Dr McAndrew on a Subgroup Analysis of NATALEE in HR+/HER2– Early Breast Cancer

Nicholas P. McAndrew, MD, MSCE, hematologist-oncologist, assistant clinical professor, medicine, University of California, Los Angeles (UCLA), David Geffen School of Medicine, UCLA Medical Center, discusses a subgroup analysis of the phase 3 NATALEE trial (NCT03701334) and clinical outcomes in patients with hormone receptor–positive/HER2-negative early breast cancer by prior systemic treatment.

In the NATALEE trial, 5101 patients were randomly assigned 1:1 to receive an aromatase inhibitor (AI) alone or in combination with ribociclib (Kisqali) at 400 mg per day for 3 weeks on and 1 week off for 3 years. Men and premenopausal women also received goserelin. Patientswith stage IIA N0 disease required additional risk factors like grade 3 disease, high Ki-67 levels, or high genomic risk factors to be eligible for enrollment. Patients were grouped based on prior chemotherapy exposure and the duration of prior endocrine therapy.

Most patients enrolled in the NATALEE trial had received prior chemotherapy, as anticipated for this high-risk population, McAndrew begins. In total, 88.1% of patients had received prior chemotherapy, either in the neoadjuvant or adjuvant setting, with most receiving adjuvant therapy. The use of neoadjuvant chemotherapy is not typically standard in this population but can be administered under specific conditions, such as in patients with larger or more aggressive tumors, he expresses. Patients who received prior neoadjuvant chemotherapy represented the highest-risk group, yet they still benefited from the addition of ribociclib to an AI. Similarly, those who received prior adjuvant chemotherapy also experienced a benefit from ribociclib, McAndrew reports. The trial, however, was not designed to assess whether adding chemotherapy alone contributes to the benefit of ribociclib, though future analyses may explore this, he states.

Most patients (68.5%) had received prior systemic endocrine treatment. Importantly, those who had received endocrine therapy for at least 26 weeks (n = 711) did not have any differences in invasive disease-free survival compared with those who started therapy just months before enrollment, McAndrew expands. This finding provides reassurance to oncologists who prefer a gradual approach to initiating endocrine therapy, such as starting with tamoxifen followed by ovarian function suppression and an AI before introducing a CDK4/6 inhibitor in premenopausal patients, McAndrew emphasizes. This stepwise method, which is sometimes considered for patients who may struggle with symptoms when receiving endocrine therapy, does not negatively affect patient outcomes, according to McAndrew. The NATALEE analysis indicates that taking months to initiate endocrine therapy does not impedesurvival outcomes, he concludes

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Nicholas P. McAndrew, MD, MSCE, discusses a subgroup analysis of the NATALEE trial in HR+/HER2– early breast cancer by prior systemic treatment.

Dr McAndrew on the Implications of the PHERGain Study in HER2+ Breast Cancer

Nicholas P. McAndrew, MD, MSCE, health sciences clinical assistant professor, Hematology/Oncology, University of California, Los Angeles (UCLA), UCLA Health, discusses the implications of the phase 2 PHERGain study (NCT03161353) of chemotherapy de-escalation in patients with HER2-positive early breast cancer.

Actively leveraging neoadjuvant studies in breast cancer is necessary to both pinpoint patients requiring escalated therapy and identify those who could benefit from chemotherapy de-escalation, McAndrew begins, adding that it is essential to recognize the variability in breast cancers, particularly in patients with HER2-positive disease. Innovative studies like the PHERGain trial aim to address this challenge, he notes. Data from the trial were presented at the 2023 ASCO Annual Meeting. The study employed a pathologic complete response (pCR)–adapted strategy to determine the feasibility of utilizing a chemotherapy-free dual HER2-blockade regimen in patients with early HER2-positive breast cancer.

In the experimental arm, participants received the least toxic and most effective therapy- targeted therapy alone, McAndrew continues. This consisted of trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without endocrine therapy. Generally, this targeted therapy is not as potent as chemotherapy for unselected patients. However, the study aimed to identify patients who did achieve a good response with the regimen.

Patients with a positive PET response or pCR after 2 treatment cycles, according to a PET scan,continued with the same treatment. Chemotherapy was added to the regimen for those who did not respond to targeted therapy alone, McAndrew expands.

The study demonstrated that approximately one-third of patients did not receive chemotherapy during the study and achieved comparable 3-year invasive disease-free survival rates to that of patients who underwent chemotherapy, he explains.

Although this PET-based, pCR-adapted strategy may not become the standard approach for all patients, it still an innovative trial design, he continues. Trials like PHERGain are crucial in moving away from a one-size-fits-all regimen. This personalized approach aims to maximize efficacy and minimize toxicity for individual patients, McAndrew concludes.

