and guides should not be relied on. This is also why we do not list the license date or number—we could not verify them from the primary source.
SGK Reimbursement Status
Lorlatinib is reimbursed by SGK. The reimbursement condition is defined as follows:
"Costs are covered by the Institution for use until progression in metastatic NSCLC patients with documented ALK positivity (rearrangement/fusion by FISH / RT-PCR / NGS, or by IHC), as monotherapy in patients not previously treated with an ALK inhibitor or whose disease progressed during/after treatment with at least one of crizotinib, alectinib, brigatinib or ceritinib."
This wording has three practical implications:
- Documented ALK positivity is required — evidence of rearrangement/fusion by FISH, RT-PCR or next-generation sequencing (NGS), or immunohistochemistry, is accepted.
- First-line use is covered; it may be started directly in a patient who has never received an ALK inhibitor.
- Later-line use is also covered if progression occurred during treatment with at least one of crizotinib, alectinib, brigatinib or ceritinib.
Reimbursement rules change frequently. The wording above reflects the condition applicable when this article was prepared. The current SUT text and pharmacy implementation should be checked separately whenever a treatment decision is made. This article does not guarantee reimbursement.
Price and Cost per Cycle
| Product | Retail price (including VAT) | Note |
|---|---|---|
| LORVIQUA 100 mg film-coated tablets, 30 tablets | 134349.11 ₺ Excluding VAT: 122135.56 ₺ |
Barcode 8681308092045 |
| LORVIQUA 25 mg film-coated tablets, 30 tablets | 40840.37 ₺ | Verified from a single source; list date could not be confirmed |
Price update: In March 2026, a 100 mg pack cost 124014.68 ₺; in the August 31, 2026 list, it rose to 134349.11 ₺—an increase of approximately 8.3%. Very old prices such as 80967.86 ₺ still circulate online; these are not valid. Because drug prices are updated regularly in Turkey, the following calculations are intended only to indicate the approximate scale.
| Scenario | Daily dose | Required for 28 days | Packs required | Approximate cost |
|---|---|---|---|---|
| Standard use first-line or later-line |
100 mg | 28 × 100 mg tablets | 1 pack (100 mg, 30 tablets) | ≈ 134349 ₺ |
| 1st dose reduction e.g., nervous system adverse effects |
75 mg | 84 × 25 mg tablets (75 mg = 3 × 25 mg) |
3 packs (25 mg, 30 tablets) | ≈ 122521 ₺ |
| 2nd dose reduction or severe hepatic impairment |
50 mg | 56 × 25 mg tablets (50 mg = 2 × 25 mg) |
2 packs (25 mg, 30 tablets) | ≈ 81681 ₺ |
These are our own calculations, not official pricing. Three factors change the actual cost: (1) The number of tablets does not divide exactly into packs: a 100 mg pack contains 30 tablets, but 28 tablets are used over 28 days. Leftover tablets carry over, so the average monthly cost is somewhat lower than calculated. (2) At 75 mg, different combinations of 100 mg and 25 mg packs may be used; pharmacy practice can vary. (3) A patient covered by SGK does not pay these amounts. The figures represent the drug's listed price, not the patient's out-of-pocket expense.
Also note: when the 75 mg dose is supplied using 25 mg packs, its cost is only slightly lower than that of 100 mg. Dose reduction therefore does not produce a proportionate reduction in cost.
Resistance: What Happens After Lorlatinib?
Lorlatinib was designed to overcome resistance mutations affecting earlier generations and has largely succeeded. But no targeted therapy lasts forever; resistance eventually develops to this drug as well.
| Mechanism | Explanation |
|---|---|
| Compound (double) mutations | The characteristic form of lorlatinib resistance: two mutations on the same gene copy, typically G1202R plus a second mutation (such as G1202R/S1206Y). Single mutations cannot stop lorlatinib; two together can |
| L1198F | A paradoxical mutation now found in textbooks: it causes resistance to lorlatinib but restores sensitivity to crizotinib. It is the clearest example of why repeat biopsy after progression matters |
| Off-target mechanisms | Epithelial–mesenchymal transition (EMT) and increased expression of certain microRNAs (miR-100-5p) have been reported |
Why Is L1198F So Instructive? Resistance in oncology is often viewed as one-way: a drug stops working and treatment moves to the next one. L1198F is an exception—the same mutation that renders lorlatinib ineffective can restore the activity of crizotinib, stopped years earlier. This shows that repeat biopsy or liquid biopsy at progression is not merely an academic curiosity but can directly change treatment decisions.
