Amg-510

證據等級: L5

預測適應症: 10 個

AMG-510 (Sotorasib): From KRAS G12C-Mutated NSCLC to Transitional Cell Carcinoma

One-Sentence Summary

AMG-510 (sotorasib, brand name Lumakras) is the world’s first approved KRAS G12C covalent inhibitor, originally developed for KRAS G12C-mutated non-small cell lung cancer (NSCLC). The TxGNN model predicts it may be effective for Transitional Cell Carcinoma (urothelial carcinoma), with a high prediction score of 97.50%. However, 0 clinical trials and 0 publications specifically supporting this combination were identified, making this a model-only prediction at this stage.

Quick Overview

Item	Content
Original Indication	KRAS G12C-mutated non-small cell lung cancer (NSCLC)
Predicted New Indication	Transitional Cell Carcinoma
TxGNN Prediction Score	97.50%
Evidence Level	L5
Canada Market Status	Not Marketed
Number of DINs	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

AMG-510 (sotorasib) works by irreversibly and covalently binding to the mutant cysteine-12 residue of the KRAS G12C oncoprotein, locking it in its inactive GDP-bound state. This prevents KRAS from cycling to its active GTP-bound conformation, thereby shutting down the downstream RAS–MAPK and PI3K–AKT signalling cascades that drive tumour cell proliferation, survival, and metastasis. Because sotorasib targets the mutation itself rather than a tissue-specific receptor, its mechanism is theoretically applicable to any tumour harbouring a KRAS G12C mutation, regardless of tissue of origin.

Transitional cell carcinoma (urothelial carcinoma) does carry KRAS mutations, including the G12C variant, though at lower prevalence (~2–5%) than NSCLC (~13%). Mechanistically, the same covalent inhibition strategy would apply if the tumour is KRAS G12C-positive. Notably, the TxGNN model also ranked several closely related urothelial subtypes highly — prostatic urethra urothelial carcinoma (#2), kidney pelvis sarcomatoid transitional cell carcinoma (#3), infiltrating bladder urothelial carcinoma sarcomatoid variant (#4), and renal pelvis papillary urothelial carcinoma (#5) — suggesting that the model has identified a coherent mechanistic cluster across the urothelial carcinoma family rather than an isolated prediction.

That said, detailed mechanism of action data was flagged as a data gap in this Evidence Pack (DG002). The mechanistic reasoning above is based on the known published pharmacology of sotorasib. No confirmatory clinical or preclinical studies specifically investigating AMG-510 in transitional cell carcinoma were identified, and the prediction currently rests entirely on the computational model.

Clinical Trial Evidence

Currently no related clinical trials registered for AMG-510 in transitional cell carcinoma.

Note: Sotorasib has been studied in broader basket trials (e.g., CodeBreaK series) for KRAS G12C-mutated solid tumours. These trials may include urothelial carcinoma cohorts, but no results were captured in this Evidence Pack’s targeted query. A broader basket trial search is recommended as a next step.

Literature Evidence

Currently no related literature available.

Canada Market Information

AMG-510 (sotorasib) is currently not approved or marketed in Canada. No Drug Identification Numbers (DINs) have been issued.

Context: Sotorasib is approved in the United States (FDA, May 2021 — Lumakras, for KRAS G12C-mutated NSCLC), and has received approval in the EU and other jurisdictions. A Canadian new drug submission has not resulted in a DIN as of the data cutoff for this Evidence Pack (2026-04-04).

Cytotoxicity

AMG-510 is an antineoplastic targeted therapy (KRAS G12C inhibitor), so the following cytotoxicity profile applies:

Item	Content
Cytotoxicity Classification	Targeted therapy — first-in-class KRAS G12C covalent inhibitor
Myelosuppression Risk	Low (myelosuppression is not a primary toxicity for this class; anaemia and thrombocytopenia occasionally reported)
Emetogenicity Classification	Low
Monitoring Items	Liver function (ALT/AST — hepatotoxicity risk), pulmonary function (interstitial lung disease / pneumonitis risk), CBC
Handling Protection	Oral targeted therapy; standard cytotoxic precautions recommended per institutional policy

Safety Considerations

Please refer to the package insert for safety information.

Full warning and contraindication data from Health Canada or the TFDA package insert was not available in this Evidence Pack (Data Gap DG001, severity: Blocking). No drug-drug interaction data was identified in the evidence search. Based on the published clinical trial programme for sotorasib, known safety concerns include hepatotoxicity (Grade ≥3 ALT/AST elevation) and interstitial lung disease/pneumonitis — both requiring active monitoring. Before any repurposing assessment can proceed, the full product monograph must be retrieved to complete the safety profile (see Next Steps).

Conclusion and Next Steps

Decision: Hold

Rationale: Although the TxGNN model produces a mechanistically plausible prediction (KRAS G12C pathway applicable across urothelial tumour subtypes, consistent cluster of urothelial carcinoma variants in the top-10 rankings), there are zero clinical trials and zero publications specifically supporting AMG-510 in transitional cell carcinoma, AMG-510 is not approved in Canada, and two blocking/high-severity data gaps remain unresolved (safety warnings and MOA). These gaps prevent a full safety and evidence-level assessment.

To proceed, the following is needed:

Resolve DG001 (Blocking): Retrieve the Health Canada product monograph or TFDA package insert to obtain complete warnings, contraindications, and special population restrictions
Resolve DG002 (High): Query DrugBank API for full mechanism of action, pharmacodynamics, and toxicity data
Broaden clinical trial search: Search specifically for CodeBreaK basket trial sub-cohorts and any tumour-agnostic KRAS G12C-targeted trials that may include urothelial carcinoma participants
Confirm mutation prevalence: Obtain KRAS G12C prevalence data in Taiwanese/Canadian urothelial carcinoma populations from genomic databases (e.g., TCGA, AACR GENIE) to assess clinical actionability
Re-run evidence pipeline after data gap resolution: Once DG001 and DG002 are remediated, re-evaluate evidence level and upgrade decision stage from Hold
Disclaimer

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