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Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET
Patrick Schöffski1, Agnieszka Wozniak2, Bernard Escudier3
1University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer Institute, Leuven, Belgium; KU Leuven, Laboratory of Experimental Oncology, Department of Oncology, Leuven, Belgium.
Purpose:
Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET-).
Experimental Design:
Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET- sub-cohorts by the sequencing of exons 16-19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety.
Results:
Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8-93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8-96.1) and 1-year OS: 75.0% (95% CI: 12.8-96.1). Among 16 MET- patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2-30.2), 1-year PFSR: 27.3% (95% CI: 8.5-50.4) and 1-year OS: 71.8% (95% CI: 41.1-88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8-90.6), 1-year PFSR: 66.7% (95% CI: 5.4-94.5) and 1-year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET- case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%).
Conclusion:
Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET- and MET? cases, suggesting the presence of other alterations of MET or alternative pathways.
Insights
Crizotinib shows efficacy in advanced papillary renal-cell carcinoma type 1 (PRCC1), particularly in patients with MET mutations or amplification. The drug is well-tolerated, with some patients experiencing durable responses regardless of MET status.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Papillary renal-cell carcinoma type 1 (PRCC1) is a subtype of kidney cancer often associated with alterations in the MET gene.
- Targeted therapies are emerging as a treatment strategy for PRCC1, with a focus on MET pathway inhibitors.
Purpose of the Study:
- To prospectively assess the efficacy and safety of crizotinib in patients with advanced or metastatic PRCC1.
- To evaluate treatment outcomes in patients with and without MET mutations (MET+ and MET-).
Main Methods:
- A phase II clinical trial was conducted, enrolling patients with confirmed PRCC1.
- Patients received oral crizotinib (250 mg twice daily).
- Patients were stratified into MET+ and MET- cohorts based on MET gene sequencing; objective response rate (ORR) was the primary endpoint.
Main Results:
- Among 23 evaluable patients, 4 were MET+. Two achieved partial response (PR), with one lasting 37.3 months. The ORR for MET+ was 50%.
- Among 16 MET- patients, one achieved a PR lasting over 9.9 months, and 11 had stable disease (SD). The ORR for MET- was 6.3%.
- Common adverse events included edema, fatigue, nausea, diarrhea, and blurred vision. Crizotinib demonstrated activity and was well-tolerated.
Conclusions:
- Crizotinib is an active and well-tolerated treatment for advanced/metastatic PRCC1, especially in patients with MET mutations or amplification.
- Durable responses were observed in MET+ patients, and some responses were also noted in MET- and MET? patients, suggesting potential roles for other genetic alterations or pathways.
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