Chapter 2: ADCs in the Frontline mTNBC Setting

Watch Chapter 3 here.

Katie Newlin: Hi everyone. My name is Katie Newlin. I'm a nurse practitioner at Washington University in St. Louis, and I'm here today with some of my colleagues, and we are talking about metastatic triple-negative breast cancer and kind of where we are today in the scheme of things.

Sanita Burgic: Good morning. My name is Sanita Burgic, and I'm a nurse practitioner at Washington University in St. Louis as well.

Ashley Martinez: Hi, I'm Ashley Martinez. I'm also a nurse practitioner at UTMD Anderson Cancer Center.

Amanda Brink: And I'm Amanda Brink. I'm a nurse practitioner in Sarah Cannon Research Institute's Drug Development Unit in Denver.

Ashley Martinez: Hi there. So we're going to talk about the evidence-based antibody drug conjugates in the frontline metastatic triple-negative breast cancer setting. So the data that drives these guideline updates really does come from several major phase three clinical trials. So, can we talk about what we know about those clinical trials and the evidence that tells us who benefits and by how much?

Katie Newlin: Yeah. So, as you mentioned, there are some phase three trials currently underway that are really going to change the landscape for triple-negative breast cancer in the metastatic setting. But first, I think we need to discuss the mechanism of action and the treatments we use in our practice. So, first, I wanted to kind of talk about the antibody drug conjugates and what they do and what they are. And so there are really three main components of an antibody drug conjugate. So the first one is a tumor-targeting monoclonal antibody that signals to those abnormal cells on the triple-negative surface, and it delivers a cytotoxic payload to those specific cells, those triple-negative cells. They're utilizing that cytotoxic payload. They're moving inward towards the intracellular level of the tumor cells. So, data DXD employs a different TROP2 targeted antibody with a DXD payload via a plasma-stable cleavable linker. DDXD is predominantly associated with stomatitis and oral mucositis rather than diarrhea and neutropenia.

All right, so ADCs have three key components. They combine a tumor-targeting cell that enters cells. The surface of the triple-negative breast cancer cells is kind of like a lock and key, saying, "Hey, here I am. I'm causing some abnormal cell growth." And so that monoclonal antibody can reach the cancer cells. It uses a cytotoxic payload that enters cells, delivering chemotherapy, sparing healthy cells, and then uses a bystander effect afterward to kill any abnormal cells floating in the area. So, in triple-negative breast cancer, the primary reason for using antibody-drug conjugates is that they target TROP2, a trophoblastic cell surface antigen. And that's a transmembrane glycoprotein that is overexpressed specifically in triple-negative breast cancer, and it's associated with tumor proliferation and an overall worse prognosis. There are now two TROP2-directed antibody drug conjugates that are currently in the frontline setting for triple-negative metastatic breast cancer. One utilizes a hydrolyzable link and an SN38 payload. The other utilizes a plasma-stable cleavable linker and a DXD payload.

Sanita Burgic: Thank you. In the next section, I'll discuss the pivotal trial evidence on this treatment option. So this is ASCENT-03, which is a phase three open-label randomized trial in the previously untreated locally advanced inoperable or metastatic triple-negative breast cancer that's not a candidate for the frontline PD-L1 therapy, PD-L1 negative, or previously treated with anti-PD-L1 in the early setting. So what it did was compare sacituzumab govitecan to chemotherapy of choice, which could have been paclitaxel, nab-paclitaxel, gemcitabine, or carboplatin. A total of 558 were evaluated. The primary endpoint, PFS, had a median of 9.7 months versus 6.9 months, with a hazard ratio of 0.62. It should be noted that the median duration of response was 12.2 months versus 7.2 months, and treatment discontinuation due to adverse events occurred in only 4% versus 12% with chemotherapy.

Ashley Martinez: Great. Thank you for that overview, Sanita. So I'm curious to hear what data to you all is most meaningful and how you communicate that to our patients?

Sanita Burgic: Yeah, I think the most meaningful data or parts of this data are that there's a longer progression-free survival, longer duration of response, and a lower treatment discontinuation rate with the ADC regimen. Overall, this suggests that patients have better disease control and remain on therapy longer.

Katie Newlin: I think one of the most meaningful things is that we're able to provide metastatic triple-negative breast cancer patients with a non-chemotherapy-based option, and something that could potentially minimize those typical chemotherapy toxicities that people tend to see. So I think being able to offer a non-chemotherapy option in metastatic triple-negative is something very revolutionary.

Sanita Burgic: I can agree with that.

Amanda Brink: And when I explain things to patients, I try to keep it very straightforward. I frame it as this is an option that is able to hopefully help control your cancer longer and with fewer toxicities so you can stay on treatment longer.

