estrogen receptor–positive, HER2-negative breast cancer.

Dr Goetz on the Early Pharmacokinetic Data With Neoadjuvant (Z)-endoxifen in ER+/HER2– Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses pharmacokinetic data for neoadjuvant (Z)-endoxifen derived from the phase 2 EVANGELINE trial (NCT05607004) of premenopausal patients with metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer.

It is hypothesized that the ability of (Z)-endoxifen to target both ERα and PKCβ1 will reduce the need for ovarian function suppression, and demonstrate noninferiority compared with ovarian function suppression and an aromatase inhibitor in ER-positive, HER2-negative disease. The ongoing, multicenter, neoadjuvant EVANGELINE trial was designed to identify the optimal dose for the potent anti-estrogen agent to demonstrate activity in this patient population without increasing toxicities, Goetz details. A total of 7 women were enrolled onto the pharmacokinetic run-in portion of the study and received 40 mg of the study drug per day, he states.

Results from the pharmacokinetic run-in, which were presented at the 

, demonstrated that concentrations observed with the 40 mg dose ranged between 200 to 400 ng/ml, which was slightly below the target range, Goetz reports. As a result, the study is progressing to evaluate the 80 mg per day dose of (Z)-endoxifen to achieve optimal therapeutic concentrations, he explains. Enrollment to this portion of the study is ongoing.

Thus far, notable anti-tumor activity was observed at the 40 mg dose, with 6 enrolled patients showing a decrease in Ki67 levels of 10% or less at day 28, Goetz states. Moreover, these patients proceeded to undergo surgery after 24 weeks with a surgical Ki-67 level less than 3%, he says, adding that surgical data will be presented at a subsequent meeting. Importantly, no concerning safety signals have emerged thus far from the study.

Based on these findings, it is expected that the 80 mg per day dose level will be identified as the ideal dosage moving forward, Goetz says. Once the optimal dose is established, the study will advance into a larger phase 2 clinical trial to further evaluate the efficacy and safety of this treatment approach in a broader patient population, Goetz concludes.

Videos

Matthew P. Goetz, MD, discusses pharmacokinetic data for neoadjuvant (Z)-endoxifen in estrogen receptor–positive, HER2-negative breast cancer.

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the available treatment options for patients with metastatic hormone receptor (HR)–positive breast cancer in the post-CDK inhibitor setting.

The treatment armamentarium for patients with HR-positive breast cancer whose disease has progressed following prior treatment with a CDK4/6 inhibitor has greatly expanded in recent years, Goetz begins. In order to guide treatment navigation and optimize outcomes for these patients, it is necessary to define their molecular subtype and identify any actionable mutations, Goetz says. For example, 

 and PALB2 mutations indicate that a patient may respond favorably to PARP inhibitors. Other actionable biomarkers include PIK3CA, which is targeted by alpelisib (Vijoice), and 

 mutations, which is targeted by elacestrant (Orserdu), Goetz lists.

In addition to these targeted therapies, several therapeutic options in this space may not require the identification of specific biomarkers, Goetz adds. One emerging option is the orally bioavailable, small-molecule AKT inhibitor capivasertib. 

The agent has been granted priority review by the FDA when administered alongside fulvestrant (Faslodex)

 for patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer who experienced recurrence or progression on or after endocrine-based therapy. Capivasertib was also granted fast track designation for use in this population in January 2023.

Data supporting the use of this agent indicate that it provides benefit regardless of whether patients' tumors harbor 

 alterations in the AKT pathway, indicating that there may not be a need to select patients based on the presence or absence of these mutations, Goetz details. Future investigations of capivasertib may continue to explore its efficacy in combination with other approved drugs in the HR-positive space, he notes.

Lastly, antibody-drug conjugates (ADCs), such as fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), provide another effective option for patients in the post-CDK4/6 inhibitor space, Goetz states. T-DXd is currently approved by the FDA for the treatment of patients with unresectable or metastatic HER2-low breast cancer, as well as HER2-positive disease, he says. Another well-established ADC is sacituzumab govitecan-hziy (Trodelvy), which is effective for patients with estrogen receptor–positive disease that is refractory to standard therapies, but is not associated with other biomarkers, Goetz concludes.

Matthew P. Goetz, MD, discusses the available treatment options for patients with metastatic hormone receptor–positive breast cancer in the post-CDK inhibitor setting.

