A number of targeted agents have been approved in the setting of metastatic breast cancer, which has allowed for more personalized treatment approaches and underscores the importance of genomic testing.
Erika P. Hamilton, MD
The breast cancer treatment landscape continues to expand with the development of new and novel therapies that improve outcomes in patients. Homing in on the setting of more advanced disease, patients with metastatic breast cancer have particular needs that modern research is aiming to meet.
Patients with metastatic breast cancer have much poorer prognoses than their counterparts without advanced disease, but the treatment landscape has evolved markedly over the last decade for this patient population with the introduction of new targeted therapies. However, treatment in this setting is primarily based on the different receptor subtypes of metastatic breast cancer that patients may present with.
The most common subtype of metastatic breast cancer is hormonally driven disease, which includes patients who are estrogen receptor (ER)-positive, or hormone receptor (HR)-positive. Hormonally driven metastatic breast cancer is observed in about 70% of patients, but other subtypes of this disease include HER2-positive disease and triple-negative breast cancer (TNBC), which is considered disease that presents negative for HER2, estrogen, and progesterone receptors.
“One of the ways that treating metastatic breast cancer has changed the most in the past decade is with the advent of molecular profiling, where we send off a small piece of the tumor and look at multiple hundreds of genes in that tumor to try to figure out what makes the cancer grow,” Erika P. Hamilton, MD, director of the breast and gynecologic cancer research program for Sarah Cannon Research Institute at Tennessee Oncology, told Targeted Oncology, in an interview for Metastatic Breast Cancer Awareness Day. “This enables true personalized medicine for patients. We're not treating cancer anymore as a 1-size-fits-all approach. We're learning about what's driving the individual cancer that our patient in front of us has, and that opens up the door to many targeted medicines.”
Debu Tripathy, MD
A number of targeted agents have been approved in the setting of metastatic breast cancer, which has allowed for more personalized treatment approaches in this space and underscores the importance of testing patients with metastatic disease. According to Debu Tripathy, MD, it is important to test patients to first verify there has been no change in the receptor subtype since an initial biopsy and secondly to determine the presence of any potential mutations that could guide treatment decisions.
“More patients now are going to have sequencing done, which can also now be done with just a simple blood test because some of the tumor DNA ends up circulating in the blood,” Tripathy, of the Department of Breast Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, told Targeted Oncology. “Rather than getting a biopsy of the tumor, we can just take a blood sample, so that's something that is helping advance the direction of breast cancer [with the new targeted therapies].”
Patients with HR-positive disease are typically treated with hormonal therapy, such as tamoxifen, but over the past several years, targeted therapies have made their way into this treatment landscape as well. For example, physicians have been using a novel class of drugs known as the CDK4/6 inhibitors. However, hormonal therapy remains an important backbone to therapy in this setting.
“CDK4/6 inhibitors are drugs that affect the cell cycle, which is a series of reactions that tell the cell when they’re growing to stop growing,” said Tripathy. “These drugs are oral pills that are taken with hormonal therapy and have very few side effects, which is 1 of the good qualities about these drugs.”
Palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) have been approved in this setting by the FDA over the last few years. Palbociclib was the first CDK4/6 inhibitor to receive approval in this setting in 2015, followed by abemaciclib in 2017, and ribociclib in 2018.
“This is a class of drugs that almost doubled progression-free survival (PFS) and had also improved overall survival (OS) for patients facing metastatic breast cancer,” said Hamilton. “Traditionally, in the first-line setting, the PFS was about 8 months to a year, and with the addition of CDK4/6 inhibitors to endocrine therapy, this has doubled up to 2 years.”
Another unique class of drugs in this space includes aromatase inhibitors (AIs). AIs are oral pills that are mainly used to treat postmenopausal women. These agents are commonly used in combination with CDK4/6 inhibitors as well, such as the FDA-approved regimens of abemaciclib plus an AI as treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer and ribociclib plus AI therapy in HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapies.
