Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an antineoplastic agent.1, 2, 3, 4
Gefitinib is used for the first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors harbor epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations as detected by an FDA-approved companion diagnostic test (e.g., therascreen® EGFR RGQ PCR Kit).1, 18, 19, 66 Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web].66 Gefitinib is designated an orphan drug by FDA for the treatment of EGFR mutation-positive NSCLC.17
The efficacy and safety of gefitinib in the first-line treatment of patients with locally advanced or metastatic EGFR mutation-positive NSCLC were demonstrated in the Iressa Follow-Up Measure (IFUM) and Iressa Pan-Asia Study (IPASS) clinical trials.1, 14, 18, 19
The IFUM study was a multicenter, single-arm, open-label study in which 106 treatment-naive patients with metastatic, EGFR mutation-positive NSCLC received gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity occurred.1, 18 The primary efficacy end point was objective response rate (as evaluated by both a blinded independent central review committee and investigators) according to the Response Evaluation Criteria in Solid Tumors (RECIST); an additional outcome measure was duration of response.1, 18 The median age of patients was 65 years (range: 32-82 years); most patients (97%) had tumors of adenocarcinoma histology, 93% had a baseline World Health Organization (WHO) performance status of 0 or 1, 71% were female, and 64% had never smoked.1, 18 All patients enrolled in the IFUM study were Caucasian and were required to have evidence of an EGFR mutation as determined by a clinical trial assay;1, 18 the majority of patients had exon 19 deletions (65%) or exon 21 (L858R) substitution mutations (31%) while 2 remaining patients (4%) had other EGFR mutations (e.g., G719X or L861Q substitution mutations).1, 18 The median duration of treatment was 8 months.1, 18
At a median follow-up of 13 months, the investigator-assessed objective response rate in the IFUM study was 70% with a median duration of response of 8.3 months;1, 18 1.9% of patients achieved a complete response.1 However, objective response rate as assessed by a blinded independent central review committee was 50% with a median duration of response of 6 months; complete response was achieved in 0.9% of patients.1, 18 The response rates were similar in patients whose tumors harbored del19 or L858R substitution mutations.1, 18 Partial responses were achieved in both patients with G719X substitution mutations with a duration of response of at least 2.8 and 5.6 months; a partial response was achieved in 1 of 2 patients with an L861Q substitution mutation with a duration of response of at least 2.8 months.1, 18 Median overall survival and progression-free survival were 19.2 and 9.7 months, respectively; 1-year progression-free survival was reported in 38.5% of patients.18 Gefitinib therapy generally was well tolerated in this study; rash and diarrhea were the most commonly reported adverse effects.18
The IPASS study was a randomized, multicenter, open-label trial in which 1217 patients with metastatic adenocarcinoma histology NSCLC were randomized to receive either gefitinib (250 orally once daily) or carboplatin (at the dosage required to obtain an AUC of 5-6 mg/mL per minute) in combination with paclitaxel (200 mg/m2 by IV infusion) in 21-day cycles for up to 6 cycles.1, 19 Efficacy outcomes included progression-free survival and objective response rate (as evaluated by a blinded independent central review committee).1, 19 In a subset of 186 patients whose tumors were EGFR mutation-positive (15% of all patients enrolled in the study), the median age was 59 years (70% were younger than 65 years of age and 7% were 75 years of age or older); most patients (96%) had never smoked, 94% had a baseline ECOG performance status of 0 or 1, and 83% were female.1 All patients included in this subset analysis were Asian.1 The median duration of treatment in the gefitinib-treated patients was 9.8 months.1
In the IPASS study, patients receiving gefitinib had a longer median progression-free survival (10.9 versus 7.4 months) and a higher objective response rate (67 versus 41%) compared with the carboplatin- and paclitaxel-treated patients.1, 19 The median duration of response was 9.6 months for the gefitinib-treated patients and 5.5 months for patients receiving carboplatin in combination with paclitaxel.1 The results of this study indicate that EGFR mutation-positive Asian patients with NSCLC respond better to gefitinib therapy than do such patients without EGFR mutations and also respond better than do such patients receiving carboplatin and paclitaxel in combination.1, 19
The manufacturer states that the safety and efficacy of gefitinib have not been established in patients with metastatic NSCLC whose tumors harbor EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.1
Gefitinib also has been used in combination with a platinum-based agent and pemetrexed† in patients with metastatic EGFR mutation-positive NSCLC.63, 64
