Dacomitinib is an oral tyrosine kinase inhibitor primarily used as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring specific EGFR gene mutations. EGFR, a cell surface receptor, is involved in processes such as cell growth, differentiation, and survival. In some NSCLC patients, specific mutations in the EGFR gene exist (e.g., exon 19 deletion or exon 21 L858R substitution mutation). These mutations lead to abnormal activation of the EGFR signaling pathway, which in turn promotes the growth and spread of tumor cells. Currently, dacomitinib has been launched in China.
Dacomitinib: Clinical Uses, Recommended Dosage, Potential Side Effects
This article provides a detailed description of its indications, dosage and administration, side effects, contraindications, clinical efficacy, and other aspects.
(I) Indications
Dacomitinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
(II) Dosage and Administration
1. Patient Selection
Patients to receive first-line dacomitinib for metastatic NSCLC are selected based on the presence of EGFR exon 19 deletions or exon 21 L858R substitution mutations in tumor specimens.
2. Recommended Dosage
(1) The recommended dosage of dacomitinib is 45 mg, administered orally once daily, until disease progression or unacceptable toxicity occurs. Dacomitinib can be taken with or without food.
(2) Take dacomitinib at the same time each day. If a patient vomits after taking a dose or misses a dose, do not take an extra dose or make up for the missed dose; instead, continue with the next scheduled dose.
3. Dosage Adjustment with Antacids
Concomitant use of proton pump inhibitors (PPIs) with dacomitinib should be avoided. As an alternative to PPIs, use locally acting antacids. If a histamine 2 (H2) receptor antagonist is used, administer dacomitinib at least 6 hours before or at least 10 hours after taking the H2 receptor antagonist.
4. Dosage Adjustment in Patients with Renal Impairment
Dosage adjustment is not recommended for patients with mild or moderate renal impairment (estimated creatinine clearance [CLcr] of 30-89 mL/min based on the Cockcroft-Gault formula). The recommended dosage of dacomitinib for patients with severe renal impairment (CLcr < 30 mL/min) has not been established.
5. Dosage Adjustment in Patients with Hepatic Impairment
Dosage adjustment is not recommended for patients with mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN, or total bilirubin > 1 to 1.5 × ULN with any AST) or moderate (total bilirubin > 1.5 to 3 × ULN with any AST) hepatic impairment. The recommended dosage for patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN with any AST) has not been established.
(III) Target Population
Adults. Children, lactating women, and elderly or debilitated patients should use this medication under the guidance of a physician.
(IV) Contraindications
Not clearly established.
(V) Side Effects
The most common adverse reactions (incidence > 20%) are diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, weight loss, alopecia, cough, and pruritus.
(VI) Precautions
1. Interstitial Lung Disease (ILD)
(1) Severe and fatal ILD/pneumonitis have occurred in patients treated with dacomitinib. Among 394 patients who received dacomitinib, the incidence of ILD/pneumonitis was 0.5%, with 0.3% of cases being fatal.
(2) Monitor patients for pulmonary symptoms that may indicate ILD/pneumonitis. Temporarily discontinue dacomitinib in patients with worsening respiratory symptoms that may suggest ILD (e.g., dyspnea, cough, fever) and promptly initiate diagnostic evaluation for ILD. If ILD of any grade is confirmed, permanently discontinue dacomitinib.
2. Diarrhea
(1) Severe and fatal diarrhea have occurred in patients treated with dacomitinib. Among 394 patients who received dacomitinib, the incidence of diarrhea was 86%, with 11% of patients reporting grade 3 or 4 diarrhea and 0.3% of cases being fatal.
(2) For grade ≥ 2 diarrhea, temporarily discontinue dacomitinib until recovery to grade ≤ 1, then resume dacomitinib at the same dose level or a reduced dose level based on the severity of diarrhea. For patients with diarrhea, initiate antidiarrheal treatment (loperamide or diphenoxylate hydrochloride with atropine sulfate) immediately.