Pi3K inhibitors have also been approved and have shown great promise in hormonally driven metastatic breast cancer as well. These agents are known to be effective in patients who have a PIK3CA-mutation. Alpelisib (Piqray) received its approval in 2019 for the treatment of postmenopausal women and men with HR-positive, HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer after progression on or after a prior endocrine-based regimen. This treatment was approved based on the phase 3 SOLAR-1 clinical trial findings, in which the median PFS was 11.0 months (95% CI, 7.5-14.5) in those treated with alpelisib plus fulvestrant versus 5.7 months (95% CI, 3.7-7.4) in those who received placebo plus fulvestrant.1
A study that was recently presented during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress also indicated a prolonged OS with alpelisib plus fulvestrant as treatment of this patient population from the SOLAR-1 trial. The median OS had been prolonged by 7.9 months with the addition of alpelisib to fulvestrant, inducing a hazard ratio of 0.86 (95% CI, 0.64-1.15; P =.15).2
Historically, TNBC is a more aggressive type of cancer, which, until recently, was primarily treated with chemotherapy due to a lack of targeted therapies. However, patients with TNBC have now demonstrated response to immunotherapeutic agents.
“In TNBC, we've also had a relatively large breakthrough in the past couple of years with immunotherapy being approved for this subset of patients with TNBC that express PD-L1, which is about 40% of patients,” said Hamilton on the approval of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane). “This also improves OS, and we've seen a lot on immunotherapy from other tumor types like lung cancer and melanoma over the past few years, so it's exciting in breast cancer because this is our first immunotherapy approval.”
The approval in 2019 of atezolizumab plus nab-paclitaxel was based on findings from the phase 3 IMpassion130 trial, which demonstrated a reduction in the risk of progression or death by 40% compared with chemotherapy alone in patients with unresectable locally advanced or metastatic PD-L1-positive TNBC.3 Immunotherapies eganelisib (IPI-549) and pembrolizumab (Keytruda) remain under evaluation in clinical trials for potential combination treatment of patients with TNBC as well.
Although the promise for immunotherapy in TNBC has been hopeful, 2020 saw approval of an antibody-drug conjugate (ADC) in this setting as well. The FDA granted an accelerated approval to sacituzumab govitecan-hziy (Trodelvy) for the treatment of patients with metastatic TNBC who have received at least 2 prior lines of therapy, based on findings from the phase 3 ASCENT clinical trial. The response rate in this study was 33.3% (95% CI, 24.6%-43.1%), which included 2.8% complete responses and 30.6% partial responses.4
“There are other immunotherapies that are being explored for TNBC. Some TNBCs that are associated with the inherited BRCA1/2 mutation can be targeted with a new class of drugs called PARP inhibitors,” said Tripathy. “These drugs are not curative, but they can induce remissions. They are used alone, so they're not used with chemotherapy or any other drugs. However, there's a lot of research going on to determine how these drugs can be combined with other drugs.”
Overall, the treatment landscape for patients with TNBC continues to expand with an array of treatments, including both targeted therapies and immunotherapies.
According to Tripathy, HER2-positive metastatic breast cancer is 1 of the most treatable cancers, although the landscape still lacks a curative therapy, and while this treatment landscape has evolved markedly over the last decade with the advent of HER2-targeting therapies, there have been 2 important FDA approvals of note, which include tucatinib (Tukysa) and fam-trastuzumab deruxtecan-nxki (Enhertu-DS-8201).
Tucatinib, an oral small molecule tyrosine kinase inhibitor (TKI) of HER2, received its approval for the treatment of patients with HER2-positive unresectable advanced or metastatic breast cancer who received at least 1 prior anti-HER2-based regimen in the metastatic setting. The agent was approved 4 months ahead of schedule earlier this year.
