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Medicine Matters oncology

So at the 2020 virtual ASCO, I had the pleasure to present the data from a randomized phase 3 by the name, of SAVOIR that addressed an unmet medical need, and that's metastatic locally advanced papillary renal cell cancer, which is the second most common type of kidney cancer, after the conventional clear cell type. And that hard to treat tumor is associated in some part was alteration of the MET gene Around 30%, 40% of patients have alteration of the MET pathway whether chromosome seven trisomy and that's where the gene resides, or MET mutations or MET amplification or actually the ligand hepatocyte growth factor amplification.



So we looked at this population that is MET-dependant, and we evaluated them in this phase 3 trial of SAVOIR versus standard of care savolitinib. This built on prior preclinical work, phase 1, as well as a phase 2 study, single arm with savolitinib And it showed 18% response rate if you are MET-dependent, you have this alteration, versus 0% if not.



So that led to SAVOIR. We aim to screen around 400 patients or randomized 180 patients. Unfortunately, what happened is at the same time we ran an epidemiological studies, assuming that the outcome, like progression free survival, with sunitinib in MET-dependent patient would be quite poor, but this did not end up panning out and MET-dependent patient in that epidemiological study did as well as the MET-dependent patient. So at that time, went back to the drawing board and we needed a much larger study to detect differences.



So the decision was to stop after 60 patients. Interestingly, after 60 patients, there was a numerical difference in the outcome. Median progression for survival with savolitinib the pure MET inhibitor versus sunitinib was different. The hazard ratio was 0.71. For overall survival, the hazard ratio was 0.51, all favoring savolitinib.



In terms of response rate, 9% with savolitinib 27% was savolitinib. And what's interesting is the side effect profile over all favors savolitinib over sunitinib So we can not draw firm conclusions at all because of these small numbers, but we are, with the sponsors, taking a seat back and thinking about next step and how to evaluate savolitinib in papillary renal cell carcinoma next.



Is there a role for savolitnib as part of combination therapy?

The question you ask is extremely important. To move forward, should we still move forward with single agent in a MET enriched? Definitely in a MET enriched population and MET-dependent. So those alternation, I talked about in 30%, 40% of cases.



But I think, should we also think about combining them, let's say was immune checkpoint blockers? This is a possibility we're discussing. There is a trial from the UK, led by Dr. Tom Powles called CALYPSO. It's in all papillary RCC that combined durvalumab the PD-L1 inhibitor with savolitinib.



And it showed some efficacy. No control arm, so it's hard to know what's contributing to what. But I think that is also a possibility in combination. Why? Because immune checkpoint inhibitor as a single agent have shown activity in papillary RCC in general.