King Khalid University Hospital

Pharmacy Services

Non-formulary Request Evaluation

Requesting Physician Dr.Khalid Alsaleh

Patient Name ALSOWAILEM, ABDULAZIZ SHALLAL ALI
MRN No. 00502445
Ward/Bed MODC
Diagnosis ALK Positive Adenocarcinoma of the Lung

Name of the Requested Crizotinib (Xalkori)

Medication
Approved Indication(s) Non-small cell lung cancer, metastatic: Treatment of patients with metastatic non-
small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase
(ALK)-positive or are ROS1-positive (as detected by an approved test)
Dose and Duration expected 250 mg twice daily for 6 months
DRUG INFORMATION
Mechanism of Action - Tyrosine kinase receptor inhibitor, which is inhibitor of receptor tyrosine
kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met),
and Recepteur d’Origine Nantais (RON).

- The gene’s expression and signaling that contribute to increased cell

proliferation and survival of the tumors become activated following the
expression of ALK oncogenic fusion proteins.

- Inhibits the signaling that promotes the expression of these oncogenic fusion
proteins, thereby inhibiting tumor cell proliferation.
.
Route of Administration Oral
Dosage Forms Capsule (250 mg)
Approved Dosing Dosing: Adult
Non-small cell lung cancer (NSCLC), metastatic (ALK- or ROS1-
positive): Oral: 250 mg twice daily, continue treatment until disease
progression or unacceptable toxicity

Adjustment required in Dosing: Renal Impairment

specific population CrCl 30 to 89 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute not requiring dialysis: Initial: 250 mg once daily.

Dosing: Hepatic Impairment

Hepatotoxicity prior to treatment: There are no dosage adjustments provided in the

manufacturer's labeling (has not been studied); crizotinib undergoes extensive
hepatic metabolism and systemic exposure may be increased with impairment; use

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with caution.

Hepatotoxicity during treatment:

Grade 3 or 4 ALT or AST elevation (ALT or AST >5 x ULN) with ≤ grade 1
total bilirubin elevation (total bilirubin ≤1.5 x ULN): Withhold
treatment until recovery to baseline or ≤ grade 1 (<3 x ULN), then
resume at a reduced dose (200 mg twice daily).

Recurrent grade 3 or 4 ALT or AST elevation with ≤ grade 1 total bilirubin

elevation: Withhold treatment until recovery to baseline or ≤ grade 1,
then resume at the next lower reduced dose (250 mg once daily).

Recurrent grade 3 or 4 ALT or AST elevation on 250 mg once daily:

Permanently discontinue.

Grade 2, 3, or 4 ALT or AST elevation (ALT or AST >3 x ULN) with

concurrent grade 2, 3, or 4 total bilirubin elevation (>1.5 x ULN) in the
absence of cholestasis or hemolysis: Permanently discontinue.

Geriatric (same adult dose)

Pediatric (safety and efficacy not established)
Pregnancy (There are no dosage adjustments provided in the manufacturer's labeling
(has not been studied)
SAFETY
Common Adverse >10%:
Reactions (%)
Cardiovascular: Edema (31% to 49%), bradycardia (5% to 14%)

Central nervous system: (27% to 29%),

Dermatologic: Skin rash (9 % to 11%)

Endocrine & metabolic: Hypophosphatemia (28% to 32%), hypokalemia (18%)

Gastrointestinal side effects : (60% to 61%)

Genitourinary: Decreased estimated GFR (eGFR) (<90 mL/min/1.73 m2: 76%;

<60 mL/min/1.73 m2: 38%; <30 mL/min/1.73 m2: 4%)

Hematologic & oncologic: Neutropenia (49% to 52%; grades 3/4: 11% to 12%),
lymphocytopenia (48% to 51%; grades 3/4: 7% to 9%)

Hepatic: Increased serum ALT (76% to 79%), increased serum AST (61% to
66%)

Neuromuscular & skeletal: Limb pain (16%)

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Ophthalmic: Visual disturbance (60% to 71%)

Respiratory: Upper respiratory tract infection (26% to 32%)

Miscellaneous: Fever (19%)

1% to 10%:

Cardiovascular: Pulmonary embolism (6%), prolonged Q-T interval on ECG

(5% to 6%), syncope (1% to 3%)

Endocrine & metabolic: Weight loss (10%), weight gain (8%), diabetic
ketoacidosis (≤2%), decreased plasma testosterone (1%; hypogonadism)

Gastrointestinal: Dysphagia (10%), esophagitis (2% to 6%)

Hepatic: Hepatic failure (1%)

Infection: Sepsis (≤5%)

Neuromuscular & skeletal: Muscle spasm (8%)

Renal: Renal cyst (3% to 5%)

Respiratory: Adult respiratory distress syndrome (≤5%), interstitial pulmonary

disease (≤5%; grades 3/4: 1%; includes acute respiratory distress
syndrome, pneumonitis), pneumonia (≤5%), respiratory failure (≤5%),
dyspnea (2%)

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, septic shock

Serious adverse Frequency not defined:

Reactions (%)
Cardiovascular: Cardiac arrhythmia, septic shock]

• Hepatotoxicity.

