Adjuvant anti-CDK thwarts early recurrence of breast cancer

The inclusion of a CDK4 / 6 inhibitor in adjuvant therapy significantly increased invasive disease free survival (iDFS) in hormone receptor (HR) positive early high-risk breast cancer patients, a large randomized trial showed.

The risk of iDFS decreased by 25.3% with the addition of abemaciclib (Verzenio) to standard endocrine therapy. The risk of distant (metastatic) recurrence decreased by almost 30% with combination therapy compared to endocrine therapy alone.

There were no new or unexpected toxicities with the addition of abemaciclib to endocrine therapy, reported Stephen RD Johnston, MD, of the Royal Marsden Hospital in London, at the 2020 European Society for Medical Oncology (ESMO) virtual conference.

“Abemaciclib is the first CDK inhibitor to show significant improvement in the setting of early breast cancer, when combined with endocrine therapy, compared to endocrine therapy alone,” Johnston said. “The results indicate the prevention of early recurrence and a clinically significant reduction in the risk of distant recurrence.”

The findings have potential implications for changing practice, but require longer follow-up to determine if early risk reduction translates into a long-term survival benefit, said ESMO guest commentator Giuseppe Curigliano, MD, of the National Institute. Cancer Center in Milan.

“It is important to understand for which patients we should intensify treatment and for whom we should decrease,” he said. “The patient population in this trial had an increased risk of relapse, and for these patients we usually give chemotherapy and then we offer endocrine therapy for 5 to 10 years. It will also be important to know the safety. Patients are supposed to receive abemaciclib for 2 years, but may only receive for 6 months. We need to know how many patients are stopping abemaciclib due to side effects. “

In this trial, 16.6% of patients discontinued abemaciclib due to adverse events (AE), most commonly diarrhea, Curigliano noted. Two thirds of the patients continued endocrine therapy

A future trial should specifically address whether some high-risk patients can forgo chemotherapy, he added. Such a trial should directly compare a CDK4 / 6 inhibitor plus endocrine therapy versus chemotherapy.

Standard therapies for HR positive / HER2 negative early breast cancer achieve a long-term non-recurrence in most patients. However, about 20% of patients have a recurrence, including a distant relapse, within the first 10 years after completing treatment. Patient risk can be stratified based on clinical and pathologic features, especially during the first few years of adjuvant endocrine therapy, Johnston said in her introductory remarks.

New agents and treatment strategies are needed to address the needs of the 20% of patients who have an early recurrence or distant metastasis. Abemaciclib is one of three FDA-approved CDK4 / 6 inhibitors for HR-positive / HER2-negative advanced breast cancer in combination with standard endocrine therapy. A phase III trial of abemaciclib and fulvestrant demonstrated a significant improvement in overall survival in the setting of advanced HR-positive / HER2-negative disease.

Johnston reported the first findings from the phase III monarchE trial to compare fulvestrant alone or in combination with abemaciclib as adjuvant therapy for high-risk early-stage HR-positive / HER2-negative breast cancer. The protocol defined high risk as four or more positive axillary lymph nodes or one to three affected nodes in association with a primary tumor size ≥5 cm, histological grade 3 and / or Ki67 ≥20%.

Pre and postmenopausal women were eligible, as were men. Prior adjuvant or neoadjuvant chemotherapy was allowed. Patients with known distant metastases were not eligible.

All patients received physician’s choice of standard endocrine therapy for 5 to 10 years, as clinically indicated, with or without 2 years of adjuvant abemaciclib. The primary endpoint was iDFS, and the key secondary endpoints were distant relapse-free survival (DRFS), overall survival, safety, patient-reported outcomes, and pharmacokinetics.

Data analysis included 5,637 randomized patients. The main analysis showed that the addition of abemaciclib resulted in an iDFS Hazard Ratio (HR) of 0.747 versus endocrine therapy alone (95% CI 0.598-0.932). The 2-year iDFS was 92.2% with abemaciclib and 88.7% without it.

Abemaciclib-treated patients had a 28.3% reduction in the risk of DRFS (95% CI: 0.559-0.920), and the 2-year DRFS was 93.6% with abemaciclib and 90.3% without he.

A prespecified subgroup analysis showed consistent benefit from the addition of abemaciclib, Johnston reported.

The most frequently reported AE in the abemaciclib group were diarrhea, neutropenia, and fatigue, compared to arthralgia, hot flashes, and fatigue in the control group.