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

The hazard for 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 as compared with endocrine therapy alone.

No new or unexpected toxicities occurred with the addition of abemaciclib to endocrine therapy, reported Stephen R. D. Johnston, MD, of the Royal Marsden Hospital in London, at the 2020 European Society for Medical Oncology (ESMO) virtual congress.

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

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

"It is important to understand for which patients we need to escalate treatment and for whom we need to de-escalate," he said. "The patient population in this trial had a higher risk of relapse, and for these patients we usually give chemotherapy and then offer endocrine therapy from 5 to 10 years. It will also be important to know about safety. Patients are supposed to receive abemaciclib for 2 years, but may only receive for 6 months. We need to know how many patients discontinue abemaciclib because of side effects."

In this trial, 16.6% of patients discontinued abemaciclib because of adverse events (AEs), most often diarrhea, Curigliano noted. Two-thirds of the patients continued with endocrine therapy

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

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

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

Johnston reported the first findings from the phase III 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 involved nodes in association with primary tumor size ≥5 cm, histologic 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 ineligible.

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 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 primary 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.

Patients treated with abemaciclib had a 28.3% reduction in the hazard for DRFS (95% CI 0.559-0.920), and the 2-year DRFS was 93.6% with abemaciclib and 90.3% without.

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

The most commonly reported AEs in the abemaciclib arm were diarrhea, neutropenia, and fatigue, as compared with arthralgia, hot flushes, and fatigue in the control arm.

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