Therapeutic Advances Rapidly Expand the Breast Cancer Armamentarium Across Subtypes

William J. Gradishar, MD, FASCO, FACP

An increasing focus on antibody-drug conjugates (ADCs) for HER2-positive breast cancer signals a potential shift in the standard of care (SOC) for this population. Several investigations have also confirmed the efficacy of CDK4/6 inhibitors in the first- and second-line treatment of hormone receptor (HR)–positive, HER2-negative breast cancer. Yet patients with historically poor prognosis require further experimentation to maximize the clinical benefit of standard chemotherapy and better understand the effect of individual risk factors on response to treatment, according to faculty from an OncLive^® Institutional Perspectives in Cancer (IPC) webinar on Breast Cancer.

The event was chaired by William J. Gradishar, MD, FASCO, FACP, Betsy Bramsen Professor of Breast Oncology, chief of Hematology and Oncology, and professor of hematology and oncology in the Department of Medicine at the Feinberg School of Medicine at Northwestern University in Evanston, Illinois. Presentations highlighted recent advances in the therapeutic landscape for several breast cancer subtypes, including the evolution of ADCs and immunotherapy in HER2-positive and HR–positive, HER2-negative breast cancer, efforts to enhance immune responses with chemoimmunotherapy combinations and endocrine therapy in triple-negative breast cancer (TNBC), and key updates from the POSITIVE (NCT02308085), TAILORx (NCT00310180) and RxPONDER (NCT01272037) trials.

Gradishar was joined by his colleagues:

• Rita Nanda, MD, director, Breast Oncology Program, The University of Chicago, Illinois
• Ruth O’Regan, MD, professor, chair, Charles Ayrault Dewey Professorship of Medicine, Department of Medicine, the University of Rochester, physician-in-chief, Strong Memorial Hospital, associate director, Education and Mentoring, the Wilmot Cancer Institute at University of Rochester Medical Center, New York
• Virginia Kaklamani, MD, professor of medicine, leader, Breast Cancer Program, UT Health San Antonio, MD Anderson Cancer Center, Texas

Below, Gradishar, Nanda, O’Regan and Kaklamani summarize the main messages from their presentations.

Trastuzumab Deruxtecan and Tucatinib May Become New SOC Regimens in HER2-positive Breast Cancer

Gradishar: The phase 3 CLEOPATRA [trial (NCT00567190) showed that] using dual-HER2 targeting with a taxane [elicits] a sustained survival benefit [in HER2-positive disease.] [Soon after], the utilization of ado-trastuzumab emtansine [Kadcyla; T-DM1] became very common [in the second line] after the [phase 3] EMILIA trial [NCT00829166], and [that agent] held that position for quite some time.

The [phase 3] DESTINY-Breast03 trial [NCT03529110] was [performed] in patients with metastatic disease who had received T-DM1 and a taxane. The comparator was fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd] vs T-DM1. Progression-free survival [PFS] and overall survival [OS] were markedly improved with T-DXd, and objective response rate was more than doubled with T-DXd. There was also the [phase 3] DESTINY-Breast02 trial [NCT03523585] which looked at T-DXd vs investigator’s choice in patients who had already received T-DM1. This trial was also positive for PFS and OS. Now there is the [phase 3] DESTINY-Breast09 trial [NCT04784715] comparing T-DXd vs T-DXd plus pertuzumab [Perjeta].

We still view [treatment] with a taxane and dual-HER2 targeting as the best therapy for most patients starting out with metastatic disease. Until we have data from DESTINY-Breast09, we are going to still be using these CLEOPATRA-like regimens.

In the second line, particularly in those who have central nervous system [CNS] disease, clinicians are preferentially using tucatinib [Tukysa] and T-DXd. Thereafter, [if a patient] has used trastuzumab deruxtecan, [clinicians would] use tucatinib [or vice versa]. At this point, there aren’t a lot of data regarding what happens if you use one ADC after another, [particularly] with T-DXd and then T-DM1.

We have a variety of different options with some of the other drugs that are available for patients in the fourth [line] and beyond. Many other drugs are currently in development, [including] trastuzumab duocarmazine.

High Unmet Need Still Exists in TNBC Despite Encouraging Additions to the Treatment Landscape

Nanda: The vast majority of patients who are diagnosed with triple-negative disease are diagnosed with early-stage TNBC. Paradoxically, TNBC can be more responsive to chemotherapy. Unfortunately, prior to the routine use of immunotherapy for patients with high-risk stage II or higher TNBC, about a third of patients who received chemotherapy and went on to have surgery and radiation would [experience] recurrence. [This] continues to remain a high unmet need, although some of [our] newer agents do seem to have CNS activity.

