Sara A. Hurvitz, MD, University of California-Los Angeles Jonsson Comprehensive Cancer Center, discusses the background, findings, and clinical significance of the MONALEESA-7 trial, the findings of which were presented at the 2019 ASCO Annual Meeting.

Transcript

This is Sara Hurvitz, Associate Professor of Medicine and Director of the Breast Cancer Clinical Trials Program at the University of California-Los Angeles Jonsson Comprehensive Cancer Center.

Hormone receptor (HR)-positive breast cancer is the most common type of breast cancer diagnosed. It accounts for roughly 2/3 to 3/4 of all breast cancers diagnosed.

We know from preclinical data generated in our own lab, around 2007 or so, that inhibiting the cyclin-dependent kinase pathway is actually very effective in HR-positive breast cancer. So this led to the clinical development of several CDK4/6 inhibitors, ribociclib being one of them.

Multiple studies were conducted looking at the addition of a CDK4/6 inhibitor to standard endocrine therapy with all of these different agents, and all of them showed a significant improvement in the median progression-free survival (PFS), on the order of 10 to 12 months of improvement, with the addition of a CDK4/6 inhibitor to standard endocrine therapy.

We developed the MONALEESA-7 study, which exclusively enrolled patients who were pre- or perimenopausal and under the age of 59 with advanced, HR-positive metastatic breast cancer, and we decided that evaluating young women with metastatic breast cancer would be an important subject matter to take on, because young women are often excluded from clinical trials of HR-positive breast cancer because their ovaries are functioning.

It's a little more complicated to achieve ovarian suppression and evaluate benefits of new therapies in this class of patients.

Young women also tend to be diagnosed at a later stage than older women, as our screening modalities are not as effective at picking up cancer earlier, and there's some evidence that the type of breast cancer from a biological perspective may be a little more aggressive in younger women, even when the HRs are co-expressed, so a higher prevalence of the Luminal B subtype of breast cancer.

Our study was designed exclusively to evaluate young women and see whether the addition of a CDK4/6 inhibitor, ribociclib, is beneficial when added to endocrine therapy.

The MONALEESA-7 study enrolled 672 young women under the age of 59, pre- or perimenopausal, who had HR-positive/HER2-negative metastatic breast cancer.

Patients were allowed, if they had received up to 1 prior line of chemotherapy—though fewer than 15% of patients had had that—and were allowed if they had never received endocrine therapy for metastatic disease.

All patients on the study received ovarian suppression in combination with either a nonsteroidal aromatase inhibitor or tamoxifen. Patients were randomized to receive either placebo on top of that endocrine therapy, or ribociclib, and it was a 1:1 randomization.

We published, in 2018, in Lancet Oncology, the median PFS results from this study, which showed that the addition of ribociclib significantly improved median PFS, up to 23.8 months, which represents over a 10-month improvement in PFS compared to patients who received endocrine therapy alone.

What we demonstrated in the past week at ASCO and published simultaneously in The New England Journal of Medicine is the overall survival (OS) results. We demonstrated for the first time that the addition of a CDK4/6 inhibitor, in this case ribociclib, statistically significantly improved median OS for patients with this type of disease.

We showed, at a 42-month landmark analysis, that 46% of the patients in the placebo arm were still alive compared to 70% of the patients in the ribo[ciclib] arm. The median OS had not yet been reached in the ribo[ciclib] arm, and it was around 40 months for those in the placebo arm.

This is the first time that a statistically significant improvement in OS has been demonstrated with one of these inhibitors, and I think that's really great news for the patients who are already using these drugs in the metastatic setting.

Ribociclib has already been FDA-approved in combination with an aromatase inhibitor or fulvestrant for the management of metastatic breast cancer, including women with premenopausal disease.

However, now we see that the OS is improved, and I think this may help patients access this type of medication globally, where healthcare systems may require survival benefits to be demonstrated prior to providing funding for a new medication.

In terms of the next steps for our research, we are now evaluating whether or not the addition of ribociclib to standard endocrine therapy improves the invasive disease-free survival for patients with early stage disease.

All of our data to date has been in the metastatic setting. Now we want to see whether we can improve outcomes for women with earlier stage disease, stage II and stage III breast cancer.

I'm very excited to see how those results pan out, because, again, this is the most common form of breast cancer diagnosed. The impact on a global perspective for women diagnosed with breast cancer is quite large.