Antibody-Drug Conjugates May Represent the Future of HER2-Low Breast Cancer Treatment

Paolo Tarantino, MD

Emerging data with novel antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan-nxki (Enhertu), vic-trastuzumab duocarmazine, and disitamab vedotin (Aidixi) are showing encouraging activity in HER2-low breast cancer. Paolo Tarantino, MD, said this data suggests that the classification of HER2 should go beyond merely positive or negative.

“In the future, we will need to evolve our understanding and classification of HER2,” he said.

In an interview with OncLive^®, Tarantino, a clinical research fellow at Dana-Farber Cancer Institute, outlined current measurement and treatment methods for HER2-low breast cancer, discussed challenges regarding drug development, and spoke about upcoming data from the phase 3 DESTINY-Breast04 trial (NCT03734029). Data from that trial has shown that patients with pretreated HER2-low tumors derive clinical benefit from trastuzumab deruxtecan.

Tarantino also voiced his hopes for the future of treatment advances in HER2-positive disease. He noted that broadening HER2 disease classification to include more patient subgroups such as those with an immunohistochemistry (IHC) score of 0 in clinical trials may help determine potential treatment benefits for a greater proportion of patients.

OncLive^®: What is important to know about the field of HER2-low breast cancer?

Tarantino: It’s important to look back, because for the past 20 to 25 years, we have been categorizing HER2 as a binary [protein], as either HER2-negative or HER2-positive. This was because, when trastuzumab [Herceptin], the first HER2 inhibitor, was developed, it showed clinical benefit in patients with HER2-positive tumors, which represent 15% to 20% of all breast cancers. However, when trastuzumab was tested in tumors with low HER2 expression, it didn’t add any clinical benefit.

The phase 3 NSABP-B-47 trial [NCT01275677] randomized [3270] patients to adjuvant trastuzumab. Once again, trastuzumab did not improve outcomes in the HER2-low population in terms of disease-free survival or overall survival [OS]. These outcomes have recently changed with the development of novel ADCs.

What constitutes HER2-low disease and how is it currently measured?

The classification for HER2-low that is used in most clinical trials [means] tumors that have an IHC expression of 1+ or 2+ with a negative in situ hybridization [ISH] assay. [These are tumors] without the amplification of the ERBB2 oncogene. With this definition, about half of all breast tumors can be defined HER2 low.

However, this definition is evolving over time. In the population of patients with an IHC score of 0, we do have some tumors with minimal HER2 expression. Today we call these ultra-low HER2 expressors. Patients with these tumors are included in some trials, for instance, the randomized phase 3 DESTINY-Breast06 trial [NCT04494425]. In the future, we’ll know if, in this category, novel ADCs can have activity, but for the moment, the definition [of HER2-low] that is mostly used is IHC 1+ or 2+ with negative ISH.

Does the evolution of that definition make clinical development and advances challenging?

Absolutely, very challenging. Our main challenge is that this definition relies on these low categories of IHC, which were not really standardized. The question used to be whether a tumor could be categorized as either 3+ or 2+, and there wasn’t a strong need in clinical practice to distinguish the 0 score from the 1+ score. And now we have this need, because [these scores] can change the potential enrollment of patients into clinical trials, and potentially change the open clinical possibilities for future new drugs.

This becomes a problem because there are some studies, such as a study from Yale, showing that there is very little concordance among pathologists when reading slides with very low HER2 expression. In the future, we might need more standardization and possibly novel assays for HER2.

Could you elaborate on why historical outcomes have created a need for better drug development for patients with HER2-low breast cancer?

HER2-low is a heterogeneous category. It’s mainly made up of 2 entities, 1 being hormone receptor [HR]–positive tumors, which are usually luminal tumors that are treated with endocrine treatment, chemotherapy, and some biologic treatments like CDK4/6 inhibitors. However, for endocrine-resistant tumors, the main treatment generally relies on several lines of chemotherapy, and outcomes with these chemotherapies are not excellent. There is an unmet need for novel treatments.

[The other category of HER2-low disease, triple-negative breast cancer (TNBC), has similar treatment methods. TNBC is] also mainly treated with chemotherapy, although some novel options are emerging, such as immunotherapy or other ADCs targeting TROP2. However, after these patients have been treated with immunotherapy or TROP2 [inhibitors], we only have chemotherapy for these patients. Once again, we need novel options.

Additionally, most HER2-low tumors also coexpress hormone receptors. Most of the HER2-low tumors are also going to be HR positive… About a third of triple-negative breast tumors will have HER2-low expression.

Some of the drugs being developed in HER2-low breast cancer include trastuzumab deruxtecan, trastuzumab duocarmazine, and disitamab vedotin. What makes these drugs exciting?

These are all evolutions of ado-trastuzumab emtansine [Kadcyla], which was the first HER2-directed ADC to be approved. Trastuzumab emtansine is a drug that we’ve been using for a long time, and it’s an active drug. The idea is that it delivers a payload of chemotherapy toward the tumor cell, targeting HER2.