Gefitinib originally received FDA accelerated approval in 2003 for the treatment of locally advanced or metastatic NSCLC following failure of both platinum-based and docetaxel regimens.21 As a condition of the accelerated approval process, the manufacturer of gefitinib was required to submit data from 3 controlled clinical studies (ISEL, IBREESE, INTEREST)21, 22 to confirm the clinical benefit of gefitinib in such patients.21 The FDA reviewed data from these studies in June 2005 and concluded that they did not provide evidence of an overall survival benefit for gefitinib in patients with locally advanced or metastatic NSCLC.21 As a result, the indication for gefitinib was revised to include only its use as monotherapy for the continued treatment of locally advanced or metastatic NSCLC following failure of both platinum-based and docetaxel regimens in patients who were experiencing, or who previously experienced, benefit from gefitinib therapy;16, 21 distribution was limited to patients who qualified for the Iressa Access Program.21 In April 2012, gefitinib was voluntarily withdrawn from the market by the manufacturer21 and a new drug application (NDA) was submitted to the FDA in September 2015 proposing use of gefitinib for the first-line treatment of metastatic NSCLC in patients whose tumors harbor EGFR del19 or L858R substitution mutations as detected by an FDA-approved diagnostic test.23 In July 2015, gefitinib was approved by the FDA for the treatment of EGFR mutation-positive NSCLC following efficacy and safety data from a single-arm, open-label, phase 4 study (IFUM), with supporting data from a subset analysis of a randomized, multicenter, open-label phase 3 study (IPASS) in patients with previously untreated EGFR mutation-positive locally advanced or metastatic NSCLC.1, 18, 19, 23
EGFR-activating mutations are present in approximately 15-22% of NSCLC cases in North America and Europe and are present in up to 30-50% of cases in patients of East Asian descent.14, 18, 27 The majority of EGFR mutations are exon 19 deletions and an L858R substitution in exon 21, which together account for about 90% of EGFR mutations in patients with NSCLC.14, 18, 29
First-line Therapy for Metastatic Non-small Cell Lung Cancer
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as EGFR mutations.35 The guideline generally supports use of gefitinib among other first- and second-line treatment options for stage IV NSCLC with driver alterations, including EGFR mutations, in certain circumstances.35 .35 For patients with previously untreated stage IV NSCLC harboring sensitizing EGFR mutations (L858R/exon 19 deletion) and a performance status of 3, monotherapy with an EGFR tyrosine kinase inhibitor may be offered based on access and toxicity.35
A 2021 Cochrane review on first-line treatment options for patients with EGFR mutation-positive NSCLC concluded that erlotinib, gefitinib, afatinib, and icotinib (not commercially available in the US market) demonstrate increased tumor response, prolonged progression-free survival, less toxicity, and greater quality of life compared to cytotoxic chemotherapy.36 The analysis also states that single agent tyrosine kinase inhibitor therapy remains the standard of care and the benefit of combining a tyrosine kinase inhibitor with chemotherapy remains uncertain.36 Cytotoxic chemotherapy is less effective for the treatment of NSCLC harboring EGFR mutations compared with erlotinib, gefitinib, afatinib or icotinib, and is associated with greater toxicity.36
Gefitinib is administered orally once daily without regard to meals.1
For patients who have difficulty swallowing solids, the gefitinib tablet can be dispersed in a container with 120-240 mL (4-8 ounces) of water.1 Stir the tablet in water for approximately 15 minutes until it is dispersed.1 Immediately drink the liquid containing the dispersed tablet or administer the liquid through a nasogastric tube, then rinse the container with 120-240 mL of water and immediately drink the remaining liquid or administer it through a nasogastric tube.1
If a dose of gefitinib is missed and cannot be taken within 12 hours, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.1
Store gefitinib tablets at room temperature between 20-25°C.1
For the first-line treatment of metastatic NSCLC in patients whose tumors harbor EGFR del19 or L858R substitution mutations, the recommended dosage of gefitinib in adults is 250 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 In the principal efficacy study (IPASS), gefitinib therapy was continued for a median duration of 8 months.1, 18
Therapy Interruption for Toxicity
Gefitinib therapy may be temporarily interrupted (for up to 14 days) in patients who develop new or worsening pulmonary symptoms (e.g., dyspnea, cough, fever), grade 2 or greater elevations in ALT and/or AST concentrations, grade 3 or greater diarrhea, severe or worsening ocular disorders (including keratitis), or grade 3 or greater dermatologic reactions.1 When the toxicity resolves completely or improves to grade 1, gefitinib may be resumed.1
