Moving Beyond Chemotherapy in Metastatic Triple-Negative Breast Cancer (mTNBC): Are We Clinically Ready? Round 1

Watch Round 2 here.

Kelly McCann: Round 1 will be: Is chemotherapy being replaced as the default first consideration for metastatic triple-negative breast cancer? So, the current first-line standard for metastatic triple-negative breast cancer is chemotherapy plus an immune checkpoint inhibitor. 

This is an example from the KEYNOTE-355 regimen, which showed an overall survival advantage among patients whose tumors expressed PD-L1 with a combined positivity score of 10% or greater, with a hazard ratio for death of 0.73. So, the types of treatments included as a chemotherapy backbone here were taxanes or GemCarbo.

Then, after several studies were reported at ESMO in Berlin in October, and then also at, is it ASCO or San Antonio? No, it was ASCO for the ASCENT-03. ESMO-4 was-So there was ASCENT-04 with saci plus pembro. There was ASCENT-03, and then there was TROPION-Breast02, which featured sacituzumab govitecan and datopotamab deruxtecan. 

So as of January 2026, the NCCN guidelines have been updated. For patients who are PD-L1-positive, regardless of BRCA1 or 2 statuses, the preferred regimens are category 1: chemotherapy plus pembrolizumab or sacituzumab govitecan plus pembrolizumab. For those patients who are PD-L1 negative and have no BRCA variant, sacituzumab, govitecan, datopotamab, deruxtecan, and systemic chemotherapy are all options. Then, for patients who are PD-L1-negative and have a BRCA1/2 variant, they can receive a PARP inhibitor as a category one preferred agent, or a platinum agent. So, the first round is Dr Mouabbi with: Chemotherapy Does Not Address the Need for Urgency.

Jason Mouabbi: All right. For today's debate. So yes, absolutely. Yes. We are ready for ADCs to replace chemotherapy, and chemotherapy does not and will not address the urgency.

All right, just look at it. When you look at data, most of our patients with triple-negative breast cancer in the metastatic setting will only receive one line of therapy. That's it. Because look at the attrition rate when you go to the second line. 50% of your patients will never reach the second line of treatment.

Even worse, when you look at the third line, only one in four patients will ever be fit enough to receive a third-line therapy. So your ground better is the first line. What does that mean? You want to give them the best treatment available. You cannot wait. This idea, I'm going to keep the more effective treatment in my back pocket, will not hold true over here because the chances are your patients are never going to make it to get that line of therapy.

Anytime you can, you have to give the best treatment available in any setting, and the winner is clear. ADCs are superior to chemotherapy. This is the ASCENT-03 and ASCENT-O4. I remember them because people always confuse three and four. Remember, four is one higher than three. That means four need to have another drug.

So, ASCENT-O3 is a single-agent ADC versus a single-agent chemo. ASCENT-O4 is two drugs. So here, you have chemo plus pembro versus SG plus pembro. There is a clear winner. There is a clear winner for the first-line setting: ADC with or without immunotherapy.

We also have the TROPION-Breast02, which was presented alongside ASCENT-03 at the ESMO Congress. Again, clear winner. That is a clear winner. The administration of ADCs in the first setting improves outcomes in our patient with metastatic triple-negative breast cancer.

Look at the hazard ratio. It's close to 0.5, which means about 50% fewer events. Events, meaning less progression and fewer deaths, with an ADC over chemotherapy. The message is clear. I'm going to call it a mic drop. All right, you're up.

Seth Wander: All right. Great to be with everybody today. Thanks for the introduction. Always a pleasure to return to South Florida. When Kelly reached out and said, "Will you do this debate?" I said, "Sure." Then, after I committed, she told me who I was debating. Then I said, "No, no, no. I can't do it." The most charismatic and convincing man in oncology, Jason, could go out to the pool and convince people to buy a North Face jacket in 85-degree weather. So I know that I'm in trouble, but I'm going to do my best here because you're right, Jason, the only point is to win.

Chemotherapy is absolutely the right thing to do, and we should keep doing it for now, and I'll tell you why. Now, overall survival, which matters most to us as clinicians. We still don't have the signal, despite Jason's enthusiasm for ACSENT-04. Those curves are very much on top of each other for the moment. There may be a little bit of a trend developing, but when I was in graduate school, my PI said that's not enough, right? You need a significant P-value here.