Nicholas P. McAndrew, MD, MSCE, discusses the implications of the phase 2 PHERGain study of chemotherapy de-escalation in patients with HER2-positive early breast cancer.


Dr McAndrew on the Impact of the KATHERINE Trial in HER2+ Breast Cancer

Nicholas P. McAndrew, MD, MSCE, health sciences clinical assistant professor, Hematology/Oncology, University of California, Los Angeles (UCLA), UCLA Health, discusses the impact of the phase 3 KATHERINE trial (NCT01772472) in patients with HER2-positive breast cancer.

McAndrew says he found it important to provide an update on the KATHERINE trial during an 

® State of the Science Summit™ on breast cancer. McAndrew explains that this phase 3 study has had an immediate impact on clinical practice. However, early-stage breast cancer studies are characterized by their long-term follow up data, which offer continuous insights for oncologists over the years, he expands. The significance of the KATHERINE trial lies in establishing a clinically meaningful rationale for neoadjuvant therapy in patients with HER2-positive breast cancer, particularly for patients with high-risk disease who may benefit from post-neoadjuvant therapy intensification, McAndrew elucidates. 

KATHERINE observed ado-trastuzumab emtansine (T-DM1; Kadcyla) vs trastuzumab (Herceptin) in patients with HER2-positive early breast cancer who had undergone neoadjuvant chemotherapy but did not achieve a pathologic complete response and instead maintained residual disease post-neoadjuvant chemotherapy, he continues. Previous analyses in this setting had indicated that these patients face a worse prognosis, which is marked by inferior disease-free survival (DFS). However, the initial analysis of KATHERINE revealed an approximate 11% benefit in 3-year invasive DFS (IDFS) with T-DM1 vs trastuzumab, translating to a notable 50% reduction in the risk of recurrence, McAndrew says.

 with a median follow-up of 8.4 years, which offered a more comprehensive evaluation of the trial. The IDFS benefit with T-DM1 increased to 13.7%, with a relative risk reduction of 46%, he explains. This extended follow up reinforces that the observed benefit with T-DM1 is not merely a delay in metastases; rather, it appears to be a sustained and meaningful IDFS advantage over time. This further emphasizes the importance of adopting neoadjuvant T-DM1 in the management of HER2-positive breast cancer, McAndrew concludes.

Nicholas P. McAndrew, MD, MSCE, discusses the impact of the phase 3 KATHERINE trial in patients with HER2-positive breast cancer.

Nicholas P. McAndrew, MD, MSCE, assistant clinical professor of Medicine, University of California, Los Angeles (UCLA), hematologist-oncologist, UCLA David Geffen School of Medicine, UCLA Medical Center, discusses the relationship between chemotherapy and ovarian function suppression in hormone receptor (HR)–positive, HER2-negative breast cancer.

Premenopausal patients with HR-positive, HER2-negative breast cancer can experience a benefit from treatment with chemotherapy, McAndrew says. However, it is unclear if that benefit stems from the cytotoxic properties of the chemotherapy, or if it is associated with ovarian function suppression in an estrogen-depleted state, leading to the indirect killing of cancer cells by restricting the amount of estrogen-related growth, McAndrew adds.

Notably, benefits from chemotherapy were observed in premenopausal patients with HR-positive breast cancer who were node negative and high risk, or node positive with involvement of 1-3 nodes in the phase 3 RxPONDER trial (NCT01272037). On the trial, patients that had a recurrence score between 0 and 25 all experienced a benefit from chemotherapy. This added to the intense debate of the relationship between chemotherapy and ovarian function suppression in this patient population, McAndrew concludes.

Nicholas P. McAndrew, MD, MSCE, discusses the relationship between chemotherapy and ovarian function suppression in hormone receptor–positive, HER2-negative breast cancer.


Dr. McAndrew on Chemotherapy Vs Ovarian Function Suppression in HR+ Breast Cancer

Since 1971, after Cole et al reported activity of tamoxifen in patients with late-stage breast cancer, endocrine therapy (ET) has been the cornerstone of systemic treatment for hormone receptor (HR)-positive, HER2-negative breast cancer.

 Starting in the ’90s, aromatase inhibitors (AIs) were developed in the metastatic setting, showing superiority over tamoxifen in postmenopausal patients.

 As tamoxifen and AIs showed benefit in late-stage disease, these drugs also succeeded in the adjuvant setting. They are now routinely used to reduce the risk of distant recurrence.

 Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been changing practice in advanced HR-positive breast cancer, with 3 agents (palbociclib [Ibrance], ribociclib [Kisqali], and abemaciclib [Verzenio]) having now FDA-approved indications for use with ET in the first-line setting.

