Building Better ADCs for GI Cancers: Targets, Timing, and Toxicities

As precision oncology continues to evolve beyond single-gene targets, more solid tumor malignancies are beginning to see the impact of emerging therapeutic classes like antibody–drug conjugates (ADCs). Combining the specificity of targeted agents with cytotoxic potency, ADCs have presented new therapeutic opportunities in gastrointestinal (GI) cancers, where tumor heterogeneity and complex biology have long precluded the durability of targeted therapies.

At Baptist Health Miami Cancer Institute’s fourth annual Precision Oncology Symposium, Sarbajit Mukherjee, MD, reviewed the clinical data on ADCs in GI malignancies in his session, “From Targets to Tumors: Redefining Precision in Gastrointestinal Cancers Through ADCs.” In an interview with Targeted Oncology ahead of the symposium, Dr Mukherjee, GI medical oncologist and chief of GI Medical Oncology at Baptist Health Miami Cancer Institute, discussed emerging strategies to optimize ADC therapy in research and in practice, emphasizing the importance of drug design and disease biology to enhance precision and ultimately maximize benefit.

Targeted Oncology: Could you provide a high-level overview of your talk at the symposium?

Sarbajit Mukherjee, MD: My talk is going to be on ADCs and [GI] cancers—not just what they are, but why some of them work and many don't. GI cancers are uniquely challenging. They're heterogeneous… and they're rarely driven by a single dominant oncogene. What I've learned over the past few years is that ADC success in this space depends less on finding the right target, but more on matching the payload behavior, the linker design, and the biology. So, I will walk through why some targets like HER2 and claudin18.2 [CLDN18.2] have shown great success and why some others have behaved differently; what the clinical data are teaching us and how we can design the next generation of ADCs; and, more importantly, how we can design clinical trials to possibly get the maximum benefit out of them.

How should clinicians think about sequencing if a patient is eligible for both an ADC and standard chemotherapy or chemoimmunotherapy?

Since we are in the GI space, the [number of] approved ADCs [is] fewer than some of the other disease areas, like breast for example. Most of the time, ADCs are being used after patients progress on standard first-line therapy whether that's chemotherapy [or] chemoimmunotherapy. However, one of the problems, and this is something I'm going to discuss in our talk, is so far, we have used them mostly in later lines of therapy when patients are already exhausted; the disease biology has changed.

What we're seeing now is ADCs are being used more in the earlier-line settings. If you just go by approved therapies, most of them are still being used after patients progress on their standard first-line treatment. However, what I envision is that the next decade will show us data from several trials showing efficacy of these agents, probably in earlier-line settings. Eventually, I would expect that a disease will be used in earlier-line settings than they are used right now.

Based on your experience, what are the ‘red flags’ for toxicities associated with ADCs such as interstitial lung disease (ILD)?

What we have learned is that the toxicit[ies] from ADCs are somewhat dependent on the payload. Some ADCs have shown more ILDs compared [with] others, where we have seen myelosuppression [and] neutropenia are more common.

Now, specifically for ILDs, fortunately, we have better guidelines now to watch out for ILDs in clinical practice. Sometimes the changes or the… symptoms are very subtle. That's why it's very important for clinicians to be very cautious about the [adverse] effects. Sometimes the patients would just complain of dry cough. Sometimes the patient will say that [they] have a little shortness of breath… patients may have some low-grade fever as well. All these things are very important, and when we are using ADCs, we should be really vigilant about these symptoms. Sometimes patients may actually forget to report the symptoms, and therefore it's very important to ask them about the symptoms, specifically at every single visit, because what we're seeing with the newer generation ADCs is that most ILDs are grade[s] 1 and 2, and with careful monitoring and dose interruptions, most of them don't require any extensive intervention and go away. The [adverse] effects are becoming more and more manageable, but again, the key is to detect them early and intervene when it's necessary.

What upcoming advancements (agents, targets, research) are you excited about in the space of ADCs for GI cancers?

I would say that what I'm more excited about is not a particular or single agent, but the platform itself. We are seeing more advancement in the technology, how we are delivering these drugs—the payload design, the linkers, and also how we're designing the next generation of trials. So far, we have learned that adding an immune checkpoint inhibitor with ADC for everybody is most likely not going to be the answer. We have to be very smart about selecting the biology; as I said, using them earlier during the disease course—those are some of the things that would give us the best shot of using them successfully.

Another important thing that often comes up is how important is target. At least from GI cancers, what we have learned [is] that target is important, but so is the design of the ADC and the disease biology. If you ask me about any particular target across GI cancers, the one that I'm very excited about and studies have shown promise in this area is CLDN18.2. There are several ADCs, some of [which] are next-generation ADCs, that are targeting CLDN18.2 which has expression across different GI malignancies [like] gastroesophageal cancers and pancreatic cancers. So, I'm really excited to see how the ADC development targeting CLDN18.2 pans out.

It is really an exciting field, particularly in GI cancer. I think ADCs are going to show great promise. I don't think that ADCs are something that we can use for everybody… and that's the importance of precision medicine, right? You have to selectively use these drugs in selective disease settings, understanding the disease biology, and that's where we're going to see the greatest success.