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OSIM

Cancer Type: Lung, Non-Small Cell  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    osimertinib - For the treatment of locally advanced (not amenable to curative therapies) or metastatic non-small cell lung cancer (NSCLC) according to clinical criteria
A - Regimen Name

OSIM Regimen
Osimertinib


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
  • First-line treatment of patients with locally advanced (not amenable to curative therapies), or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations).
     
  • Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy

    (Refer to EAP criteria)

Supplementary Public Funding

osimertinib
Exceptional Access Program (osimertinib - For the treatment of locally advanced (not amenable to curative therapies) or metastatic non-small cell lung cancer (NSCLC) according to clinical criteria) (EAP Website)

 
B - Drug Regimen

osimertinib
80 mg PO Daily

(available as 40mg and 80 mg tablets)

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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

Regular application of moisturizers to skin and nails, practice of good hand hygiene and keeping hands dry to help prevent and control skin and nail adverse effects.

 
E - Dose Modifications

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

A validated test is required to identify EGFR mutation-positive status prior to first-line NSCLC treatment.

A validated test to confirm EGFR T790M mutation-positive status should be conducted before starting treatment for NSCLC that has progressed on or after EGFR TKI.

Electrolyte abnormalities should be corrected prior to treatment.

Dosage with toxicity

Dose Level Osimertinib Dose (mg/day)
0 80
-1 40

 

Toxicity Dose modification
ILD/pneumonitis Hold and investigate. Discontinue permanently if confirmed.
Asymptomatic LVEF < 50% and absolute decrease of 10% from baseline

Hold for up to 4 weeks.

If recovery to baseline, restart.

If no recovery to baseline, discontinue permanently.

QTc interval > 500 msec on at least 2 separate ECGs

Hold until QTc interval is < 481 msec or recovery to baseline if baseline is ≥ 481 msec.

Then restart at 1 dose level ↓.

QTc interval prolonged with signs/symptoms of serious arrhythmia (e.g. Torsade de pointes, polymorphic VT)

OR Symptomatic congestive heart failure

Discontinue permanently.
Signs & symptoms suggestive of keratitis Refer promptly to an ophthalmology specialist.
Other ≥ grade 3 toxicity

Hold for up to 3 weeks.

If recovery to ≤ grade 2, restart at the same dose or at 1 dose level ↓.

If no recovery, discontinue permanently.



Hepatic Impairment

epatic impairment Osimertinib dose

Mild (total bilirubin ≤ ULN and AST > ULN OR total bilirubin 1-1.5 x ULN and any AST) or

Moderate (total bilirubin 1.5 to 3 x ULN and any AST)

No dosage adjustment required
Severe No data; use with caution

Renal Impairment

Renal impairment (creatinine clearance)

Osimertinib dose

Mild to moderate (30 to <60 mL/min)

No dosage adjustment required

Severe (15 to < 30 mL/min)

End stage renal disease (<15 mL/min)

No data


Dosage in the Elderly

No dosage adjustment is required.

No overall differences in efficacy or predicted steady state exposure of osimertinib were observed between patients ≥ 65 years of age and younger patients.

Patients ≥ 65 years of age experienced more ≥Grade 3 adverse reactions compared to younger patients (13% versus 9%) and had more reported adverse reactions that led to drug dose interruptions or reductions (13% versus 8%).

Dosage based on ethnicity

No dosage adjustment required due to ethnicity.

In clinical trials, the incidence of ILD was higher in Japanese patients compared to other Asians and non-Asian patients (10.4% vs. 1.9% and 2.8 %, respectively).

 


 
F - Adverse Effects

Refer to osimertinib 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

  • Myelosuppression ± infection, bleeding (maybe severe)
  • Diarrhea
  • Rash (may rarely be severe)
  • Dry skin
  • Nail disorder
  • Mucositis
  • Increased LFTs 
  • Anorexia
  • Cough, dyspnea
  • Nausea, vomiting
  • Fatigue
  • Constipation
  • Musculoskeletal pain
  • Headache
  • QT interval prolonged
  • Cardiotoxicity
  • Arterial/venous thromboembolism
  • Eye disorders
  • Pneumonitis
  • Bronchiolitis obliterans organizing pneumonia
  • Creatinine increase
 
G - Interactions

Refer to osimertinib drug monograph(s) for additional details


  • Avoid co-administration with strong CYP3A4 inducers as reduced osimertinib concentration and/or efficacy is possible.  If coadministration is unavoidable, closely monitor therapy and increase osimertinib dose to 160mg daily during concurrent use. Continue this dose for 3 weeks after discontinuation of the strong CYP3A4 inducer. Then, resume osimertinib dose at 80mg daily.