The Next Drug in This Field: Neladalkib
| Patient group | Objective response rate | Note |
|---|---|---|
| All previously TKI-treated patients (n=253) | 31% (95% CI 26–37) | Duration of response: 64% at 12 months, 53% at 18 months |
| Previously TKI-treated but lorlatinib-naive (n=63) | 46% | Duration of response: 80% at 12 months, 60% at 18 months |
| ALK G1202R-positive (n=47) | 68% | In the lorlatinib-naive G1202R subgroup (n=12): 83% |
The rationale for developing neladalkib directly addresses lorlatinib's weakness: the molecule was designed to spare TRK kinase. Lorlatinib's cognitive and mood effects are thought to arise from TRK inhibition; a drug that avoids TRK could theoretically do the same job without these effects. Reported adverse effects are mostly mild: elevated liver enzymes 44–47%, constipation 28% and altered taste 23%.
Regulatory status: An application for neladalkib approval has been submitted to the FDA, and it has received priority review , with a decision date of November 27, 2026 . The proposed indication is previously TKI-treated ALK-positive disease—positioning it not in place of lorlatinib but after it . Indeed, the response rate in lorlatinib-naive patients (46%) is substantially higher than in those previously treated with lorlatinib, raising questions about sequencing. It is not licensed in Turkey.
Its Place in Guidelines
| Guideline | Recommendation |
|---|---|
| ASCO (current living guideline) | For first-line treatment of an ALK rearrangement, alectinib, brigatinib or lorlatinib —all three are equally preferred. Ceritinib and crizotinib only when the preferred agents are unavailable |
| NICE (England) | Has recommended first-line lorlatinib for newly diagnosed ALK-positive disease |
| NCCN, ESMO | We could not verify the exact categories and wording in the current versions. Both are expected to list lorlatinib among preferred first-line options, but this is unconfirmed |
The Practical Question: Alectinib or Lorlatinib? Guidelines rank three drugs equally, but their profiles differ. Lorlatinib provides substantially stronger brain protection (92% had no intracranial progression at 7 years) and longer progression-free survival figures. Alectinib, however, has a milder side-effect profile without the same cognitive effects. Alectinib is also the drug approved as adjuvant treatment for resected early-stage disease (ALINA); lorlatinib has no role in that setting. Decisions depend on brain metastases, the patient's occupation and tolerance for cognitive burden, comorbidities and lipid levels. No randomized head-to-head comparison exists.
Early-stage disease: There is no phase 3 adjuvant trial of lorlatinib after surgery. Preoperative use is being investigated in two studies: NEOLORA (neoadjuvant treatment in stage IB–IIIB) and LORIN (induction in locally advanced disease). We could not access results from either. The established drug in this setting is alectinib based on ALINA. In addition, in resected ALK-positive disease, adjuvant ensartinib has been reported to improve disease-free survival.
Frequently Asked Questions
- How long will I take this drug?
- There is no predetermined end date. Treatment continues until disease progression or side effects become unmanageable. In CROWN, 44% of patients were still taking it after seven years. Here, "long term" truly means a long time.
- There are seven-year data, but longer survival has not been demonstrated. Is that a bad sign?
- No—the opposite. Overall survival analysis requires enough deaths, and CROWN had not reached that number even after seven years. Still, we must be candid: randomized evidence has not proven that lorlatinib extends life. It has been proven to prevent progression for a very long time and substantially prevent spread to the brain. Patients in the other arm will also have received stronger ALK drugs after progression, diminishing a survival difference.
- I have brain metastases. Can this drug reach the brain?
- Yes. Lorlatinib was designed to cross the blood–brain barrier, its greatest strength. In CROWN, the hazard ratio for intracranial progression was 0.06—meaning that the risk falls to approximately one sixteenth. In the seventh year, 92% of patients had no intracranial progression compared with 16% in the crizotinib arm. There were also no new intracranial progression events after month 30.
- Cognitive effects worry me. How frequent and serious are they?
