entrectinib
Regulatory sources consulted
Approved indications
- In adults and pediatric patients older than 1 month with NTRK gene fusion-positive solid tumors that are locally advanced or metastatic, or where surgery is likely to cause severe morbidity, with no prior NTRK inhibitor and no satisfactory options.
- In adults with advanced ROS1-positive non-small cell lung cancer who have not previously received a ROS1 inhibitor.
Contraindications
Absolute
- Hypersensitivity to entrectinib or its excipients.
Clinical warnings
- Major warning · It can cause congestive heart failure. Assess ejection fraction before treatment in patients with risk factors or symptoms and monitor clinical signs; withhold, reduce, or discontinue according to severity. — DailyMed, ROZLYTREK set_id c7c71b0c-2549-4495-86b6-c2807fa54908
- Major warning · It can cause central neurologic effects and fractures, with a higher fracture incidence in pediatric patients. Avoid driving if cognitive, mood, sleep disturbances, or dizziness occur; evaluate pain or mobility changes. — DailyMed, ROZLYTREK set_id c7c71b0c-2549-4495-86b6-c2807fa54908
- Major warning · Check ALT and AST every 2 weeks for the first month, then monthly. Check uric acid before and during treatment. Assess QT, electrolytes, and concomitant medicines; avoid with baseline QTc >450 ms or long-QT syndrome. — CIMA/AEMPS, ficha técnica ROZLYTREK 100 mg, registro 1201460001
Drug interactions
- HighStrong or moderate CYP3A inhibitors
Mechanism: They increase entrectinib exposure and toxicity.
Recommendation: Avoid the combination. If unavoidable for up to 14 days in patients older than 2 years, for a moderate/strong inhibitor reduce 600 mg to 200/100 mg; 400 to 200/50 mg; 300 to 100/50 mg; and 200 to 50 mg daily/50 mg every other day. Avoid the combination with a starting dose <200 mg or in children under 2 years.
DailyMed, ROZLYTREK set_id c7c71b0c-2549-4495-86b6-c2807fa54908https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908
- HighStrong or moderate CYP3A inducers
Mechanism: They reduce exposure and may compromise efficacy.
Recommendation: Avoid the combination.
CIMA/AEMPS, ficha técnica ROZLYTREK 100 mg, registro 1201460001https://cima.aemps.es/cima/dochtml/ft/1201460001/FT_1201460001.html
- HighQT-prolonging medicines
Mechanism: They may increase the risk of QT prolongation and arrhythmia.
Recommendation: Avoid if possible; if required, monitor ECG and electrolytes.
CIMA/AEMPS, ficha técnica ROZLYTREK 100 mg, registro 1201460001https://cima.aemps.es/cima/dochtml/ft/1201460001/FT_1201460001.html
Adverse events
Common (≥1%)
fatigue · constipation · diarrhea · dizziness · dysgeusia · edema · weight gain · anemia · increased creatinine · nausea · vomiting · fever · arthralgia · dyspnea · cough
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy before starting. Females must use highly effective contraception during treatment and for 5 weeks afterward; add a barrier method with hormonal contraception. Males must use contraception during treatment and for 3 months afterward. Do not breastfeed during treatment or for 7 days afterward.
Recent literature (PubMed)
ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.
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
- Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions.
ROS1 rearrangements define a molecular subset of non-small cell lung cancer (NSCLC) by accounting for 1%-2% of cases. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients. First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood-brain barrier penetration have limited the long-term efficacy of early-generation agents. Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges. These agents show enhanced central nervous system (CNS) penetration and activity against on-target ROS1 resistance mutations. Repotrectinib, a potent, CNS-penetrant ROS1 inhibitor, has demonstrated superior activity in both TKI-naive and -resistant tumors, including those harboring the G2032R mutation. Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability. Ongoing research is focused on optimizing sequencing strategies for ROS1 inhibitors and exploring combination approaches to prevent or overcome resistance. In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life. No information is available on the clinical use of entrectinib during breastfeeding. Because entrectinib and its active metabolite are >99% bound to plasma proteins, the amount in milk is likely to be low