• Ocular toxicities

• Pulmonary toxicity

• QT prolongation: QTc prolongation

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Contra-indications / Contraindications
Precautions
Known hypersensitivity to crizotinib or any component of the formulation;
congenital long QT syndrome or with persistent Fridericia-corrected QT
interval (QTcF) ≥500 msec

COST
Cost/pack 28983.2 SR for each pack (which contains 60 capsules)

Cost/month (or treatment 173899.2 SR (for 6 months)

course)

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Efficacy and Safety Evidence:

Please summarize the evidence in PICO format and attach the references. It is
recommended to describe the patient characteristics briefly from the articles selected

1- Article # 1
First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer, The
new England journal of medicine, 2014;371:2167-77

Ref. Population Intervention Comparison Outcome

N Engl J Inclusion criteria: Patients were randomly open-label, Progression-free survival

Med - if they had assigned, in a 1:1 ratio, phase 3 trial was significantly longer with
2014;371:21 histologically or to receive comparing crizotinib than with
67-77. cytologically confirmed - Oral crizotinib, at crizotinib chemotherapy
locally advanced, a dose of 250 mg with
(median, 10.9 months vs. 7.0
recurrent, or metastatic twice chemotherap
y
months; hazard ratio for
nonsquamous daily,
in 343 patients progression or death with
- NSCLC that was positive - Or intravenous
for an ALK rearrangement with advanced crizotinib, 0.45; 95%
chemotherapy confidence interval [CI],
and if they had received no ALK-positive
(pemetrexed, at nonsquamous 0.35 to 0.60; P<0.001).
previous systemic a dose of 500 mg per
treatment for advanced NSCLC who
square meter of body-
disease. had - Objective response rates
surface
- Included an age of 18 received no were 74% and 45%,
area, plus either
years or older; measurable previous respectively (P<0.001).
cisplatin, at a dose of
disease as assessed systemic
75 mg per square
treatment for
according to the Response meter, or carboplatin,
advanced
Evaluation Criteria in target area under the
disease
Solid Tumors (RECIST), curve of 5 to 6 mg per
milliliter per minute)
administered every 3
weeks for a maximum
of six cycles.

- ECOG performance
status (0 or 1 vs. 2),
Asian or non-Asian Median overall survival
race, and presence was not reached in either
or absence of brain group (hazard ratio for death
metastases. with crizotinib,
- Treatment 0.82; 95% CI, 0.54 to 1.26; P
was continued until = 0.36); the probability of 1-
RECIST-defined year survival was 84% with
disease progression, crizotinib and 79% with
development of
chemotherapy.
unacceptable toxic
effects, death, or

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withdrawal of consent.

The most common adverse

events with crizotinib were
vision disorders, diarrhea,
nausea, and edema, and the
most common events with
chemotherapy were nausea,
fatigue, vomiting, and
decreased appetite. As
compared with
chemotherapy, crizotinib
was associated with greater
reduction in lung cancer
symptoms and greater
improvement in quality of
life.

CONCLUSIONS
Crizotinib was superior to
standard first-line
pemetrexed-plus-platinum
chemotherapy in patients
with previously untreated
advanced ALK-positive
NSCLC.

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Efficacy and Safety Evidence:

1- Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines

for diagnosis, treatment and follow-up. 2016
Based on- European society for medical oncology, first line treatment for stage IIIB-IV
lung carcinoma with ALK translocation is Crizotinib [I,A] (Non formulary)

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Case summary:
46 years old man. Diagnosed with ALK + Metastatic lung cancer with multiple bone
metastasis without any brain metastasis. He is non-smoker, received 3 cycles of
Pemetrexed and carboplatin last in Dec 2017 was well tolerated.

26th of Aug, The EGFR mutation was NEGATIVE, ALK FISH GENE
REARRANGEMENT REPORT Evidence of a POSITIVE signal profile this patient may
respond to treatment using ALK Inhibitors.

12 oct 2017, They plan to continue the same treatment since he responding according
the following Ct result and consider crizotinib will be considered for second line or
maintenance after chemotherapy if labs is abnormal.

CT POST third cycle of Pemetrexed and carboplatin showed:

- Resolution of the previously seen complete left lung collapse and adjacent pleural
effusion.
- Appearance of small lobulated peribronchial nodule at the left base as described and
sable right lung apical small 5 mm nodule.
- Reduction in the size of left peripheral mass obstructing the left main bronchus with
reopening of the bronchus in the current study and tissue residual as described.
- Reduction of the mediastinal and peripheral lymphadenopathy.
- Re-demonstration of multiple sclerotic bony lesions.

14 Dec 2017
CT POST 6 cycles of Pemetrexed and carboplatin showed:
- Ongoing decrease in size of left hilar mass and lobulated left lower lobe nodule with no
significant changes of multiple sclerotic metastasis of thoracic skeleton concerning for
therapeutic response.
- Diffuse bone metastasis with no significant interval changes. No other distant metastasis
to abdomen and pelvis.

Patient is well tolerated and they decide to start maintenance therapy on

Pemetrexed and continue folic acid and vitamin B12 and request cirzotinib as
non-formulary!

Conclusion:

ALK fish gene rearrangement for this patient report evidence of a POSITIVE signal
profile this patient may respond to treatment using ALK Inhibitors. So the patient is
eligible for Cirzotinib.

Prepared by: Yasmin Ahmed Elsharawy, PharmD, DPIC pharmacist

Asma Alfarhan, PharmD , Clinical pharmacy resident)

Date: 28 Dec 2017

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March 2017

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