DS-8201 and Tucatinib in HER2+ Metastatic Breast Cancer

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Adam Brufsky, MD, PhD: Let’s talk about DS-8201[trastuzumab deruxtecan]. This is the decade of the ADC [antibody-drug conjugate]/ We have all the Trop2 stuff with sacituzumab, we are probably going to add SYD985, biospecific antibodies, there is going to be all sorts of cool stuff coming out. Virginia, what is your take on DS-8201, the phase 2?

Virginia Kaklamani, MD:Looking at the data, you see a little over 60% response rate in relatively heavily pretreated patients, but when you look at the waterfall plot, I think there were 3 patients that had a little bit of an increase in their tumor volume and everybody else had a decrease in their tumor volume. Pretty impressive data, but it comes at a price. There’s over 10% rate of pneumonitis and several deaths. Definitely not a benign drug, a little more toxic, as far as I’ve seen, than T-DM1 [trastuzumab emtansine] and just people not feeling as well. T-DM1, most people, besides a little bit of neuropathy, barely know that they’re taking something. DS-8201 is a little bit worse than that.

Adam Brufsky, MD, PhD: Comments on DS-8201. Mark, what do you think?

Mark D. Pegram, MD: The nausea we’ve seen within our group tends to be delayed nausea. You have to warn patients to be prepared for that and make sure they have scripts at home to accommodate it. You have to warn them about alopecia, as well. It’s got toxicities very much like a TOPO-1 [topoisomerases type 1] inhibitor chemotherapy drug. It’s not as bad as irinotecan or topotecan, but the same types of toxicities, albeit a little bit lower level. You have to be prepared to co-medicate, dose adjust, et cetera. Fatigue is another feature you have to worry about, as well as cytopenias. It’s real chemotherapy. It just happens to be linked to an antibody.

Adam Brufsky, MD, PhD: I’m very impressed by this. The trials clearly are going to come out. They had the trial and I gave Daichi a real hard time about this because it still is a trial of DS-8201 versus capecitabine/trastuzumab. I said, “Everybody has already had capecitabine/trastuzumab. Why are you doing this?” I understand, now, why they did it because it’s a control arm of HER2CLIMB. I don’t think they knew that when they did it, but it will be very nice comparison. Do you think we can get that done anymore in the United States? I don’t think we can get that done anymore. It is all going to be ex-United States.

Carey K. Anders, MD: Not with the advent of the HER2CLIMB data.

Adam Brufsky, MD, PhD: We’re just not going to get that trial done, and not only that, but on the DS-8201 side, as well. This is a question everyone wants to know: Do you have a patient in mind for DS-8201 versus tucatinib? Is there a particular person that you would treat one way or the other? Carey, we will start with you and go around the table.

Carey K. Anders, MD: I do think the status of the CNS [central nervous system] disease matters because, as Virginia said, the evidence that we have in progressive brain metastasis is much higher level with randomized data for HER2CLIMB. If I have a patient who presents with metastatic disease, extracranial, yes or no, but progressive CNS disease, I’m going to reach for HER2CLIMB regimen. In a setting of stable brain metastasis, I think it would be a discussion with the patient, looking at what their prior toxicities have been and their compliance with the oral therapies. I completely agree giving trastuzumab/deruxtecan is not like giving T-DM1. It’s really important for us to warn our patients about that because I have also seen the fatigue and the nausea in my patients who’ve had trastuzumab/deruxtecan. The response rate matters, as well. The 60% response rate in the DESTINY-01 study was quite impressive. All of those patients had received T-DM1, so if I had someone who was near visceral crisis, maybe with liver disease, I might favor the DS-8201 over the HER2CLIMB regimen that had about a 40% response rate. Those would be some of the things that would be going through my mind in making that decision.

Adam Brufsky, MD, PhD: Before we go to someone else, being the brain metastasis expert, what do you think of the data that was presented from Carsten? It was Carsten Denkert, MD, or someone, about the brain metastasis in DESTINY-01.

Carey K. Anders, MD: For DESTINY-01, I think it’s really interesting. We just need more data. There were 180-some patients in DESTINY-01, of which 24 had brain metastasis, and their progression-free survival was very similar to what we saw on the nonbrain metastasis population. All of the patients in DESTINY-01 were deemed stable at the time of entry, nonprogressive. When you look at the subset analysis for the CNS disease, there were very few CNS events at the site of progressive disease. Of the 48 patients who progressed on the study globally, only 4 had CNS events and there were documented responses in the brain. We just need more data there. We need a study that is dedicated to CNS response rate, intracranial PFS, and such before we know more. I think it has great potential.

Adam Brufsky, MD, PhD: Mark, what do you think?

Mark D. Pegram, MD: For the nonbrain metastases patients. I’m very impressed by DS-8201 and, albeit, it has some toxicities these are very manageable. We’re all oncologists. We’re used to dealing with all these side effects that are very routine. They all can be mitigated with dose modification or co-medications, so I have no hesitation to give the drug in those patients. Given its extraordinary efficacy and duration of response in DESTINY-01, it’s unbelievable. It’s just very impressive. If it were me, I wouldn’t use DS-8201. That said, I’ll give a balanced discussion of both possibilities with the patients because you know the tucatinib HER2CLIMB regimen is not without toxicity, either. Adverse events include diarrhea, PPE [palmar–plantar erythrodysesthesia], nausea, vomiting, fatigue, hepatotoxicity, stomatitis, headache, anemia, and rash. I mean, all those are mitigating factors for that regimen, as well. A balanced discussion is appropriate but if the patient says, “Well, what would you do, Doctor?” I would take DS-8201.

Adam Brufsky, MD, PhD: Virginia, what do you think?

Virginia Kaklamani, MD:I agree and the good news with the tucatinib is that it works in progressive brain metastasis, which we don’t have data from any of the other agents. I feel very comfortable giving DS-8201 for the patients that have stable brain metastasis. Now, when they progress, I have a great option to give them.

Adam Brufsky, MD, PhD: Rashmi, I know your answer because you’re the PI [primary investigator] of the trial, but I have to ask you anyway, what would you do?

Rashmi K. Murthy, MD, MBE: I think that the DESTINY-01 data is very striking. That was probably one of the most impressive plots that many of us have seen across oncology trials. Certainly, for our patients without brain metastases, I would give strong consideration for the use of DS-8201. I saw some of the toxicities in patients, as well as the nausea, hair loss, and fatigue. As Mark pointed out, they are manageable and that that wouldn’t make me shy away from use of the drug.

Now, the one toxicity that I think is of concern is the ILD [interstitial lung disease] and pneumonitis and we definitely need to keep caution and consider it carefully in patients who have any kind of underlying pulmonary issues. Outside of that, this presents a really great option for our patients, especially those who have a high systemic burden of disease. For those in whom we need to achieve a quick, rapid response, I would certainly be pushed to use the DS-8201. For patients with brain metastases, my go-to choice would probably be tucatinib, just given the response rates that we’ve seen in the brain and the survival benefits in those patients.

Transcript Edited for Clarity