Progress Made Across Breast Cancer Paradigm Sets the Stage for Improved Sequencing and Future Research

Sarah Sammons, MD

Across all breast cancer subtypes, substantial progress with novel therapies has been made to improve outcomes for patients, determine optimal sequencing in earlier-stage disease, and spark ongoing research efforts featuring these newer agents, said Sarah Sammons, MD, in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

The virtual meeting covered escalation and de-escalation strategies in early-stage HER2-positive breast cancer; the emergence of fam-trastuzumab deruxtecan-nxki (Enhertu) in metastatic HER2-positive breast cancer; the role of CDK4/6 inhibitors in hormone receptor (HR)–positive, HER2-negative breast cancer; and recent advances that have expanded options for patients with triple-negative breast cancer (TNBC).

“What struck me across all of the different discussions among my colleagues was the fact that we are making progress in every tumor type, [as well as in] early and metastatic disease,” said Sammons, an assistant professor of medicine in the Department of Medicine at Duke University School of Medicine, and a member of the Duke Cancer Institute of Duke Health.

During the interview, Sammons, who chaired the IPC event, highlighted key advances made across the spectrum of breast cancer, including HER2-positive, HR-positive, and triple-negative disease, as well as key data that have reshaped these paradigms.

OncLive^®:During the IPC meeting, Gretchen Kimmick, MD, MS, of Duke Cancer Institute, discussed escalation and de-escalation strategies in early-stage HER2-positive breast cancer. What stood out to you from her presentation?

Sammons: We are using pathologic complete response [pCR] to determine adequate adjuvant therapy, which is great. Several escalation and de-escalation trials are ongoing with the goal of trying to minimize the toxicity of chemotherapy for patients and maximize the HER2- targeted therapies, which tend to have less toxicity vs cytotoxic chemotherapies.

Kelly Westbrook, MD, of Duke Cancer Institute, talked about metastatic HER2-positive breast cancer. What activity has been observed with trastuzumab deruxtecan in this space and where is it being utilized in the sequence of therapy?

The topline results of the DESTINY-Breast03 trial [NCT03529110] showed an astounding improvement in progression-free survival [PFS] with trastuzumab deruxtecan vs ado-trastuzumab emtansine [T-DM1; Kadcyla] in the second-line HER2-positive disease setting. In that clinical trial, we saw a median PFS of nearly 25 months vs nearly 7 months, respectively, which is remarkable. It was too early to see overall survival [OS] data, but this has clearly led to a change in practice in the second-line setting.

Another thing about DESTINY-Breast03 was that about 20% of patients in that trial had stable brain metastases. Those patients still derived a substantial benefit from trastuzumab deruxtecan. Therefore, patients with HER2-positive breast cancer and stable brain metastases [should receive] trastuzumab deruxtecan as standard second-line therapy.

What will sequencing look like now that trastuzumab deruxtecan is a second-line standard of care in metastatic HER2-positive breast cancer? Are there ongoing research efforts you would like to highlight?

With trastuzumab deruxtecan as the new standard second- line therapy, this opens a lot of questions about where we go with subsequent therapies. We don’t, at this point, know the efficacy of other agents after progression on trastuzumab deruxtecan in HER2-positive metastatic breast cancer. Further trials and real-world data will hopefully be coming out in the next few years to determine the efficacy of tucatinib [Tukysa]- or T-DM1–based regimens after trastuzumab deruxtecan. These are still options that we will be offering our patients, but their efficacy post trastuzumab deruxtecan is unclear.

Ongoing research in metastatic HER2-positive breast cancer is still exciting. DESTINY-Breast09 [NCT04784715] is the ongoing clinical trial of trastuzumab deruxtecan with or without pertuzumab [Perjeta] compared head-to-head to standard first-line therapy, which is a taxane plus trastuzumab [Herceptin] and pertuzumab, in metastatic HER2-positive breast cancer. In the coming years, we could see trastuzumab deruxtecan move into the first-line setting.

Another ongoing and exciting trial is HER2CLIMB-02 [NCT03975647], which we have open at our site and is near full accrual. [The study is evaluating] T-DM1 with or without tucatinib. We would hope to see a positive trial of T-DM1 plus tucatinib, but those results are pending. We should [see them] in the coming 12 to 18 months. That would lead to another very exciting option for patients with HER2-positive metastatic breast cancer with and without brain metastases.

Susan Dent, MD, of Duke Cancer Institute, spoke to updates in early-stage and late-stage HR-positive, HER2-negative breast cancer, particularly regarding the role of CDK4/6 inhibitors. What should be underscored about her presentation?

In the advanced setting, we are finally seeing OS benefits with CDK4/6 inhibitors, whether given in the first-line or second-line settings. Dent discussed the MONALEESA-2 trial [NCT01958021], which was the first study to show an OS benefit with ribociclib [Kisqali] added to an aromatase inhibitor [AI] in the first-line setting. That trial also showed the longest OS benefit in general—more than 5 years—that we have ever seen in HR-positive, HER2-negative metastatic breast cancer. It’s exciting to see that all this research is leading to women living longer.