Gefitinib should be permanently discontinued in patients who develop confirmed interstitial lung disease, severe hepatic impairment, GI perforation, or persistent ulcerative keratitis.1
Dosage Modification for Concomitant Therapy
If gefitinib is used concomitantly with a potent inducer of CYP3A4, the dosage should be increased to 500 mg once daily in the absence of severe adverse drug reactions.1 If concomitant use of the CYP3A4 inducer is discontinued, the usual gefitinib dosage (250 mg once daily) may be resumed 7 days following discontinuance of the CYP3A4 inducer.1
The manufacturer makes no specific dosage recommendations for gefitinib in patients with hepatic impairment; however, patients should be monitored for adverse effects.1 Discontinue gefitinib in patients with severe hepatic impairment.1
The manufacturer makes no specific dosage recommendations for gefitinib in patients with renal impairment.1
Gefitinib has not been studied in patients with severe renal impairment.1
The manufacturer makes no specific dosage recommendations for gefitinib in geriatric patients.1
Because of the possibility of increased systemic exposure in patients who are poor metabolizers of CYP2D6, monitor such patients closely for adverse effects.1 Routine dosage adjustment not necessary.1
The manufacturer states that no dosage adjustment based on patient gender is necessary.1
Interstitial lung disease (ILD) or interstitial lung disease-like events, sometimes fatal, have been reported in patients receiving gefitinib.1, 18 In clinical trials, such events (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome [ARDS], pulmonary fibrosis) occurred in 1.3% (grade 3 or 4 in 0.7%) of 2462 patients receiving gefitinib; fatal ILD occurred in 3 of these patients.1 Patients with CYP2D6 poor metabolizer genotype may be at increased risk for ILD.1
In patients experiencing worsening of pulmonary symptoms (e.g., dyspnea, cough, fever), withhold gefitinib therapy for up to 14 days and promptly evaluate the patient.1 If a diagnosis of interstitial lung disease is confirmed, permanently discontinue gefitinib.1
Abnormal liver function tests have been reported in patients receiving gefitinib.1 In clinical trials, elevations in ALT, AST, and bilirubin concentrations have occurred in 11.4, 7.9, and 2.7% (grade 3 or 4 in 5.1, 3, and 0.7%), respectively, of patients receiving gefitinib; fatal hepatotoxicity occurred in 0.04% of patients.1
Perform liver function tests periodically during gefitinib therapy.1 Withhold therapy for up to 14 days in patients who develop grade 2 or greater elevations in aminotransferase concentrations (ALT and/or AST).1 Permanently discontinue gefitinib in patients who develop severe hepatic impairment.1
GI perforation has been reported in patients receiving gefitinib.1 In clinical trials, GI perforation occurred in 3 of 2462 patients (0.1%) receiving gefitinib.1
Permanently discontinue gefitinib in patients who develop GI perforation.1
Severe diarrhea has been reported in patients receiving gefitinib.1 In clinical trials, grade 3 or 4 diarrhea occurred in 3% of 2462 patients receiving gefitinib.1
If severe (grade 3 or greater) or persistent (lasting up to 14 days) diarrhea occurs, withhold gefitinib therapy for up to 14 days.1
Ocular Disorders including Keratitis
Ocular disorders have occurred in patients receiving gefitinib.1 In clinical trials, keratitis (0.1%), corneal erosion and abnormal eyelash growth (0.2%), and conjunctivitis, blepharitis, and dry eye (6.7%) were reported in patients receiving gefitinib.1 Grade 3 ocular disorders were reported in 0.1% of patients receiving the drug.1
If severe or worsening ocular disorders, including keratitis, occur, withhold gefitinib therapy for up to 14 days.1 If persistent ulcerative keratitis occurs, permanently discontinue gefitinib.1
Bullous conditions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, have been reported rarely in patients receiving gefitinib.1 In 3 randomized studies in patients with metastatic non-small cell lung cancer (NSCLC), erythema multiforme and dermatitis bullous were reported in 2 patients (0.08%) receiving gefitinib.1
Interrupt or discontinue gefitinib therapy in patients who develop severe bullous, blistering, or exfoliating dermatologic conditions.1 If grade 3 or greater dermatologic reactions occur, withhold gefitinib therapy for up to 14 days.1
Fetal/Neonatal Morbidity and Mortality
Gefitinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Fetal toxicity (e.g., decreased fetal weight, abortion) and neonatal mortality shortly after parturition were observed in animals receiving gefitinib at dosages approximately 0.2-2 times the recommended human dosa the incidence of neonatal mortality increased at dosages approximately equal to the recommended human dosage.1 Gefitinib crosses the placenta.1, 26
Pregnancy should be avoided during gefitinib therapy.1 (See Females and Males of Reproductive Potential under Cautions.) Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1
Gefitinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Gefitinib and its metabolites are distributed into milk in rats.1 It is not known whether gefitinib is distributed into human milk.1 Because of the potential risk in nursing infants, advise women not to breast-feed while receiving gefitinib.1
