Shifting Treatment Sequencing Patterns and New Approaches Transform Breast Cancer Paradigm

Jennifer M. Matro, MD

Data from key studies are changing the standards of care across breast cancer, including early-stage and metastatic HER2-positive breast cancer; hormone receptor (HR)–positive, HER2-negative breast cancer; and triple-negative breast cancer (TNBC), said Jennifer M. Matro, MD, in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

Matro specifically added that nuanced decision-making is needed to tailor treatment to an individual patient’s disease features, course of therapy plans, and goals of treatment.

During the interview, Matro, who chaired the IPC event, provided an in-depth look at clinical trials that have added to the breast cancer paradigm and how she is interpreting the f indings for clinical practice. She is a medical oncologist and associate professor of medicine at the Moores Cancer Center of the University of California (UC) San Diego Health.

OncLive^®: To start with the presentation you gave during the IPC meeting on early-stage HER2-positive breast cancer, could you describe what is most interesting about the mechanism of action of ado-trastuzumab emtansine (T-DM1; Kadcyla) and the components that make up the agent?

Matro: T-DM1 is an antibody-drug conjugate [ADC], which means it is a chemotherapy drug. The payload emtansine linked to an antibody, in this case, trastuzumab [Herceptin]. The trastuzumab part of the compound homes in on the HER2-expressing breast cancer cells so that the molecule gets internalized into the cancer cells, and the linker—between the payload and the trastuzumab—gets dissolved to deliver the payload of chemotherapy directly into the cancer cell.

How did the results of the phase 3 KATHERINE trial (NCT01772472) shift the standard of care for patients with HER2-positive breast cancer with residual disease following preoperative therapy?

The KATHERINE trial evaluated the use of T-DM1 in the adjuvant setting for patients who did not have a complete response to neoadjuvant chemotherapy. That trial showed that among patients who have residual disease, 1 year of T-DM1 compared with 1 year of trastuzumab improved [invasive disease-free survival (iDFS)] by more than 11%. Overall survival [OS] appears to be trending toward improvement, although those data are still a bit immature. There were higher rates of discontinuation in the T-DM1 arm [vs the trastuzumab arm], but overall, despite that, T-DM1 had significant benefit over trastuzumab.

Regarding the phase 3 FeDeriCa trial (NCT03493854), what did the results indicate about the utility of fixed-dose subcutaneous trastuzumab plus pertuzumab (Perjeta) vs intravenous (IV) administration of the doublet? What advantages does the fixed-dose regimen provide?

The IV and fixed-dose subcutaneous modes of administration were equally effective and well tolerated overall. The [FeDeriCa] trial was designed to evaluate whether the fixeddose subcutaneous [regimen] was noninferior to standard IV [administration], and it met that end point. A separate trial showed that patients preferred the subcutaneous vs IV formulation.

The advantage of the fixed-dose subcutaneous [formulation] is that for patients who are on trastuzumab and pertuzumab alone, instead of having to sit for an IV infusion, they can get a quick subcutaneous injection. The [subcutaneous formulation] could potentially [let patients] get their ports [taken] out. It [means] a lot less time in the infusion room, which opens more chairs for other patients in clinic who need IV therapy….Potentially, in some settings, it could be given at home by a visiting nurse. That would be something we could strive toward.

During the 2021 San Antonio Breast Cancer Symposium (SABCS), findings from an arm of the I-SPY trial (NCT01042379) were presented. This evaluated tucatinib (Tukysa) with paclitaxel, pertuzumab, and trastuzumab in patients with early-stage, high-risk HER2-positive breast cancer. What did these findings show in terms of toxicity?

This arm of the I-SPY trial evaluated tucatinib in combination with paclitaxel, trastuzumab, and pertuzumab, which is the standard backbone. [The combination] was effective; 86% of patients had a more than 80% reduction in MRI volume of their tumors at the end of that portion of chemotherapy. However, the combination was too toxic, with unacceptably high rates of grade 3 liver function test elevations and diarrhea. Only 20 patients ultimately were able to be enrolled before that arm was closed. Based on the efficacy, it suggests that maybe studying tucatinib in combination with an ADC or some other [agent] may be a more feasible approach in the future.

Where does pyrotinib stand as a potential treatment option?

Pyrotinib [was evaluated] in the neoadjuvant setting in China and nearly doubled the pathologic complete response [pCR] rate from 22% with placebo to 41%. In the group that got pyrotinib, most gastrointestinal adverse effects [AEs] like diarrhea, nausea, and vomiting had greater toxicity, although these were manageable. This is certainly an appealing option in countries like China where pyrotinib is more available and is approved. [It’s an area] where other HER2-directed medications like pertuzumab may be less available.

What factors play into your decision to pursue neoadjuvant therapy in a patient with HER2-positive breast cancer?

