Entrectinib

證據等級: L5

預測適應症: 10 個

Entrectinib: From NTRK/ROS1-Positive Solid Tumors to Multiple Endocrine Neoplasia

One-Sentence Summary

Entrectinib is a pan-TRK, ROS1, and ALK kinase inhibitor, developed internationally for the treatment of NTRK fusion-positive solid tumors and ROS1-rearranged malignancies. The TxGNN model predicts it may be effective for Multiple Endocrine Neoplasia (MEN), with a model confidence score of 98.58%. However, only 2 clinical trials were identified for this pairing — and critically, neither trial directly addresses MEN — meaning the biological rationale remains unvalidated at this time.

Quick Overview

Item	Content
Original Indication	Not approved in Canada (no DINs on file)
Predicted New Indication	Multiple Endocrine Neoplasia
TxGNN Prediction Score	98.58%
Evidence Level	L4
Canada Market Status	✗ Not Marketed
Number of DINs	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in this Evidence Pack. Based on clinical trial descriptions within the pack, Entrectinib is a small-molecule inhibitor that selectively targets three receptor tyrosine kinases: TRK (encoded by NTRK1, NTRK2, NTRK3), ROS1, and ALK. Its established utility lies in tumors driven by gene fusions involving these kinases — including NTRK fusion-positive solid tumors across multiple histologies and ROS1-rearranged non-small cell lung cancer, as evidenced by the STARTRK-2 basket trial (NCT02568267, n=534).

Multiple Endocrine Neoplasia is a syndrome driven by germline alterations in RET (MEN2A/2B), MEN1 (MEN1 syndrome), and CDKN1B (MEN4) — none of which are primary targets of Entrectinib’s TRK/ROS1/ALK inhibitory profile. A minority of MEN-associated tumor subtypes, such as papillary thyroid carcinoma occurring in MEN2 patients, may occasionally harbor NTRK fusions, but NTRK rearrangement is not a defining molecular feature of MEN as a syndrome.

The high TxGNN prediction score most likely reflects indirect topological proximity in the knowledge graph: Entrectinib’s connections to broad oncology pathways place it near multiple cancer-associated disease nodes, including MEN. This is a known limitation of graph-based predictions when the drug has wide coverage across cancer biology. The current evidence does not support a direct mechanistic hypothesis for Entrectinib in MEN.

Clinical Trial Evidence

The following trials were retrieved for the Entrectinib × Multiple Endocrine Neoplasia query. Neither trial directly targets MEN — both represent semantic co-retrieval artifacts:

Trial Number	Phase	Status	Enrollment	Key Findings
NCT04551495	Phase 2	Active, Not Recruiting	65	Neoadjuvant Entrectinib targeting ROS1 combined with endocrine therapy in ROS1+ invasive lobular breast carcinoma. The word “endocrine” in the trial title caused a semantic cross-match with MEN; this trial has no MEN-specific design or cohort.
NCT03878524	Phase 1	Terminated	2	SMMART PRIME basket trial exploring precision drug combinations in refractory solid tumors. Terminated early with only 2 participants enrolled; no MEN-specific design. No usable evidence.

Cytotoxicity

Entrectinib is an antineoplastic kinase inhibitor used for solid tumor treatment.

Item	Content
Cytotoxicity Classification	Targeted therapy (Pan-TRK / ROS1 / ALK kinase inhibitor) — not conventional cytotoxic
Myelosuppression Risk	Low to Moderate — anemia and thrombocytopenia (Grade 3–4 ~5–8%) reported in basket trials; less severe than conventional chemotherapy
Emetogenicity Classification	Low
Monitoring Items	CBC with differential, liver function tests (AST/ALT), serum creatinine, neurological assessment (cognitive function, dizziness — due to CNS penetration), QTc interval, body weight
Handling Protection	Standard oncology targeted therapy precautions; does not require cytotoxic drug handling protocols applied to conventional chemotherapy

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: MEN is defined by RET/MEN1/CDKN1B germline mutations, none of which are targets of Entrectinib’s TRK/ROS1/ALK inhibitory mechanism. The two retrieved clinical trials are semantically mismatched and provide no direct evidence for this indication. The TxGNN score reflects knowledge graph topology rather than a validated biological link.

To proceed, the following is needed:

Systematic review of NTRK fusion prevalence in MEN-associated tumor subtypes (especially papillary thyroid carcinoma in MEN2 patients) to determine whether a molecularly-selected subpopulation exists
Retrieval of complete mechanism of action data from DrugBank (DB11986) to support or refute the mechanistic hypothesis
Review of FDA/EMA pharmacovigilance and registry data from approved Entrectinib indications for any MEN-related clinical signals
If NTRK fusion frequency in a MEN-associated tumor subtype is confirmed to be clinically meaningful (> ~1%), escalate to a feasibility assessment for a molecularly-selected basket trial cohort
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.