Females and Males of Reproductive Potential
Advise women of childbearing potential to use effective contraception while receiving gefitinib and for at least 2 weeks after discontinuance of therapy.1
Animal studies suggest that gefitinib may reduce female fertility.1 In a dedicated fertility study, increased incidence of irregular estrous, decreased corpora lutea, and decreased uterine implants and live embryos per litter were observed in rats receiving gefitinib at dosages approximately equal to the recommended human dosage.1
Safety and efficacy of gefitinib have not been established in pediatric patients.1
In 2 controlled clinical studies, 45% of patients were 65 years of age or older and 11% were ≥75 years of age.1 No overall differences in safety were observed between geriatric and younger adults.1 The manufacturer states that insufficient data are available to determine differences in efficacy between geriatric patients and younger adults.1
Following oral administration in one study, mean systemic exposure of gefitinib increased by 40, 263, or 166% in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment due to cirrhosis, respectively, compared with healthy individuals with normal hepatic function.1 In another study, systemic exposure of gefitinib was similar in patients with moderate hepatic impairment (grade 3-5 elevations in AST, alkaline phosphatase, and bilirubin concentrations) and concomitant liver metastases and those with liver metastases and normal hepatic function.1 The manufacturer recommends that patients with hepatic impairment be monitored for adverse effects during gefitinib therapy.1
Population pharmacokinetic analyses suggest that creatinine clearance (>20 mL/minute) does not have a clinically important effect on steady-state trough concentrations of gefitinib.1 Gefitinib has not been studied in patients with severe renal impairment; however, less than 4% of the drug and its metabolites are excreted by the kidneys.1
Pharmacogenomic Considerations
Poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2D6 may experience a clinically important increase in exposure to gefitinib; therefore, patients with a known CYP2D6 poor metabolizer genotype should be closely monitored for adverse effects.1 The manufacturer states that no dosage adjustment is necessary in such patients.1
Adverse effects reported in ≥20%of patients receiving gefitinib include skin reactions/rash (e.g., acne, maculopapular rash, erythema, generalized rash, papular rash, pruritic rash, macular rash, dry skin) and diarrhea.1, 18
Gefitinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2D6.1, 14 In vitro, gefitinib does not inhibit CYP isoenzymes 1A2, 2C9, and 3A4, but may inhibit 2C19 and 2D6 at high drug concentrations.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4 or CYP2D6
Concomitant use of gefitinib with potent CYP3A4 inhibitors may result in decreased metabolism and increased systemic exposure (AUC) of gefitinib.1, 25 Concomitant administration of the CYP3A4 inhibitor itraconazole (200 mg daily for 12 days) and gefitinib (single 250-mg dose) in healthy males increased peak plasma concentrations and the mean AUC of gefitinib by 51 and 80%, respectively.1, 14
Because gefitinib is a substrate of CYP2D6,14 concomitant use of CYP2D6 inhibitors may increase systemic exposure of gefitinib; however, this potential interaction has not been systematically evaluated to date.1
The manufacturer states that patients concurrently receiving gefitinib and potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole) or CYP2D6 inhibitors should be monitored for adverse effects.1
Concomitant use of gefitinib with potent inducers of CYP3A4 may result in increased metabolism and decreased plasma concentrations of gefitinib.1, 25 Concomitant administration of the potent CYP3A4 inducer rifampin (600 mg daily for 16 days) with gefitinib (single 500-mg dose) decreased mean peak plasma concentrations and AUC of gefitinib by 65 and 83%, respectively.1, 14, 25
If gefitinib is used concomitantly with a potent CYP3A4 inducer (e.g., phenytoin, rifampin, tricyclic antidepressants), the dosage of gefitinib should be increased to 500 mg once daily, if tolerated.1 If concomitant use of the CYP3A4 inducer is discontinued, the usual gefitinib dosage (250 mg once daily) may be resumed 7 days following discontinuance of the CYP3A4 inducer.1
Drugs Affecting Gastric Acidity
Drugs that increase the pH of the upper GI tract (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) may decrease plasma gefitinib concentrations.1 Concomitant administration of high doses of ranitidine with sodium bicarbonate (to achieve a gastric pH of 5 or higher) and gefitinib in healthy individuals decreased the mean AUC of gefitinib by 47%.1, 14
Concomitant use of gefitinib and proton-pump inhibitors should be avoided, if possible.1 Use of histamine H2-receptor antagonists or antacids, administered 6 hours before or after a dose of gefitinib, should be considered instead.1 However, if concomitant use with a proton-pump inhibitor cannot be avoided, gefitinib should be administered 12 hours before or after the dose of the proton-pump inhibitor.1