So, we see improvement in progression-free survival, but we don't yet see that translating into overall survival now for these combos. Again, we see the trend here. Things are moving in the right direction for TROPION-Breast02. But one of the things my friend Jason neglected to point out was that the control arm here was a little weaker than what we saw in the ASCENT studies. We're only considering single-agent chemotherapy in the control arm. So, this is like picking a fight, but the other person must tie one hand behind their back while they're facing you.

So yes, we have the trend here. Yes, it's moving in the right direction, but I think we need more mature data for the overall survival of both. Now, to me, this is the most concerning and convincing aspect. Jason's point is well taken. You want to have your first and best shot at this disease, where many folks don't make it to the second- and third-line settings. But for those of us who treat a lot of these patients, anecdotally, at least I think many of my patients are getting to two or three plus lines of therapy. So, part of that is earlier diagnosis, intervention, and education.

Here's the thing that worries me the most: the idea of kind of stacking the PFS value. So, we know right now that if you look at KEYNOTE-355 and then at data from the earlier ASCENT trial, the benefit of sacituzumab in the second-line setting. So you have the PFS on regimen one, which is KEYNOTE-355. Then after that, you have the PFS on regimen two, which is sacituzumab, monotherapy.

The big concern here is that if Jason wins this debate and everybody starts using ADC upfront, we don't know how well people will benefit in the second-line setting, or from conventional regimens. So when you start to stack PFS-1 plus PFS-2 and we're moving these drugs earlier, I am concerned, and I think many of us are concerned that the magnitude of benefit for PFS-2 is going to fall off dramatically, such that when you add them together, actually, you may have more time on drug, right? More time on PFS-2.

Now, the details here are going to be borne out in overall survival, right? If you can still get benefit in the second- and third-line settings, plus after upfront use of ADCs, that's going to translate into overall survival when you add up PFS-1 and 2, et cetera. If not, if the disease is much more aggressive and falling off more rapidly, you're not going to see an overall survival benefit with earlier deployment of ADCs. So, I think that's something we need to think about. I'm going to turn it back over to Dr McCann.

Jason Mouabbi: I need to respond. I have to respond.

Kelly McCann: Hold on. Hold on. Hold on. We'll respond during the discussion. So let's say we have a newly diagnosed metastatic triple-negative breast cancer patient presenting for initial therapy. What factors influence urgency in this patient?

Jason Mouabbi: So, it's going to tie in a bit with what you said in your last message about the patient going to the second line. 50% of patients will not proceed to second-line therapy. So, if you're going to wait for how those agents are going to do in the second line, half your patients, you're never going to know.

Kelly McCann: That's not really true.

Jason Mouabbi: The data speak for themselves. Half of the patients—just putting her finger on the scale for me. Did you see that? She's backing me up.

Seth Wander: I can see that.

Kelly McCann: At your institution, is that true?

Jason Mouabbi: Well, the academic center is a little bit different from the community, but in the community, it is. I practice in the community, and we used to see that. Half the patients don't make it to the second line because either the disease progresses very quickly and they're not candidates, or because of other attrition factors. So that's one.

Number two is that when you look for overall survival, I agree, we like to have it. However, remember on the ASCENT studies, they allowed crossover. 80% of patients crossover to the ADC, a second-line drug, because the company offered to pay for it. So you're not going to see... It's hard to see overall survival when most patients on the control arm who received second-line treatment received the same treatment as first-line. So it's hard to see overall survival.

Now, on the TBO2, they did not allow crossover because Dato-DXd is not yet approved for other reasons. That's why you see a separation; time will tell, but it looks like they're separating and not meeting again. So, I just think with a little follow-up, we're going to get.

Now, back to your question. So, what factors influence the urgency in patient triple-negative breast cancer, a deadly disease, the most aggressive disease? Truly, if we need to do one thing right now, we can improve outcomes a lot for our hormone-positive and HER2-positive patients. By the way, HER2-positive used to be the nastiest one, and now it's the most treatable one. We need to have that aha moment with HER2 for our triple-negative patients, and we are moving the needle with ADCs. It is time.

Seth Wander: Yeah. I don't disagree, and I actually think this debate isn't just about the idea of earlier deployment of ADCs. There's a philosophical question here, with two parts. The first is, if you have better drugs, not just for triple-negative disease, should you be moving them earlier, right? We see the same thing in ER-positive disease. We see earlier deployment of next-generation antiestrogens and PI3K inhibitors. Should we be using them in the adjuvant setting to help cure more patients?

The second part of the question is: what is the effect of our adjustments on the biology and molecular genomics of the disease? So, if we had had this debate 10 years ago, and it was about fulvestrant and ER-positive, and I said, "What do you expect the second-line magnitude of benefit for fulvestrant to be before CDK inhibitors?" Everybody would have said eight to 12 months.