[Most] patients who develop metastatic disease [also] have a median survival of 12 to 18 months, although we are pushing the needle with some of our therapies. We’re making modest advances in endocrine therapy, and we have CDK4/6 inhibitors, which are now associated with a survival advantage. Oral selective estrogen receptor degraders [SERDs] are in development, and some other ADCs show promising [activity]. [Although] we have had a number of advances in the past few years, TNBC continues to remain the form of breast cancer with the poorest prognosis after a diagnosis of advanced stage disease.

[Overall], when thinking about how [to] treat patients with advanced TNBC it’s a no-brainer that we would use pembrolizumab [Keytruda] plus chemotherapy in patients with PD-L1–positive, BRCA wild-type [disease]. For those who have PD-L1–negative, BCRA wild-type [tumors, clinicians should consider] chemotherapy or enroll [patients in clinical] trials of ADCs. For individuals who have PD-L1–negative disease [with] BRCA mutations, we want to [use] PARP inhibitors.

Exploratory analyses suggest that earlier use [of] PARP inhibitors in patients with BRCA mutations [increases the likelihood of] substantial PFS advantage. Patients who have PD-L1–positive [disease] and BRCA mutations [should] consider using immunotherapy-based approaches given the survival advantage with pembrolizumab. [However,] we don’t have data on [whether] it is better to start with a PARP inhibitor or chemotherapy plus pembrolizumab.

CDK4/6 Inhibitors Remain Effective SOC in First-line HR-positive Metastatic Breast Cancer

O’Regan: Across all guidelines, the standard-of-care in the first-line setting [for HR-positive metastatic breast cancer] is CDK4/6 inhibitors along with endocrine therapy. [This is] usually a nonsteroidal aromatase inhibitor, but fulvestrant [Faslodex] is also an option.

[Key] trials show that all the CDK4/6 inhibitors are effective in prolonging PFS. [OS data are less conclusive] but [we know OS] was improved in the MONALEESA trials and signaled [a trend toward improved OS] in the [phase 3] MONARCH 3 trial [NCT02246621]. There are no available biomarkers [for these agents] yet, [but] if the cancer is estrogen receptor[–positive], they appear to work.

It is important to check genomics [in the] second line, [as there are] a lot of treatment options in the second line. Oral SERDs appear [to be] more effective than other chemotherapies in [patients with] a PI3K mutation or ESR1 mutation.

[Finally], ADCs will likely supplant standard chemotherapy in patients with endocrine-resistant disease based on [data] from the [phase 3] TROPiCS-02 trial [NCT03901339].

POSITIVE, TAILORx, and RxPONDER Trials Elucidate Individual Factors Affecting Patient Outcomes in ER-positive Breast Cancer

Kaklamani: The POSITIVE trial really [helps us] discuss the discontinuation of therapy with patients that have endocrine receptor [ER]–positive breast cancer. It is now [more] accepted that women who want to get pregnant [can] discontinue endocrine therapy [after] 18 months to 2 years and then resume it once they’re done having children. [This] is not going to adversely affect their outcomes.

Longer follow-up from TAILORx [provides a] similar conclusion but helps us [to] clarify [which] women in the intermediate [risk] subgroups will potentially benefit from chemotherapy.

Data from RxPONDER [have] opened the door [for continuing] research on why black women with ER-positive breast cancer have worse outcomes [compared with other ethnicities]. [Results show that] endocrine therapy and chemotherapy adherence [did not cause] the discrepancy in [patient] outcomes in this clinical trial, [nor did] the type of treatment that they’re receiving.

Finally, cognitive impairment is [commonly observed] with chemotherapy. [A sub analysis of] the RxPONDER trial looked at cognitive impairment in women receiving chemotherapy as part of this clinical trial. Unsurprisingly, there was a decrease in mean cognitive function score [seen across all] patients in this trial. The [decrease was] especially [pronounced] in premenopausal patients. This cognitive impairment can persist [for longer] than what we initially thought, which was around two years. [These data] suggest that [clinicians] should think twice before giving chemotherapy to these patients.

Editor’s Note:

Dr. Gradishar reports serving as a consultant or on a paid advisory board for Genentech/Roche, AstraZeneca, Macrogenics, Seagen, Merck; he has received research grants from the Breast Cancer Research Foundation; he is on the editorial board for Clinical Breast Cancer; Oncology, Annals of Surgery, Breast Cancer Research and Treatment.

Dr. Nanda reports serving as a consultant or on a paid advisory board for AstraZeneca, BeyondSpring, FujiFilm, GE, Gilead, Infinity, Iteos, Merck, OBI, Oncosec, Sanofi, Seagen; she has received research grants from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Gilead/Immunomedics, Merck, OBI Pharma OncoSec, Pfizer, Relay, Seattle Genetics, Sun Pharma, Taiho.

Dr. Kaklamani reports serving as a consultant or on a paid advisory board for Puma, AstraZeneca, Athenex and Gilead; she is on the speaker’s bureau for Pfizer, Gilead, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo and Seagen and Research with Eisai.

Dr. O’Regan reports relationships with Biotheranostics, Novartis, AstraZeneca, and Pfizer.