Nivolumab plus ipilimumab improves efficacy versus standard of care in non-clear-cell renal cell carcinomas

Prof Lothar Bergmann - University Hospital Frankurt, Frankfurt am Main, Germany

The study we performed was an academic investigator initiated trial in non-clear cell renal cell carcinoma comparing the combination of ipilimumab/nivolumab versus standard of care. This was a trial performed in different European countries. Due to the rarity of this disease, we needed many centres for participation and we included all non-clear cell histological entities and made a stratification according to histology, papillary versus non-papillary renal-cell carcinoma, and according to the risk score, IMDC. There was a one-to-one randomisation. In total, we included about 306 patients in this trial and the primary endpoint was the overall survival rate at 12 months. This primary endpoint was met. We had a significant increase by the combination with ipilimumab/nivolumab versus the standard of care, and also the overall survival was a median longer in the combination arm than the standard of care arm.

The question is which agents have been used in the standard of care arm. Predominantly there was given a monotherapy with tyrosine kinase inhibitor, mostly sunitinib. A few patients had the combination of a tyrosine kinase inhibitor with an immune checkpoint inhibitor after this has been approved by the EMA in Europe, but as in most European countries there was not yet any reimbursement for this combination, this special indication, most patients have been treated in standard of care with a monotherapy of tyrosine kinase inhibitor. There was no increase in the progression free survival, but this can also sometimes be observed in other solid cancers with immune checkpoint inhibitors. We have no clear increase in progression free survival, but a benefit in overall survival.

If we are looking a little bit more in detail, the patients who had no expression of PD-L1 on the bystander cells, on the tumour cells, if the CPS score was below 1, these patients are doing worse or have not so clear benefit by the combination of the immune checkpoint inhibitors than those who have at least 1% PD-L1 expression as a combined score. Other sub-populations who seem to respond very well are the chromophobe renal cell carcinoma and, of course, the non-papillary renal cell carcinoma and papillary in total.

What conclusions can be drawn from this trial?

That’s an interesting question. What are the conclusions or the take-home message of this clinical trial? We can say that this has been the largest randomised trial in non-clear-cell carcinoma comparing an IO combination with standard of care. As we have a significant improvement with IO combination in this disease, we can say this might be a new standard in this sub-population of renal cell carcinoma.