Crizotinib achieves long-lasting disease control in rare kidney cancers with MET mutations

Patients with advanced papillary renal cell carcinoma type 1 (PRCC1) with MET mutations treated with crizotinib attained objective responses and long-lasting disease control, according to a landmark clinical study published in the European Journal of Cancer.

Currently, there is no standard treatment for advanced, inoperable, or metastatic PRCC1 and it is poorly sensitive to traditional cytokine-based immunotherapy or cytotoxic chemotherapy.

The European Organisation for Research and Treatment of Cancer (EORTC) initiated CREATE, a multinational, multi-tumor, prospective phase 2 clinical trial to evaluate the efficacy and safety of crizotinib in patients with advanced tumors characterized by MET and/or anaplastic lymphoma kinase (ALK) alterations. CREATE included ALK- or MET-driven tumor types in several disease-specific cohorts, including PRCC1.

Patrick Schöffski, MD, MPH, from the Leuven Cancer Institute in Belgium, led the study, which reported results from patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET−).

Patients were eligible if they had a diagnosis of advanced and/or metastatic PRCC1 deemed incurable by conventional surgery, radiotherapy or systemic therapy, and if a tumor-containing tissue block was available from a primary and/or metastatic tumor site.

To avoid delay in starting the treatment, documentation of the presence of a specific MET alteration was not required for a patient to enter the clinical screening and treatment phase. The analysis for mutations was done simultaneously while patients were already receiving therapy.

Eligible patients were treated with oral crizotinib 250 mg twice daily in 21-day cycles. Treatment continued until disease progression, unacceptable toxicity, or patient refusal.

Safety information was collected at baseline, at day 15 of cycles 1 and 2, and at the end of every cycle. Tumors were assessed every other cycle with computer tomography or magnetic resonance imaging.

Patients were assigned to MET+ or MET− sub-cohorts based on the presence or absence of a mutation in exons 16-19 of the MET gene.

The main objective was to study anti-tumor activity of crizotinib in MET+ PRCC1 patients; the primary endpoint was the objective response rate (ORR).

Secondary endpoints included duration of response (DOR) and disease control rate (DCR), defined as the percentage of patients achieving either a complete response (CR), partial response (PR), or stable disease (SD) as best response to crizotinib. Other endpoints included progression-free survival (PFS), PFS rate (PFSR), overall survival (OS), OS rate (OSR), and safety.

A total of 23 eligible patients with confirmed PRCC1 started treatment with crizotinib and were evaluable for the primary and secondary endpoints: four were MET+, 16 were MET−, and three patients had unknown MET status (MET?) due to insufficient quality of the available biological material or other reasons.

Disease control (CR+PR+SD as best response) was achieved in three of four MET+ patients, 12 of 16 MET− patients, and two of three MET? patients.

Among the four MET+ patients, two achieved PR; of these, the DOR was 21.8 and 37.3 months. The best response observed was SD in one patient with 1-year PFSR of 75.0% and 1-year OS of 75.0%. One patient had disease progression.

Two MET− and MET? responders were still responding and receiving active treatment at the study cut-off. The DOR was >9.9 months and >6.9 months, respectively.

The 1-year PFSR in MET+, MET−, and MET? patients was 75.0%, 27.3%, and 66.7%, respectively. The median PFS for all PRCC1 patients was 5.8 months; 3.0 months for MET− patients.

The 1-year OSR in MET+, MET−, and MET? patients was 75.0%, 71.8%, and 100.0%, respectively. The median OS for all PRCC1 patients was 30.5 months; 14.5 months for patients in the MET− cohort.

In a post-hoc analysis of MET amplifications, two patients had MET amplifications (MET/CEP7 ratio ≥2); one in the MET+ and one in the MET− group. The best response to crizotinib in these patients was PR (MET+) and SD (MET−), and their total treatment duration was 23.9 and 28.8 months, respectively.

Combining the five cases with either a documented MET exon 16-19 mutation and/or MET amplification showed that two patients achieved a PR and three had SD; the ORR was 40.0%. Both the PFSR and the OSR at 1 year was 80.0% in these patients.

No new or unexpected safety signals were detected in PRCC1 patients. The most common treatment-related adverse events occurring in more than 10% of patients were limb edema, fatigue, nausea, diarrhea, and blurred vision.

Only two serious adverse events—transaminase increase in one patient and respiratory failure leading to death in one patient—were considered possibly related to study treatment. A total of 16 deaths occurred on treatment or within 4 weeks of treatment discontinuation, including one treatment-related death.

“Crizotinib is well tolerated and shows activity in PRCC1 patients with MET mutations and/or amplification,” the authors concluded. In addition, they feel that results from this trial are noteworthy as they provide more information on this rare tumor type and improve our knowledge on patient outcomes with PRCC1 and MET alterations.

The investigators explained that performing large prospective trials in ultra-rare diseases is complex, as they have inherent imitations. Moreover, they suggested that innovative trial methodology, as well as new regulatory mechanisms, are needed to provide active treatments to patients with orphan malignancies.

To read more about this study, click here.