The SWOG PAPMET study was one of the first randomized trials in papillary RCC that tested different TKIs sunitinib and cabozantinib. Other MET inhibitors were tested based on the belief that MET signaling can drive this subtype, but those inhibitors did not have activity and the arms were closed. This trial showed that cabozantinib had advantages in response rate and PFS over sunitinib. This may be due to the more broad targeting of cabozantinib or potentially due to its MET inhibiting activity, noting above the negative results of the MET-targeting agents. In the absence of being able to give an IO-based regimen, single agent Cabozantinib is a suitable standard of care in papillary RCC.

A single arm trial of IO monotherapy using pembrolizumab (KEYNOTE 427) was conducted including all non-clear cell histologies. This trial demonstrated activity as measured by objective response rates in the 30% range for unclassified and papillary RCC, with less activity in chromophobe (ORR less than 10%). The overall median PFS was modest (4.2 months) and many patients had progressive disease as best response. Overall, while there is modest activity in general, some patients can have durable effect. IO monotherapy could be suitable in patients who are unable to receive a TKI.

Ipilimumab plus nivolumab has become a standard of care in front line clear cell RCC with durable response benefits among others. This trial tested Ipi/nivo in all non-clear cell histologies. The response rate was less than 20% and the overall benefit modest, although as usual for immune therapy there were notable durable responses. Overall, Ipi/nivo appears to have limited activity in non-clear cell RCC.

Various IO/TKI regimens have become a standard of care in front line clear cell RCC based on clinical benefits over TKI monotherapy as shown in several phase 3 trials. This single arm trial tested cabozantinib plus nivolumab across all non-clear cell RCC histologies. The overall response rate was 48% excluding chromophobe RCC (in which no responses were seen) and the median PFS was 12.5 months. Durable responses were also seen. While the activity of this combination is not quite as robust as in clear cell RCC, it has the significant activity including durable responses and thus represents a standard of care in non-clear cell RCC.

Another IO/TKI combination tested in non-clear cell RCC is lenvatinib plus pembrolizumab in the B61 study. The response rate was 49%, and notably 28% in the chromophobe subset which has been historically less responsive to IO-based regimens. The median PFS was 17.9 months and durable response were seen. Thus, this IO/TKI combination is also a standard of care in non-clear cell RCC.