A comprehensive overview of trastuzumab deruxtecan (T-DXd) as a treatment for patients with HER2+ metastatic colorectal cancer.
Aparna Parikh, MD: One of the compelling things from the T-DXd [trastuzumab deruxtecan; Enhertu] data was that patients who had prior HER2-directed therapy still derive benefit from T-DXd. When I’m thinking about sequencing for patients particularly knowing that we have the toxicity issue with the T-DXd, I liked the TKI [tyrosine kinase inhibitor]/Herceptin [trastuzumab] combination or antibody combination first and then reserving the T-DXd for later on.
Cathy Eng, MD, FACP, FASCO: Do you want to mention quickly for the audience just in case they missed it? What is the toxicity that we’re discussing that may be concerning with T-DXd?
Aparna Parikh, MD: The most concerning toxicity is ILD [interstitial lung disease]. Rapid recognition and being very -
Cathy Eng, MD, FACP, FASCO: Meaning interstitial lung disease.
Aparna Parikh, MD: Yes. Sorry. Exactly. This is a class effect and we know that this is an issue with this ADC [antibody-drug conjugate]. The recognition of symptoms; asking patients about shortness of breath; paying attention to their stats and their vitals and making sure they’re not developing some kind of insidious hypoxia; checking early CT scans to see if you’re picking up any signs of this; prescribing aggressive steroids early on can mitigate this. But it’s an important consideration for these patients.
Besides that, Dr Foote mentioned earlier, maybe Dr Kamath mentioned this as well. But the cytopenias with the T-DXd. You get neutropenias. You get anemia. I think just thinking carefully about your toxicity profile for sequencing. The other unique feature of T-DXd is some benefit for the RAS mutants as well. That’s a really important consideration. If you do happen to have a HER2 patient that’s RAS mutant perhaps maybe you would start with T-DXd, but I’m curious to see what other panelists thoughts are on that too. But without the RAS mutation, the sequencing is, for me at least starting with Herceptin/tucatinib and then moving to T-DXd later.
Cathy Eng, MD, FACP, FASCO: I think it’s important to keep in mind that ILD, or interstitial lung disease, can happen at any time. Once again, it’s really important to communicate with your clinical team about any symptoms you may be having.
Aparna Parikh, MD: Absolutely.
Cathy Eng, MD, FACP, FASCO: Thank you so much. Can you mention the fact that we know that there appears to be activity for T-DXd in breast cancer and gastric cancer at the low expression of HER2. But it does not necessarily work well in colorectal cancer in that same fashion. Do you want to mention that briefly?
Aparna Parikh, MD: Unfortunately, it was hugely disappointing. There was no activity in the HER2-low patients. The study looked at those low expressors as well, and we didn’t unfortunately see any activities. We’re still not seeing the bystander effect that we’re seeing in tumor types like breast cancer, unfortunately.
Cathy Eng, MD, FACP, FASCO: Thank you so much. Then is there anything else you would recommend since we’re still looking at T-DXd as an option? I think the DESTINY 2 (NCT04744831) study, we’re hoping we’re going to get some results soon. That’s looking at dosing as well. Maybe a difference in toxicities. I don’t know. What are your thoughts?
Aparna Parikh, MD: Yes. I’ve only had a handful, so I don’t have tons of experience with this, but in talking to breast colleagues and gastro colleagues too, I think there is not only early recognition of symptoms, but I think the dosing exactly for this reason is being looked at to see if we can mitigate some of this toxicity. But yes. I’m curious about the RAS mutations and what other panelists think about that for T-DXd.
Arvind Dasari, MD, MS: Yes. I think that’s the neat thing about antibody-drug conjugates. We’re using the receptor not so much to modulate the signaling pathway but to deliver the cytotoxic payload. So really the downstream alteration should not matter. So absolutely, I think it’s definitely an option.
Michael Foote, MD: Icouldn’t have said it any better. Yes.
Cathy Eng, MD, FACP, FASCO: Any other thoughts?
Suneel Kamath, MD: I agree. I think the one thing I struggle with a little bit too in terms of treatment sequencing is, I would agree, I would favor the tucatinib and trastuzumab combination before I would reach for T-DXd. But I also fear you add progression knowing the toxicities. Could that patient now not have enough performance status at that juncture to get T-DXd? So I do struggle with that tension but I would agree, I still did go with tucatinib and trastuzumab first.
Transcript edited for clarity.