DESTINY-CRC02: Trastuzumab Deruxtecan in HER2+ Metastatic Colorectal Cancer

Transcript:

Tanios S. Bekaii-Saab, MD: We’ve heard at ASCO [American Society of Clinical Oncology Annual Meeting] the results of DESTINY-CRC02 [NCT04744831], which comes at the heels of DESTINY-CRC01 [NCT03384940]. That [trial] is looking actually at a different way to target HER2-targeted tumors or colorectal cancers. It’s essentially trastuzumab deruxtecan [Enhertu], what I would consider a targeted chemotherapy. It’s still chemotherapy with a linker and trastuzumab, and finds its way to the receptor and then breaks the linker and then the chemotherapy is dumped into the tumor to the vicinity of the cancer cells. It is a smart way to target cancer with chemotherapy. That is important to keep in mind because, ultimately, when we put all this in perspective, it starts making sense, where do we put all these things?

Trastuzumab deruxtecan, first, the DESTINY-CRC01 showed an interesting response rate, a little bit more than 40%, and a duration of response about 5.5 months, which is what you would expect with chemotherapy. The toxicities were a little bit more significant than desired for the targeted agent, including about close to 10% of the patients who have experienced interstitial lung disease [ILD] and 2 patients actually died from ILD, which is certainly something that can be devastating. A lot of the patients have improved their ILD grading and maybe 1 may have recovered, but overall patients end up living with this or are unfortunately dying from it. DESTINY-CRC02 was looking at a lower dose of trastuzumab deruxtecan, 5.4 mg/kg versus the 6.4 mg/kg that was looked at in DESTINY-CRC01. Interestingly, it did show that a lower dose perhaps is even a little bit better, although there was no formal comparison, the response rate was a little bit higher. Now looking at the response rates, they’re overall lower than where they were with the DESTINY-CRC01. Still meaningful enough, about 37% were the 5.4 mg/kg [dose]. The toxicities were improved with the lower dose, not gone, but they were improved. The pneumonitis went from 12% to 8%, and no death from interstitial lung disease. So that’s good, but nonetheless, still has an element of toxicity.

When we start breaking down the subgroups of the study, many things start emerging. One [thing] is this study allowed for prior treatment with anti-HER2 therapies. Now that makes sense because, as I said, trastuzumab deruxtecan doesn’t care about how active the receptor is. All it cares about is if [the receptor] is present. Once we actually fail other HER2 therapies, say trastuzumab [Herceptin] [plus] tucatinib [Tukysa], which essentially blocks activity, but the receptor is still expressed, then we can use trastuzumab deruxtecan. That is good, seeing that the prior anti-HER2 treatment did not compromise the level of activity is great, because now we have the second layer after trastuzumab [plus] tucatinib, which is approved by the FDA for patients with HER2-expressing colon cancer.

The second thing that also comes about is that the presence of RAS mutations did not affect the activity of this agent. I think that’s another important element as well because RAS mutations do predict for lack of activity, for say trastuzumab/tucatinib, trastuzumab/pertuzumab [Perjeta]. So now in that subgroup of patients that are IHC [immunohistochemistry] 3+, the presence of a RAS mutation that excludes normally HER2 other anti-HER2 treatments, those patients would still be eligible for trastuzumab deruxtecan. So that’s actually important. Now, the last piece is for the patients who actually were IHC 2+ /FISH-positive [fluorescence in situ hybridization] versus IHC 3+. IHC 3+ appeared to benefit quite a bit from this. The IHC 2+ /FISH-positive did not appear to benefit from this toxic agent. So now we when we look at a patient who is an IHC 2+ and FISH-positive, the option of trastuzumab deruxtecan is probably not a good option. Those patients though, from the MOUNTAINEER [NCT03043313] study, still seem to benefit. Although, a little bit less than those with IHC 3+, but still seem to benefit from trastuzumab/tucatinib. We’ve shown that data already. In that subgroup of patients, you can eliminate trastuzumab deruxtecan and those patients would receive trastuzumab/tucatinib.

So just to summarize this, if you have [IHC] 3+ and wild-type following chemotherapy, you go with trastuzumab/tucatinib and then trastuzumab deruxtecan at some point. If you have IHC 2+ /FISH-positive wild-type, those patients will receive trastuzumab and tucatinib. Unfortunately, those patients will not benefit from trastuzumab/tucatinib. If it’s [IHC] 2+ /FISH but RAS-mutated, those patients unfortunately won’t benefit from any HER2 targeted therapy. Those patients with a [IHC] 2+, FISH-positive, and wild type will see only trastuzumab [plus] tucatinib.

Transcript edited for clarity.