Abemaciclib: Another First-Line CDK4/6 Inhibitor for Breast Cancer

Alexander M. Castellino, PhD

September 11, 2017

MADRID, Spain — Abemaciclib (Lilly), the third in the class of cyclin-dependent kinase (CDK) 4/6 inhibitors, has shown positive results in the phase 3 MONARCH 3 (NCT02246621) study of its use in the first-line treatment of treatment-naive postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative (HER2–) advanced breast cancer.

The results show that the addition of abemaciclib to anastrazole or letrozole was associated with significantly prolonged progression-free survival (PFS).

MONARCH 3 is expected to provide a front-line indication for abemaciclib as combination therapy.

However, abemaciclib is not yet on the market, and the new drug application with the US Food and Drug Administration for abemaciclib is based on results from both the MONARCH 2 and the MONARCH 1 study. In those studies, abemaciclib monotherapy demonstrated objective responses in women with HR+/HER2– advanced or metastatic breast cancer that had progressed after one or more endocrine-based therapies.

In the new study, the treatment effect was seen across all subgroups of patients, and the safety signal confirms what has already been reported from the MONARCH 1 and 2 trials: more diarrhea and less neutropenia when compared with other CDK 4/6 inhibitors. (Two are already on the market: palbociclib [Ibrance, Pfizer] and ribociclib [Kisqali, Novartis].)

Commenting on the new findings, Giuseppe Curigliano, MD, director, Division of New Drug Development, European Institute of Oncology, University of Milan, Italy, said in a statement: "Abemaciclib is the third CDK4/6 inhibitor to be tested in advanced breast cancer and the MONARCH 3 trial confirms the role of this new class of agents in combination with endocrine therapy in the treatment of metastatic breast cancer."

"Many patients with metastatic disease still receive chemotherapy, despite guidelines and data from clinical trials," he added. "This study confirms that we should avoid chemotherapy in hormone receptor positive, HER2 negative metastatic breast cancer if visceral crisis is not present."

MONARCH 3 Details

The MONARCH 3 study was presented at the meeting by lead author, Angelo Di Leo, MD, PhD, from the Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.

This double-blind, phase 3 study randomly assigned treatment-naive, postmenopausal women with ER+ HER2– advanced breast cancer to receive abemaciclib in combination with a nonsteroidal aromatase inhibitor (anastrozole or letrozole) or placebo and anastrazole/letrozole.

Women enrolled in the study had not received endocrine therapy or had relapsed more than 12 months after adjuvant or neoadjuvant endocrine therapy. All patients received anastrazole or letrozole daily at the standard dose. In addition, patients (n = 328) received abemaciclib 150 mg, twice daily on a continuous dosing schedule, or matching placebo (n = 165).  

The primary objective was investigator-assessed PFS. Secondary objectives included objective response rate (ORR) and safety.

MONARCH 3 Results

The patients were balanced across the treatment groups. Dr Di Leo highlighted that more that approximately 53% of women in each group had visceral disease, more than 80% had measurable disease, and more than half had not received endocrine therapy in the neoadjuvant or adjuvant setting.  

At the interim analysis at 18 months, median PFS was 14.7 months for the control group and had not been reached for patients receiving the abemaciclib combination (P = .000021). With a significantly prolonged PFS, patients receiving the abemaciclib combination had a 46% reduced risk for disease progression. A blinded review confirmed these results.

ORR was 48% for patients receiving the abemaciclib combination and 34.5% for the control group (P = .002). For patients with measureable disease at baseline, ORRs were 59% and 44% for the abemaciclib and control groups, respectively (P = .004).

"The data also show we may be able to better distinguish benefit among groups of patients," commented Dr Di Leo.

In an exploratory analysis, he showed that patients who had a treatment-free interval of less than 36 months were more likely to benefit from the abemaciclib combination. Landmark PFS rates (6, 12, and 18 months) were substantially higher for patients receiving the abemaciclib combination (n = 42) compared with patients in the control group (n = 36). 

In patients with more challenging disease characteristics, such as liver metastases, patients had substantial benefit from the addition of abemaciclib, he reported. Median PFS for patients with liver metastases at baseline was 15 months for the abemaciclib group and 7.2 months for the control group.

