Crizotinib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Crizotinib: From Non-Small Cell Lung Cancer to Gingival Fibromatosis
One-Sentence Summary
Crizotinib is an oral kinase inhibitor originally used to treat non-small cell lung cancer (NSCLC). The TxGNN model predicts it may be effective for gingival fibromatosis, but this is a computational prediction only, with 0 clinical trials and 0 publications supporting it. Among the other top-ranked predictions, only the lung-related ones have any supporting studies, and these mostly describe the drug's existing NSCLC use rather than a new indication.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Non-small cell lung cancer (the Singapore licence records contain no indication text; this is taken from the knowledge-graph indication data) |
| Predicted New Indication | Fibromatosis, gingival |
| TxGNN Prediction Score | 99.81% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on the literature retrieved, crizotinib is an ATP-competitive inhibitor of the receptor tyrosine kinases ALK, ROS1 and c-MET. Its efficacy is well established in ALK-rearranged and ROS1-rearranged NSCLC.
For the top-ranked prediction, gingival fibromatosis, no plausible link to ALK, ROS1 or MET inhibition is supported by the available data. The very high score (0.998) is a model output and should not be read as evidence of benefit. The same applies to most of the other top-ten predictions (fibroma of lung, pulmonary sulcus neoplasm, VCP-related myopathy, junctional epidermolysis bullosa and a rare pigmentation syndrome).
A few lower-ranked predictions are lung-related and have some supporting material, but it is indirect:
- Lung hilum carcinoma: Two case reports describe crizotinib in ROS1-positive and ALK-positive lung adenocarcinoma. This is the already approved NSCLC use. The hilar location is incidental, so it is not a new indication.
- Lung benign neoplasm: The literature consists of Phase 3 trials in malignant ALK-positive NSCLC. These do not show benefit in benign lung tumours.
- Lung germ cell tumour: Two broad trials exist, but neither is shown to enrol this tumour type.
Clinical Trial Evidence
No clinical trials are registered for the top-ranked predicted indication (gingival fibromatosis). Currently no related clinical trials registered.
For reference, two trials were found for the rank-6 prediction, lung germ cell tumour. Both are only indirectly relevant:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01121588 | Phase 1 | Terminated | 44 | Safety and activity of crizotinib in ALK-positive tumours other than NSCLC; germ cell tumours not shown to be enrolled |
| NCT02465060 | Phase 2 | Active, not recruiting | 6452 | NCI-MATCH genotype-directed basket trial; no evidence of lung germ cell tumour enrolment |
Literature Evidence
No publications were found for gingival fibromatosis. Currently no related literature available.
For reference, the most relevant items retrieved for other lung-related predictions are listed below. They mostly concern the approved NSCLC indication:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25470694 | 2014 | RCT | N Engl J Med | First-line crizotinib vs chemotherapy in ALK-positive lung cancer (PROFILE 1014) |
| 23724913 | 2013 | RCT | N Engl J Med | Crizotinib vs chemotherapy in previously treated advanced ALK-positive lung cancer |
| 28586279 | 2017 | RCT | N Engl J Med | Alectinib vs crizotinib in untreated ALK-positive NSCLC |
| 30280657 | 2018 | RCT | N Engl J Med | Brigatinib vs crizotinib in ALK-positive NSCLC |
| 39716454 | 2024 | Case report | Am J Case Rep | Pathological complete response to neoadjuvant crizotinib plus chemotherapy in ROS1-positive lung adenocarcinoma |
| 32830600 | 2021 | Case report | J Oncol Pharm Pract | 68-month progression-free survival on crizotinib in ALK-positive lung adenocarcinoma with sarcoidosis |
| 34011083 | 2021 | Case report | Medicine | ALK-negative lung inflammatory myofibroblastic tumour; at best indirect relevance |
| 33568345 | 2021 | Clinical study | Clin Cancer Res | Crizotinib activity in ALK-aberrant relapsed/refractory neuroblastoma (Children's Oncology Group ADVL0912) |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14248P | Xalkori Capsules 250mg | Capsule | Not stated in the licence record |
| SIN14247P | Xalkori Capsules 200mg | Capsule | Not stated in the licence record |
Both licences are valid single-ingredient products from Pfizer Manufacturing Deutschland GmbH. The only route is oral.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (ALK/ROS1/MET tyrosine kinase inhibitor), not a conventional cytotoxic agent |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Liver function, cardiac monitoring (heart rate, ECG/QT) and blood counts, based on the adverse events reported in the literature; please confirm against the package insert |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Package insert warnings and contraindications were not available in the data compiled for this report. Please refer to the package insert for safety information.
Drug Interactions: The interaction screen returned 100 interacting drugs. The first 20 reviewed include these Major interactions:
- Clarithromycin
- Cisapride
- Dolasetron
- Eliglustat
- Granisetron
Several Moderate interactions were also noted, including famotidine, metformin, loperamide, bupropion, aprepitant, dexamethasone and budesonide.
Safety signals from the literature (case reports): The retrieved publications describe fatal fulminant liver failure, multiple cardiac toxicities (bradycardia, QT prolongation, ventricular arrhythmia, pericarditis), sick sinus syndrome, erythema multiforme, erosive oesophagitis and dysgeusia during crizotinib treatment. These are individual reports and do not establish incidence.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction, gingival fibromatosis, rests on a model score alone (Evidence Level L5). No trials or publications support it, and no plausible mechanism has been identified. The lung-related predictions with some evidence either duplicate the existing NSCLC indication (lung hilum carcinoma, where the evidence is limited to case reports) or are only indirectly supported (lung benign neoplasm, lung germ cell tumour). The safety signals, including hepatotoxicity and cardiac effects, also argue against pursuing weakly supported indications.
To proceed, the following is needed:
- Mechanism of action data, to assess whether ALK, ROS1 or MET signalling is relevant to gingival fibromatosis
- Package insert warnings and contraindications from the HSA, to complete safety screening
- Preclinical or case-level evidence showing an ALK, ROS1 or MET driver in gingival fibromatosis
- A review of the lung hilum carcinoma case reports to confirm whether they represent a distinct indication or the existing molecularly defined NSCLC use
- A benefit-risk assessment covering hepatic and cardiac monitoring and the major drug interactions, if any indication advances
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.