On September 27, 2018, dacomitinib (Vizimpro) received approval for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations, as detected by a test approved by the U.S. Food and Drug Administration (FDA).1,2
Supporting Efficacy Data
Approval was based on the open-label phase III ARCHER 1050 trial (ClinicalTrials.gov identifier NCT01774721), in which 452 patients were randomly assigned to receive oral dacomitinib once daily (n = 227) or oral gefitinib at 250 mg once daily (n = 225) until disease progression or unacceptable toxicity.2,3 Patients had no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic non-EGFR tyrosine kinase inhibitor–containing therapy. The median age of patients was 62 years (40% ≥ 65 years); 60% were female; 77% were
Dacomitinib has warnings/precautions for interstitial lung disease, diarrhea, dermatologic adverse reactions, and embryofetal toxicity.
Asian and 23% were white; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; 59% had exon 19 deletion and 41% had exon 21 L858R substitution; 8% had stage IIIB and 92% had stage IV disease; 64% were never smokers; and 1% had received adjuvant or neoadjuvant therapy.
The hierarchical statistical testing order for the trial was progression-free survival, followed by overall response rate and then overall survival. The median progression-free survival was 14.7 months in the dacomitinib group vs 9.2 months in the gefitinib group (hazard ratio = 0.59, P < .0001). The overall response rate was 75% vs 72% (P = .39). The median duration of response was 14.8 vs 8.3 months. No formal testing of overall survival was conducted, since the comparison of overall response rate was not statistically significant.
How It Works
Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR-activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). The agent also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 in in vitro studies. Dacomitinib showed dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice with implanted human tumor xenografts driven by HER-family targets including mutated EGFR. The agent also exhibited antitumor activity in mice with intracranial human tumor xenografts driven by EGFR amplifications.
How It Is Used
Patients should be selected for treatment based on the presence of EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
The recommended dosage of dacomitinib is 45 mg once daily until disease progression or unacceptable toxicity. Recommended dose reductions for adverse events are to 30 mg once daily and then to 15 mg once daily.
Product labeling provides instructions on withholding treatment and dose modification for interstitial lung disease, grade 2 to 4 diarrhea, grade 2 to 4 dermatologic adverse events, and other grade 3 or 4 adverse events. For diarrhea and dermatologic adverse reactions, dacomitinib should be withheld until improvement and resumed at a reduced dose depending on the severity of adverse events. Dacomitinib should be permanently discontinued for any grade of interstitial lung disease.
For use of acid-reducing agents, concomitant use of proton pump inhibitors, which reduce dacomitinib exposure, should be avoided. As an alternative, locally acting antacids can be used. If a histamine 2 (H2)-receptor antagonist is used, dacomitinib should be given at least 6 hours before or 10 hours after the H2-receptor antagonist.
Concomitant use with CYP2D6 substrates (eg, -dextromethorphan, thioridazine, pimozide) increases exposure to these substrates; thus, concomitant use with CYP2D6 substrates for which minimal increases in concentration of the substrate may lead to serious or life-threatening toxicities should be avoided.
In the ARCHER 1050 trial, the most common (> 20%) adverse events of any grade in the dacomitinib group were diarrhea (87% vs 56% in the gefitinib group), rash (69% vs 47%), paronychia (64% vs 21%), stomatitis (45% vs 19%), decreased appetite (31% vs 25%), dry skin (30% vs 19%), decreased weight (26% vs 17%), alopecia (23% vs 13%), cough (21% vs 19%), and pruritus (21% vs 15%). The most common grade 3 or 4 adverse events in the dacomitinib group included rash (23% vs 0.4%), diarrhea (8% vs 0.9%), paronychia (8% vs 1.3%), and stomatitis (4.4% vs 0.4%). Interstitial lung disease was observed in 2.6% of patients treated with dacomitinib. No single laboratory measure had a change from baseline to grade 3 or 4 in at least 3% of patients treated with dacomitinib.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Serious adverse events occurred in 27% of patients who received dacomitinib, with the most common side effects being diarrhea (2.2%) and interstitial lung disease (1.3%). Adverse events led to dose interruption in 57% of patients treated with dacomitinib, with the most frequent causes being rash (23%), paronychia (13%), and diarrhea (10%), and to dose reductions in 66% of patients, with the most common causes again being rash (29%), paronychia (17%), and diarrhea (8%). Adverse events led to discontinuation of treatment in 18%, with the most common causes being rash (2.6%), interstitial lung disease (1.8%), stomatitis (0.9%), and diarrhea (0.9%).
Dacomitinib has warnings/precautions for interstitial lung disease, diarrhea, dermatologic adverse reactions, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving dacomitinib. ■
1. U.S. Food and Drug Administration: FDA approves dacomitinib for metastatic non-small cell lung cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621967.htm. Accessed November 8, 2018.
2. Vizimpro (dacomitinib) tablets prescribing information, Pfizer, Inc, September 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Accessed November 8, 2018.
3. Wu YL, Cheng Y, Zhou X, et al: Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol 18:1454-1466, 2017.