When metoprolol, a CYP2D6 substrate, was administered concomitantly with gefitinib (500 mg daily for 28 days) in patients with solid tumors, systemic exposure of metoprolol was increased by 30%.1
Elevation of international normalized ratio (INR) and/or hemorrhage has been reported in some patients receiving warfarin sodium concomitantly with gefitinib.1 Patients receiving warfarin should be monitored regularly for changes in prothrombin time or INR.1
Gefitinib, a synthetic anilinoquinazoline, inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including epidermal growth factor receptor (EGFR) tyrosine kinase.1, 2, 3, 4 EGFR is expressed on the cell surface of many cancer cells, as well as many normal cells;1 activation of EGFR tyrosine kinase is thought to initiate a cascade of intracellular signaling events leading to cell proliferation and influencing processes critical to cell survival and tumor progression (e.g., angiogenesis, apoptosis, metastasis).2, 4 Some EGFR-activating mutations, such as exon 19 deletion (del19) and exon 21 (L858R) substitution mutation, contribute to increased cell proliferation and survival in non-small cell lung cancer (NSCLC) cells harboring these mutations.1 Gefitinib has been shown to inhibit phosphorylation and proliferation of cell lines expressing wild-type EGFR and cell lines expressing del19 or L858R mutations.1 Gefitinib has demonstrated a greater affinity for cell lines expressing del19 or L858R mutations than for wild-type EGFR.1 Gefitinib also has been shown to inhibit insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) at clinically relevant concentrations.1
Following oral administration, peak plasma concentrations of gefitinib are achieved within 3-7 hours.1 Administration of gefitinib (single 250-mg dose) with a high-fat meal increased peak plasma concentrations and AUC of the drug by 32 and 37%, respectively, compared with administration in the fasted state;14 however, these changes are not considered clinically important and the drug may be administered without regard to food.1 Gefitinib is extensively metabolized by the cytochrome P-450 (CYP) enzyme system, principally by CYP3A4 and, to a lesser extent, by CYP2D6.1, 2, 14 In vitro studies using human hepatic microsomes indicate that gefitinib does not inhibit CYP1A2, CYP2C9, or CYP3A4 but may inhibit CYP2C19 and CYP2D6 at high drug concentrations.1 CYP2D6 metabolizes gefitinib to its major metabolite, O -desmethyl gefitinib, which has similar activity inhibiting EGFR tyrosine kinase as gefitinib, but is significantly less potent compared with gefitinib in vitro.1 The mean exposure of gefitinib was twofold higher in healthy poor metabolizers of CYP2D6 than in extensive metabolizers; however, plasma concentrations of O -desmethyl gefitinib were undetectable.1 Following administration of gefitinib, 86% of the drug and its metabolites was recovered in feces and less than 4% was recovered in urine.1 Following IV administration of gefitinib, the elimination half-life was 48 hours.1
Analysis of population pharmacokinetic data indicates that age, body weight, and ethnicity have no clinically important effects on exposure to gefitinib.1 Although a 27% increase in systemic exposure to the drug has been observed in women compared with men in population pharmacokinetic analyses in one clinical study, analyses from other clinical studies did not identify differences in exposure based on gender.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Gefitinib can only be obtained through select specialty pharmacies and distributors.67 Consult the manufacturer's website for specific ordering and availability information.67
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg |
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3. Anon. Gefitinib (Iressa®) for advanced non-small cell lung cancer. Med Lett Drugs Ther . 2002; 44:77-8. [PubMed 12205428]
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14. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206995Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
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17. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2022 Apr 10. [Web]
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21. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206995Orig1s000: Summary review. From FDA website. [Web]
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23. Food and Drug Administration. Center for Drug Evaluation and Research. Approval package for application number 206995Orig1s000. From FDA website. [Web]
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29. Jotte RM, Spigel DR. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance. Cancer Med . 2015; 4:1621-32. [PubMed 26310719]
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66. Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (in vitro and imaging tools). 2022 Apr 11. From FDA web site. [Web]
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