Entrectinib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Entrectinib
- Entrectinib: From Oncology Use (NTRK/ROS1-Positive Tumours) to Multiple Endocrine Neoplasia
Entrectinib: From Oncology Use (NTRK/ROS1-Positive Tumours) to Multiple Endocrine Neoplasia
One-Sentence Summary
Entrectinib is an oral TRK/ROS1/ALK kinase inhibitor, marketed in Singapore as Rozlytrek capsules; the approved indication text is not available in the data compiled for this report. The TxGNN model ranks multiple endocrine neoplasia as its top prediction, but only 1 clinical trial (terminated, 2 patients) and 1 publication (indirect, preclinical/mechanistic) are linked to it. Of the top 10 predictions, female breast carcinoma has the strongest supporting evidence (3 clinical trials and 7 publications), so it is discussed alongside the top-ranked prediction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available in the compiled data (the approved indication text is blank on both licences) |
| Predicted New Indication | Multiple endocrine neoplasia |
| TxGNN Prediction Score | 98.58% |
| Evidence Level | L3 (as assigned in the compiled data; the supporting evidence is only indirect, so it is effectively close to L4–L5) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold (for multiple endocrine neoplasia); Proceed with Guardrails for biomarker-selected breast carcinoma (see below) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the compiled data. Based on known information, entrectinib is a kinase inhibitor that targets TRKA/B/C, ROS1 and ALK, and it has some activity against RET in certain contexts.
Multiple endocrine neoplasia type 2 (MEN2) is driven by activating germline RET mutations. Inhibiting RET signalling is therefore mechanistically plausible. However, the only publication linked to this prediction concerns resistance to selective RET inhibitors (selpercatinib, pralsetinib) in a RET-driven medullary thyroid carcinoma. This is indirect and does not show that entrectinib works in MEN. The one linked trial is a precision-oncology platform study, not specific to MEN.
For the second-tier candidate, female breast carcinoma, the rationale is stronger. NTRK fusions (e.g., ETV6-NTRK3) occur in rare breast secretory carcinoma, and entrectinib is a potent TRK inhibitor. Evidence is strongest for NTRK-fusion-positive tumours, not for unselected breast cancer.
Clinical Trial Evidence
Multiple endocrine neoplasia (top prediction)
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03878524 | Phase 1 | Terminated | 2 | SMMART PRIME precision-oncology platform trial testing patient tumour samples to find drug combinations. Not MEN-specific; no interpretable efficacy or safety data |
Female breast carcinoma (best-supported prediction)
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02568267 | Phase 2 | Active, not recruiting | 534 | STARTRK-2 basket study of entrectinib in NTRK1/2/3, ROS1 or ALK fusion-positive solid tumours; includes fusion-positive breast cancer and underpins tumour-agnostic approval |
| NCT02650401 | Phase 1/2 | Active, not recruiting | 69 | STARTRK-NG paediatric/adolescent study in solid and primary CNS tumours; supports NTRK-fusion activity, limited breast relevance |
| NCT05238831 | Early Phase 1 | Withdrawn | 0 | SMMART-ACT adaptive feasibility study; no data |
Literature Evidence
Multiple endocrine neoplasia
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38438731 | 2024 | Preclinical/Mechanistic | NPJ Precision Oncology | Off-target resistance mechanisms to selective RET inhibitors in a RET-driven medullary thyroid carcinoma; indirect, no entrectinib efficacy shown |
Female breast carcinoma
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35695563 | 2022 | Phase 2 trial design (ROS1-targeting, neoadjuvant) | Future Oncology | ROSALINE: neoadjuvant ROS1 targeting plus endocrine therapy in invasive lobular carcinoma |
| 38852701 | 2024 | Preclinical | Cancer Letters | Entrectinib plus pacritinib (TrkA/JAK2 co-inhibition) suppressed growth and metastasis in HER2-positive and triple-negative breast cancer models |
| 34176200 | 2021 | Case report | The Oncologist | Locally recurrent secretory breast carcinoma with NTRK3 fusion |
| 41064088 | 2025 | Case report | Frontiers in Oncology | Breast secretory carcinoma (ETV6::NTRK3) with pleural and mediastinal metastases, 10-year follow-up |
| 37330338 | 2023 | Review | Pathology | NTRK fusions in solid tumours and their targeting with larotrectinib and entrectinib |
| 35927900 | 2023 | Review | Current Medicinal Chemistry | Progress in small-molecule TRK inhibitors, including secretory breast cancer |
| 35163586 | 2022 | Review | Int J Mol Sci | Mechanisms and emerging therapies for chemotherapy-resistant triple-negative breast cancer |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16087P | ROZLYTREK HARD CAPSULE 200MG | Capsule | Not available in compiled data |
| SIN16086P | ROZLYTREK HARD CAPSULE 100MG | Capsule | Not available in compiled data |
Both licences are valid single-ingredient products (oral route).
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (TRK/ROS1/ALK tyrosine kinase inhibitor), not a conventional cytotoxic |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert; routine monitoring of blood counts and liver and renal function is generally prudent for oral oncology kinase inhibitors |
| Handling Protection | Please refer to the package insert and local institutional handling policy |
Safety Considerations
- Drug Interactions: The interaction screen returned 100 interacting drugs; the 20 reviewed here include several rated Major:
- Aprepitant
- Dexamethasone
- Clarithromycin
- Dolasetron
Many Moderate interactions were also noted, for example famotidine, loperamide, bisacodyl, budesonide, cimetidine, levofloxacin, naltrexone, saxagliptin, empagliflozin and several bowel-preparation laxatives. Minor interactions include naloxegol and metronidazole. The pattern of Major interactions with aprepitant and clarithromycin suggests a CYP3A-related liability, but the data do not state the mechanism.
- Safety signal from the literature: A 2025 case report describes pulmonary tumour thrombotic microangiopathy (PTTM) progressing despite tumour response during entrectinib therapy in NTRK fusion-positive colon cancer.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold (multiple endocrine neoplasia, the top-ranked prediction)
Rationale:
- The high TxGNN score (98.58%) is not backed by interpretable evidence. The only trial was terminated with 2 patients and is not MEN-specific, and the only publication is indirect and about other RET inhibitors.
- By contrast, female breast carcinoma could be considered Proceed with Guardrails, restricted to biomarker-selected (NTRK/ROS1/ALK fusion-positive) patients, because of the large STARTRK-2 basket study. Since entrectinib already holds tumour-agnostic approval for NTRK fusion-positive tumours elsewhere, this is largely an extension of established use rather than a new repurposing finding.
- The other predictions (amenorrhoea, thrombocytopenia, cytomegalovirus infection, pulmonary hypertension and others) have no therapeutic evidence and should stay on Hold. Thrombocytopenia and pulmonary hypertension are more plausibly adverse-event contexts than treatment targets.
To proceed, the following is needed:
- The HSA package insert (approved indications, warnings, contraindications), which is currently missing and blocks safety screening
- Detailed mechanism of action data (e.g., from DrugBank), including RET activity relevant to MEN2
- For MEN2: preclinical or early clinical data on entrectinib against RET-mutant disease, compared with approved selective RET inhibitors
- For breast carcinoma: breast-specific results from STARTRK-2 and an NTRK-fusion testing and patient selection plan
- A drug-interaction management plan, especially for strong CYP3A-related interacting drugs
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.