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Chemotherapy and other systemic treatment regimens may change due to COVID-19. Find out more at Systemic Treatment Regimens During COVID-19.

A - Regimen Name

LORL Regimen
Lorlatinib


Disease Site
Lung - Non-Small Cell

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For treatment of ALK-positive non-small-cell lung cancer 

 
B - Drug Regimen

lorlatinib
100 mg PO Daily
(This drug is not currently publicly funded for this regimen and intent)
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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. 

Patients must have a documented ALK-positive status, based on a validated ALK assay, prior to starting treatment with lorlatinib.

Dosage with toxicity

Dose level Dose (mg/day) 
0 100
-1 75
-2 50
-3 Discontinue

 

 

Dose Modification for Toxicity:

Toxicity

Action

Grade 1 or 2 hypercholesterolemia (cholesterol ULN to 10.34 mmol/L)

OR

Grade 1 or 2 hypertriglyceridemia (triglycerides between 1.71 to 5.7 mmol/L)

Continue lorlatinib at the same dose.

Introduce or modify lipid-lowering therapy.

Grade 3 hypercholesterolemia
(cholesterol between 10.35 to 12.92 mmol/L)

OR

Grade 3 hypertriglyceridemia
(triglycerides between 5.71 and 11.4 mmol/L)

Continue lorlatinib at the same dose.

Introduce lipid-lowering therapy. If currently on lipid-lowering therapy, increase the dose of this therapy or change to a new lipid-lowering therapy.

Grade 4 hypercholesterolemia (cholesterol over 12.92 mmol/L)

OR

Grade 4 hypertriglyceridemia (triglycerides over 11.4 mmol/L)

Hold lorlatinib dose*.

Introduce lipid-lowering therapy. If currently on lipid-lowering therapy, increase the dose of this therapy or change to a new lipid-lowering therapy

Resume lorlatinib at same dose. 

If severe hypercholesterolemia/hypertriglyceridemia recurs despite maximal lipid-lowering therapy, ↓ by 1 dose level.

Grade 1: Mild CNS effects

Continue at the same dose.

OR 

Hold dose until recovery to baseline;

Resume at same dose or 1 dose level ↓.

Grade 2: Moderate CNS effects

OR

Grade 3: Severe CNS effects

Hold dose*.

Resume at 1 dose level ↓.

Grade 4: Life-threatening CNS effects/Urgent intervention indicated Discontinue.
Symptoms of Interstitial Lung Disease (ILD)/Pneumonitis (treatment–related) Hold dose and investigate; discontinue dose if confirmed for any grade.
Other Grade 1 or 2 toxicity Continue at same dose or ↓ by 1 dose level, as clinically indicated.
Other Grade 3 or 4 toxicity

Hold dose*.

Resume at 1 dose level ↓.

*Do not restart treatment until hypercholesterolemia/hypertriglyceridemia resolve to ≤ Grade 2, other non-CNS toxicities resolve to ≤ Grade 2 or baseline and CNS toxicities resolve to ≤ Grade 1.

 

Dose modifications for PR Prolongation/AV Block:

  Asymptomatic Symptomatic
  Action
First-degree AV block

Continue at same dose.

Monitor closely.1,2

Hold dose.

Monitor closely.1,2

If symptoms resolve, then resume at same dose or at 1 dose level ↓.
Second-degree AV block

Hold dose.

Monitor closely.1,2

If subsequent ECG does not show second-degree block, resume at same dose or 1 dose level ↓.

Hold dose.

Monitor closely.1  Refer for cardiac observation and monitoring. 

Consider pacemaker placement if symptomatic AV block persists.

If symptoms and the second-degree block resolve or if patients revert to asymptomatic first-degree AV block, resume at 1 dose level ↓.
Complete AV Block

Hold dose.1 Refer for cardiac observation and monitoring.

Temporary pacemaker placement may be indicated. If AV block does not resolve, placement of a permanent pacemaker may be considered.

If pacemaker placed, resume at full dose.

If no pacemaker placed, resume at 1 dose level ↓ only when symptoms resolve AND PR interval is less than 200 msec.

1Assess medications and electrolyte imbalance that may prolong PR interval. 
2Monitor ECG/symptoms potentially related to AV block closely. 



Hepatic Impairment

Patients with AST or ALT >2.5 × ULN (or >5.0 × ULN if due to underlying malignancy) or with total bilirubin >1.5 × ULN, were excluded in clinical trials.  

Hepatic impairment Lorlatinib Dose

Mild (total bilirubin ≤ ULN with AST > ULN

or total bilirubin >1 to 1.5 x ULN with any AST)

No dose adjustment required.
Moderate or Severe No data available.

Renal Impairment

Renal impairment Lorlatinib Dose
Mild or Moderate
(CrCl ≥ 30 mL/min)
No dose adjustment required.
Severe
(CrCl < 30 mL/min)
Limited data available.

