CDK4/6 Inhibitors Continue to Change Practice in HR+ Breast Cancer

Sarah Sammons, MD

Overwhelming interest is swarming CDK4/6 inhibitors as a treatment modality following impressive progression-free survival (PFS) data with palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) in patients with advanced hormone receptor (HR)—positive, HER2-negative breast cancer, said Sarah Sammons, MD.

Now, the community is eagerly awaiting further data poised to show an overall survival (OS) benefit with these practice-changing agents.

Updated results of the phase III MONALEESA-7 trial, which evaluated the addition of ribociclib plus endocrine therapy in peri- or premenopausal women with advanced HR-positive, HER2-negative breast cancer, showed that the estimated median OS at 42 months was 70.2% with ribociclib compared with 46.0% in the placebo arm (HR, 0.712; 95% CI, 0.54-0.95; P = .00973).

OS data from the phase III MONARCH 2 trial (NCT02107703) of abemaciclib combined with fulvestrant (Faslodex) in patients with HR-positive, HER2-negative advanced breast cancer will be presented at the 2019 ESMO Congress.

"Women live extremely well on CDK4/6 inhibitors. We are prolonging their lives, but, [moreover], they are living well," Sammons exclaimed. "They are working and continuing to care for their families. The toxicity is extremely manageable compared to other targeted therapies that we use in advanced breast cancer."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Sammons, an assistant professor of medicine and member of the Duke Cancer Institute at Duke University School of Medicine, discussed the MONALEESA-7 and MONARCH 2 studies and how CDK4/6 inhibitors are changing the breast cancer space.

OncLive: What CDK4/6 inhibitors are available and how are they impacting the advanced HR-positive, HER2 negative breast cancer space?

Sammons: Three CDK4/6 inhibitors are approved: palbociclib, abemaciclib, and ribociclib. All of them have shown impressive, comparable activity in several phase III clinical trials, both in the first- and second-line settings. Those trials have shown advances for progression-free survival in terms of women's cancers.

Until now, we had not had any OS data, but we had data telling us that there is benefit in both first- and second-line settings. Therefore, there has been a little confusion as to when to use CDK4/6 inhibitors.

Now that these CDK4/6 inhibitors have shown favorable PFS data, how are you navigating therapy selection? Does toxicity carry as much weight now in these decisions?

That's a really good question. MONALEESA-7 was a phase III clinical trial, which randomized pre/perimenopausal women to ovarian suppression plus an aromatase inhibitor or tamoxifen versus placebo plus ribociclib.

The primary endpoint of that clinical trial was PFS. We already knew there was a [PFS] benefit, but we didn't have OS [data] until [June 2019]. Importantly, there was an OS benefit with the addition of ribociclib to endocrine therapy plus ovarian suppression for pre/perimenopausal women. That was tremendous because if we're not improving the OS of these women, what are we doing?

This was practice changing, and I believe everyone would agree with that, that the new frontline standard of care for pre/perimenopausal women with metastatic HR-positive, HER2-negative breast cancer is ovarian suppression plus endocrine therapy and an aromatase inhibitor.

Pending the OS data of MONARCH 2 have similar results, how would you then navigate treatment selection?

MONARCH 2 is a phase III clinical trial of abemaciclib. Women who had prior exposure to endocrine therapy were randomized to abemaciclib/fulvestrant versus fulvestrant/placebo.

We know already that there was a very profound improvement in terms of PFS. However, we now have the press release showing that those women also have an OS benefit, which is tremendous.

Patients of MONARCH 2 were a much more homogenous population than those in PALOMA-3 who were a bit more heavily pretreated. One-third of patients in PALOMA-3 had prior chemotherapy exposure and more than half had received at least 2 lines of endocrine therapy. Patients in MONARCH 2 and up to 1 line of endocrine therapy in the advanced setting and none had chemotherapy exposure. Sixty percent of patients had prior endocrine therapy in the adjuvant setting. Therefore, a good portion of them were actually treated with fulvestrant and abemaciclib in the first-line setting, with prior exposure in the adjuvant setting.

An OS benefit will be really exciting when it is shown. It will change the standard of care for our women who have had progressions on a previous aromatase inhibitor in the adjuvant setting, or who have had monotherapy with endocrine therapy to receiving fulvestrant and a CDK4/6 inhibitor.

The MONARCH 2 and the MONALEESA-7 data are pointing toward an OS benefit for introducing a CDK4/6 inhibitor early in a patient's metastatic breast cancer journey. At this point, most of us are encouraging CDK4/6 inhibitor use in the first-line setting unless you have a compelling reason not to do so.

We still have work to do in terms of the financial toxicity of CDK4/6 inhibitors because they can be very expensive. Patient assistance programs are helpful, but they are not the end-all be-all.

Turning to mechanisms of resistance, what is understood in this arena?

The treatment of patients with advanced HR-positive, HER2-negative breast cancer is evolving into a disease that is developing molecular subsets within itself. We know that about 35% of patients with HR-positive breast cancer will have activating mutations in the PIK3CA gene, which are targetable.

About 40% of patients who had prior endocrine exposure will develop ESR1 mutations, which lead to aromatase inhibitor resistance. That has therapeutic implications now and will have more likely in the future. Patients can develop FGFR1 amplifications, which will soon become targetable but like they will lack CDK4/6 inhibition response with endocrine therapy.

As we move forward, molecular and genomic sequencing are going to become more important as we tease out which women are going to benefit from certain targeted therapies and who aren't.

Hurvitz SA, Im S, Lu Y, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: overall survival (OS) results. J Clin Oncol. 2019;37(suppl 18; abstr LBA1008). doi: 10.1200/JCO.2019.37.18_suppl.LBA1008.