dacomitinib
Sources réglementaires consultées
Indications approuvées
- Traitement de première ligne du CBNPC métastatique avec délétion de l’exon 19 d’EGFR ou mutation L858R de l’exon 21 confirmée par test.
Contre-indications
Absolues
- CIMA : hypersensibilité à la substance active ou aux excipients ; l’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- En cas de symptômes pulmonaires, suspendre et explorer ; toute PID confirmée impose un arrêt définitif. Commencer antidiarrhéique et liquides dès le premier épisode et appliquer une photoprotection cutanée. — OpenFDA, set_id 4ab27d2f-e385-4e9c-b324-fa69c10b855a
Interactions médicamenteuses
- SévèreSuppresseurs de l’acidité gastrique
Mécanisme: Ils réduisent l’exposition au dacomitinib.
Recommandation: Éviter les IPP. Administrer le dacomitinib au moins 6 heures avant ou 10 heures après les antagonistes H2.
OpenFDA, set_id 4ab27d2f-e385-4e9c-b324-fa69c10b855a
- SévèreSubstrats CYP2D6 à marge thérapeutique étroite
Mécanisme: Le dacomitinib peut augmenter leur exposition.
Recommandation: Éviter l’association.
OpenFDA, set_id 4ab27d2f-e385-4e9c-b324-fa69c10b855a
Effets indésirables
Communs (≥1%)
diarrhée · éruption cutanée · paronychie · stomatite · diminution de l’appétit · sécheresse cutanée
Grossesse et allaitement
Vérifier la grossesse. Les femmes doivent utiliser une contraception pendant et 17 jours après. Ne pas allaiter pendant ni 17 jours après.
Bibliographie récente (PubMed)
The most common oncogenic driver in non-small-cell lung cancer (NSCLC) is the epidermal growth factor receptor (EGFR) gene mutations that occur more frequently among Asians (30%-50%) as opposed to Caucasians (10%-15%). Lung cancer is one of the most prevalent cancers in India, with a reported adenocarcinoma positivity ranging between 26.1% and 86.9% in NSCLC patients. The prevalence of EGFR mutations in adenocarcinoma patients (36.9%) in India is higher than that of Caucasian patients and lower than that of East Asian patients. The exon 19 deletion (Ex19del) is more common than exon 21 L858R mutations in Indian patients with NSCLC. Studies have shown that the clinical behaviour of patients with advanced NSCLC differs between EGFR Ex19del and exon 21 L858R mutation status. In this study, we investigated the differences in clinicopathological features and survival outcomes after first line and second-line treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC patients with Ex19del and exon 21 L858R EGFR mutation status. This study also focuses on the role and potential benefits of dacomitinib, a second-generation irreversible EGFR TKI, in patients with Ex19del and exon 21 L858R EGFR mutation-positive advanced NSCLC in Indian settings. No information is available on the clinical use of dacomitinib during breastfeeding. Because dacomitinib is 98% bound to plasma proteins, the amount in milk is likely to be low. However, because of its potential toxicity in the breastfed infant and its half-life of 70 hours, the manufacturer recommends that breastfeeding be discontinued during dacomitinib therapy and for at least 17 days after the last dose.
In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.
This Phase 1b study (B2151002) evaluated the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with other anti-tumour agents in advanced solid tumours. Patients with various malignancies were administered gedatolisib (90‒310 mg intravenously every week [QW]) plus docetaxel (arm A) or cisplatin (arm B) (each 75 mg/m2 intravenously Q3W) or dacomitinib (30 or 45 mg/day orally). The safety and tolerability of combination therapies were assessed during dose escalation; objective response (OR) and safety were assessed during dose expansion. Of 110 patients enrolled, 107 received gedatolisib combination treatment. Seven of 70 (10.0%) evaluable patients had dose-limiting toxicities; the most common was grade 3 oral mucositis (n = 3). Based upon reprioritisation of the sponsor's portfolio, dose expansion focused on arm B, gedatolisib (180 mg QW) plus cisplatin in patients (N = 22) with triple-negative breast cancer (TNBC). OR (95% CI) was achieved in four of ten patients in first-line (overall response rate 40.0% [12.2-73.8%]) and four of 12 in second/third-line (33.3% [9.9-65.1%]) settings. One patient in each TNBC arm (10%, first-line; 8.3%, second/third-line) achieved a complete response. Gedatolisib combination therapy showed an acceptable tolerability profile, with clinical activity at the recommended Phase 2 dose in patients with TNBC. ClinicalTrial.gov: NCT01920061.
Epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, and mutated in multiple cancers. In normal cell physiology, EGFR signaling controls cellular differentiation, proliferation, growth, and survival. During tumorigenesis, mutations in EGFR lead to increased kinase activity supporting survival, uncontrolled proliferation, and migratory functions of cancer cells. Molecular agents targeting the EGFR pathway have been discovered, and their efficacy has been demonstrated in clinical trials. To date, 14 EGFR-targeted agents have been approved for cancer treatments. This review describes the newly identified pathways in EGFR signaling, the evolution of novel EGFR-acquired and innate resistance mechanisms, mutations, and adverse side effects of EGFR signaling inhibitors. Subsequently, the latest EGFR/panEGFR inhibitors in preclinical and clinical studies have been summarized. Finally, the consequences of combining immune checkpoint inhibitors and EGFR inhibitors have also been discussed. As new mutations are threatened against EGFR-tyrosine kinase inhibitors (TKIs), we suggest the development of new compounds targeting specific mutations without inducing new mutations. We discuss potential future research on developing EGFR-TKIs specific for exact allosteric sites to overcome acquired resistance and reduce adverse events. The rising trend of EGFR inhibitors in the pharma market and their economic impact on real-world clinical practice are discussed.