Entrectinib
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Using the evidence pack as given (no invented data). One flag up front: predicted_indications[0] (multiple endocrine neoplasia) is the weakest-supported candidate in this pack — its own repurposing_rationale says the cited evidence doesn’t actually back it. Rank 8 (female breast carcinoma, L2, Proceed with Guardrails) is far stronger. I built the report around rank 1 per the spec, and flagged the stronger candidate at the end rather than silently swapping it in.
Entrectinib: From NTRK/ROS1-Driven Solid Tumours to Multiple Endocrine Neoplasia
One-Sentence Summary
Entrectinib (DrugBank DB11986) has no EU marketing authorization on record in this pack, so its registered original indication cannot be confirmed here; literature evidence within this pack identifies it as a TRKA/B/C, ROS1 and ALK kinase inhibitor used in NTRK-fusion / ROS1-positive solid tumours. The TxGNN model’s top prediction is Multiple Endocrine Neoplasia (MEN), but the only supporting clinical trials and literature retrieved are judged not relevant to MEN by the pack’s own relevance grading — this is a Hold, not a promising lead.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available — no EU licenses on record; literature (PMID 31862477) describes use in NTRK1/2/3- and ROS1-driven solid tumours |
| Predicted New Indication | Multiple Endocrine Neoplasia |
| TxGNN Prediction Score | 98.58% |
| Evidence Level | L4 |
| EU Market Status | ✗ Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed original mechanism-of-action data is not available from DrugBank in this pack (original_moa: [Data Gap]). Based on literature retrieved elsewhere in this evidence pack (PMID 31862477, PMID 35695563), entrectinib is a small-molecule inhibitor of TRKA/B/C, ROS1 and ALK, developed for tumours driven by NTRK, ROS1 or ALK gene fusions/rearrangements.
Multiple Endocrine Neoplasia type 2 (MEN2) is driven predominantly by germline RET mutations, not by NTRK, ROS1 or ALK alterations. The single literature hit returned for this pairing (PMID 38438731) discusses acquired resistance mechanisms to selective RET inhibitors (selpercatinib, pralsetinib) in RET-driven medullary thyroid carcinoma — it does not evaluate entrectinib itself, and entrectinib is explicitly characterized in the rationale as having only weak/off-target RET activity. The two clinical trials returned (NCT04551495, NCT03878524) enrolled breast cancer and general precision-oncology basket populations, not MEN patients, and both are graded “C” relevance (topic mismatch).
In short, the mechanistic case for entrectinib in MEN is weak: the TxGNN score is high, but none of the retrieved real-world evidence actually supports this specific pairing.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04551495 | Phase 2 | Active, not recruiting | 65 | ROSALINE: neoadjuvant ROS1-targeted therapy + endocrine therapy in invasive lobular breast carcinoma — not a MEN study (relevance grade C) |
| NCT03878524 | Phase 1 | Terminated | 2 | SMMART-PRIME precision-oncology basket trial, terminated with only 2 enrolled; not MEN-specific (relevance grade C) |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38438731 | 2024 | Preclinical/Mechanistic | NPJ Precision Oncology | Describes resistance mechanisms to selective RET inhibitors (selpercatinib/pralsetinib) in RET-driven medullary thyroid carcinoma; does not study entrectinib in MEN |
EU Market Information
No EU marketing authorizations found in this evidence pack (market_status: Not Marketed, total_licenses: 0).
Cytotoxicity
Entrectinib is an antineoplastic targeted kinase inhibitor (per literature evidence in this pack, PMID 31862477: an FDA-approved small-molecule protein kinase inhibitor used in oncology), so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor) |
| Myelosuppression Risk | Not formally characterized in this pack. A case report elsewhere in the evidence set (PMID 41002576) associates entrectinib therapy with thrombocytopenia occurring alongside pulmonary tumour thrombotic microangiopathy (PTTM), rather than classic marrow suppression |
| Emetogenicity Classification | Please refer to the SmPC warnings and precautions |
| Monitoring Items | Platelet count/CBC, pulmonary status (dyspnoea, hypoxemia), liver and renal function |
| Handling Protection | Please refer to the SmPC warnings and precautions |
Safety Considerations
Please refer to the SmPC for safety information (key_warnings, contraindications, and DDI query all returned no data in this pack).
Literature-derived safety signal (not from the formal safety dataset, but present in this evidence pack): a 2025 case report (PMID 41002576) describes PTTM with worsening pulmonary hypertension and thrombocytopenia occurring during entrectinib therapy for NTRK-fusion-positive colon cancer — this is an adverse-event signal, not treatment evidence, and should not be mistaken for support of the “thrombocytopenia” or “pulmonary hypertension” predictions elsewhere in this pack.
Conclusion and Next Steps
Decision: Hold
Rationale: The MEN prediction has a high TxGNN score but no supporting clinical or mechanistic evidence — the retrieved trials and literature are off-target (breast cancer basket trials, RET-inhibitor resistance biology unrelated to entrectinib). Two Blocking/High data gaps (TFDA/EMA label warnings, confirmed MOA) also block any safety pre-assessment (S1).
To proceed, the following is needed:
- TFDA/EMA label data (warnings, contraindications) — currently Blocking (DG001)
- Confirmed mechanism-of-action data via DrugBank API — currently High priority (DG002)
- If MEN2 is still of interest: dedicated RET-relevant pharmacology data for entrectinib (current evidence suggests only weak/off-target RET activity)
Note on this evidence pack: a separate candidate in the same pack — female breast carcinoma (rank 8, TxGNN score 97.76%, evidence level L2, recommendation Proceed with Guardrails) — is substantially better supported, with a Phase 2 basket trial (STARTRK-2, n=534) and a completed Phase 2 RCT (ROSALINE) targeting NTRK/ROS1-fusion-positive breast cancers. That pairing aligns with entrectinib’s known mechanism and may warrant its own evaluation report rather than being folded into this one.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.