Crizotinib for advanced papillary renal cell carcinoma with MET mutations or amplification

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Published: 9 Feb 2018
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Prof Patrick Schöffski - The Katholieke Universiteit Leuven, Leuven, Belgium

Prof Schöffski speaks with ecancer at the 2018 ASCO Genitourinary Cancers Symposium about the final results of the CREATE phase II trial, looking at the effect of crizotinib on disease control in patient with advanced papillary renal cell carcinoma type 1 (PRCC1) with MET mutations or amplification.

He describes the few MET patients had a good objective response rate (ORR) to crizotinib (50%) with good PFS.

The MET- patients responded more sporadically with lower ORR and PFS. 

Therefore crizotinib could be suitable for those PRCC1 patients with MET mutations in tumour tissue.

Also, the sporadic results in patients with MET- mutations suggests other alterations of MET signalling - this could mean there is still a way for these patients to receive benefits from crizotinib.

The results are promising, however PRCC1 is such a rare disease that it will be difficult to achieve a large enough patient cohort for a definitive trial.  

A few years ago I wrote a study protocol in collaboration with EORTC and Pfizer to test the efficacy of the drug crizotinib in six different tumour types driven by genetic alterations of ALK or MET. The study was a phase II multi-tumour study where we explored the safety and efficacy of the drug crizotinib in six tumour types in parallel and here at this meeting I'm presenting one of these cohorts, the papillary renal cell carcinoma type 1 cohort of this trial.

This was a small signal-seeking hypothesis-generating clinical trial where we enrolled only a limited number of patients with PRCC type 1. From each of these patients we collected an archival tissue block and analysed whether these tumours were driven by MET alterations or not. We treated both patients, with and without mutation, with a drug crizotinib with the same dose of the drug that is also used in the labelled indication of lung cancer.

What were the main findings?

Our primary aim was to study the objective response rate that can be achieved with crizotinib in these two subsets of this rare subtype of renal cell carcinoma. We found in a very small number of patients with MET mutations that the response rate to crizotinib was 50%. Half of the patients had a good response to the treatment and patients were kept on treatment for a very long period of time. This correlated with very good PFS and overall survival outcomes.
In the reference group without mutation we saw only sporadic responses and a much poorer progression free survival and overall survival.

What does this tell us?

This could tell us that the targeted agent crizotinib, which hits MET, is an active drug in PRCC1 patients with well-documented MET mutation. The fact that we also saw sporadic responses in patients without MET mutation, according to the definition that we used in the protocol, suggests to me that there might be other alterations of MET signalling in those patients and they can still benefit from this drug. But the chance to respond and to gain patient benefit from such an agent is much higher than in patients who don't have MET mutations.

What is the take home message?

The take home message of this trial is that crizotinib is a very valuable compound for the treatment of patients with MET mutated PRCC type 1. PRCC type 1 is a very rare disease, it took us several years to collect a small number of patients and to find a handful of patients with MET mutation. It is extremely difficult to perform a large prospective or even randomised trial in this subset. So I'm not quite sure where this will take us in the future because it's almost impossible to do a very definitive trial in such an orphan disease. But for the individual patient with this condition, PRCC type 1 with mutation of the MET gene, it is a very important treatment option.