neratinib
Sources réglementaires consultées
Indications approuvées
- Traitement adjuvant prolongé de l’adulte atteint d’un cancer du sein HER2 positif précoce après traitement adjuvant à base de trastuzumab ; et, avec capécitabine, cancer du sein HER2 positif avancé ou métastatique après au moins deux schémas anti-HER2 antérieurs en situation métastatique.
Contre-indications
Absolues
- CIMA : hypersensibilité ; inducteurs puissants du CYP3A4/P-gp tels que carbamazépine, phénytoïne, rifampicine ou millepertuis ; et insuffisance hépatique Child-Pugh C. L’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- La diarrhée peut provoquer déshydratation, hypotension et insuffisance rénale. Utiliser l’escalade ou la prophylaxie prévue ; traiter rapidement par antidiarrhéiques, liquides et électrolytes puis suspendre ou arrêter selon la gravité. — OpenFDA, set_id d1e41dcf-e82a-47c2-a0ad-6c6eef621834
- Peut provoquer une hépatotoxicité. Contrôler ALAT, ASAT et bilirubine avant le traitement, chaque mois pendant 3 mois, puis tous les 3 mois et selon la clinique. — OpenFDA, set_id d1e41dcf-e82a-47c2-a0ad-6c6eef621834
Interactions médicamenteuses
- SévèreModulateurs du CYP3A4/P-gp
Mécanisme: Les inhibiteurs augmentent et les inducteurs diminuent l’exposition au nératinib.
Recommandation: Éviter les inhibiteurs puissants ou modérés et les inducteurs puissants ou modérés ; les inducteurs puissants sont contre-indiqués par CIMA.
OpenFDA, set_id d1e41dcf-e82a-47c2-a0ad-6c6eef621834
- SévèreRéducteurs de l’acidité gastrique
Mécanisme: Ils réduisent l’absorption du nératinib.
Recommandation: Éviter les IPP ; administrer le nératinib ≥2 h avant ou 10 h après les antagonistes H2 et ≥3 h après les antiacides.
OpenFDA, set_id d1e41dcf-e82a-47c2-a0ad-6c6eef621834
Effets indésirables
Communs (≥1%)
diarrhée · nausées · douleur abdominale · fatigue · vomissements · éruption cutanée · stomatite · diminution de l’appétit
Grossesse et allaitement
Peut provoquer une atteinte fœtale. Femmes : contraception pendant le traitement et 1 mois après ; ajouter une méthode barrière avec une contraception hormonale. Hommes ayant une partenaire susceptible de concevoir : méthode barrière pendant le traitement et 3 mois après. Ne pas allaiter pendant le traitement ni pendant le mois suivant.
Bibliographie récente (PubMed)
Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment benefits and risks is scattered widely through the literature. To inform clinical practice we collated and reviewed the highest quality evidence. Guidelines were searched to identify adjuvant or neoadjuvant treatment options recommended in early invasive breast cancer. For each option, systematic literature searches identified the highest-ranking evidence. For radiotherapy risks, searches for dose-response relationships and modern organ doses were also undertaken. Treatment options recommended in the USA and elsewhere included chemotherapy (anthracycline, taxane, platinum, capecitabine), anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab, trastuzumab emtansine, neratinib), endocrine therapy (tamoxifen, aromatase inhibitor, ovarian ablation/suppression) and bisphosphonates. Radiotherapy options were after breast conserving surgery (whole breast, partial breast, tumour bed boost, regional nodes) and after mastectomy (chest wall, regional nodes). Treatment options were supported by randomised evidence, including > 10,000 women for eight treatment comparisons, 1,000-10,000 for fifteen and < 1,000 for one. Most treatment comparisons reduced breast cancer mortality or recurrence by 10-25%, with no increase in non-breast-cancer death. Anthracycline chemotherapy and radiotherapy increased overall non-breast-cancer mortality. Anthracycline risk was from heart disease and leukaemia. Radiation-risks were mainly from heart disease, lung cancer and oesophageal cancer, and increased with increasing heart, lung and oesophagus radiation doses respectively. Taxanes increased leukaemia risk. These benefits and risks inform treatment decisions for individuals and recommendations for groups of women.
Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Meanwhile, several HER2-targeted drugs, such as T-DXd, neratinib, afatinib, poziotinib and pyrotinib, have been evaluated in patients with advanced NSCLC, with several of them demonstrating clinical benefit. Therefore, identifying HER2 alterations is pivotal for NSCLC patients to benefit from these targeted therapies. Recent guidelines on HER2 testing were developed for breast and gastric cancer, however, and have not been fully established for NSCLC. The expert group here reached a consensus on HER2 alteration testing in NSCLC with the focus on clinicopathologic characteristics, therapies, detection methods and diagnostic criteria for HER2-altered NSCLC patients. We hope this consensus could improve the clinical management of NSCLC patients with HER2 alterations.
The availability of HER2-targeted therapy has dramatically improved patient outcome in HER2-positive (HER2+) early breast cancer (EBC) as recently demonstrated by the EBCTCTG metaanalysis on trastuzumab in HER2+ EBC: Adding trastuzumab to chemotherapy has reduced recurrence rates and breast-cancer related mortality by a third [1]. Today, neoadjuvant therapy has become standard of care for women with stage II or III tumors as pathological complete response (pCR) status after surgery can be used to individualize adjuvant systemic therapy. pCR is correlated with favorable patient outcome, particularly in hormone receptor (HR) negative HER2+ EBC, as demonstrated by the FDA meta-analysis. Moreover, for patients with non-pCR, 14 cycles of adjuvant T-DM1 have become a new adjuvant therapy standard based on the results of the KATHERINE trial. Primary surgery can be offered to patients with low tumor burden (cN0 cT1). For this low-risk subgroup, 12 weeks of adjuvant paclitaxel + trastuzumab for one year are correlated with excellent outcome based on the APT trial results. A multidisciplinary team is essential right from the beginning for optimal locoregional and systemic therapy in such a complex neoadjuvant - adjuvant continuum of care. Clinical trials in HER2+ EBC are currently evaluating further therapy de-escalation in low-risk disease or patients with pCR whereas for patients with non-pCR, escalation trials are also ongoing. Newly approved drugs for HER2+ MBC like tucatinib or trastuzumab-deruxtecan or even immunotherapy combinations are being evaluated to improve upon efficacy of T-DM1 alone in the non-pCR setting. Regarding de-escalation, the WSG ADAPT trial demonstrated feasibility of avoiding overtreatment and individualizing neoadjuvant therapy without compromising outcome. Further de-escalation trials (e.g. DECRESCENDO, COMPASS-HER2) are currently ongoing.
Biliary tract cancers (BTCs) encompass a heterogeneous group of rare tumors, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC) and ampullary cancer (AC). The present first-line palliative treatment regimen comprises gemcitabine and cisplatin in combination with immunotherapy based on two randomized controlled studies. Despite the thorough investigation of these palliative treatments, long-term survival remains low. Moving beyond conventional chemotherapies and immunotherapies, the realm of precision medicine has demonstrated remarkable efficacy in malignancies such as breast and gastric cancers, characterized by notable HER2 overexpression rates. In the context of biliary tract cancer, significant HER2 alterations are observed, particularly within eCCA and GBC, heightening the interest in precision medicine. Various anti-HER2 therapies, including trastuzumab, pertuzumab, trastuzumab-deruxtecan, zanidatamab and neratinib, have undergone investigation. The objective of this review is to summarize the current evidence and outline future directions of targeted HER2 treatment therapy in patients with biliary tract tumors, specially extrahepatic cholangiocarcinoma and gallbladder cancer.
HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. The benefit of N + F + T for HR+ HER2-m