It’s always an individualized decision with each patient and their oncologist, taking into account certain things like the size of the tumor; how many lymph nodes, if any, are involved; and the goal of giving chemotherapy preoperatively. Is the goal to downstage the axilla? Is it to allow for a lumpectomy if somebody [would otherwise] need a mastectomy? Do we want to assess the treatment response and use that to make adjuvant therapy decisions, even though the patient will still be operable? How may [neoadjuvant therapy] potentially affect a patient’s adjuvant therapy?

Does anthracycline-based therapy still have a role in this patient population?

The initial trastuzumab trials more than 15 years ago were mostly in combination with anthracyclines because anthracyclines were among the first chemotherapy medications that came out and were shown to be beneficial for breast cancer. However, we saw higher rates of cardiotoxicity and leukemia with anthracycline- containing regimens.

Over the years, we have gotten long-term follow-up data from some of those early trials showing that, between regimens that do and don’t contain anthracyclines, the efficacy is the same, even for the highest-risk patients with positive lymph nodes. However, with anthracyclines, there are higher rates of cardiotoxicity, congestive heart failure, ejection fraction reductions, and leukemia.

At this point for HER2-positive breast cancer, there is not a great reason to use an anthracycline, but in certain cases it would be appropriate. If a patient has a heterogeneous tumor—in which HER2 is not strongly positive or is equivocal—but you want to give HER2-directed therapy, including an anthracycline in the regimen would be appropriate for these more triple-negative phenotypes.

How do you manage patients with HER2-positive breast cancer tumors that are small? Is there a standard approach?

At this point, in patients with positive lymph nodes or larger tumors, it is well established that giving them neoadjuvant chemotherapy and allowing for individualized decision-making is helpful. [This is a product of] the KATHERINE trial era: We know that if patients get full neoadjuvant chemotherapy and they have residual disease, they will benefit from adjuvant T-DM1 vs trastuzumab, which used to be the standard of care.

The controversy comes in with the smaller, lymph nodenegative tumors. Several studies have shown that those patients have good outcomes overall, but the question is: Should we be treating them with preoperative therapy? We know it is safe to deescalate chemotherapy in the adjuvant setting, but we don’t know at this point if it is OK to deescalate chemotherapy in the neoadjuvant setting.

Ultimately, if we give somebody neoadjuvant chemotherapy, the goal is to get a pCR; we want to set patients up for success so all that they’ll need in the adjuvant setting is 1 year of trastuzumab. However, if we deescalate chemotherapy or give single HER2-directed therapy vs dual [HER2-directed therapy], are we setting patients up to have residual disease and to need 1 year of adjuvant T-DM1? We could be undertreating patients initially and then overtreating them in the adjuvant setting. Since we know patients do well with trastuzumab and paclitaxel in the adjuvant setting, are we overtreating them if we give them more than that in the neoadjuvant setting?

That is where the controversy comes in. It’s a discussion among the patient, their oncologist, and the surgeon [to establish] what the goals [of therapy] are. Then, of course, if we are planning on surgery first, followed by adjuvant therapy, the main risk that should be discussed is: Could the imaging be underestimating the tumor size?

For example, [sometimes] we think a patient has a 1.3-cm tumor and the nodes are negative, because nothing is suspicious on imaging. Then, they have surgery, and [we find that] the sentinel lymph node has a small amount of cancer in it. We have [therefore] missed the opportunity at that point to give neoadjuvant chemotherapy and individualized adjuvant treatment. That is the main risk with our imaging techniques. This [scenario is] less common [than it once was] because many people are getting MRIs, but even small amounts of cancer in lymph nodes are sometimes missed.

Pivoting to the presentation given by Angelique E. Richardson, MD, PhD, of UC San Diego Health, on HR-positive, HER2-negative breast cancer, what findings from the monarchE trial (NCT03155997) stood out to you with abemaciclib (Verzenio)?

The monarchE trial included patients with HR-positive breast cancer who were considered at high risk for recurrence, meaning they had N2 disease, [with] 4 or more positive lymph nodes, or N1 disease with some other high-risk feature like grade III [disease] or elevated Ki-67. The investigators randomized patients to standard endocrine therapy with abemaciclib for 2 years or no abemaciclib. iDFS [had] significant improvement. The 2-year iDFS rate was 92.2% with abemaciclib vs 88.7% [without abemaciclib]. The 3-year iDFS absolute benefit rate was 5.4%. In subsequent analyses, we saw that Ki-67 was prognostic, but the abemaciclib benefit was consistent regardless of Ki-67.

How did the results of the PALLAS (NCT02513394) and PENELOPE-B (NCT01864746) trials complicate the use of CDK4/6 inhibitors as adjuvant therapy in HR-positive breast cancer?

The PALLAS and the PENELOPE-B trials were negative studies. PALLAS included a slightly lower-risk population and evaluated palbociclib for 2 years. PENELOPE-B was enriched for a higher- risk population. Neither trial [showed] improvement in iDFS. At this point, abemaciclib is approved in the adjuvant setting for high-risk patients, but palbociclib is not.