  • Monitor therapy with coadministration of moderate CYP3A4 inducers. No dose adjustments required.

  • Avoid co-administration with BCRP and P-gp substrates with narrow therapeutic indices given increased risk of substrate toxicity.

  • Reduced effectiveness of oral hormonal contraceptives is possible. Consider alternative contraception.

  • Avoid drugs that may prolong the QT interval and those that may disrupt electrolyte levels given increased risk of QT prolongation.

 
H - Drug Administration and Special Precautions

Refer to osimertinib drug monograph(s) for additional details


Administration

  • Osimertinib may be taken orally with or without food at the same time once a day.

  • The tablet should be swallowed whole with water and not crushed, split or chewed.

  • If a dose is missed, it may be taken within 12 hours. If there are less than 12 hours until the next dose, the missed dose should be skipped and the next dose should be taken at the scheduled time.

  • If the patient has difficulty swallowing, the tablet may be dispersed in 50 ml of non-carbonated water (room temperature) and swallowed immediately. An additional 50 ml of water should be added to capture drug residue and immediately swallowed. No other liquids should be added.

  • For nasogastric administration, the tablet may be dispersed in 15 mL of noncarbonated water; using an additional 15 mL of water for residue rinses. The 30 mL of liquid should be administered within 30 minutes via the nasogastric tube and flush appropriately as per the nasogastric tube manufacturer’s instructions.

  • Store tablets at room temperature (15-30oC)

 

Contraindications

  • Patients who are hypersensitive to this drug or to ingredients in the formulation or component in the container

 

Other Warnings/Precautions

  • Not recommended in patients with congenital long QT syndrome or those taking other medications know to prolong QTc

  • Patients at risk for prolonged QTc such as those with cardiac disease, history of arrhythmias, electrolyte disturbances or conditions leading to electrolyte disturbances, bradycardia, acute neurological events, diabetes mellitus and autonomic neuropathy should be monitored closely and electrolyte abnormalities corrected prior to treatment.

  • Patients with abnormal LVEF or those with significant cardiac history were excluded from clinical trials.

  • Exercise caution in patients with cardiac risk factors and those with conditions that can affect LVEF.

  • Patients with a history of ILD/pneumonitis, evidence of clinically active ILD or those with radiation pneumonitis requiring steroids were excluded from clinical trials.

  • Ocular events have been reported. Contact lens use is risk factor for ocular toxicity, including keratitis. Caution should be used when driving or operating machinery in patients who experience visual disturbances.

 

Pregnancy and lactation

  • Osimertinib is not recommended for use in pregnancy. Adequate contraception (including a barrier method in females using hormonal contraception and/or a change to a non-oral method of contraception) should be used by both sexes during treatment, and for at least 2 months after the last dose (for females) and 4 months after the last dose (for males).

  • Breastfeeding is not recommended.

  • Fertility effects: Documented in animals

 
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

  • CBC; Baseline and at each visit

  • ECG and electrolytes (calcium, potassium and magnesium), especially in patients at risk of electrolyte abnormalities; Baseline and as clinically indicated

  • Liver function tests; Baseline and at each visit

  • LVEF; Baseline, every 12 weeks during treatment, and as clinically indicated for patients with cardiac risk factors and those who develop cardiac signs/symptoms during treatment.

  • Renal function tests; Baseline and at each visit; more frequent in patients with severe renal impairment

  • Clinical toxicity assessment for GI, skin and respiratory effects, signs and symptoms of CHF, infection, bleeding, thromboembolism and ocular effects; At each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, et al.; AURA3 Investigators. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629-640.

Osimertinib drug monograph, Cancer Care Ontario.


June 2020 Updated adverse effects, dose modifications, interactions and administration sections. Added EAP funding information.


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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.