New Discoveries in Breast Cancer Trials Demand Reconstruction of Disease Subtypes

New treatments such as ado-trastuzumab emtansine (Kadcyla), fam-trastuzumab deruxtecan-nxki (Enhertu), and CDK4 / 6 inhibitors revolutionize treatment across breast cancer subtypes, according to Gregory Vidal, MD, and PhD. I am. Vidal said that distinguishing HER2-low as another form of disease can broaden the treatment environment for this population.

“future [of breast cancer] It’s bright, “said Vidal in the next interview. OncLive^® The current status of the Science Summit ™ on Breast Cancer, chaired by him. “We will definitely introduce new treatments to our arsenal and we need to think about what we think of breast cancer as a whole.”

In the interview, Vidal, a medical oncologist at the West Cancer Center & Research Institute, summarized the key points of each presentation shared at the conference, including HER2 low breast cancer and the evolution of treatment options for new antibody-drug conjugates (ADCs). Survival of HER3 as a new target for triple-negative disease and breast cancer. In addition, he emphasized ribociclib (Kisqali) as a potential drug in combination with hormone therapy and benefited from oral selective estrogen receptor blockers (SERDs) in estrogen receptor (ER) -positive and HER2-negative breast cancer. He explained the importance of careful consideration. ..

OncLive^®: How was neoadjuvant and adjuvant breast cancer treatment affected by the results of the Phase 3 FeDeriCa (NCT03493854) and KATHERINE (NCT01772472) trials?

Vidal: FeDeriCa trial does not change neoadjuvant or adjuvant care. Our behavior hasn’t changed because it just offered another option, another way to use the already approved medicines.

Catherine has changed our behavior. [Trastuzumab emtansine]Originally only approved for use in metastatic settings, [was found to be active] In a subpopulation of patients, high-risk HER2-positive patients [breast cancer]..These findings have dramatically changed the way we think of that population, and we now have options for those patients that go beyond what we have done as a standard. Is [of care]..nevertheless [this treatment option includes] More maintenance chemotherapy, it’s [a small amount of chemotherapy overall]For example, changed what did more than FeDeriCa.

The KATHERINE trial found that the combination of trastuzumab (Herceptin) and trastuzumab emtansine worsened the outcome of patients with HER2 low breast cancer. How do you approach the treatment of a population of patients with low HER2?

Traditionally, trastuzumab-based regimens have not been indicated for patients with low HER2 disease. [In this population, these treatments were no more effective than] Standard treatment. If you had either hormone receptor-positive or triple-negative disease, you had anti-hormone therapy or chemotherapy.

In HER2 low disease, [the potential of] Trastuzumab derkustecan as a treatment option is now creating an essentially different category and will definitely change the mindset of these patients. [of breast cancer].. The use of drugs that are effective in the low HER2 population also reduces the number of patients who are considered triple-negative breast cancer. [Instead, we consider them to have] HER2-Low, ER-negative disease. It’s as if a fourth category has been created. HER2-Low breast cancer [is a different category]Where trastuzumab or other ADC can be used [trastuzumab deruxtecan] Even Trastuzumab emtansine is potentially.

The Phase 3 DESTINY-Breast 04 trial (NCT03734029) investigated how trastuzumab delxtecan works in patients with low HER2 disease. What do these data mean for this particular patient subset, and how do these findings help further identify patients with low HER2 disease as a targetable subset within breast cancer?

[These findings create] Another category [of breast cancer].. This classification can be structured in the following cases: [trastuzumab deruxtecan] You can see that it is still active by default. Currently, in a metastatic setting, [this different category is evident]..

[HER2-low disease] After triple-negative breast cancer, we will focus on a population with significant unmet needs. [Trastuzumab deruxtecan is] A new drug for patients traditionally considered triple-negative breast cancer.

Even in ER positive situations [a category of HER2-low disease], This medicine has excellent survival effect. What we need to think about now is where to put the medicines in order. Progression-free survival is seen after CDK4 / 6 inhibitors [PFS] From endocrine therapy [of around 3 months], And now we may see Trastuzumab derkustecan give us 10 months of PFS in the late population. Eventually, [sequencing is] Reducing tolerability and patient quality of life, anti-hormone therapy certainly provides a better patient experience.

What are the new investigational drugs that may change the way patients are treated for triple-negative breast cancer (TNBC), a population that is historically more difficult to treat than other breast cancer subgroups?

I am looking forward to seeing what the future holds. At TNBC [these future therapies may include] More ADCs. Using ADCs can be more responsive and less toxic. In order to achieve a high effect, it may be possible to use other medicines that are highly toxic when used alone. For example, at ASCO, Ian Krop, MD, PhD, [of the Dana-Farber Cancer Institute]Presents data from Phase 1/2 trials [NCT02980341] ADC Patritsumab derkustecan study [(U3-1402) in HER3-expressing metastatic breast cancer].. This drug was also active in TNBC.

Several ADC and immune checkpoint combinations are being studied.There is also [agents with] Other targets, such as PI3K inhibitors, [that are being explored] In that triple-negative landscape. The future of that population looks bright.

Ultimately, unmet needs [in TNBC] I’m finding a cure [produces] More durable response. Patients with TNBC have been found to respond well to chemotherapy. However, the response is short. We are trying to get a drug that elicits a longer and more durable response with TNBC to improve survival.

