NCCN Updated Guideline Adds Treatment Options for HER2-Positive Breast Cancer, Emphasizing CDK4/CDK6 Inhibition in Hormone-Sensitive Disease

An updated guideline from the National Comprehensive Cancer Network (NCCN) on the management of breast cancer (version 1.2018) expands treatment options for hormone receptor (HR)-positive, HER2-positive disease to include extended adjuvant neratinib (Nerlynx) treatment after trastuzumab (Herceptin) therapy in patients at high risk for recurrence, and recognizes a third cyclin-dependent kinase (CDK)4/CDK6 inhibitor in hormone-sensitive breast cancer.

At the 2018 NCCN conference, Sharon H. Giordano, MD, MPH, FASCO, Professor of Medicine, Department of Breast Medical Oncology, M.D. Anderson Cancer Center, Houston, provided an update on the treatment of patients with HER2-­positive breast cancer, noting an “explosion of new therapies” in recent years that have had a tremendous impact on survival.

Standard First- and Second-Line Therapies

The CLEOPATRA clinical trial defined pertuzumab (Perjeta) plus trastuzumab and docetaxel (Taxotere) as the standard of care for patients with HER2-positive, metastatic breast cancer. The final overall survival (OS) analysis demonstrated an additional 15.7 months of survival by adding pertuzumab to trastuzumab and docetaxel. This triplet therapy is now a preferred treatment for stage IV disease in the NCCN guideline (category 1).

“It’s also really remarkable that the median survival now is almost approaching 5 years for patients with metastatic, HER2-positive breast cancer,” said Dr Giordano.

The standard second-line therapy in the HER2-positive metastatic setting is now trastuzumab emtansine (Kadcyla), based on an improvement in OS versus capecitabine (Xeloda) plus lapatinib (Tykerb) in the ­EMILIA clinical trial.

In patients with early-stage disease, dual-targeted therapy in the neoadjuvant setting has led to improvement in the rates of pathologic complete response. Dr Giordano cautioned that attempts to de-escalate therapy by removing chemotherapy and relying solely on trastuzumab and pertuzumab have not resulted in equivalent outcomes to those of maintaining chemotherapy.

In the APHINITY clinical trial, an improvement in invasive disease-free survival (DFS) with the addition of pertuzumab to chemotherapy and trastuzumab in the early-stage adjuvant setting led to the FDA approval of pertuzumab for the adjuvant treatment of patients with HER2-positive breast cancer.

The ExteNET adjuvant clinical trial demonstrated a modest improvement in invasive DFS with 1 year of neratinib after trastuzumab therapy in the treatment of early-stage, HER2-positive breast cancer, and led to FDA approval of neratinib for this indication. Patients with HR-positive disease in the study derived slightly greater benefit than the HR-negative subset.

The updated NCCN guideline on the systemic adjuvant treatment of HR-positive, HER2-positive breast cancer reflects this finding, and now includes neratinib as an option after adjuvant trastuzumab therapy in patients with HR-positive, HER2-positive disease and a high risk for recurrence. The guideline also states that the benefits or toxicities associated with extended use of neratinib in patients who have received pertuzumab are unknown.

In another de-escalation clinical trial known as APT, the combination of adjuvant paclitaxel (Abraxane) and trastuzumab was associated with “excellent” outcomes, with a 7-year DFS of 93.3% in patients with T1 node-negative, HER2-positive breast cancer, Dr Giordano said.

Hormone-Sensitive Breast Cancer

William J. Gradishar, MD, Chief, Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, updated the status of treatment for patients with estrogen receptor–positive, HER2-negative disease, saying that this is “the era of the CDK4/6 inhibitors.”

The most recent addition to the CDK4/CDK6 inhibitor options is abemaciclib (Verzenio), which received FDA approval in 2017, in combination with an aromatase ­inhibitor, for the initial endocrine-based treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

The data to support the use of CDK4/CDK6 inhibitors for this indication have risen to the level of category 1, said Dr Gradishar.

In the first-line setting, adding a CDK4/CDK6 inhibitor to endocrine therapy approximately doubled median progression-free survival (PFS) compared with endocrine therapy alone in 3 large clinical trials (PALOMA-2, MONALEESA-2, and MONARCH-3).

“To a large extent, the results are fairly superimposable in the sense that they show a fairly striking improvement in PFS favoring the doublet over simply giving monotherapy,” Dr Gradishar said. Every subgroup of patients examined derived a PFS benefit with the addition of the CDK4/CDK6 inhibitor.

In MONARCH-3, the magnitude of benefit from adding a CDK4/CDK6 inhibitor was greater in patients with poorer prognosis than in those with good prognosis.

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