Dent also briefly discussed the monarchE trial [NCT03155997] update. We now have FDA approval for abemaciclib [Verzenio] in high-risk, node-positive, highKi67, HR-positive, HER2-negative, early-stage breast cancer. We were able to see that abemaciclib added to standard adjuvant endocrine therapy leads to a diseasefree survival [DFS] benefit. There is still more to come for us to understand which patients we may choose to use abemaciclib in, but for very high-risk patients, we are all excited to have that option.

What are some key takeaways from the phase 3 MONALEESA-2 trial?

The MONALEESA-2 data were exciting for a couple of reasons. That trial [included] patients with newly diagnosed, metastatic HR-positive, HER2-negative breast cancer with de novo metastatic disease or relapsed [disease] greater than 12 months after adjuvant therapy. Patients were treated with the addition of ribociclib vs placebo to an AI. It was wonderful to see that not only are we prolonging the time until a patient’s disease progresses, but we are substantially prolonging the amount of time these patients live by about 1 year. That is, of course, wonderful to see.

This trial also showed the longest median OS that we have ever seen in metastatic HR-positive, HER2-negative breast cancer. The median OS was over 5 years, which is exciting to us as oncologists. I don’t think 5 years is long enough in patients’ minds, but at least they know that we are making incremental improvements, which is always what we are trying to do.

I generally use CDK4/6 inhibitors in the first-line setting. Ribociclib has now shown OS advantages in 3 clinical trials: ribociclib added to letrozole, ribociclib added to fulvestrant [Faslodex], and ribociclib added to either an AI and ovarian suppression or tamoxifen in premenopausal women. Across the board, the compound is prolonging the amount of time that women with HR-positive, HER2-negative disease live. That’s very important and is showing us a strong signal.

Everyone always has questions. Are there differences among the 3 CDK4/6 inhibitors? There are certainly differences in toxicity and now we are showing a hint toward some differences in efficacy. Overall, time will tell, and we are still waiting on the OS data from the first-line clinical trials of abemaciclib and palbociclib [Ibrance].

Finally, Carey Anders, MD, of Duke Cancer Institute, highlighted updates in early-stage TNBC. What have been some of the main advances in TNBC and what ongoing research are you keeping an eye on that could further shift the paradigm?

We have made some substantial progress in early-stage and late-stage TNBC.

We now have immunotherapy for the neoadjuvant treatment of patients with early-stage, high-risk TNBC given the results of the KEYNOTE-522 study [NCT03036488]. The FDA approved pembrolizumab [Keytruda] added to paclitaxel and carboplatin followed by doxorubicin and cyclophosphamide in patients with stage II and stage III TNBC. This led to improvements in pCR rates and, more importantly, invasive DFS [iDFS]. That was very exciting to see. Certainly, this is something we’re already offering patients in the clinic, but it is very important to discuss the risks and benefits of immunotherapy with patients in whom we would consider using pembrolizumab. As we know, there can be permanent endocrinopathies, such as hyperthyroidism and hypothyroidism. However, [the addition of pembrolizumab] seems to be improving outcomes, which is exciting.

Benefit was observed across all subgroups in terms of iDFS, whether patients were lymph node–positive or lymph node–negative. Overall, toxicity was consistent with what we have seen when immunotherapy is added to chemotherapy. However, because we are using this in the curative setting in young women and given that it is TNBC, it’s important to have a candid conversation about the risks and benefits of immunotherapy and discuss potential lifelong adverse effects.

In the metastatic setting, immunotherapy has provided us with somewhat of a whiplash over the past few years. We had an approval from IMpassion130 [NCT02425891] of atezolizumab [Tecentriq] added to chemotherapy in PD-L1–positive patients with the SP142 assay. That was recently withdrawn, so our only immunotherapy approval in the metastatic setting is pembrolizumab added to chemotherapy, which could be gemcitabine/carboplatin/nab-paclitaxel [Abraxane] or paclitaxel in the first-line setting. That is only for patients who are PD-L1 positive by combined positive score with the 22C3 assay of greater than or equal to 10%.

So, in the metastatic setting, it is imperative to get the 22C3 PD-L1 assay, pembrolizumab should be added to chemotherapy in the first-line setting for patients who are PD-L1 positive.

Moving to second-line and third-line treatments, we have an antibody-drug conjugate [ADC] approved with sacituzumab govitecan-hziy [Trodelvy]. Several trials are ongoing to add sacituzumab govitecan to immunotherapy or other targeted agents. Another TROP2-directed ADC is being developed by Daiichi Sankyo that also looks exciting. We also now have, in this HER2-low category of patients, trastuzumab deruxtecan showing good early efficacy. With these new-generation, highly potent HER2-targeted ADCs, we are seeing activity in the HER2-low space, which is also exciting in TNBC and HR-positive breast cancer. We are making a lot of progress and there is a lot to come.