- Approximately 30% experience some cognitive effect, but grade 3 or higher effects occur in 5%of patients. More importantly, 60% of these effects resolve and 58% can be managed without any medical intervention. They occur after an average of 3.8 months. At grade 2–3, treatment is interrupted and resumed at the next lower dose, usually resolving the problem. Permanent discontinuation because of cognitive effects is very uncommon.
- How will I recognize these effects?
- Often, someone close to you notices, rather than you. Signs include difficulty finding words, forgetfulness, unusual irritability or elation, and disturbed sleep. You may dismiss them as tiredness or aging. Someone close to you should therefore also be informed when treatment begins, and these issues should be asked about explicitly at every visit. Effects recognized early can be managed readily through dose reduction.
- My cholesterol and triglycerides have risen sharply. Should I stop the drug?
- No. This is expected and almost the rule: it occurs in 71–73% and begins, on average, within the first two weeks. Management means adding lipid-lowering medication rather than reducing the dose —71% of events were managed this way, and the product information reports that 83% of patients needed lipid-lowering treatment. Treatment is interrupted only at life-threatening levels.
- Does a lower dose make the drug less effective?
- Dose reduction is not a sign of failure with this drug. It has been used in approximately one third of patients, and efficacy has reportedly been maintained at reduced doses. The steps are 100 mg → 75 mg → 50 mg. The key is remaining on treatment at a tolerable dose rather than stopping entirely; permanent discontinuation because of side effects is only 5%.
- Can I eat grapefruit?
- No. Grapefruit and grapefruit juice inhibit CYP3A4, which breaks down lorlatinib, increasing blood levels and side effects. Products that induce the same pathway must also be avoided entirely, particularly St. John's wort. Tell your physician about every herbal product you use.
- What should I watch for when another physician prescribes medication?
- Always say that you take lorlatinib. The most critical group consists of strong inducers of the liver enzyme CYP3A: rifampin, carbamazepine, phenytoin and phenobarbital. They cannot be used with lorlatinib: they may not only reduce efficacy but also cause severe liver injury. Certain antibiotics and antifungals, such as clarithromycin, ketoconazole and itraconazole, act in the opposite direction and increase toxicity.
- I use a contraceptive pill. Is that enough?
- No. Lorlatinib may reduce the effectiveness of hormonal contraception. Because it may harm an unborn baby, during and after treatment use an effective nonhormonal method of contraception . Ask your physician how long it is needed.
- Does SGK cover it in Turkey?
- Yes. Use until progression is covered for metastatic disease with ALK positivity documented by FISH, RT-PCR, NGS or immunohistochemistry, both in patients who have never received an ALK inhibitor and those whose disease progressed while using at least one of crizotinib, alectinib, brigatinib or ceritinib. Because reimbursement rules can change, confirm the current situation with your treatment team and pharmacy.
- How much does the drug cost?
- According to the official price list dated August 31, 2026, LORVIQUA 100 mg, 30 tablets, costs 134349.11 ₺(it was 124014.68 ₺ in March 2026). This is the listed price; an SGK-covered patient does not pay this amount. Much older and lower prices circulate online and should not be relied on.
- Is alectinib or lorlatinib better?
- Guidelines consider both, along with brigatinib, equally preferred first-line choices, and there is no randomized head-to-head trial. Lorlatinib offers stronger brain protection and longer progression-free survival figures, while alectinib has a milder side-effect profile without the same cognitive effects. Also, alectinib is the drug approved for adjuvant treatment of resected early-stage disease, rather than lorlatinib. The decision is made together, considering brain metastases, your occupation and tolerance for cognitive burden, lipid levels and comorbidities.
- What happens if this drug stops working?
- At progression, repeat biopsy or liquid biopsy is important because options vary with the cause of resistance. For example, L1198F causes lorlatinib resistance but restores crizotinib sensitivity. A new drug is also on the way: neladalkib, submitted to the FDA for previously TKI-treated ALK-positive patients, with a decision date of November 27, 2026. It is not licensed in Turkey.
Glossary
- ALK (anaplastic lymphoma kinase)
- An enzyme governing cell growth. In a small proportion of lung cancers, this gene joins another gene (fusion), producing a growth signal that remains switched on.
