Ben Levy, MD: Let’s round this up with the ADCs [antibody-drug conjugates], which are a new class coming into the lung cancer field. There’s a lot of experience with the breast cancer colleagues teaching us about these drugs. We’ve got some new agents. Trastuzumab deruxtecan was mentioned for HER2, but there are others. Martin, do you want to briefly take us through a couple of these emerging antibody-drug conjugates for lung cancer? It’s a crowded field. It’s very exciting, but extremely confusing.

Martin Dietrich, MD: We’ve gotten the enthusiasm from the breast cancer field. The replacement of Kadcyla [trastuzumab emtansine] by trastuzumab deruxtecan was basically paving the way here. We’re basically seeing a similar level of response for HER2-mutated non–small cell lung cancer with trastuzumab deruxtecan. We have other markers that are probably even more broadly applicable than HER2, with anti-HER3 antibody-drug conjugates with patritumab deruxtecan, which is a study that came out of Dana-Farber Cancer Institute that looked at post-progressors on first-line TKI [tyrosine kinase inhibitor] therapy in the EGFR-mutated space. Interestingly, the dosing was a little higher. The deruxtecan payload was equivalent to a higher dosing of about 5.6 mg/kg body weight, higher than we’d see in the breast cancer space. There are more expected cytopenias, but a respectable 40% response rate.

This is a very crowded space. We’ll see the TROP2 ADCs with datopotamab deruxtecan, which is basically the same payload but different target. We have to look at whether those are really directed therapies. Somebody mentioned earlier that this is chemotherapy delivered in a targeted fashion. But when you look at some of the discordance between delivery and efficacy, it doesn’t seem to be quite clear what the markers of attraction have to be for an antibody-drug conjugate to be specific.

The patritumab deruxtecan data for EGFR-mutated disease are going to be competitive for the next-line space. To add to my earlier discussion, in the patritumab trial, the experience is very similar in management to what we see with the deruxtecan experience with HER2. There are other targets. The list is endless. We have CEACAM5 as an additional target that has been looked at with a microtubule inhibitor and an antibody-drug conjugate. Interestingly, this is the payload dependence that is requiring specific delivery. We see a higher level of specificity here that’s dependent on CEACAM5 expression. We see better response rates in a CEACAM5-enriched population: greater than 50%. The list is going to be endless.

Once we think about the second-line space—for example, in EGFR between chemoimmunotherapy, amivantamab is certainly of interest here, along with patritumab and datopotamab—it’s going to be very difficult to choose the proper next-line therapy. The proper sequence is going to get very crowded. The earliest data show that the future here is very bright. Fortunately, a lot of these therapies are able to overcome resistance. But what’s clear is that they’re particularly sensitive in the oncogenic driver subset. Even for the ADCs, biomarker selection remains key to select the right patient for the right drug at the right time. That’s my take on ADCs. They require a lot more supportive care than targeted therapy. They have a chemotherapy and a targeted therapy flavor, but they combine those 2 adverse effects and need a little more management than a regular TKI.

Ben Levy, MD: Well stated. Nice overview. With the integration of ADCs, the sequencing strategies for all these genotypes is where do they fit in? Where do they fit in for KRAS G12C? Where do they fit in for EGFR? Where do they fit in for wild type? This is where there’s starting to be a layer of extraordinary complexity. The running joke is that I went into lung cancer 15 years ago because it was easy. There were just 3 drugs. With the explosion of what we now have in our therapeutic armamentarium and all the genotypes, how to sequence all these drugs is very complex but very exciting for patients. It’ll be a big win once we figure out the optimal sequencing strategies.

Transcript edited for clarity.