Breast Cancer Paradigm Pushes Forward With Neoadjuvant, Adjuvant Advances

Reshma L. Mahtani, DO

CDK4/6 inhibitors, immunotherapy, and PARP inhibitors throughout breast cancer, investigators are keen to learn more about the activity of these agents in the neoadjuvant and adjuvant settings, according to Reshma Mahtani, DO, who cited the NATALEE (NCT03701334), KEYNOTE-522 trial (NCT03036488), and OlympiA trial (NCT02032823) trials among those to follow.

“During our whole evening’s presentation, all the speakers made it a point to highlight several ongoing studies that stand to change how we’ll be treating [patients with] breast cancer in the future. I’m proud to say that at Baptist Health’s Miami Cancer Institute, we have many of these trials open,” Mahtani said in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which she chaired.

“It’s our goal to have a trial for every patient with breast cancer, encompassing the preventative setting, early-stage breast cancer, metastatic disease, and even into survivorship. We continue to expand our clinical trial portfolio, so I’m very happy to be leading that effort,” Mahtani added.

In the interview, Mahtani, chief of breast medical oncology at Baptist Health’s Miami Cancer Institute, discussed the use of antibody-drug conjugates (ADCs), tyrosine kinase inhibitors, CDK4/6 inhibitors, and PARP inhibitors across HER2-positive breast cancer, hormone receptor (HR)–positive, HER2-negative breast cancer, and triple-negative breast cancer (TNBC).

OncLive^®: How have approaches toward neoadjuvant treatment shifted in early-stage HER2-positive breast cancer according to the presentation given by Naomi Dempsey, MD, of Lynn Cancer Institute?

Mahtani: In the treatment of [patients with] early-stage HER2-positive breast cancer, there’s been a shift towards more use of neoadjuvant therapy given that this approach allows us to risk-stratify patients after surgery based on their response to preoperative treatment.

Dr. Dempsey did a great job reviewing the prognostic implications of achieving a pathologic complete response in early-stage HER2-positive disease. She went through the data that support the use and rationale for neoadjuvant treatment, as well as opportunities to de-escalate therapy in the setting of smaller node-negative tumors, and the data that support the omission of anthracyclines.

She also reviewed opportunities to escalate treatment with the incorporation of some of the newer agents. Finally, during her presentation, and throughout the evening, all the speakers made it a point to highlight ongoing trials, which stand to change what we’re doing in the future, so everyone keeps those studies on their radar.

What are some of these clinical trials that could change those standards?

There are several studies that are ongoing that Dr Dempsey highlighted, specifically, the CompassHER2-pCR trial [NCT04266249], which is looking at an opportunity to offer de-escalated chemotherapy in the neoadjuvant setting. Then, in the situation where there’s residual disease, looking at partnering our standard treatment ado-trastuzumab emtansine [T-DM1; Kadcyla] with additional therapy for patients who are at high risk of recurrence.

Your presentation focused on metastatic HER2-positive breast cancer. What have been some of the most notable advances in this setting?

During my presentation, I mainly focused on some of the newer studies that have made a dramatic effect in changing how we treat [patients with] metastatic HER2-positive breast cancer. We reviewed the groundbreaking data with fam-trastuzumab deruxtecan-nxki [Enhertu], which really shifted that agent into the second-line setting after it was shown to be superior to our standard second-line therapy of T-DM1 in the head-to-head DESTINY-Breast03 trial [NCT03529110].

We also reviewed the HER2CLIMB study [NCT02614794], which showed us impressive overall survival [OS] benefits in patients with and without brain metastases with a combination of tucatinib [Tukysa], capecitabine [Xeloda] and trastuzumab [Herceptin]. We also discussed the expanded indication for neratinib [Nerlynx] in combination with capecitabine in the metastatic setting based on the NALA trial [NCT01808573]. Finally, we reviewed our newest addition to the armamentarium for HER2-positive breast cancer, which is margetuximab-cmkb [Margenza], our newest novel, FC-engineered monoclonal antibody.

What ongoing or planned research do you see building on these advances, and how might this research change the treatment paradigm if positive?

The wave of future studies in HER2-positive disease will hopefully allow us to understand how to optimally sequence some of these treatments, as we try to better understand mechanisms of resistance. There are ongoing studies with ADCs like trastuzumab deruxtecan and others in patients with brain metastases. Some of the results of those studies may challenge our current thought, which is that these larger agents don’t get into the central nervous system. Finally, we’re looking forward to several ongoing studies that are combining some of our newer therapies. Of course, there are several novel therapies that are under investigation as well.

Lauren Carcas, MD, of Baptist Health’s Miami Cancer Institute, gave a presentation on HR-positive, HER2-negative breast cancer. How have adjuvant advances affected the treatment paradigm?

Fortunately, we’ve had some exciting updates in estrogen receptor–positive, HER2-negative breast cancer this year, and Dr Carcass did a wonderful job taking us through a lot of data in a short amount of time. She focused on the approval of adjuvant abemaciclib [Verzenio] in high-risk patients by reviewing the monarchE data [NCT03155997]. She also took us through the OlympiA trial with the PARP inhibitor olaparib [Lynparza], which is now an important, new adjuvant therapy for patients with germline BRCA mutations in the early-stage setting.

Then she spent some time taking us through the SOFT [NCT00066690] and TEXT [NCT00066703] updates, which now after about 13 years of follow-up continue to highlight the importance of ovarian suppression in premenopausal women. Then she reviewed the OS benefit that was seen in the MONALEESA-2 trial [NCT01958021], which incorporated the use of the CDK4/6 inhibitor ribociclib [Kisqali] in combination with hormonal therapy. The OS benefit that we’re seeing with ribociclib seems quite consistent in many of the trials reported with ribociclib, so that’s good news for patients with metastatic ER-positive, HER2-negative breast cancer.

It will be interesting to see if the benefit with ribociclib in the metastatic setting extends to the adjuvant setting when we see the results of NATALEE.

Yeah, absolutely. In the adjuvant setting, we have information now with abemaciclib. We didn’t see that same benefit with palbociclib [Ibrance] based on the PALLAS trial [NCT02513394], but we are still waiting on the NATALEE data.

Kevin Kalinsky, MD, of Winship Cancer Institute of Emory University, gave a presentation on TNBC. What therapeutic classes have had the greatest effects on current treatment standards and why?

In breast cancer, we have sort of lagged behind our colleagues in other tumor types with incorporating immunotherapy into our treatment options. Fortunately, that’s changed as of late because now we have immunotherapy as an option for adjuvant and neoadjuvant treatment. Adjuvant treatment is based on data from the KEYNOTE-522 trial. Dr Kalinsky also took us through some of the data in the metastatic setting with the combination of chemotherapy and pembrolizumab [Keytruda]. We are happy to know that immunotherapy now is an option for our patients with early-stage and metastatic triple-negative cancer.

The other class of therapy that has made a considerable effect is the ADC sacituzumab govitecan-hziy [Trodelvy], as we have improvements in OS demonstrated in that group of patients that really have been our greatest unmet need. We need to do better for these patients. They don’t do as well, and there are novel treatments that are under investigation, even with other ADCs. Dr Kalinsky did a wonderful job as always in taking us through a lot of those data sets.