How Trodelvy and Keytruda May Reshape First-Line Metastatic TNBC

For patients newly diagnosed with PD-L1-positive metastatic triple-negative breast cancer (mTNBC), the treatment landscape is undergoing a significant shift. While the combination of chemotherapy and immunotherapy has served as the standard of care for several years, recent data from the ASCENT-04 trial suggests a more potent alternative may be on the horizon.

Dr. Sara Tolaney, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute in Boston, sat down for an interview with CURE to discuss the results of combining the TROP-2-directed antibody-drug conjugate (ADC) Trodelvy (sacituzumab govitecan) with the immunotherapy Keytruda (pembrolizumab). The trial demonstrated a clinically meaningful improvement in progression-free survival, or how long patients lived without their disease spreading or worsening, extending stability from 7.8 months with traditional chemo-immunotherapy to 11.2 months.

Tolaney explained why this three-month gain is so critical for a patient population where nearly half of individuals never reach a second line of therapy. By moving effective ADCs into the first-line setting, clinicians hope to capitalize on synergistic effects and the unique "bystander effect" of Trodelvy to improve long-term outcomes.

CURE: For a patient newly diagnosed with PD-L1-positive metastatic triple-negative breast cancer, how does the combination of Trodelvy and Keytruda fundamentally changed the treatment conversation compared to the traditional chemo plus immunotherapy approach?

Tolaney: For several years now, our standard of care for someone who has metastatic triple-negative breast cancer that has a tumor that's PD-L1 positive and has not previously received treatment in the metastatic setting has really been to use chemotherapy with [Keytruda], but we've seen antibody-drug conjugates and their very robust activity in patients with triple-negative breast cancer, particularly in the pretreated triple-negative state, where we've seen how robust [Trodelvy] performs, where it's really improved both progression-free and overall survival compared to standard chemotherapy.

And so, there had been a lot of interest to see if we could combine [Trodelvy] with immunotherapy, knowing that it works better than chemo does when used alone, and knowing that it potentially can lead to synergistic activity when given with immunotherapy. And so the ASCENT-04 trial compared [Trodelvy] and [Keytruda] to chemotherapy and [Keytruda] in patients with previously untreated, metastatic triple-negative breast cancer who had tumors that were PD-L1 positive, and did find that the combination of [Trodelvy] and [Keytruda] in fact did significantly improve progression-free survival, going from about 7.8 months to 11.2 months. So a difference between the two arms of about 3.4 months with a hazard ratio of 0.65, so I think a robust and clinically meaningful difference between the two arms, and I hope, will lead to an approval for [Trodelvy] and [Keytruda] in this setting,

How do those extra months of stability impact a patient's quality of life and their overall treatment journey?

So, in someone with metastatic triple-negative breast cancer, unfortunately we know that this is a very aggressive form of disease, and in general, survival has been quite limited, usually ranging somewhere between 18 to 20 months. And so moving a very effective treatment into the first line setting and improving progression-free survival is super critical, because we know that about half of our patients who initiate their first treatment for metastatic triple-negative disease will never be able to get on to a second line of therapy, with about a third of them actually dying before getting second line treatment. So this 3.4 month improvement in PFS, I think, is quite critical for our patients in that upfront setting, and so hopefully, will have tremendous impact for patients moving forward.

We're talking about a TROP-2-directed antibody-drug conjugate. Can you explain how the bystander effect works, and why this specific delivery mechanism makes it such a potent partner for immunotherapy?

The way these antibody-drug conjugates work is that they are taking an antibody that is targeting a particular receptor that is very commonly expressed on a cancer cell, but not really seen on most of our normal cells. That way, we can target something on the cancer cell, and then they take this antibody and they link it to a bunch of very potent chemotherapy. So in the case of [Trodelvy], it is a TROP-2-directed antibody, so it's going to bind to TROP-2 on the cancer cell, and it is linked via a cleavable linker to a chemotherapy agent, in this case, SN-38, where there are eight different chemo molecules per antibody. So you're able to deliver a ton of chemotherapy into one cancer cell.

And so, when the antibody binds to TROP-2, you can have that whole antibody with its chemo attached to get taken into the cancer cell, and then it releases the chemo in the cancer cell so it can kill that cancer cell. But then that chemotherapy actually has the ability to diffuse through the cell membrane of the cancer cell into the neighboring cancer cell, and so it can kill the neighbor as well, even if that neighbor doesn't even express TROP-2. Because it's just simply diffusion of the chemotherapy agent through the cell membrane into the neighboring cancer cell with [Trodelvy], there is also some payload release just outside the cancer cell before it goes into the cancer cell. And so there is some free chemotherapy in the tumor microenvironment that can also diffuse into neighboring cancer cells. And so, this bystander effect simply means that you are having the chemo diffuse from the cancer cell into the neighbor, and so you're killing neighboring cancer cells, which can be particularly important when the neighbors may not have as robust target expression, so when there's heterogeneous target expression, having bystander effect actually becomes quite critical at killing tumor cells.

Fewer patients discontinued treatment due to side effects on the Trodelvy-Keytruda arm compared to the chemo-Keytruda arm. What does this tell us about the tolerability of this combination?

With [Trodelvy], we know that it is, in essence, delivering chemotherapy which is a topoisomerase one inhibitor, and the major toxicities do include neutropenia and a risk of diarrhea. So I'd say about half of our patients do end up requiring growth factor support to maintain their blood counts. And so it's really important to consider if a patient may have high risk of neutropenia, and consider growth factor utilization. And for diarrhea, usually I find just intermittent lopermide seems to work quite well.

But, when you're comparing [Trodelvy] to our traditional chemotherapy agents like taxane or carboplatin gemcitabine, we do find that those agents can have what we call dose-limiting toxicities. For example, with taxol chemotherapy, you can run into neuropathy, which can become so severe that you have to stop the chemo drug, or with carboplatin gemcitabine, maybe you run into troubles with severe cytopenias, where you just really can't treat through it anymore. And so we do see that you don't seem to have as much trouble with dose-limiting toxicities with [Trodelvy] as you do with traditional chemo drugs. And so that, I think, is probably why we see that rates of discontinuation are lower with [Trodelvy] compared to the standard chemotherapy agents.

The NCCN recently added this combination as a category 2A preferred option for PD-L1-positive patients, and Trodelvy monotherapy is category 1 for PD-L1-negative patients. For patients whose clinics may not yet be using this combination, how significant are these guideline updates?

One, I think it's really important to see these drugs in the guidelines, because technically, we haven't yet gotten FDA approval for [Trodelvy] and [Keytruda], nor for [Trodelvy] alone in the first-line metastatic triple-negative setting. At the time these guidelines were put together by the NCCN, we did have the publication for ASCENT-03, and so I think that's what led to the recommendation for use of [Trodelvy] as category 1. I think the 2A for [Trodelvy] and [Keytruda] is probably in part related to the fact that it wasn't also published at the time they put these guidelines together, and now it is published. So hopefully these categories will change over time as we get them updated, and hopefully we'll see approval shortly, so they'll be standardly approved. But, by having them in the guidelines, it often means that it's much easier to get insurance coverage for these agents, and so I think it allows us to start prescribing them, at least within the United States, and often seeing no challenges with insurance coverage.

Transcript has been edited for clarity and conciseness.

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