Dr Goetz on Post-CDK4/6 Inhibitor Treatment Options in HR-Positive Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the clinical significance of the phase 2 ELAINE-1 trial (NCT03781063) of lasofoxifene in patients with 

-mutated, estrogen receptor (ER)–positive/HER2-negative metastatic breast cancer.

ELAINE-1 evaluated the safety and efficacy of lasofoxifene vs fulvestrant (Faslodex) in this patient population. Lasofoxifene demonstrated clear evidence of antitumor activity as monotherapy in ELAINE-1, Goetz says. Additionally, the combination of lasofoxifene and abemaciclib (Verzenios) demonstrated activity in patients with 

-mutated, ER-positive/HER2-negative advanced breast cancer who progressed on a CDK4/6 inhibitor during the phase 2 ELAINE-2 trial (NCT04432454), Goetz explains.

Additional trials evaluating lasofoxifene and other selective estrogen receptor modulators will be critical for the further development of these agents, Goetz continues. The overarching goal is to develop improved therapies to treat patients with 

 mutations and potentially prevent them, Goetz concludes. 

Matthew P. Goetz, MD, discusses the clinical significance of the phase 2 ELAINE-1 trial of lasofoxifene in patients with ESR1-mutated, estrogen receptor-positive/HER2-negative metastatic breast cancer.


Dr. Goetz on the Clinical Significance of Lasofoxifene in ER+/HER2- Breast Cancer

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the progression-free survival (PFS) benefit derived with lasofoxifene in patients with 

The phase 2 ELAINE-1 trial (NCT03781063) compared the safety and efficacy of lasofoxifene with that of fulvestrant (Faslodex) in this patient population. Enrolled patients were required to have experienced disease progression on an aromatase inhibitor and a CDK4/6 inhibitor, Goetz says. Participants were randomly assigned to receive oral lasofoxifene at 5 mg daily or 500 mg of fulvestrant administered intramuscularly on days 1, 15, and 29, and every 4 weeks thereafter, Goetz adds. 

Data presented at the 2022 ESMO Congress showed that treatment with lasofoxifene (n = 52) resulted in a median PFS of 6.04 months (95% CI, 2.82-8.04) compared with 4.04 months (95% CI, 2.93-6.04) with fulvestrant (n = 51; HR, 0.699; 95% CI, 0.445-1.125; 

= .138). Although it was not determined to be statistically significant, the difference in median PFS was a positive signal, and there was clear evidence of antitumor activity with lasofoxifene in this population, Goetz concludes.

Matthew P. Goetz, MD, discusses the progression-free survival benefit derived with lasofoxifene in patients with ESR1-mutated, ER-positive/ HER2-negative metastatic breast cancer.


Dr. Goetz on the ELAINE-1 Trial of Lasofoxifene in ESR1-Mutated, ER+/HER2- Breast Cancer

Matthew Goetz, MD, medical oncologist, professor of Oncology, associate professor of Pharmacology, and professor of Pharmacology, Mayo Clinic, discusses a phase III study looking at capecitabine (Xeloda) in patients with residual breast cancer following neoadjuvant chemotherapy and surgery.

The study found that the disease-free survival rate with capecitabine was 74.1% versus 67.6% with standard therapy alone and overall survival for patients receiving capecitabine was 89.2% compared with 83.9% for those in the standard therapy arm, after 5 years of follow-up.

These findings are not only statistically significant, but clinically significant, says Goetz.

This study suggests that, going forward, it may be beneficial to consider taking a neoadjuvant chemotherapy approach before identifying which patients respond to chemotherapy and determining which may be eligible for capecitabine, says Goetz.

View more from the 2015 San Antonio Breast Cancer Symposium

Matthew Goetz, MD, medical oncologist, professor of Oncology, associate professor of Pharmacology, andprofessor of Pharmacology at Mayo Clinic, discusses a phase III study looking at capecitabine (Xeloda) in patients with residual breast cancer following neoadjuvant chemotherapy and surgery.


Matthew Goetz, MD

Articles

Dr Goetz on the Early Pharmacokinetic Data With Neoadjuvant (Z)-endoxifen in ER+/HER2– Breast Cancer

Dr Goetz on Post-CDK4/6 Inhibitor Treatment Options in HR-Positive Breast Cancer

Dr. Goetz on the Clinical Significance of Lasofoxifene in ER+/HER2- Breast Cancer

Dr. Goetz on the ELAINE-1 Trial of Lasofoxifene in ESR1-Mutated, ER+/HER2- Breast Cancer

Dr. Goetz on Adjuvant Capecitabine Following Neoadjuvant Chemotherapy and Surgery