Ashley Martinez: Exactly.

Amanda Brink: And an effective treatment for longer.

Ashley Martinez: Yeah, great. Definitely.

Amanda Brink: Okay. Let's talk about ASCENT-04. This was a phase three trial evaluating sacituzumab plus pembrolizumab compared with the physician's choice of chemotherapy plus pembrolizumab in patients with previously untreated PD-L1-positive metastatic triple-negative breast cancer. The progression-free survival benefit was clinically meaningful. The median PFS was 11.2 months compared with only 7.8 months in the physician's choice arm. There were also improvements in overall response rate and duration of response, with a median duration of 16.5 months compared with 9.2 months. In terms of tolerability, it's also encouraging that the treatment discontinuation rate in the sacituzumab arm was less than the physician's choice of chemotherapy arm.

Sanita Burgic: That's great.

Ashley Martinez: Yeah, absolutely. Great overview of Ascent 04, Amanda. Thank you. So, for your PD-L1-positive patients, what does this combination approach change in how you counsel patients?

Amanda Brink: I really counsel patients about how closely we'll be working together to manage any potential toxicities that might arise, so they can stay on treatment as long as possible.

Katie Newlin: Yeah. I think one of the things I always make sure to mention to patients is the layered benefit and the layered toxicity profile. So we're looking at something more like chemotherapy: two things running at once. So part of the treatment is fast control, and then the immunotherapy comes in, and it's kind of more of your chronic delayed reactivity or activation. And so they don't work on the same timeline, so just making sure they know they shouldn't be disappointed if they're not seeing the response they want right away; they may see that benefit. They may see some benefit upfront, but we'll continue to see that long-term benefit as the immunotherapy continues to work.

Sanita Burgic: Yeah. Good point, pointing out the ADC and the pembrolizumab. I also like to explain that the side-effect profiles for those two drugs will differ, so we educate them on both and make sure they report these side effects to us early so we can respond and help them manage them.

Katie Newlin: I do. And I think it's important for APPs, specifically, to work together to ensure the patient understands what immunotherapy is. I think it's really hard to differentiate between immunotherapy and chemotherapy. And I still have patients who've been on immunotherapy for quite some time, and they don't fully understand what immunotherapy is doing. So I think it's very important to make sure they're aware of what immunotherapy does, how it boosts your system, and the labs you'll be checking regularly that go along with that.

Ashley Martinez: Great point, Katie. So, can we talk a little bit about the broader class picture now?

Katie Newlin: Yeah. Okay. I'm going to talk about the TROPION BRASTO2 trial. So that's a phase three trial of datopotamab deruxtecan versus investigator's choice of chemotherapy and the frontline metastatic triple negative breast cancer setting of those patients not candidates for PD-L1 inhibitor therapy. So the participation included about 644 patients. There were dual endpoints. So there were two endpoints being looked at, and the data showed that progression-free survival differed, with a hazard ratio of 0.57 (10.8 months versus 5.6 months) in favor of chemotherapy. And again, the second primary endpoint for that was overall survival. So that showed a median overall survival of 23.7 months with datopotamab, versus 18.7 months with the chemotherapy arm. So just to talk about Dato-DX, or datopotamab, it uses a different TROP2-targeting antibody with the DXD payload, and it has that stable, cleavable linker. This is a distinct mechanism from the SN38-based agent, predominantly associated with stomatitis-mucositis rather than diarrhea or neutropenia, as you can see with the other ADC.

Ashley Martinez: Yeah, great. So, how do you think about a landscape where there are two TROP2-directed antibody drug conjugates that may ultimately have frontline data, and how do you think about the nuanced differences between the randomized trial designs in this space?

Katie Newlin: So, as far as thinking about there being two different ADCs in the frontline preferred setting for metastatic triple negative, I think it's really exciting. I think it's exciting for metastatic triple-negative patients that we have two options to offer, and being able to go through them together, trying to decide which is best and which aligns more with the patient's wishes and comorbidities. And I think it's important and so overly exciting that we have more options in the metastatic triple-negative breast cancer setting.

Amanda Brink: I agree with Katie that it's exciting to have two TROP2 ADCs, but it just adds to the complexity of the TNBC landscape. So it really pushes us to think about the toxicity profile, the payload, and where each one might fit in sequencing.

Katie Newlin: Yeah.

Ashley Martinez: Absolutely.

Sanita Burgic: I agree. And then, considering the different side-effect profiles and trying to choose patients based on their clinical status at that time, which one would do better with one ADC versus the other?

Ashley Martinez: Great insights. Thank you.

Katie Newlin: Yeah.