ASCO GU 2018: Effect of Crizotinib on Disease Control in Patients with Advanced Papillary Renal Cell Carcinoma - Final Results of EORTC 90101 CREATE

San Francisco, CA ( Dr. Schoffski presented on EORTC 90101, a multinational, prospective phase II trial, evaluating the efficacy and safety of crizotinib in patients with advanced tumors characterized by alterations leading to MET and/or ALK pathway mutations.  The trial included 6 disease cohorts: 1) papillary RCC type 1 2) alveolar soft part sarcoma 3) clear cell sarcoma 4) anaplastic large cell lymphoma 5) inflammatory myofibroblastic tumor 6) alveolar rhabdomyosarcoma.  Herein, Dr. Schoffski presented the final clinical results of the independent papillary RCC type 1 cohort. 

Papillary RCC type 1 is associated with alterations of the MET proto-oncogene, which can lead to prolonged tumor cell survival and enhanced cell growth.  This promoted tumor cell migration, invasion and angiogenesis. The presence of these genetic alterations provide a strong rationale to target MET mutations in PRCC type 1. 

Crizotinib is a small molecule tyrosine kinase inhibitor targeting the MET pathway by competitively inhibiting adenosine triphosphate from binding to the MET receptor, causing inhibition of its activation.  Therefore, this molecule blocks growth and survival of MET dependent cells, and has been approved for treatment of non-small cell lung cancer. 

Patients were including if they were metastatic and or advanced PRCC1, deemed incurable by surgery, radiotherapy or systemic therapy with good functional status and measurable disease according to RECIST v1.1.  The presence of MET alteration was not required to enter the treatment phase.

Crizotinib was given at a starting dose of 250mg BID with cycles 21 days in duration.  Treatment was continued until progression, unacceptable toxicity or patient refusal.  Patient were attributed to MET+ versus MET- cohorts based on mutation in exons 16-19 of the MET gene.  Primary endpoint was the objective response rate per RECIST v1.1.  Secondary endpoints included duration of response, disease control rate, progression free survival, overall survival, safety, translational endpoints, amongst others.

41 patients were recruited with the local diagnosis of PRCC1 with 65.9% confirmed on central review.  Median age was 62.5 years.  82.5% had been treated with prior surgery.  Only 14.8% had a mutation in exons 16-19 (MET+), where as 70.5% of patients were MET-.  The remaining 4 patients were unable to be determined (MET?).  In the MET+ patients (n=4), 2 achieved a partial response and 1 had stable disease (ORR 50%; 95% CI: 6.8-93.7%). One year overall survival was 75.0%. Amongst MET- patients (n=16), 1 year overall survival was 71.8%. Among 3 pts with unknown MET status (MET?) due to technical failure, 1 year overall survival was 100%.  Common treatment-related adverse events included edema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhea (39.1%), and blurred vision (34.8%).

In summary, Dr. Schoffski demonstrated that local misclassification of PRCC1 is relatively high and actual incidence of MET mutation was 14.8%.  Results compare favorably to previously published studies (Ravaud et al, 2015).  This study shows that Crizotinib can be considered a treatment option for PRCC1 patients with MET mutation or amplifications. 

Presented by: Patrick Schoffski, MD, MPH University Hospitals Leuven

Written by: David B. Cahn, DO, MBS @dbcahn, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA