Breast cancer

Evidence builds for CDK4/6 inhibitors in advanced breast cancer

Two new trials presented here at ESMO Congress 2019 strengthen the case for using CDK4/6 inhibitors plus endocrine therapy in patients with HR-positive/HER2 negative advanced breast cancer.

The Monarch 2 study evaluated abemaciclib plus fulvestrant in pre, peri and post-menopausal women with HR-positive/HER2 negative advanced breast cancer that had progressed despite endocrine therapy.

The results were simultaneously published in JAMA Oncology.

Patients were randomised to abemaciclib 150mg twice a day plus 500mg fulvestrant or placebo plus 500mg fulvestrant and were followed up for a median of 47.7 months.

Those who received abemaciclib had a median PFS of 16.9 months compared to 9.3 months in the placebo plus fulvestrant group (HR 0.536 CI 0.445 to 0.645).

Patients who received the CDK4/6 inhibitor also had a median of 9.3 months OS benefit (secondary endpoint) compared to the placebo plus fulvestrant group (median OS 46.7 months vs 37.3 months; HR 0.757 CI 0.606 to 0.945 P=0.0137).

Lead author Professor George Sledge from the Stanford University School of Medicine, USA, said, “this is statistically significant but I would also argue clinically relevant and important for patients with advanced breast cancer”.

He added that the OS benefit was consistent across the subgroups, including patients with poor prognostic factors such as visceral metastasis and primary endocrine therapy resistance.

An exploratory analysis conducted by the authors also revealed a 60 percent delay in time to chemotherapy in women treated with abemaciclib compared to the placebo plus fulvestrant group (median TTC delay of 50.2 months vs 22.1 months; HR 0.625 CI 0.501 to 0.779 P<0.0001).


The MONALEESA-3 study investigated ribociclib plus fulvestrant as first-or second-line therapy in 726  postmenopausal patients with HR positive/HER2 negative metastatic breast cancer.

Patients were randomised 2:1 to receive ribociclib 600mg daily (3 weeks on, 1 week off) plus 500mg fulvestrant or placebo plus fulvestrant.

“What was unique about this study was that about half of the patients were getting their therapy as front line –  they had not previously received any therapy for their metastatic cancer – and they were being compared to those who were getting fulvestrant in that same setting,” explained study lead Professor Dennis Slamon, University of California Los Angeles, USA.

The median duration of follow-up at data cut-off was 39.4 months and 25% of patients in the ribociclib arm were still on treatment compared to 13% in the placebo arm.

Ribociclib plus fulvestrant significantly prolonged overall survival compared to placebo plus fulvestrant (Median not reached versus 40 months HR 0.724 CI 0.568-0.924; p=0.00455).

“The P value of 0.00455 crossed the prespecified boundary to claim superior efficacy (P < 0.01129),” Prof. Slamon noted.

One particularly notable finding according to Prof. Slamon was the OS benefit was seen in the first line (median NR versus 45.1 months; HR 0.700 CI 0.479 – 1.021) and second-line settings (median 40.2 versus 32.5 months HR 0.730 CI 0.530-1.004).

The OS benefit in the ribociclib group was consistent across all subgroups and no new safety signals were observed.

“This is a significant, practice-changing report, in that we are now saying that patients with advanced breast cancer will have an overall survival benefit if they get the CDK4/6 inhibitor ribociclib upfront at the time of their recurrence, even if they have not had any prior endocrine therapy at the time of presenting with metastatic disease,” Prof Slamon concluded.

“The argument has always been by some experts that you should first treat with endocrine therapy alone and then if patients recur, you would add something like a CDK4/6 inhibitor… The data from MONALEESA-3 clearly show that if postmenopausal patients receive this right up front there is a very significant benefit – not only in progression free survival, which had already been published – but now with this new report in overall survival – which is the hardest endpoint to reach, and the most important one in terms of making an impact on the disease,” he added.

The take home message

Commenting on the two studies Professor Nadia Harbeck, from the University of Munich, Germany, described the delay in time to chemotherapy seen in the Monarch 2 trial as “game-changing” for metastatic breast cancer.

She also noted that the MONA-LEESA 3 trial for the first time gave the oncology community data in the first and second-line setting.

“Patients will not have received any endocrine therapy before that and so that makes it highly clinically meaningful because we were always struggling as to whether to give these drugs first or second-line and now we can see there’s a first-line survival benefit,” she said.

According to Prof. Harbeck the data from both trials suggested that CDK4/6 inhibitors should be a first-line treatment option for metastatic breast cancer.

“Prof. Slamen was one of the pioneers of the HER2 story and he cannot say this…. But I think these drugs will be a similar success as the HER2 story for our patients with advanced HR+ HER2- breast cancer,” she concluded.

Monarch 2 was funded by Eli Lilly.  The MONA-LEESA-3 trial was funded by Novartis.

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