DESTINY-CRC01: Role of Trastuzumab Deruxtecan in HER2-Positive Metastatic CRC


Shared perspective on the use of trastuzumab deruxtecan in HER2+ metastatic colorectal cancer following results from the DESTINY-CRC01 trial.


Cathy Eng, MD: Thank you so much. Next, I'd really love to touch upon, Kristen, if you could talk about the new antibody-drug conjugate, deruxtecan, how that comes into play for colorectal cancer. We've seen the data. We've seen gastric and breast, and obviously, breast is now a whole new entity that allows even one-plus now. Can you mention the DESTINY trial, and what are your thoughts in regards to sequence? And I'm so sorry, and one more other thing. Do you think, as a medical provider, should we retest for HER2 if the patient had previously tested positive?

Dr. Kristen Ciombor: All great questions. So I'll try to tackle those one by one. So DESTINY-CRC01 was an open-label phase two study that has been presented and updated over the last couple of years, specifically for patients with HER2 expressing metastatic colorectal. Interestingly, these patients all had to be RAS [00:27:00] and BRAF V600E type and had to had several prior regimens of chemotherapy. Different from some of the other anti-HER2 studies is that prior anti-HER2 therapy was allowed in this study, and that will be important as I tell you the results. But in the DESTINY study, there were actually patients of all different positivity, HER2 positivity included. There were different cohorts based on the IHC and FISH testing, as Jackie mentioned. The dose of trastuzumab deruxtecan antibody-drug conjugate was a little bit higher, I believe, than what is typically given in breast cancer. But that is an important thing to note, and the primary endpoint here was response rate. So patients who were treated on the study, the response rate in the highest HER2 expression, so the patients who are IHC3+ or IHC2+ with FISH positivity, the response rate in this fairly refractory population was about 45%, and we did not see any confirmed responses in the other two cohorts. So as opposed to some other tumor types, you really need that overexpression or amplification, and the higher the better, as it pertains to response to these agents. So that's a little bit different than other tumor types. What we saw was that the treatment duration in the cohort that responded the best was about five months and a really good disease control rate of 83%. So even if you didn't hit that resist criteria for response, there were quite a few patients who had stable disease for a decent amount of time. So that's really encouraging, especially when we think that about a third of patients had already received a different anti-HER2 therapy. And so that kind of goes into how I decide how to sequence. I'll mention in a minute, but overall progression-free survival was quite good, almost seven months with a median overall survival of 15 months, which is really incredible in this refractory population, and I think highlights the need to know if your patients are HER2 amplified and know what to do with that information. Overall, the toxicities were fairly reasonable. GI toxicities were what we saw the most, which you might expect. One quick note, that there was some interstitial lung disease seen, and a couple of deaths, in fact, in this study from that, and the time to onset of these symptoms, pneumonitis-type symptoms, really varied. And patients, despite good treatment with steroids, not everyone recovered from that. So that's a very important adverse event to be aware of if you're using trastuzumab deruxtecan, and it just takes a little bit more understanding and recognition of that [00:30:00] so you can be aware. In my practice, we have several options now in the guidelines, particularly in the NCCN guidelines. Lots of studies that have been done with various regimens in the anti-HER2 space. Where I see trastuzumab deruxtecan fitting in at the current time is after prior anti-HER2 therapy. So that is at the current time what I do, but you never what we may learn in the future in terms of how we can sequence these, given that we're learning more and more about different regimens every day.

Cathy Eng, MD: Thank you so much, Kristen. And I agree with you. I know that about nine percent or so of patients, roughly, were noted to have that interstitial lung disease. I don't think it's going to just swayed us. I hope we could just learn more from this because, obviously, it is currently approved in breast and gastric cancer, and we still have our DESTINY-2 trial that's ongoing here, overall, but I'm looking forward to the data, so I agree with you completely.

Transcript edited for clarity.

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