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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Preclinical evaluation of dacomitinib showed that it inhibits HER2 signaling in both wild-type and mutant HER-1 (EGFR) forms of NSCLC cells resistant to currently available HER-1 (EGFR) inhibitors such as erlotinib and gefitinib. Other studies demonstrated that dacomitinib is also effective in tumor cells with gefitinib-resistant oncogenic HER2 mutations. In vitro experiments have shown that dacomitinib can reduce phosphorylation of HER-family proteins and inhibit downstream AKT and ERK pathways, as well as induce apoptosis and cause G0/G1 arrest.
Oral Mucosal Reactions to Anticancer Therapies
Published in Gabriella Fabbrocini, Mario E. Lacouture, Antonella Tosti, Dermatologic Reactions to Cancer Therapies, 2019
Emmanuelle Vigarios, Vincent Sibaud
Pan-HER tyrosine kinase inhibitors: Conversely, with the new generation of pan-HER tyrosine kinase inhibitors, mucositis appears to be one of the main toxicities, after paronychia, diarrhea, and papulopustular rash (52). The incidence of all-grade mucositis induced by afatinib appears to be significantly higher than that of erlotinib or gefitinib, and ranges from 29 to 64%. All-grade incidence reported with dacomitinib appears to be very similar to afatinib (about 40%). Finally, high-grade (≥3) mucositis induced by afatinib and dacomitinib may occur in 3–7% of treated patients (4).
Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Penelope Bradbury, John Hilton, Janet E. Dancey
Dacomitinib initially showed promise in early phase trials in patients with NSCLC after prior chemotherapy and an EGFR TKI. In a phase I trial of patients with advanced solid malignancies, 57 patients of the total 121 patients accrued had NSCLC, of which 4 had a partial response and 28 had stable disease >6 weeks. All 4 patients that had a partial response had been previously treated with erlotinib or gefitinib (Jänne, 2011). In a phase II trial of dacomitinib versus erlotinib in patients after the failure of prior chemotherapy and erlotinib, dacomitinib had a response rate of 5% for patients with adenocarcinoma and 6% for patients with non-adenocarcinoma (Reckamp, 2014). Responses occurred in patients with EGFR positive mutation NSCLC, and in patients with EGFR mutation wildtype disease, but with HER-2 amplification. Overall progression-free survival was 12 weeks and 16 weeks in patients with EGFR mutation positive disease (Reckamp, 2014). The Canadian Cancer Trials Group (previously NCIC Clinical Trials Group), launched the BR.26 double blind randomized phase III clinical trial ofdacomitinib versus placebo in patients with molecularly unselected NSCLC after the failure of prior chemotherapy and an EGFR TKI for advanced disease. The trial did not meet its primary endpoint with no prolongation of overall survival in this heavily pretreated NSCLC population, although there was a small improvement in progression-free survival (median 2·66 months versus 1·38 months; HR 0·66 (95% CI 0·55–0·79) (Ellis, 2014). Dacomitinib was also compared with erlotinib in a phase III trial in patients with molecularly unselected advanced NSCLC after chemotherapy failure, with co-primary endpoints of progression-free survival for all patients, and for patients with KRAS wildtype tumors. There was no improvement in progression-free survival with dacomitinib compared with erlotinib in all patients or the subset of patients with KRAS wildtype disease (HR 0·941, 95% CI 0·802–1·104, p = 0–229; HR 1–022, 95% CI 0·834–1·253, one-sided p = 0·587, respectively) (Ramalingam, 2014).
Epidermal growth factor receptor-targeted therapy for the treatment of non-small cell lung cancer: a review of phase II and III trials
Published in Expert Opinion on Emerging Drugs, 2022
Hong-Lian Lu, Guang-Ling Jie, Yi-Long Wu
Dacomitinib was another potent second-generation EGFR-TKI with promising efficacy. A randomized phase III trial (ARCHER 1050) reported that dacomitinib was more effective compared with gefitinib with median PFS of 14.7 months and 9.2 months, respectively (HR = 0.59; P < 0.001), and median OS of 34.1 months and 27.0 months, respectively (HR = 0.76; P = 0.044) [30]. This was the first therapeutic TKI agent that showed significant OS benefits compared with the first-generation TKIs; however, patients with CNS metastases and rare EGFR mutations were excluded from this study. In addition, the dacomitinib arm had significantly higher toxicity: approximately 51% of the patients in this arm experienced grade ≥3 AEs (most commonly rash or diarrhea), while only 30% in the gefitinib arm experienced grade ≥3 AEs [31]. Considering its efficacy and side effects, the clinical utility of dacomitinib remains controversial, but this drug is still used as a treatment option. In 2018, dacomitinib was approved by the FDA for the first-line treatment of patients with advanced EGFR common mutation-positive NSCLC.
Safety of EGFR-TKIs for EGFR mutation-positive non-small cell lung cancer
Published in Expert Opinion on Drug Safety, 2020
Jia-Ying Zhou, Si-Yang Liu, Yi-Long Wu
Dacomitinib is an irreversible inhibitor for oral administration, which targets HER1 (EGFR), HER2, and HER4 in solid tumors [24]. A phase III clinical trial of dacomitinib indicated that the most common severe AEs (grade 3–4) related to dacomitinib were diarrhea (8–12.3%) and rash/acne (4–24%). In NSCLC patients receiving dacomitinib in the ARCHER 1050 clinical trial, almost the overall incidence of each AEs associated with treatment was more frequent than with gefitinib, with the exception of hepatotoxicity [25–27] (Table 4). Several clinical trials indicated that the incidence of adverse reactions with dacomitinib is high, but can be reduced by reducing the dose. The dose adjustment scheme for dacomitinib is shown in Figure 1 [28].
Dacomitinib: an investigational drug for the treatment of glioblastoma
Published in Expert Opinion on Investigational Drugs, 2018
Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, María Ángeles Vaz Salgado, Ricardo Gargini, Carmen Balañá
Second-generation TKIs are potentially superior to gefitinib or erlotinib because they irreversible block multiple receptors with a better pharmacokinetic profile [8]. Dacomitinib is under review by US FDA and European Medicines Agency to treat metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations. The submission to the agencies is based on results from the phase III ARCHER 1050 trial that showed an improvement in PFS (14.7 compared with 9.2 months) over gefitinib in locally advanced or metastatic NSCLC with EGFR-activating mutations [9]. The main adverse events observed with dacomitinib in this pivotal study were diarrhea (87%), onycholysis (62%), rash (50%) and mucositis (44%) with a discontinuation rate of 10% due to AEs, significantly higher than the discontinuation rate observed in the gefitinib arm.