PD-1–refractory advanced melanoma: how do we get to the finish line?

Dr Meredith McKean - Sarah Cannon Research Institute, Nashville, USA

On the discussion section for the oral melanoma section discussing the clinical trials ongoing in the PD-1 refractory setting, on that discussion I laid the groundwork stating that the response rate of 30% is really the bar in the refractory setting, based on data looking at combination ipilimumab/nivolumab and combination anti-PD-1/LAG-3 in the refractory setting.

There were three abstracts presented, all of them were phase I/II studies, really signal-seeking studies, but none of these studies really met that bar of greater than 30% objective response rate. But these were early studies. So these three different clinical trials looked at a number of different therapies, including the KEYMAKER umbrella study looking at anti-TIGIT, anti-CTLA-4, a multi-targeted TKI and a vitamin A derivative. Another study evaluated SX-682 which is a CXCR1/2 small molecule inhibitor. A third abstract discussed brenetafusp which is a PRAME x CD3 bispecific.

So in reviewing these abstracts there were certainly some exciting signals. In general these were well-tolerated regimens, but the question was are we really adding more by exploring triplet therapies versus adding toxicity. There will be further exploration of brenetafusp, the PRAME x CD3 bispecific, in a frontline study in combination with anti-PD-1. More to come on SX-682. The umbrella study, because those molecules did not meet their pre-specified objective response rates, will not be moving forward.

So, in general, the takeaway was how do we find the best treatment for these patients in the refractory setting and it’s really understanding the mechanism of action, designing thoughtful clinical trials where we’re using the best pre-clinical data that we have to identify the patients most likely to respond and then embedding biomarkers, even in the early clinical trials so we can use that information to move forward.