“Tucatinib is a pill, an oral TKI that blocks HER2, and it's given in combination with a chemotherapy pill called capecitabine and an antibody called trastuzumab,” Hamilton said. “This addition of this drug improves OS, PFS, and objective response rate (ORR), but what is exciting about this drug is that it also crosses the blood brain barrier, which is an unmet medical need for patients with HER2-positive disease. Up to 50% of patients with HER2-positive BC will develop brain metastases over the course of their lifetime. Having drugs that cross into the brain well and work there is important because most of our intravenous therapies can't get into the brain well, which is one of the reasons we see so many brain metastases.”
The approval indicates that patients with brain metastases are eligible to receive tucatinib. In the phase 2 HER2CLIMB study (NCT02614794), which was the study that served as the basis of this approval, tucatinib added to trastuzumab and capecitabine induced a median PFS of 7.8 months versus 5.6 months in the control arm, and among patients with brain metastases, the median PFS was 7.6 months versus 5.4 months, respectively.5
“The second agent in the HER-2 positive space to have a recent approval was trastuzumab deruxtecan,” said Hamilton. “What was exciting about the trastuzumab deruxtecan data was that over 90% of patients received benefit from it.. It's in a larger confirmatory trial now to confirm this benefit because it was approved early based off of a phase 1 trial.”
Trastuzumab deruxtecan, an ADC targeting HER2, was approved for the treatment of patients with unresectable or metastatic breast cancer who are HER2-positive and have received at least 2 prior lines of anti-HER2-based regimens in the metastatic setting. The approval was based on findings from the phase 2 DESTINY-Breast01 clinical trial (NCT03248492), which demonstrated an ORR of 60.3% with this treatment. The disease-control rate with this therapy was 97.3% (95% CI, 93.8-99.1).
The treatment paradigm of metastatic breast cancer could not have evolved as much as it has over the last few years without continued enrollment to these important clinical trials, and as the landscape continues to evolve, enrolling patients to trials will remain of the utmost importance to continue developing more targeted approaches to treating patients with this difficult disease.
The importance of clinical trials was recently underscored by a draft guidance issued by the FDA. This guidance recognizes that premenopausal women with breast cancer have historically been underrepresented in clinical trials.6 Similarly, the FDA issued a guidance in 2019 calling for inclusion of male patients with breast cancer in clinical trials.7 These recommendations encourage including these populations in clinical trials in order to determine the efficacy and safety of select agents in these populations that are often underserved in trials.
Participation in and enrollment to clinical trials fuel the great number of advances that are coming out in the field, and in order to continue accelerating the development of new therapies and to improve our understanding of the disease itself, Tripathy explained that it is important that patients and physicians continue enrolling to these trials.
“My biggest message is just how hopeful I am with the drugs that are coming in the pipeline and how much belief I have in clinical trials,” said Hamilton. “We know that patients that are treated on clinical trials do just as well as standard of care, if not actually better. All of the drugs of tomorrow are in clinical trials today, and so I encourage physicians to think about clinical trials as an option for patients and also for patients to ask their physician whether there may be a clinical trial that is right for them.”
Tripathy had a similar message to share with colleagues in the field. He said, “My message is to involve the patient in the decision-making process, make sure that any opportunities for clinical trials are made available to them, and get patients to participate in decision making as well.”
1. André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. Presented at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3.
2. André F, Ciruelos EM, Juric D, et al. Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020. LBA18
3. Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). Presented at: 2018 ESMO Annual Congress; October 19-23, 2018; Munich, Germany. Abstract LBA1_PR
4. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019;380 (8):741-51. doi: 10.1056/NEJMoa1814213
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382:597-609. doi: 10.1056/NEJMoa1914609
6. FDA in brief: FDA encourages inclusion of premenopausal women in breast cancer clinical trials. News Release. FDA. October 7, 2020. Accessed October 9, 2020. https://bit.ly/2GtsIc3
7. FDA in brief: FDA encourages inclusion of male patients in breast cancer clinical trials. News Release. FDA. August 26, 2019. Accessed October 10, 2020. https://bit.ly/3dekJLE