It’s not clear why abemaciclib was effective and palbociclib was not. It doesn’t look like the early discontinuation rates of palbociclib in the PALLAS trial contributed [to the negative f indings]. It may be the dosing schedule; abemaciclib is continuous while palbociclib is intermittent. [Ultimately], different studies have different patient populations, so it is not entirely clear at this point, but that is what the data showed and that is what the FDA has approved.

In the metastatic setting, all 3 of the CDK4/6 inhibitors seem to have equal efficacy. Finding their place in the earlystage setting is still an area of active investigation.

Kay T. Yeung, MD, PhD, of UC San Diego Health, spoke about metastatic HER2-positive breast cancer. Starting with the phase 2 HER2CLIMB trial (NCT02614794), what did the updated results presented at the 2021 SABCS indicate?

HER2CLIMB was a noteworthy study because it was one of the first to enrich for and include patients who have central nervous system [CNS] or brain metastases. Patients were able to be enrolled if they had brain metastases. The addition of tucatinib to trastuzumab and capecitabine significantly improved the progression-free survival [PFS] and OS in the entire population, but also in the population with CNS metastases: There, the 1-year PFS rate was 25% in the tucatinib group and 0% in the group that did not get tucatinib.

Findings from the study led to the approval of that regimen and has provided a good treatment option for our patients with CNS metastases. We know that up to 50% of patients with HER2-positive metastatic breast cancer will develop CNS metastases at some point.

How have the results of the phase 3 DESTINY-Breast03 trial (NCT03529110) affected standard practice patterns in the metastatic setting?

After patients progressed on a taxane and a HER2-directed therapy, they were randomized to fam-trastuzumab deruxtecannxki [Enhertu] or T-DM1. Up until now, based on the EMILIA trial [NCT00829166], T-DM1 has been the standard-of-care second-line therapy.

There was significant benefit [with trastuzumab deruxtecan vs T-DM1]. If we look at the Kaplan-Meier curve, it is impressive: a 72% reduction in the risk of progression with trastuzumab deruxtecan compared with T-DM1. The [median] PFS at 16 months was 25.1 months in the trastuzumab deruxtecan group and 7.2 months in the T-DM1 group. There was also a trend toward improved OS.

These data are bringing trastuzumab deruxtecan earlier in the order of treatment, and the agent is a very appealing second-line treatment option. We’ll have to wait for studies to be done to see whether [trastuzumab deruxtecan] is superior to the standard taxane, trastuzumab, and pertuzumab regimen, which has been our first-line treatment for several years.

Finally, Rebecca A. Shatsky, MD, of UC San Diego Health, closed out the night with a presentation on TNBC. What have been some of the most significant updates in this paradigm in recent years?

For early-stage TNBC, the main update in the past couple of months was the KEYNOTE-522 trial [NCT03036488], which showed that the addition of pembrolizumab [Keytruda] to chemotherapy improved pCR and event-free survival rates after neoadjuvant chemotherapy. Findings from the study led to the approval of pembrolizumab with carboplatin and paclitaxel followed by doxorubicin and cyclophosphamide with pembrolizumab. Pembrolizumab is given for 9 cycles.

In metastatic breast cancer, the KEYNOTE-355 trial [NCT02819518] showed an improvement in DFS with pembrolizumab added to chemotherapy. In that study, the 3 chemotherapy options were paclitaxel, carboplatin/ gemcitabine, and nab-paclitaxel [Abraxane]. In patients who were PD-L1 positive, particularly with a combined positive score [CPS] greater than 10, PFS and OS [both had] significant improvement. Pembrolizumab is now approved in the first-line setting for PD-L1–positive patients who have high CPS.

In metastatic breast cancer, the KEYNOTE-355 trial [NCT02819518] showed an improvement in DFS with pembrolizumab added to chemotherapy. In that study, the 3 chemotherapy options were paclitaxel, carboplatin/ gemcitabine, and nab-paclitaxel [Abraxane]. In patients who were PD-L1 positive, particularly with a combined positive score [CPS] greater than 10, PFS and OS [both had] significant improvement. Pembrolizumab is now approved in the first-line setting for PD-L1–positive patients who have high CPS.

How does the introduction of immunotherapy in TNBC underscore the need for PD-L1 testing? Is it indicated for patients with early-stage disease?

In metastatic TNBC, PD-L1 testing is an essential part of our initial workup for newly diagnosed patients because these trials have shown that patients benefit [with immunotherapy] only if they express PD-L1. We also know that immunotherapy is most effective when it is used early in metastatic treatment. Getting that information early and trying to get patients on f irst-line immunotherapy is important.

In early-stage breast cancer, PD-L1 testing is not necessary. The KEYNOTE-522 trial showed that the benefit was seen regardless of PD-L1 expression, but more patients are getting this regimen. Therefore, we are seeing more AEs and immune-related AEs, such as thyroid dysfunction, adrenal insufficiency, and other [inflammatory diseases]. As breast oncologists, we need to get more comfortable in managing these AEs now that we are going to be seeing more patients on these drugs.