Comprehensive insight on the adverse event profile of antibody drug conjugate therapy as it compares to other agents in HER2+ metastatic colorectal cancer management.
Kristen K. Ciombor, MD: Dr Raghav, elucidate a little about toxicities with trastuzumab deruxtecan. Dr Hecht has told us about the ILD [interstitial lung disease] we need to keep track of. Do you feel it’s very chemotherapy-like? What’s your opinion?
Kanwal P. Raghav, MD: Most of the toxicities of this drug are sort of chemotherapy-like. However, it should be remembered that these trials were done in a highly treatment-refractory population that had a lot of chemotherapy.
Kristen K. Ciombor, MD: Yes.
Kanwal P. Raghav, MD: The best part about ADCs [antibody-drug conjugates] is that they give you an opportunity to do a more targeted chemotherapy. The payload in this drug is a topoisomerase poison, which very similar to irinotecan but much more potent. We know from literature that with these topoisomerase poisons, dose is the limiting factor. If you keep increasing the dose, you’ll keep seeing increased response rates. But you can’t give irinotecan above a certain dose.
Kristen K. Ciombor, MD: There’s a limit.
Kanwal P. Raghav, MD: There’s GI [gastrointestinal] toxicity and bone marrow toxicity. In this drug, there was some bone marrow toxicity, but the neutropenia rate and anemia rate in this heavily treated population was still less than 20%. That’s great for a drug like this, especially with a response rate of about 40%. It opens up all kinds of opportunities—combination therapies, combining it with novel therapeutics that also have bone marrow toxicities. Bone marrow toxicity is an affect that you’d see with any chemotherapy drug unless it’s targeted chemotherapy. But it’s a manageable adverse effect.
The second group was GI toxicity, which was very manageable. Grade 3 toxicity rates were about 30% to 40%, which is great with regard to the responses it brings about. ILD is the big 1. The DESTINY-CRC01 study was done with a 6.4 mg/kg, which is a high dose. We have literature from breast cancer, which made it clear that the 5.4 mg/kg dose improves the amount of adverse effects, especially ILD adverse effects. The ILD rate with the 6.4 mg/kg dose is around 10% or so, and you can reduce it by half. More important, you don’t see a lot of higher-grade interstitial lung disease. This is a tough adverse effect once it occurs. The only way to manage this is to recognize it early. The earlier you recognize it, and the earlier you stop the drug and take the necessary corrective action, the better it is. Remember, in the study, few ILD cases were caused by the drug and had a fatal outcome. Overall, it’s a fairly well-tolerated drug. The 5.4 mg/kg dose is being evaluated in the DESTINY-CRC02 study. If that also shows results similar to breast cancer, where in the lower doses it doesn’t compromise the efficacy, then we really have something at our hands.
Kristen K. Ciombor, MD: What do you think about the RAS mutational status? Is that important?
Kanwal P. Raghav, MD: That’s a very good question. This is where the strategy of an ADC trumps the strategy of dual anti–HER2 [human epidermal growth factor receptor 2] therapy. It’s very clear that dual anti-HER2 therapy, whether it’s trastuzumab lapatinib or trastuzumab pertuzumab, doesn’t work in the RAS-mutant population for obvious reasons. On the other hand, ADC strategy can circumnavigate that limitation. The CRC02 study allows the RAS-mutant population. There was an explorational…biomarker analysis. Some patients had ctDNA [circulating tumor DNA] evidence of RAS mutations, and response rates were still seen in those patients.Whereas, we know the response rate with an anti-HER2 [agent].
Joel R. Hecht, MD: As we get more active anti-HER2 agents, 1 thing to think about is that this shows the lung toxicity. That was also seen with anti-HER2 CAR [chimeric antigen receptor] T cell [therapies], where you could also get lung inflammation. There haven’t been a lot of them, but as we get better or more potent, it’s something to be concerned about. We’re so used to GI toxicity in GI cancer. The lung is another place we don’t look at as much.
Kristen K. Ciombor, MD: Yes.
Pashtoon M. Kasi, MD: To some extent, the proportion of severe ILD may not necessarily be with the dose. It also may be the earlier recognition that has come through. Because the earlier trials definitely had higher numbers in the teens, in terms of the proportion, and it’s 1 of those things every clinician is looking out for.
Joel R. Hecht, MD: That’s what I was saying about our breast cancer colleagues. They’re in the community and treat HER2-positive breast cancer all the time. They see a lot more of this drug and know how to deal with it than someone who’s purely a GI oncologist.
Kristen K. Ciombor, MD: It also speaks to the fact that it’s not just us who need to be on the lookout; it’s our teams. We’re often not the ones getting the calls about a cough or shortness of breath. We need to remember what our teams need to know and have that alert.
Transcript edited for clarity.