ADCs in HR+/HER2- Advanced BC: Results From TROPICS-02 and DESTINY-Breast04

Transcript:

Hope S. Rugo, MD, FASCO: In the whole idea of being chefs instead of cooks, we are going to move past endocrine therapy into what we’re doing in patients who now have endocrine-resistant metastatic hormone receptor-positive disease. I presented the data from TROPiCS-02 here at ASCO [American Society of Clinical Oncology annual meeting] 2022. Tell us a bit about that trial, Aditya, and your take on it.

Aditya Bardia, MD, MPH: TROPiCS-02 was a phase 3 randomized clinical trial evaluating a Trop-2 antibody-drug conjugate [ADC], sacituzumab govitecan, vs treatment of physician’s choice. One important thing to note is that it was a later line trial. It was a third line-plus study in heavily pretreated patients. The majority of patients had visceral metastases. In this setting, patients who received sacituzumab govitecan had improvement in progression-free survival [PFS] compared to treatment of physician’s choice, with a hazard ratio of about 0.65. Median PFS in the control arm was about 4 months, and with sacituzumab govitecan, it was 5.5 months. If you just look at the medians, it’s a bit misleading because looking at the curves carefully, you see the initial drop, and then you see a separation. Landmark analysis like 6-month PFS and 12-month PFS is a much better metric. In that setting, you clearly see a separation between sacituzumab and treatment of physician’s choice.

In terms of overall survival, we haven’t seen mature overall survival data yet. With the immature overall survival data from a hazard ratio perspective, there seems to be a benefit with sacituzumab govitecan, but it was not statistically significant. It’s immature at this time, we need more follow-up. In terms of adverse effect profile, it was a profile we’ve known in terms of neutropenia, diarrhea, alopecia being the common adverse effects. The study did meet its primary end point. In terms of how it would change practice and how it fits with other antibody-drug conjugates, I think that’s up for discussion.

Hope S. Rugo, MD, FASCO: It is interesting. At 1 year, 3 times as many patients were free of progression or death with sacituzumab vs chemotherapy or physician’s choice. But it is tough. These were patients who had a median of 3 lines of endocrine therapy, 3 lines of chemotherapy, 95% had visceral metastases. We’re thinking about median survivals, being over 5 years is great. These patients were a median of 4 years from their diagnosis of metastatic disease. It was really heavily pretreated.

We also saw the data from the DESTINY-Breast04 trial, at the plenary session. I have to say it was surprising, since I knew the data and am an author, it was an incredibly moving presentation. I think the response from the audience even more so, a standing ovation, for being able to make a big difference in a quite different population, even though hormone receptor positive. Tell us a little about those data and how you put the two together.

Aditya Bardia, MD, MPH: It’s a game changer. I think it’s great news for the field of ADCs in general because we have active antibody-drug conjugates that are leading to improvement in progression-free survival and even overall survival. That’s why the results from DESTINY-Breast04 were presented in the plenary session at ASCO. As a brief reminder, it was a trial that looked at trastuzumab deruxtecan vs treatment of physician’s choice. This was a bit earlier line than TROPiCS-02, it was a second line-plus study. The trial showed improvement in both progression-free survival and overall survival—more than doubling of progression-free survival with trastuzumab deruxtecan [T-DXd], close to 12 months—compared to the control group and a clear improvement in overall survival as well. It was interesting when Shanu [Modi, MD,] presented the clinical trial, as soon as the presentation was done, it was a standing ovation, and the claps went on and on to the point that the moderator had to say stop. When the discussant was presenting the results, multiple times there was applause, just speaking to the excitement, and I think it highlights the in-person meetings. You have that excitement, and you could palpate that with the presentation of these data. It’s great news for the field of breast oncology. It reminds us of the early Herceptin days, where again, it was an oral presentation and standing ovation. It’s great to have these antibody-drug conjugates. Now the question would be, how do we sequence them when we have more than 1 option?

Hope S. Rugo, MD, FASCO: DESTINY-Breast04 has remarkable results. The median number of chemotherapy regimens was 1. Patients did have disease refractory to endocrine therapy. Most but not at all had received CDK4/6 inhibitors, 3 median lines of endocrine therapy, and a little less visceral disease. Exactly what you would expect in this less heavily pretreated population. There was still toxicity from T-DXd [trastuzumab deruxtecan] that’s different from treatment of physician choice. What did you think about the toxicity part of DESTINY-Breast04?

Komal Jhaveri, MD, FACP: It seemed like this is something we knew about this agent from the get-go. We knew that from DESTINY-Breast01, and in fact even the phase 1 trial leading up to DESTINY-Breast01. Then we saw results from DESTINY-Breast03, where at least we were reassured that when we utilized that in the HER2-positive setting early, we did not have grade 4 or 5 events there, and no grade 3 that was serious as well. The rate was about 10% for ILD [interstitial lung disease]. In this trial it was about 12%. There were 3 deaths. This highlights, of course, we have definitely been very excited about this class of agents. They are here to stay, and we have to do so much more.

One question to understand is, what is the right patient population? What is the right biomarker to identify that right patient population? How do we understand mechanisms of resistance to this? How do we use that knowledge to then sequence the various ADCs that we’re developing in this space? But I think it’s very important for us to recognize that these have their own toxicities, and we have to be very vigilant as a community to educate our patients about them, to identify if they have preexisting conditions that would make them more vulnerable, at risk for getting this toxicity, and identify it, and treat it very quickly. We cannot just be excited blindly by the efficacy result, and we have to put all of that together for our patient.

Hope S. Rugo, MD, FASCO: We’re certainly not going to help their survival if they die of ILD, but that was 0.8% of the population, so it’s pretty rare, but you do really need to recognize this. I think a lot of work will go into educating people about ILD. The other toxicity from T-DXd, nausea, is quite prominent, and then for sacituzumab, neutropenia and diarrhea are higher-grade toxicities.

Transcript edited for clarity.