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

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Published: 14 Jun 2024
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Dr Meredith McKean - Sarah Cannon Research Institute, Nashville, USA

Dr Meredith McKean speaks to ecancer about a talk she presented at ASCO 2024 on 'PD-1–refractory advanced melanoma: how do we get to the finish line?'

She begins by explaining that a 30% response rate is really the 'bar' for the refractory melanoma setting.

Dr McKean then details three signal seeking studies in this area which showed exciting signals but perhaps didn't improve on this marker of response - while also adding extra regimens and toxicity.

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.