CDK4/6 inhibitors restrict progression through the cell cycle.

 Under normal conditions, the G1 to S phase transition is tightly regulated by the retinoblastoma (Rb) protein to halt abnormal growth. Through their interaction with cyclin proteins, CDK 4 and 6 phosphorylate and inactivate Rb, allowing G1 to S phase conversion. Inhibition of CDK4/6 by these drugs results in dephosphorylation of Rb and subsequent G1 phase arrest.

 Preclinical studies revealed that HR-positive breast cancer cell-line growth was particularly sensitive to CDK4/6 inhibition. These studies also suggested synergism with ET.

 This observation led to a series of phase II and III trials utilizing these agents in the metastatic breast cancer setting.

Through the subsequent PALOMA-2, MONALEESA-2, and MONARCH 3 studies, palbociclib, ribociclib, and abemaciclib, respectively, were shown to drastically improve progression-free survival (PFS) in HR-positive, HER2-negative advanced breast cancer when added to AIs as first-line therapy.

 Additionally, PALOMA-3, MONALEESA-3, and MONARCH 2 all demonstrated significant improvement in PFS after progression on prior ET when these agents were added to fulvestrant.

 Abemaciclib, because of its increased potency and continuous dosing schedule, was also evaluated as monotherapy in a single-arm, phase II study.

 In addition, these drugs, while generally well tolerated, have similar toxicity profiles, which include fatigue, uncomplicated neutropenia, and diarrhea. QTc prolongation is seen only in ribociclib, and it is isolated to doses ≥600 mg daily.

 These trials are the basis for which the FDA approved these drugs for metastatic breast cancer, and their use has been widely adopted.

Table. Clinical Trials of CDK4/6 Inhibitors in High-Risk Adjuvant Setting

Although ET significantly reduces the risk of recurrent HR-positive/HER2-negative early breast cancer, the cumulative risk of distant recurrence has remained steady for decades and is worsened with increased nodal involvement.

 Adjuvant systemic therapy has, therefore, not been optimized for these high-risk patients and it remains a clinically unmet need. In a series of open-label, phase III trials, CDK4/6 inhibitors are now being studied in the high-risk adjuvant setting (

 PALLAS (NCT02513394), which opened enrollment in September 2015, is a phase III Alliance Foundation Trials, LLC/Austrian Breast & Colorectal Study Group trial comparing adjuvant palbociclib plus ET of physician’s choice (including tamoxifen) with ET alone in stage II to III HR-positive, HER2-negative breast cancer.

 The dosing of palbociclib in PALLAS is the same as in the metastatic setting and will be administered for 2 years concurrently with ET. The primary endpoint is invasive disease-free survival (iDFS). Patients must enroll within 12 months of diagnosis and within 6 months of beginning adjuvant ET. Also active and enrolling patients is monarchE (NCT03155997), a phase III National Surgical Adjuvant Breast and Bowel Project trial comparing adjuvant abemaciclib plus ET (including tamoxifen) with ET alone.

 MonarchE opened in July 2017 and is similar to PALLAS in terms of the primary endpoint, dosing schedule, and study drug administration period. However, monarchE excludes patients with node-negative disease and allows only up to 12 weeks of prior ET.

NATALEE (NCT03701334) is an international, phase III trial led by Translational Research in Oncology and Novartis that will study adjuvant ET with or without ribociclib. NATALEE, like PALLAS, will include subjects with both anatomic stage II and III breast cancer and assess iDFS as its primary endpoint. However, NATALEE differs from PALLAS and monarchE in that ribociclib will be given over a period of 3 years instead of 2 and at a reduced dose of 400 mg, which may eliminate QTc prolongation.

 Additionally, up to 12 months of prior ET is allowed, and premenopausal women and men will be given a nonsteroidal AI plus goserelin as ET in both arms (excluding tamoxifen). NATALEE opened for enrollment in December 2018 and along with PALLAS and monarchE will clarify the potential role of these agents in helping patients with curable breast cancer remain free of disease.

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Articles

Recently, CDK 4/6 inhibitors have been changing practice in advanced HR-positive breast cancer, with 3 agents now having FDA-approved indications for use with endocrine therapy in the first-line setting.

Nicholas Patrick McAndrew MD, MSCE

Articles

Dr McAndrew on a Subgroup Analysis of NATALEE in HR+/HER2– Early Breast Cancer

Dr McAndrew on the Implications of the PHERGain Study in HER2+ Breast Cancer

Dr McAndrew on the Impact of the KATHERINE Trial in HER2+ Breast Cancer

Dr. McAndrew on Chemotherapy Vs Ovarian Function Suppression in HR+ Breast Cancer

CDK4/6 Inhibitors Explored in Adjuvant Breast Cancer Setting