Novel ADCs, in comparison with trastuzumab emtansine, have some engineering improvements and they usually have a higher drug-to-antibody ratio. For instance, trastuzumab deruxtecan has 8 molecules of payload compared with 3.5 molecules with trastuzumab emtansine. Also, most novel ADCs have cleavable linkers and membrane diffusible payloads, which allow for what we call the bystander effect. This means that in those tumors with heterogeneous HER2 expression, the payload can be fused to non-HER2 expressing cells and prompt bystander killing.

These hypotheses suggest that these effects could show activity in HER2-low tumors. In fact, we have seen that when trastuzumab emtansine was tested in HER2-low breast cancer, the response rate was around 5%. That was unsatisfactory. But with all these novel agents, such as trastuzumab deruxtecan, trastuzumab duocarmazine, and disitamab vedotin, we have around a 30% to 40% response rate, which is much more interesting and encouraging.

[We now also have a press release announcing data from the phase 3 DESTINY-Breast-04 trial], suggesting that these drugs might come to the clinic. DESTINY-Breast04 was the first phase 3 trial to confirm the paradigm of HER2 low. Basically, this trial included patients with pretreated HER2-low tumors, both with HR-positive and triple-negative disease. Patients had to have received at least 1 or 2 lines of chemotherapy, and they were randomized to trastuzumab deruxtecan or physician’s choice chemotherapy.

The press release announced that progression-free survival, which was the primary end point, and OS were improved with trastuzumab deruxtecan compared with chemotherapy. We will see these data presented at the 2022 ASCO Annual Meeting and the EHA 2022 Congress. These data might change the way we treat patients who have been pretreated with chemotherapy with or without endocrine treatment.

What do you hope the results of DESTINY-Breast04 will show in terms of safety?

This agent has been tested in several trials now. What we have seen in the first phase 1 trials with trastuzumab deruxtecan is that it’s a manageable agent. Most of the adverse effects were either hematologic or gastrointestinal toxicity, meaning nausea or vomiting, but usually low grade.

In these first trials, we have also seen a 10% to 15% rate of interstitial lung disease [ILD]. This was concerning because there were some fatal effects. However, with further trials, particularly the DESTINY-Breast03 trial [NCT03529110], which was a randomized study in HER2-positive disease. We saw that when we improved our detection and management of ILD, there were [fewer] severe cases and no lethal cases. In DESTINY-Breast03, there was around a 10% rate of ILD and no grade 4 or 5 adverse effects [AEs]. This means that we are learning to better manage [the toxicities with] this agent.

I would expect the AE profile in the DESTINY-Breast04 trial to be similar to what we have seen in DESTINY-Breast03, which would mean that trastuzumab deruxtecan is a manageable agent.

If trastuzumab deruxtecan, trastuzumab duocarmazine, and disitamab vedotin all move forward in development and show positive phase 3 data, do you see each agent carving out a role in this population?

[The answer to this question] goes beyond HER2-directed ADCs. Other big news in HER2-low disease is that the phase 3 TROPiCS-02 trial [NCT03901339] is positive, meaning that sacituzumab govitecan-hziy [Trodelvy], a TROP2 inhibitor ADC that is approved in triple-negative disease, is also more active than chemotherapy in HR-positive disease. In this pretreated population, we might have different ADCs available and we might need to decide which one to prioritize.

We don’t really know if 1 is active after the other, but we may gather these data in upcoming months and years. For the moment, we may need to do cross-trial comparisons, [which, though not ideal are sometimes necessary when choosing treatments]. The presentation of the data from DESTINY-Breast04, TROPiCS-02, and other trials with disitamab vedotin and trastuzumab duocarmazine [will help us understand the roles of these agents going forward].

What other future perspectives on HER2-low breast cancer would you like to offer?

One trial that shocked the scientific community with its scientific importance, even though it studied only a small cohort of patients, was the phase 2 DAISY trial [NCT04132960]. This was a study conducted in France that tested trastuzumab deruxtecan in patients with advanced breast cancer, regardless of HER2 expression.

The DAISY trial had a HER2-positive cohort where the drug was very active, showing a 69.1% [best objective] response [BOR] rate, which is what we have seen in other trials in HER2-positive disease. This trial also had a HER2-low cohort where we saw a 33.3% BOR rate, which we had observed in other phase 1 trials. This trial also had a cohort of patients with an IHC score of 0, which is a cohort we had never seen before. This cohort demonstrated a [30.6%] response rate, which is unexpected and raises many questions regarding the best categorization of HER2. With the categorization of 1+ or 2+ ISH-negative disease, we are possibly excluding patients that could derive benefit from trastuzumab deruxtecan.

[We also want to know] why trastuzumab deruxtecan had activity in patients with IHC 0 scores. Is it because there is minimal HER2 expression, even in this population? Or is it because the diffusing payload that is detached from the antibody can still have antitumor effects? These are all open questions. Studying these questions in depth will be important, especially because there might be a population out there that is currently excluded from treatment with trastuzumab deruxtecan but may still derive benefits from it.

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