Adam M. Brufsky, MD, PhD

This is the decade of the ADC. Since the first report of an ADC in breast cancer in 2012, we now have three approved for treatment of metastatic breast cancer — ado-trastuzumab emtansine (Kadcyla, Genentech), often called T-DM1; fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) and sacituzumab govitecan (Trodelvy, Gilead) — as well as one of them, T-DM1, approved in the post-neoadjuvant early setting.
It is remarkable that both trastuzumab deruxtecan and sacituzumab govitecan have OS benefit in multiple metastatic breast cancer settings, particularly for those patients who progressed through multiple prior treatments. The treatment landscape and natural history of metastatic breast cancer has been changed remarkably for the better by the development of these compounds.
ADCs are classified by (1) the antibody, often a biosimilar, against a particular tumor antigen; (2) the payload, often a chemotherapeutic agent too toxic to be used on its own; (3) the ratio of payload to antibody, with more payload to antibody being optimal; and (4) the linker, with linkers cleavable in the acidic extracellular peri-tumoral space allowing for a “bystander effect” in which parts of a heterogeneous tumor low in antigen expression are targeted by the payload brought into proximity by tumor with higher antigen expression.
Building on the success of trastuzumab deruxtecan, T-DM1 and sacituzumab govitecan, there are multiple ADCs in development for breast cancer. Datopotamab deruxtecan builds on the success of trastuzumab deruxtecan through use of a cleavable linker, as well as the payload deruxtecan, one of the more potent known topoisomerase-I inhibitors. Like sacituzumab govitecan, datopotamab deruxtecan uses an antibody to the TROP2 antigen to target payload to the tumor. In phase 1 trials, datopotamab deruxtecan had promising activity in heavily pretreated metastatic triple negative breast cancer — in particular for disease that had progressed on sacituzumab govitecan.
An ESMO presentation revealed results of the first phase 3 study of datopotamab deruxtecan vs. standard chemotherapy in second-line estrogen-positive metastatic breast cancer that had progressed through one chemotherapy regimen.
We will need more follow-up and survival events to determine whether this trial will meet its co-primary endpoint. At this point, however, it is interesting to note that the HR for PFS is very similar to that of sacituzumab govitecan in this ER-positive metastatic breast cancer population. Absolute differences in PFS between the two studies likely reflect the more heavily pretreated population (two to four prior chemotherapy regimens) in the TROPICS-02 study of sacituzumab govitecan in ER-positive metastatic breast cancer.
Assuming TROPION-Breast01 meets its co-primary endpoint and obtains FDA approval, which TROP2-directed ADC — datopotamab deruxtecan or sacituzumab govitecan — will we use in the hormone-refractory ER-positive metastatic breast cancer setting? It appears at first glance that the efficacy of both ADCs is similar, and it is likely that toxicity and tolerability of either agent will be weighed in this selection. Additionally, as we await further data on ADCs in metastatic breast cancer (eg, TROPION-Breast02 in triple-negative breast cancer and DESTINY-Breast06 in HER2-ultra low metastatic breast cancer, among others), an exciting chapter in the treatment of a previously refractory disease continues to unfold.

Sarat Chandarlapaty, MD, PhD

We have heard a lot about ADCs at this meeting, as well as the last several large meetings. These drugs are sort of an imagining of what Paul Ehrlich described as a magic bullet — a way of delivering a drug to a pathogen or cancer but not to normal cells. The goal is to have increased efficacy and less toxicity. That is realized through this antibody platform that brings the toxic payload into the cancer cell. There, it releases its payload, both to the cancer cell and potentially to other cells in the tumor microenvironment.

One question with datopotamab deruxtecan is whether it matters how much TROP2 is expressed on the cancer cell in order to see efficacy for this drug. There have been some studies, including one led by Dr. Bardia, looking at high expression of TROP2 vs. low expression that showed some signal for high expression being a relevant parameter for a different TROP2 ADC, sacituzumab govitecan (Trodelvy, Gilead). However, TROP2 immunohistochemistry has actually been quite tricky to develop clinically, and when looking at broad sections of breast cancers and lung cancers, the vast majority do have very high expression of TROP2. From a pragmatic standpoint, the decision was made to not use any biomarker to select for TROP2 expression.

The key study question is: Which is more effective for unselected, chemotherapy-treated metastatic breast cancer — new chemotherapy for datopotamab deruxtecan? There was a clear improvement in PFS with datopotamab deruxtecan. There also was less toxicity overall, with numerically less grade 3 toxicity and less hematologic toxicity. There was some increase of nausea and stomatitis, which — while not high grade — still could be clinically meaningful to patients.

So, would I rather prescribe datopotamab deruxtecan or more chemotherapy after one to two lines of chemotherapy in unselected hormone receptor-positive, HER2-negative breast cancer? The answer is datopotamab deruxtecan. However, it leaves several unanswered questions.

First, we have two ADCs approved in hormone receptor-positive breast cancer — sacituzumab govitecan and fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo). Would I rather give datopotamab deruxtecan over one of these? I don’t have an answer.

Moreover, can I give these drugs in sequence? They have the same topoisomerase-targeting payload. Would datopotamab deruxtecan work after, say, sacituzumab govitecan or trastuzumab deruxtecan? We don’t have an answer for that, either.

Finally, would I rather prescribe datopotamab deruxtecan or some small molecules that might work in this context, like inhibitors of the PI3 kinase pathway?

But I would say the elephant in the room is really another question: Is datopotamab deruxtecan in this context delivering on the promise of an ADC? Although it is an incredibly high bar to say "Does it meet up to trastuzumab deruxtecan in HER2-positive breast cancer?", I would suggest this is where we want to be. You could say "This is just HER2-positive breast cancer" or "It’s just a unique situation." That’s exactly the point. It is a biomarker-selected group that is deriving a very significant benefit. Why? Because HER2 is overexpressed massively and because HER2 is a driver in this case. So, we found a sweet spot for a biomarker for this particular drug and context.

We have learned over the past 20 years that we need to be giving selected therapy in these diseases. We really think of the biology of ER-positive breast cancer based on these oncogenic events that are both defining the biology of these cancers, the mechanisms of resistance and ultimately defining what therapies work and which ones do not.

We are not at the end of ADC development. There are many new ADCs coming that vary both the antigen targeting as well as the payload utilized. The question is, how are we going to use them in comparison to some of the established standards? Are we going to simply run them up against each other in unselected patients, or are we going to figure out which ones work the best for which patients?

We need to do the hard translational work now. We need to figure out who the rapid progressors are. Who were the patients who did really well who were on therapy 9 months, 12 months or beyond? What are the features of those cancers? And in those cases, how did they develop resistance after having a prolonged benefit?

Translational research is urgently needed to elucidate the mechanisms of drug action and generate effective biomarkers in this space. The research field can aim higher than beating standard-of-care chemotherapy given the enormous potential of this class of therapy.