larotrectinib
Regulatory sources consulted
Approved indications
- In adults and pediatric patients with solid tumors harboring an NTRK gene fusion that are locally advanced or metastatic, or where surgery is likely to cause severe morbidity, when no satisfactory treatment options are available.
Contraindications
Absolute
- Hypersensitivity to larotrectinib or its excipients.
Clinical warnings
- Major warning · It can cause hepatotoxicity and drug-induced liver injury. Check ALT, AST, alkaline phosphatase, and bilirubin before treatment, every 2 weeks for the first 2 months, then monthly; withhold, reduce, or discontinue according to severity. — DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fd
- Major warning · It can cause central neurologic effects, including dizziness and cognitive, mood, or sleep disturbances. Avoid driving or operating machinery if they occur. — DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fd
- Major warning · Fractures have been reported, with a higher incidence in pediatric patients. Evaluate pain or mobility changes and manage according to clinical practice. — DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fd
Drug interactions
- HighStrong or moderate CYP3A, P-gp, or BCRP inhibitors
Mechanism: They may increase larotrectinib exposure and toxicity.
Recommendation: Avoid the combination; if a strong CYP3A inhibitor is unavoidable, reduce larotrectinib by 50% and monitor toxicity.
DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fdhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd
- HighStrong or moderate CYP3A inducers
Mechanism: They reduce exposure and may decrease efficacy.
Recommendation: Avoid the combination, including St John’s wort.
CIMA/AEMPS, ficha técnica VITRAKVI 100 mg, registro 1191385002https://cima.aemps.es/cima/dochtml/ft/1191385002/FT_1191385002.html
- ModerateSensitive CYP3A substrates with a narrow therapeutic index
Mechanism: Larotrectinib may increase their exposure.
Recommendation: Avoid the combination; if unavoidable, closely monitor toxicity and coordinate substrate adjustment with the prescribing team.
DailyMed, VITRAKVI set_id 0c8ca614-58b2-4aa4-83d3-0387a8f782fdhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd
Adverse events
Common (≥1%)
increased ALT · increased AST · vomiting · anemia · constipation · diarrhea · nausea · fatigue · dizziness
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy before starting. Females and males with partners who can become pregnant must use effective contraception during treatment and for at least 1 month afterward; add a barrier method if systemic hormonal contraception is used. Do not breastfeed during treatment; the CIMA profile requires 3 days afterward and the FDA profile 1 week afterward.
Recent literature (PubMed)
Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumour. Recently, there has been outstanding progress in the treatment of GBM. In addition to the newest form of GBM removal using fluorescence, three-dimensional (3D) imaging, tomoradiotherapy, moderate electro-hyperthermia, and adjuvant temozolomide (post-operative chemotherapy), new developments have been made in the fields of immunology, molecular biology, and virotherapy. An unusual and modern treatment has been created, especially for stage 4 GBM, using the latest therapeutic techniques, including immunotherapy and virotherapy. Modern oncological medicine is producing extraordinary and progressive therapeutic methods. Oncological therapy includes individual analysis of the properties of a tumour and targeted therapy using small-molecule inhibitors. Individualised medicine covers the entire patient (tumour and host) in the context of immunotherapy. An example is individualised multimodal immunotherapy (IMI), which relies on individual immunological tumour-host interactions. In addition, IMI is based on the concept of oncolytic virus-induced immunogenic tumour cell death. In this review, we outline current knowledge of the various available treatment options used in the therapy of GBM including both traditional therapeutic strategy and modern therapies, such as tomotherapy, electro-hyperthermia, and oncolytic virotherapy, which are promising treatment strategies with the potential to improve prognosis in patients with GBM. This newest therapy, immunotherapy combined with virotherapy (oncolytic viruses and cancer vaccines), is displaying encouraging signs for combating GBM. Additionally, the latest 3D imaging is compared to conventional two-dimensional imaging.
Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promisin
Tumor-agnostic, or histology-agnostic, cancer therapy marks a groundbreaking evolution in the realm of precision oncology. In stark contrast to conventional cancer treatments that categorize malignancies based on their tissue of origin (eg, breast, lung, renal cell, etc), tumor-agnostic therapies transcend histologic boundaries, honing in on the genetic and molecular attributes of tumors, regardless of their location. This article offers a comprehensive review of the current landscape of tissue-agnostic cancer therapies and provides clinical insights to empower surgical oncologists with a deeper understanding of these innovative therapeutic approaches.
Advanced cholangiocarcinoma and gene fusions Cholangiocarcinomas (CCAs) are rare digestive tumors classified as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCAs. These tumors are most often diagnosed at an advanced stage, unresectable or metastatic, and associated with a poor prognosis. The identification in recent years of multiple molecular alterations of interest, particularly in iCCA, has nevertheless allowed the development of new targeted therapeutic options for a significant proportion of patients. Gene fusions are among the most frequent alterations, involving FGFR2 in 10-15% of iCCAs in particular, and NTRK genes at a lower frequency (<1%). A dedicated analysis, most often based on RNA sequencing, is required to identify such alterations. Three FGFR inhibitors, pemigatinib, infigratinib and futinatinib, have recently received FDA approval for use in pre-treated patients. These compounds are currently being evaluated as first-line therapy in several phase III trials. Promising results have also been reported with new-generation inhibitors such as RLY-4008, which may soon constitute new therapeutic options. In the case of NTRK fusion, larotrectinib and entrectinib have also demonstrated their efficacy. The objectives of this review are to clarify the specific diagnostic modalities for gene fusions and to summarize the results of the main trials and developments underway for the management of advanced CCA with gene fusions.