Antibody-Drug Conjugates in Breast Cancer

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Transcript:

Benjamin P. Levy, MD: We’re going to shift gears. The breast [cancer] team is going to be front and center first here because ADCs [antibody–drug conjugates] have landed in breast cancer first. Once again, we’re trying to learn about ADCs from breast cancer because you guys have had a lot of clinical experience. Kevin, I’ll start with you. There have obviously been 2 drugs. We’ll start with the HER2 [human epidermal growth factor receptor 2] story and how you’re already testing for HER2 in lung cancer potentially. What are the drugs that are approved for HER2, what ADCs target HER2, and then we can go into some of the data.

Kevin Kalinsky, MD, MS: Sure. We hadsome experience with HER2 targeted by ADCs with T-DM1 [trastuzumab emtansine (Kadcyla)], which was an agent that was originally approved in metastatic HER2-positive [HER2+] breast cancer. It is now approved also in patients with operable breast cancer, where [in] patients who have neoadjuvant chemotherapy, HER2 therapy, and any residual disease, we saw a significant improvement in [those] who received T-DM1 compared [with] just giving trastuzumab. Then we saw the results with trastuzumab/deruxtecan [T-DXd], which was approved in patients with HER2+ breast cancer. It was compared directly [with] T-DM1 in a randomized phase 3 trial in the metastatic setting with T-DXd, which had an impressive response rate, PFS [progression-free survival], and overall survival. Clearly [we are] moving it up in terms of how we’re treating patients with HER2+ breast cancer and [it] is now the ADC of choice. That then led to the HER2-low story. For those who are old like me, we remember a day when there was interest in looking at trastuzumab in patients who had quote-unquote HER2-low disease. There was actually an adjuvant study looking at trastuzumab alone in patients with HER2-low disease and it was a negative study. But now we have seen T-DXd with HER2-low disease and just to make sure we’re all on the same page, that is HER2 1 plus or 2 plus and nonamplified. We have the approval for giving patients with HER2-low metastatic disease T-DXd and have seen about two-thirds of ER+ [estrogen receptor–positive] disease, and about one-third [of patients have] ER- [negative] disease.

The lastthing I’ll say, because I mentioned this at the beginning, is we will likely have a shift where we go to the ultralow population because one of the things that we hear from our pathologists is it’s a bit stressful for them because now they feel like the weight of the world is on their shoulders in defining HER2 low or HER2 -0. There’s a study that we should be hearing about, reporting out, I suspect, within the next year. That’s DESTINY-Breast06 [NCT04494425], which is essentially looking to include this ultralow category, which is really any staining with HER2. And I suspect that will be a positive study that will further increase our utilization of T-DXd in these patients.

Benjamin P. Levy, MD: I just want to back up for several reasons. This is interesting. I barely passed my recertification boards and breast was my lowest number. Right now, as it stands, when you have a patient who walks through your door with advanced stage HER2+ [disease,] would [you] first go to T-DM1? Where did that fit in, was it in the first line or second line before T-DXd in any line? [Did T-DM1 come] first?

Kevin Kalinsky, MD, MS: Yes. So if you have a…patient with [newly diagnosed] HER2+ metastatic breast cancer, the first line and this remains the first line is the CLEOPATRA [NCT00567190] regimen, which is giving trastuzumab, pertuzumab, and docetaxel. And then the second line was T-DM1, but now T-DM1 has been displaced…[CROSSTALK] T-DXd [CROSSTALK]...in HER2 overexpressed [disease].

Benjamin P. Levy, MD: And then HER2 low has approval for T-DXd?

Kevin Kalinsky, MD, MS: Correct. And those are in patients who, for instance, have tumors that have progressed [after] endocrine therapy and have received at least 1 line of chemotherapy. And that could evolve in both of those contexts, in HER2+ and in HER2-low [disease] where we’re giving T-DXd even earlier.

Benjamin L. Musher, MD: May I ask a question about that?

Benjamin P. Levy, MD: Yes.

Benjamin L. Musher, MD: What are your thoughts on why this works? Do you all think this works because of the heterogeneity of the cancer? Or do you think it works because maybe HER2 isn’t the only target or…as important of a target as you think it is or as we thought it is?

Benjamin P. Levy, MD: I’ll give Kevin the floor because he’s doing breast, but I have a whole postulate that I’ll open up at the very end. But I’ll let Kevin go first. The question is really good. Ben, correct me if I’m wrong. Why is this drug working not only in HER2 overexpressed [disease] but also in HER2 low? Is that because the target is not there in HER2 low? How is this drug eliciting any activity with no target on the cell?

Kevin Kalinsky, MD, MS: I’m going to give you my personal opinion, and others may disagree, but my feeling is we’ve been debating for a long time, since the mid-2000s, about how we define HER2 status. If you look at ASCO [American Society of Clinical Oncology] guidelines, including those that are led by Ben’s colleague Antonio Wolfe, we see that HER2 has been redefined multiple times. We’ve not been as precise with discrimination of HER2 status. You know, we’d like to think that we are. So to me, there is the question of how well we’ve been defining it, and now that we have a really active agent, we may not be appropriately defining HER2 status. That’s on the one hand. And then I do think that there can be some bystander effects. One of the experts in HER2 pathology is Michael Frederick Press, MD, PhD, who’s Keck School of Medicine at USC. His reporting of actually having heterogeneity of HER2 is quite low, less than 5% [of patients]. So I think that it’s probably a biomarker issue in addition to some bystander effect.

Benjamin P. Levy, MD: Kevin, and I then want Kayla [Freeman, DNP, APRN, FNP-C] to also comment on toxicities and what you’re seeing, is it safe to say right now that…––and again, I’m learning here that T-DM1 is no longer on the shelf for patients with breast cancer because the head-to-head trial [data] showed that T-DXd was better––there is still a place for T-DM1?

Kevin Kalinsky, MD, MS: There is definitely still a place for T-DM1. We utilize it quite frequently in the adjuvant setting with residual disease in HER2+ breast cancer with the understanding that there’s a clinical trial now that’s comparing T-DXd to T-DM1. And I suspect that will potentially get displaced, but we still use it in that context. Also patients with HER2 + breast cancer, we treat with HER2 therapy during the duration of their life, so we may not use it [in the] second line, but I would argue that we utilize it now [in the] fourth line plus.

Benjamin P. Levy, MD: Got it. So there is at least a biological rationale for sequencing strategy in the continuum of a patient[’s treatment] if you started with T-DXd––at some point they may still get T-DM1?

Kevin Kalinsky, MD, MS: Yes, correct.

Transcript is AI-generated and edited for clarity and readability.