Antibody-Drug Conjugates Could Be the Future of HER2-Low Breast Cancer Treatment

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

“Going forward, we will need to evolve our understanding and classification of HER2,” he said.

In an interview with Live®, Tarantino, a clinical researcher at the Dana-Farber Cancer Institute, described current methods for measuring and treating HER2-low breast cancer, discussed drug development challenges, and talked about upcoming trial data phase 3 DESTINY-Breast04 (NCT03734029). Data from this trial showed that patients with pretreated HER2-low tumors derive clinical benefit from trastuzumab deruxtecan.

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

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

Tarantino: It is important to look back, because for 20-25 years we have been categorizing HER2 as a binary [protein], as HER2-negative or HER2-positive. Indeed, when trastuzumab [Herceptin], the first HER2 inhibitor, has been developed, it has shown clinical benefit in patients with HER2 positive tumors, which account for 15-20% of all breast cancers. However, when trastuzumab was tested in tumors with low HER2 expression, it provided no clinical benefit.

The NSABP-B-47 Phase 3 trial [NCT01275677] random [3270] adjuvant trastuzumab patients. Again, trastuzumab did not improve outcomes in the HER2-low population for disease-free survival or overall survival [OS]. These results have recently changed with the development of new ADCs.

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

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

However, this definition is changing over time. In the patient population with an IHC score of 0, we have tumors with minimal expression of HER2. Today, we call these ultra-low expressors HER2. Patients with these tumors are included in some trials, for example the phase 3 randomized trial DESTINY-Breast06 [NCT04494425]. In the future, we will know if, in this category, new ADCs can have an activity, but for the moment, the definition [of HER2-low] which is mainly used is IHC 1+ or 2+ with negative ISH.

Does the evolution of this definition complicate clinical development and progress?

Absolutely, very difficult. Our main challenge is that this definition is based on these low categories of IHC, which were not really standardized. Previously, the question was whether a tumor could be classified as 3+ or 2+, and there was little need in clinical practice to distinguish score 0 from score 1+. And now we have this need, because [these scores] may alter the potential recruitment of patients into clinical trials and potentially alter the clinical possibilities open for future new drugs.

It becomes a problem because there are some studies, such as a yale study, showing that there is very little agreement between pathologists when reading slides with very low HER2 expression. In the future, we may need more standardization and possibly new tests for HER2.

Could you explain why the historic results have created a need for better drug development for patients with low HER2 breast cancer?

HER2-low is a heterogeneous category. It is mainly composed of 2 entities, 1 being a hormone receptor [HR]– positive tumors, which are usually luminal tumors that are treated with endocrine therapy, chemotherapy and certain biological treatments such as CDK4/6 inhibitors. However, for endocrine-resistant tumours, the main treatment is generally based on several lines of chemotherapy, and the results of these chemotherapies are not excellent. There is an unmet need for new treatments.

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

Moreover, most HER2-low tumors also co-express hormone receptors. Most HER2-low tumors will also 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-driven ADC to be approved. Trastuzumab emtansine is a drug we’ve been using for a long time, and it’s an active drug. The idea is that it delivers a chemotherapy payload to the tumor cell, targeting HER2.

The newer ADCs, compared to trastuzumab emtansine, have some technical improvements and they generally have a higher drug-to-antibody ratio. For example, trastuzumab deruxtecan has 8 payload molecules versus 3.5 molecules with trastuzumab emtansine. Additionally, most new ADCs have cleavable linkers and membrane diffusible payloads, allowing for what we call the bystander effect. This means that in tumors with heterogeneous HER2 expression, the payload can fuse to non-HER2-expressing cells and cause control death.

These hypotheses suggest that these effects might show activity in HER2-low tumors. In fact, we saw that when trastuzumab emtansine was tested in HER2-low breast cancer, the response rate was around 5%. It was not satisfactory. But with all these new agents, such as trastuzumab deruxtecan, trastuzumab duocarmazine and disitamab vedotin, we have a response rate of around 30% to 40%, 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 could come to the clinic. DESTINY-Breast04 was the first phase 3 trial to confirm the low HER2 paradigm. Basically, this trial included patients with pretreated HER2-low tumors, with both HR-positive and triple-negative disease. Patients were required to have received at least 1 or 2 lines of chemotherapy, and they were randomized to receive trastuzumab deruxtecan or chemotherapy of physician’s choice.

The Press release reported that progression-free survival, which was the primary endpoint, and OS were improved with trastuzumab deruxtecan compared with chemotherapy. We will see this data presented at the 2022 ASCO Annual Meeting and the 2022 EHA Congress. This data could change the way we treat patients who have been chemotherapy pretreated with or without endocrine therapy.

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

This agent has been tested in several trials now. What we’ve seen in early phase 1 trials with trastuzumab deruxtecan is that it’s a manageable agent. Most of the adverse effects were haematological or gastrointestinal toxicity, ie nausea or vomiting, but generally of low intensity.

In these early trials, we also observed a 10% to 15% rate of interstitial lung disease [ILD]. This was concerning because there were fatal effects. However, with other trials, especially the DESTINY-Breast03 trial [NCT03529110], which was a randomized study in HER2-positive disease. We have seen that when we improve our detection and management of ILDs, there is [fewer] serious cases and no fatal cases. In DESTINY-Breast03 there was approximately 10% ILD rate and no Grade 4 or 5 adverse reactions [AEs]. This means that we learn to better manage [the toxicities with] this officer.

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

If trastuzumab deruxtecan, trastuzumab duocarmazine and disitamab vedotin are all advancing in development and showing 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. Another big news in HER2-low disease is that the TROPiCS-02 Phase 3 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 one is active after the other, but we may collect this data in the months and years to come. For now, we may need to make comparisons between trials, [which, though not ideal are sometimes necessary when choosing treatments]. Presentation of 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 insights into the future of HER2-low breast cancer would you like to offer?

One trial that shocked the scientific community with its scientific significance, even though it only studied a small cohort of patients, is the DAISY Phase 2 trial. [NCT04132960]. This is 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 highly active, showing a rate of 69.1% [best objective] answer [BOR] rate, which is what we’ve seen in other trials in HER2-positive disease. This trial also had a HER2-weak cohort where we observed a BOR rate of 33.3%, which we had observed in other phase 1 trials. This trial also had a cohort of patients with an IHC score of 0 , a cohort we’ve never seen before. This cohort demonstrated a [30.6%] response rate, which is unexpected and raises many questions as to the best categorization of HER2. With 1+ or 2+ ISH-negative disease categorization, we may be excluding patients who might benefit from trastuzumab deruxtecan.

[We also want to know] why trastuzumab deruxtecan had activity in patients with IHC scores 0. Is it because there is minimal expression of HER2, even in this population? Or is it because the diffusing payload that detaches from the antibody may still have antitumor effects? These are all open questions. It will be important to investigate these issues in depth, particularly because there could be a population that is currently excluded from treatment with trastuzumab deruxtecan, but may still benefit from it.

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