Amit Jain, MD of the Center for Health Sciences, University of Tennessee, talked about Patrizmab derkustecan as a HER3 target. How feasible is HER3 as a new target for breast cancer patients?

I knew that HER3 existed. HER1, HER2, HER3, and HER4 EGF Receptor family. Since HER3 itself is a more cleaved protein, it needs to be dimerized to gain activity, but it acts as a target.

The ADC acts as a target and by having an antibody that carries the payload. HER3 is expressed in over 50% of breast cancers, including ER-negative, ER-positive, and HER2-positive breast cancers. HER3 acts as an antibody target, carrying a payload called delxtecan, which has the same payload as trastuzumab dercustecan, and exhibits activity.Sacituzumab gobitecan-used that strategy at TNBC for drugs like hziy [Trodelvy], TROP-2 is targeted. However, as far as we know, the target is inactive and the pathway itself does not affect tumorigenesis. It only acts as a target to carry the payload to the tumor. HER3 can also serve that purpose.

S. Sameer Nasir, MD of the West Cancer Center & Research Institute presented a CDK4 / 6 inhibitor with a focus on ribociclib. How are these patients using the drug in combination with various endocrine therapies?

Ribociclib is one of three CDK4 / 6 inhibitors [available]And used in combination with either Fulvestrant [Faslodex] Or an aromatase inhibitor. [The agent is] It is approved for use in primary and secondary metastatic settings and is used like the other three drugs on the market. [Ribociclib] Differentiated based on recent publications and overall survival presentations [OS]It is an active ingredient combined with hormone therapy.this [will likely distinguish] From Palbociclib itself [Ibrance]This is the most commonly used drug in this setting.

teeth [ribociclib] Finally different [from palbociclib]?? Many details still need to be recognized.First, research [looking at ribociclib vs palbociclib] OS results may reflect that, as everything employs slightly different populations. * However, ribociclib continues to have OS benefits, with mature results in all of its trials.

OS results are still waiting [associated with] Abemaciclib [Verzenio] Combined with an aromatase inhibitor, but we know there is an OS [data for abemaciclib] In combination with Fulvestrant.

The problem with ribociclib is the systematic change that needs to occur in the clinic to use it, namely EKG. That’s probably the main reason why this drug isn’t being used in large quantities, as it should be.But in the end [the hope is that] If you can get the benefits of these medicines in different populations, [abemaciclib plus aromatase inhibitors] Succeed [in providing an OS benefit]..

Emily Miller, MD of Messino Cancer Centers, announced oral SERDs in ER-positive and HER2-negative breast cancers. How do you think these drugs are compatible with therapeutic weapons?

Oral SERDs will take some time to fully understand. There are quite a few on the market.Unfortunately, the research carried out [with SERDs] Is a dominance study and means determining if a drug is better than what is on the market.

Since SERDs are known to be active, non-inferiority trials in this population should be considered. The question is, is it better or equivalent than what is on the market?Because they are oral prescriptions of what they have now [also administered intramuscularly]Patients often use the oral version rather than the intramuscular version, as many patients do not want to receive injections. Companies need to start thinking about their strategies when designing oral SERDs.

But in the end, these drugs will be part of the weapon for combating ER-positive metastatic breast cancer. Companies are also considering oral SERDs in the early stages and are looking forward to how these data will evolve.

What are the ongoing breast cancer clinical trial studies at the West Cancer Center & Research Institute?

There are many of the DESTINY trials taking place in [those with] HER2-low and HER2-positive disorders — especially in early situations. We look forward to solving these studies. [trastuzumab deruxtecan] You may have been active before.

At TNBC, there are several combinations [that are under exploration], Combination of immunotherapy and chemotherapy, etc. In patients with homologous recombination deficiency, we are also investigating whether some drugs, mainly a combination of PARP inhibitors and immunotherapy, show some activity.

I am looking forward to seeing what the future holds. Many of the tests being conducted that have not yet produced results are active and may change what we do in the future.

What is the main message you would like to leave to your colleagues regarding all the research and new treatments currently underway in breast cancer?

From a pathological point of view, we need to make systematic changes to our practice. For example, for HER2 low breast cancer, immunohistochemical analysis should also be initiated in institutions that conduct only fluorescence in situ hybridization tests. The institution should also examine the population of patients with HER2-negative disease and classify patients with low HER2 so that trastuzumab delxtecan is an option.

Many of the medicines we see that are very impressed with the metastatic setting have also been tested in the initial setting. The future for bridging the mortality gap in breast cancer patients looks bright. I look forward to what the future holds and may further improve breast cancer survival in my lifetime.

*Editor’s note: The results of the Phase 3 PALOMA-2 trial reported at the 2022 ASCO Annual Meeting show that first-line treatment with palbociclib (NCT01740427) and letrozole (Femara) is monotherapy with OS and letrozole in ER-positive patients. HER2-negative advanced breast cancer, which showed no significant benefit to the patient, is missing a secondary endpoint of the study.¹

reference

Finn RS, Rugo HS, Dieras VC, etc. Estrogen receptor-positive / human epidermal growth factor receptor 2-negative advanced breast cancer (ER + / HER2-ABC): Analysis from PALOMA-2. J Clin Oncol.. 2022; 40 (suppl 17): LBA1003. doi: 10.1200 / JCO.2022.40.17_suppl.LBA1003