- Fusion / rearrangement
- The joining of two genes following a chromosomal break. In ALK-positive lung cancer, the most common partner is EML4.
- Tyrosine kinase inhibitor (TKI)
- A targeted drug, generally taken orally, that prevents an enzyme from generating a signal. Lorlatinib is an ALK TKI.
- Third generation
- A drug designed to overcome resistance mutations affecting earlier generations. Lorlatinib fits this description: its macrocyclic structure allows it to fit the binding pocket of mutated ALK.
- G1202R
- A mutation in ALK's solvent-front region and the most common cause of resistance to second-generation ALK inhibitors. This is lorlatinib's most notable area of superiority.
- Compound (double) mutation
- Two mutations occurring together on the same gene copy. This is characteristic of lorlatinib resistance: single mutations cannot stop the drug, but two together can.
- L1198F
- A paradoxical mutation causing lorlatinib resistance while restoring crizotinib sensitivity. A textbook example of why repeat biopsy at progression is important.
- Progression-free survival (PFS)
- The time from starting treatment until the tumor begins to grow on imaging.
- Overall survival (OS)
- The patient's total survival time. It remains immature in CROWN even after seven years, meaning too few events have accumulated.
- Hazard ratio (HR)
- A number comparing two groups. 1.00 means no difference; 0.19 indicates that the risk falls to approximately one fifth, and 0.06 to one sixteenth.
- Intracranial progression
- Disease beginning to grow in the brain. Very common in ALK-positive lung cancer and a major determinant of treatment success.
- Blood–brain barrier
- A structure protecting the brain from substances in the blood. It prevents many drugs from entering the brain; lorlatinib was designed to cross it.
- CYP3A4
- A liver enzyme that breaks down many drugs. Lorlatinib is metabolized through this pathway and therefore interacts with drugs that inhibit or induce the enzyme.
- PR prolongation / AV block
- Slowing of electrical conduction in the heart. Monitored by ECG; advanced cases may require a pacemaker.
- Interstitial lung disease (ILD) / pneumonitis
- Drug-induced inflammation of lung tissue. Uncommon but potentially serious; new cough and shortness of breath must not be ignored.
- SmPC (Summary of Product Characteristics)
- The official information document for a drug in Turkey. The only reliable source for its licensing status in Turkey; searched by active ingredient at titck.gov.tr/kubkt.
DROZDOGAN Akademi Commentary
Lorlatinib is the clearest example of what targeted treatment makes possible in metastatic lung cancer. Seven-year CROWN data show this once again. But describing a good drug accurately means avoiding exaggeration.
⚡ Why this drug matters
In metastatic lung cancer, 55% remaining progression-free for seven years —compared with 3% in the other arm—would have been unimaginable a decade ago. Brain protection adds to this: 92% had no intracranial progression in the seventh year, with no new brain events after month 30. Because ALK-positive lung cancer spreads to the brain so often, this is more than a numerical advantage.
✅ Its strengths
The hazard ratio is 0.19 and remains 0.19 after seven years, so the effect does not diminish with time. For intracranial progression it is 0.06. 44% remain on treatment after seven years. Only 5% discontinue for toxicity, all within the first 26 months; the drug does not impose a progressively accumulating burden. Perhaps the most practical finding is that a patient progression-free at month 24 has a probability of remaining so in the seventh year of 79%.
⚠️ Limitations and cautions
Even after seven years, overall survival data are unavailable; randomized evidence has not shown that lorlatinib extends life and probably never will, because patients in the other arm switch to stronger drugs. The rate of grade 3 or higher adverse effects is high at 77%. Although much of this is elevated lipids, it cannot be dismissed. Cognitive and mood effects are real and often concern someone close to the patient more than the patient. In Turkey, third-party drug websites still circulate the old indication restricted to second-line use ; the SmPC must be verified through TİTCK.
🩺 What to do in practice
1. At the start of treatment, also inform someone close to the patient —they usually notice cognitive effects.
2. Manage elevated lipids by adding lipid-lowering medication rather than reducing the dose ; 83% of patients need this.
3. Do not view dose reduction as failure: the steps are 100 → 75 → 50 mg, and efficacy is maintained at reduced doses.
4. Strong CYP3A inducers are absolutely prohibited —rifampin, carbamazepine, phenytoin and St. John's wort. This is a firm restriction, not merely a warning.