 


Dosage in the Elderly

Limited data suggest that dose adjustment is not required in patients aged 65 years and older. The following adverse events were more frequently reported in elderly patients in clinical trials: cognitive effects, dyspnea, fatigue, arthralgia, diarrhea, anemia, myalgia, vomiting, back pain and rash. No clinically relevant differences in safety and efficacy were observed between patients ≥ 65 years and younger patients.

 


 
F - Adverse Effects

Refer to lorlatinib drug monograph(s) for additional details of adverse effects.


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • ↑ Cholesterol (may be severe)
  • ↑ Triglycerides (may be severe)
  • Edema
  • Hyperglycemia
  • Anemia
  • Peripheral neuropathy
  • ↑ LFTs
  • Cognitive disturbance
  • Cough, dyspnea (may be severe)
  • Fatigue
  • ↑ Amylase / lipase
  • Weight gain
  • Myelosuppression ± infection, bleeding
  • Musculoskeletal pain
  • Diarrhea
  • Other CNS effects (mood changes, dizziness, speech or sleep effects)
  • Abnormal electrolyte(s) (↓ PO4, K or Mg)
  • Headache
  • Nausea, vomiting
  • Constipation
  • Visual disorders
  • Rash
  • Hallucinations
  • AV block
  • QT interval prolongation
  • Pneumonitis
 
G - Interactions

Refer to lorlatinib drug monograph(s) for additional details.


  • CONTRAINDICATED with strong CYP3A4 inducers due to increased risk of severe hepatotoxicity and/or decreased lorlatinib concentration. Discontinue strong CYP3A4 inducers for at least 3 plasma half-lives before starting lorlatinib.
  • Avoid moderate CYP3A4 inducers due to increased risk of hepatotoxicity (theoretical) and/or decreased lorlatinib concentration. 
  • Avoid co-administration with strong CYP3A4 inhibitors due to increased risk of toxicity. If co-administration is unavoidable, ↓ dose to 75 mg daily. If the strong CYP3A4 inhibitor is discontinued, resume at the dose used prior to initiation of the strong CYP3A4 inhibitor, after a washout period of 3 to 5 half-lives of the CYP3A4 inhibitor.
  • Avoid co-administration with CYP3A4 substrates with narrow therapeutic index due to possible ↓ substrate concentration and/or efficacy.
 
H - Drug Administration and Special Precautions

Refer to lorlatinib drug monograph(s) for additional details.


Administration

  • Lorlatinib may be taken with or without food.
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during lorlatinib treatment.
  • Tablets should be swallowed whole and should not be chewed, crushed or split. 
  • If a dose is missed, patient may take if there are > 4 hours until the next dose. If there are < 4 hours until the next dose, the dose should be skipped and the next dose should be taken at the scheduled time. Patients should not take 2 doses at the same time to make up for a missed dose.
  • If the patient vomits after taking lorlatinib, do not give an extra dose; give the following dose at the next scheduled time.
  • Store at room temperature (15⁰C to 30⁰C) in the original package. Protect from light. Keep away from children.


Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container
  • Concomitant use of strong CYP3A inducers due to the potential for serious hepatoxicity.

 

Warnings/Precautions

  • Avoid concomitant use of lorlatinib with moderate CYP3A inducers.
  • Patients at risk for AV block/PR prolongation should be monitored closely.
  • Use caution when driving or operating machinery due to CNS effects.
  • Tablets contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

 

Pregnancy/Lactation

  • Lorlatinib is not recommended for use in pregnancy or in women of childbearing potential who are not using contraception.
  • Adequate contraception should be used by both sexes during treatment, and for at least 21 days after the last dose (for females) and 97 days after the last dose (for males).
  •  A highly effective non-hormonal contraception method is required for female patients during lorlatinib treatment (Refer to Interactions section). If a hormonal contraception method must be used, then a condom must be used together with the hormonal contraception.
  • Breastfeeding is not recommended during treatment, and for at least 7 days after the last dose.
  • Fertility Effects: Probable
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • Liver function tests; Baseline and as clinically indicated. (If co-administration with a moderate CYP3A inducer is unavoidable: 48 hours after initiating lorlatinib and at least 3 times during the first week after initiation.)
  • ECG; Baseline, monthly (especially in patients with risk factors for clinically significant cardiac events), and as clinically indicated
  • Cholesterol and triglycerides; Baseline, 2, 4, and 8 weeks after initiation, and as clinically indicated
  • Lipase, amylase; Baseline and as clinically indicated
  • Clinical toxicity assessment for CNS adverse events (e.g. hallucination and changes in cognition, mood, mental status, or speech), edema, peripheral neuropathy, GI effects and pneumonitis; As clinically indicated
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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K - References

Lorlatinib drug monograph. Ontario Health (Cancer Care Ontario).

Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018;19:1654-67.

July 2020 Expanded into full regimen monograph


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.