Now, if I ask you, two to four months, right? So we did that. We moved CDK inhibitors earlier. We put more pressure on the disease. Yes, they're better drugs. Yes, in some cases, they improve overall survival, but the molecular genomic changes result in a more aggressive phenotype, which we need to address and develop better drugs for the second and third lines. I do truly believe that this maneuver, moving ADCs earlier with or without immune therapy, will put different pressure on the tumor, will create a different kind of disease.

At the moment, we do not have the tools in hand to address that. But Jason's point is well taken about the severity of the disease and the desire to treat with optimal. Thank you for being on my side. I gave you one point.

Kelly McCann: I think we kind of hit the first two.

Seth Wander: We have two more rounds.

Kelly McCann: Yes, we do. Why do you think chemo remains the reflexive choice for many clinicians?

Seth Wander: I mean, I think it's evolving. I think it's comfort, right? People have used chemotherapy for this disease for many years. This is a highly chemosensitive disease. They're used to seeing responses. They know how to deal with toxicity. We're going to talk about toxicity in a moment.

I do think ADCs are increasingly widely deployed across many tumor types. So, general oncologists in community settings are using a lot of TDXD and treating many different tumors, and I think you're seeing a bit of a shift. I don't know. Do you feel differently?

Jason Mouabbi: No, I agree. I think they're used to it. At the end of the day, when we're used to something and we have used it for such a long time, we're comfortable with it. We're comfortable giving it to our patient. We know what to expect from it. We know how to deal with that side effect and all that. Those ADCs are newer, right? Many physicians don't have much experience with them, which is why they're a little reluctant.

But I would say always focus on the patient. If we are a patient, put ourselves in the patient's shoes. If we are a patient, what do we want? We want the most effective therapy. The therapy that can set us up for success, right? That starts with the first line, and that will start with ADCs.

Kelly McCann: I think, in my practice, we're sometimes lucky. We're in an academic center, where our authorization team (if you have one) can get these drugs quickly, but in community practices, they might not be able to get an ADC. Sometimes I even do peer-to-peer, just saying: "If you've tried to get either of these, sacituzumab, govitecan, or datopotamab deruxtecan in the first-line setting, I've had pushback in the last few months, even though NCCN guidelines have changed too." This would be a little provocative because a lot of times we are being very reactive to a metastatic triple-negative breast cancer patient, because if you're waiting for symptoms, she might come in liver failure or respiratory failure.

I know you do a lot of ctDNA in the adjuvant setting. How would that change this, if at all? If you caught it early. What can you say?

Jason Mouabbi: Yeah. So, triple-negative: the problem is that when you catch it in the adjuvant setting with ctDNA, the time... Every time you have a positive ctDNA, if you're doing it, always get a scan, right? The majority of patients who are triple-negative, when they're turned positive, the time you scan them, you find metastatic disease.

So, unfortunately, for that special type of breast cancer, ctDNA is not really trying to catch it before you see overt metastatic disease. We don't see that lead time that we see with hormone-positive breast cancer, which is a challenge. That's why the idea of just moving ADCs to the first-line setting doesn't work; those ADCs have to move to the edge of the setting, because, truly, the sooner you can tackle that cancer with the most effective therapies, the better our patients will eventually feel. What do you think?

Seth Wander: I think you're pushing them farther, so they'll be more willing to agree to the debate topic, which is the first line. If you convince them of the adjuvant, they'll agree on first-line treatment. I think it's the same challenge, right? More toxicity is always a bit of a bigger hurdle in the adjuvant curative intensive setting. Again, what comes out of that, particularly for the rapid progressors, is a big issue. KEYNOTE-522, which has become the dominant standard of care, all of us who treat many patients have seen great responses and higher rates of path CR.

We've also seen the patients who progress on or shortly thereafter, and they are exceedingly difficult to treat because you've given them anthracycline, you've given them taxane, you've given them platinum, you've given them IO, and they're still growing, and even the ADCs are not carrying much weight in that situation. So the point's the same. We're moving more aggressive, more effective therapies earlier. We might be moving the needle in terms of cure rates, but we are creating a more virulent and difficult-to-treat disease.

Jason Mouabbi: I would say that TROPION-Breast02 included patients who hyperprogressed from the early setting within 6 months of their curative-intent treatment after receiving adjuvant androgen treatment. So, in that study, about 15% of patients within six months, and you can see that the TBO2 showed those patients also benefited from the use of ADCs.