The Evolution of ADC's: Q&A with Ethan Smith

ADCs continue to be a major focus in oncology. While these therapies show promise across multiple cancer types, researchers are working to address key challenges around sequencing and safety. Ethan Smith, therapy area director of Oncology at Norstella, spoke with Pharmaceutical Executive about how ADCs are evolving, including the need for real-world evidence to manage interstitial lung disease and the potential for companion diagnostics to expand patient access.

A transcript of Smith’s conversation with Pharmaceutical Executive can be found below.

Pharmaceutical Executive: With the evolving landscapes of ADCs, what do you see as the most critical scientific or regulatory hurdle that needs to be addressed to broaden their therapeutic application across all tumor types?

Ethan Smith: I think there's probably no one single answer to that. So, I think one interesting thing that's been a value proposition of ADCs is the fact that you can re-challenge after using a monoclonal antibody before. You can use HER2 ADC after using a HER2 map, and that means that patients get an additional option in an additional line of therapy. Because ADCs are moving into earlier lines of therapy, I think sequencing now is coming into the fore, and it's going to be challenging for physicians to work out they've got they've got several ADC options available, which ones to use in which order. So, I think understanding the sequencing, understanding which payloads can be used one after another, is probably one of the biggest challenges that may not always be found out just through regular clinical trials, but maybe through, you know, academic trials. I think that will be a scenario that's going to play out in quite a few solid tumors.

PE: How do you see real world evidence shaping the clinical and commercial trajectory of ADCs compared to the traditional oncology therapies?

Smith: I think one of the big things that we'll need from will real-world evidence, particularly for ADCs where you have interstitial lung disease. We saw this with bispecific T cell engagers with CRS risk. We've now got this class effect of ILD with ADC. So, I think using real world evidence to know how to kind of prophylactically try and prevent it happening, managing it when it's happening, making sure that we're not over diagnosing ILD as well. It's another one that may not be worked out just through clinical trials, but through more real-world studies and sort of academic interventions. I think that'll be a key to helping drive the uptake, making sure that physicians are comfortable with the safety profile.

PE: What are some key considerations when evaluating the value proposition of ADCs, especially in the context of payer expectations and access challenges in oncology?

Smith: I think it's the same as really any other drug to be honest, you're just looking. If you take the German example, where they always look for a benefit over standard of care. You've got to make the reimburses feel like they have no choice but to add you to their reimbursement list if you're in the EU or to add to the list of drugs that you use on your program in the U.S. Making sure that you have a well-designed trial, an appropriate comparator, you've shown how to mitigate the toxicity, and you've used the correct endpoints to show benefit, I don't think that really changes too much against other oncology drugs that we see.

PE: As ADC pipelines become increasingly crowded, how do you think differentiation will be defined beyond efficiency?

Smith: Yeah, I think we're seeing a lot of innovation now as ADCs become a pretty mainstream drug, they're pretty much front and center everything. I think we're seeing a lot of innovation in a few different elements, including the targets themselves. We're seeing different targets now that you don't see in traditional maps, different linkers and then different payloads, and a lot of people are trying to differentiate on payload. One to become more potent, or secondly, to become safer, and you want to have your payload internalize its good bystander effect and not get a lot of off target effect. So, I think that's the main point of innovation to differentiators. I also think there are other ways that people are sort of constructing their ADCs that are interesting. Now, sort of dual conjugate ADCs, radio conjugates, degrade, antibody conjugates. These are all sort of increasingly novel, trying to have a step forward over sort of traditional ADCs, like in HER2. Companion diagnostics are an interesting thing with ADCs, because they have really reinvented how we think about biomarkers, and I think about drugs like in HER2 basically invented the HER2 ultra-low patient segment. That's simply just because they're so much more potent now we may have surprises in the future when it comes to the segmentation.

PE: What is the response of the rise of ADCs, and what implications might this have on launch strategy and market access planning?

Smith: I think there's maybe three things that I'm seeing happening in terms of development strategies for ADCs. There are a few things that are happening, one is a lot of companies are now trying to push ADCs earlier in the treatment paradigm. So, like many novel drugs starting off in heavily pretreated settings, they go forward through the lines of therapy. So, I think we'll see other therapies, like the Trop-2 therapies with ADCs. We're seeing that and that’s one kind of trend that we're seeing. Another one will respond by trying to get an advantage with combination therapies. So many of these manufacturers, we're seeing them with their early-stage ADCs, combining it with other therapies that they already have on the market, or they've licensed in another one. I think that'll be a common strategy if you're comfortable with a toxicity, that you'll combine it with another. Finally, this doesn't just go for ADCs, but in general, we're seeing a huge amount of licensing from China, with so much innovation now coming from there, an increased amount of R&D is also being outsourced to China.