5. Hormonal contraception is insufficient; nonhormonal contraception is recommended.
6. At progression, perform repeat biopsy or liquid biopsy ; a mutation such as L1198F may completely change treatment selection.
7. The only reliable source for licensing and indications in Turkey is titck.gov.tr/kubkt as the official database.
❓ Unanswered questions
Alectinib or lorlatinib first-line? There is no randomized head-to-head study and probably never will be. Does using lorlatinib first-line mean using up the strongest drug at the outset, or is this the right sequence? Approval of neladalkib would sharpen this question, given the substantially higher response rate in lorlatinib-naive patients (46% versus 31%). Will lorlatinib have a role in resected early-stage disease? NEOLORA and LORIN are ongoing. And the most human question: the cost of living for seven years with mild cognitive effects appears in none of the endpoints we measure.
Our brief verdict: In ALK-positive metastatic lung cancer, lorlatinib holds disease in check longest and protects the brain best, a conclusion reinforced by seven-year data. In return, it raises blood lipids and causes cognitive effects in some patients, both largely manageable. The choice depends on balancing the drug's potency with the patient's daily life, and that balance differs from person to person.
Transparency note. CROWN's 7-year data are based on the ASCO 2026 presentation and Annals of Oncology publication in 2026. We could not access the full text; the numbers were taken from the abstract and two independent, mutually corroborating conference sources. For overall survival, no hazard ratio has been reported at any data cutoff; the data remain immature. Adverse-event columns come from different cutoffs: any-grade rates from the 7-year analysis, most grade 3–4 rates from the 5-year analysis, and lung inflammation and AV block rates from the product information's pooled safety population , rather than CROWN alone. An adverse-event-specific grade 3–4 breakdown has not been published for the 7-year analysis. A separate elevated liver enzyme rate could not be found for the lorlatinib arm in CROWN: the 83% figure in the text comes from the rifampin interaction study, not a CROWN adverse-event rate. Sources disagree slightly on the proportion continuing treatment (44% at 7 years versus 50% at 5 years); these may be different time points, which we could not reconcile.
Turkey information: titck.gov.tr could not be accessed while preparing this article because of a robots.txt restriction. Indication and reimbursement wording was taken from available sources; the license date and number were omitted because they could not be verified. Third-party SmPC mirrors still circulate the old indication restricted to second-line use, as specifically warned in the text. Prices are based on the official price list dated August 31, 2026. The 25 mg pack price came from a single source, and its list date could not be confirmed. Cycle costs are our own calculations, not official pricing, and may differ from actual costs because of leftover tablets, pharmacy practice and reimbursement. Exact wording in the current NCCN and ESMO versions could not be verified. NEOLORA and LORIN results could not be accessed. This text is informational and does not replace diagnostic or treatment decisions.
References
- CROWN trial 7-year update: first-line lorlatinib versus crizotinib in advanced ALK-positive NSCLC. Ann Oncol. 2026; ASCO 2026 abstract 8502. NCT03052608.
- Solomon BJ, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive NSCLC: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42:3400-3409.
- Kinetics and management of adverse events after 5 years of lorlatinib in the CROWN study. The Oncologist. 2025.
- LORBRENA (lorlatinib) US product information, Pfizer.
- LORVIQUA (lorlatinib) European product information (SmPC), European Medicines Agency (EMA). Initial approval May 6, 2019.
- Republic of Turkey Ministry of Health, Turkish Medicines and Medical Devices Agency — Summary of Product Characteristics and Patient Information Leaflet database. titck.gov.tr/kubkt
- Turkey Ministry of Health drug price list, August 31, 2026.
- Social Security Institution Health Implementation Communiqué — list of reimbursable medicines and conditions of use.
- ASCO living guideline — systemic therapy for metastatic non-small cell lung cancer with driver alterations.
- ALKOVE-1 study: neladalkib (NVL-655) in TKI-pretreated ALK-positive NSCLC.
- Shaw AT, et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Engl J Med. 2016.
- Compound ALK resistance mutations after lorlatinib: G1202R-based double mutations in cis.
- NEOLORA (neoadjuvant lorlatinib, stage IB–IIIB) and LORIN (induction lorlatinib in locally advanced disease) — ongoing studies.
Sources
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