However, in the subgroups with bone metastases only, or with an indolent disease, relapsing years after stopping adjuvant endocrine therapy, patients had an excellent prognosis with endocrine therapy alone.

"It is well known that these patients have a better prognosis than those with liver or lung metastases, or who relapse early during the course of adjuvant endocrine therapy," Dr Di Leo said in a statement.

Dose reductions were seen at a greater frequency with abemaciclib (43% vs 6% for control), as were discontinuations (20% vs 3% for control). The most frequent adverse events with abemaciclib (vs control) were diarrhea (81.3% vs 29.8%), neutropenia (41.3% vs 1.9%), and fatigue (40.1% vs 31.7%).

Who Is Appropriate for CDK 4/5 Inhibitor Therapy

ESMO expert commentator Dr Curigliano indicated that the major question that still needs to be answered is the optimal sequence of treatment in the era of CDK 4/6 inhibitors. "Should we use these agents in the first-line setting, or is there a space to start with endocrine therapy alone and to add CDK 4/6 inhibitors at progression?" he asked.

Nicholas Turner, MD, from the Institute of Cancer Research, London, United Kingdom, expressed similar sentiments in his discussion of the study. He noted that with mature data, it is likely that the abemaciclib combination will result in a PFS benefit of approximately 12 months.

Dr Turner also noted that the PALOMA 2 and PALOMA 3 trials for palbociclib and the MONALEESA2 study for ribociclib provided hazard ratio and risk reduction benefits similar those seen in MONARCH 3 for abemaciclib , as well as MONARCH 2, which was recently published.

"The consistency in hazard ratios across these studies and in slightly different indications suggests a class effect," he said. He noted, however, that neutropenia occurred at a higher frequency with palbociclib and ribociclib and thus these drugs had to be dosed at an intermittent dosing schedule. However, with continuous dosing the incidence of diarrhea is higher with abemaciclib compared with its two counterparts, he pointed out.

Although survival data are not mature, Dr Turner suggested that all studies with CDK 4/6 inhibitors were underpowered for survival. "Median OS on letrozole alone is approximately 50 months," he noted. Regardless of this, he said that the new data  were practice-changing.

But do these data indicate who will receive CDK 4/6 inhibitors? Dr Turner echoed Dr Curigliano's views that most patients with HR+ HER2– advanced breast cancer continue to receive chemotherapy — a practice that goes against clinical guidelines.  

Dr Di Leo suggested that metastases at presentation may provide a clue. "In our study, nearly one third of patients had bone metastases only or a tumor relapsing several years after stopping adjuvant endocrine therapy," he noted. "This is a clinically relevant proportion of patients for whom we may consider delaying use of a CDK 4/6 inhibitor. This may be a more optimal treatment strategy for some patients since it can avoid the toxicity of first-line CDK 4/6 inhibitors and save costs," he added.

"Now, for the first time, we have insights suggesting that patients with certain clinical characteristics may benefit differently from treatment with a CDK 4/6 inhibitor, including the possibility that some patients with a good prognosis may be able to start on endocrine therapy alone. In such patients, CDK 4/6 inhibitors could potentially be reserved as a next line of treatment for metastatic disease. This idea warrants further study given our data," he said.

Summarizing these data, Dr Turner noted that endocrine therapy–naive patients and those with nonvisceral, low-volume disease are more likely to do better on aromatase inhibitors alone. Still, the absolute benefit from CDK 4/6 inhibitor therapy is likely to be higher for these patients, he noted. 

The study was funded by Eli Lilly and Company. Dr Di Leo reported receiving honoraria and travel funds from and consults with Sankyo, Roche, Novartis, Pfizer, AstraZeneca, Genomic Health, Eisai, Lilly, Pierre Fabre, Bayer, and Celgene. He also consults for and receives travel funds from Puma Biotechnology, and research funds from Novartis, Pfizer, and AstraZeneca. Dr Turner reported receiving advisory board honoraria from Pfizer, Novartis, Lilly, Roche/Genentech, AstraZeneca, ADC Therapeutics, Clovis, and Servier. He has also received research funding from Pfizer, AstraZeneca, and Roche.

European Society for Medical Oncology (ESMO) 2017 Congress. Presented September 10, 2017. Abstract 236O.

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