3. Cutaneous Adverse Reactions
(1) Rash and exfoliative cutaneous reactions have occurred in patients treated with dacomitinib. Among 394 patients who received dacomitinib, the incidence of rash was 78%, with 21% of patients reporting grade 3 or 4 rash. Exfoliative cutaneous reactions of varying severity were reported in 7% of patients, and grade 3 or 4 exfoliative cutaneous reactions were reported in 1.8% of patients.
(2) For persistent grade 2 or any grade 3 or 4 cutaneous adverse reactions, temporarily discontinue dacomitinib until recovery to grade ≤ 1, then resume dacomitinib at the same dose level or a reduced dose level based on the severity of the cutaneous adverse reaction. The incidence and severity of rash and exfoliative cutaneous reactions may increase with sun exposure. When initiating dacomitinib, use moisturizers and take appropriate sun protection measures. Once grade 1 rash occurs, initiate treatment with topical antibiotics and topical steroids. After the occurrence of grade ≥ 2 cutaneous adverse reactions, initiate oral antibiotic treatment.
4. Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to pregnant women. In animal reproductive studies, oral administration of dacomitinib to pregnant rats during organogenesis at doses resulting in exposures similar to those at the 45 mg human dose increased the incidence of post-implantation loss and decreased fetal weights. Disruption of EGFR signaling leads to embryonic lethality and postnatal death in animals. Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential should use effective contraception during treatment with dacomitinib and for at least 17 days after the last dose.
(VII) Therapeutic Efficacy
Safety and Efficacy of First-Line Dacomitinib in Asian Patients with EGFR Mutation-Positive Non-Small Cell Lung Cancer
Study Design
In this ongoing, randomized, open-label phase 3 study, eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg once daily or oral gefitinib 250 mg once daily. Randomization was performed via a central computer system, stratified by ethnicity and EGFR mutation type. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review.
Study Results
Among 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS between dacomitinib and gefitinib was 0.509. The HR for overall survival (OS) between dacomitinib and gefitinib was 0.759. Patients who received stepwise dose reductions of dacomitinib (to 30 mg/day and 15 mg/day) still maintained OS benefit. The most common adverse events (AEs) with dacomitinib were diarrhea (154 patients [90.6%]), paronychia (110 patients [64.7%]), acneiform dermatitis (96 patients [56.5%]), and stomatitis (87 patients [51.2%]). With gefitinib treatment, the common AEs were diarrhea (100 patients [56.8%]), increased alanine transaminase (81 patients [46.0%]), and increased aspartate transaminase (75 patients [42.6%]).
Study Conclusion
In Asian patients with advanced EGFR mutation-positive NSCLC, first-line dacomitinib is associated with a significantly longer PFS and improved OS compared with gefitinib. The AE profiles of dacomitinib and gefitinib in Asian patients are consistent with those in the overall population of ARCHER 1050.
(VIII) Drug Interactions
1. Effect of Other Drugs on Dacomitinib
Concomitant use with PPIs decreases dacomitinib concentrations, which may reduce the efficacy of dacomitinib. Avoid concomitant use of dacomitinib with PPIs. Locally acting antacids or H2 receptor antagonists can be used as alternatives to PPIs. Administer dacomitinib at least 6 hours before or at least 10 hours after taking an H2 receptor antagonist.
2. Effect of Dacomitinib on CYP2D6 Substrates
Concomitant use of dacomitinib increases the concentrations of CYP2D6 substrate drugs, which may increase the risk of toxicity of these drugs. Avoid concomitant use of dacomitinib with CYP2D6 substrates, as even a small increase in the concentration of CYP2D6 substrates may result in severe or life-threatening toxicity.
(IX) Storage Conditions
Dacomitinib is blue film-coated tablets, which appear white or off-white after removing the coating.
Store below 30°C.
【Warm Reminder】: The package insert of some products is updated frequently. Please refer to the actual product for details.
