Pivotal Trials With CDK4/6, PI3K Inhibitors Propel Progress in HR+ Breast Cancer

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Partner | Cancer Centers | <b>Weill Cornell Medical College Sandra & Edward Meyer Cancer Center</b>

Leticia Varella, MD, discusses the progression of available treatments in hormone receptor-positive, HER2-negative metastatic breast cancer.

Leticia Varella, MD

Findings of the MONALEESA-7 and SOLAR-1 studies demonstrated intriguing findings for patients with hormone receptor (HR)—positive, HER2-negative metastatic breast cancer, and those with PIK3CA-mutated breast cancer, respectively, explained Leticia Varella, MD.

The phase III MONALEESA-7 trial examined ribociclib (Kisqali) and endocrine therapy in previously untreated pre- and perimenopausal women. Updated data showed that, at a median follow-up of 42 months, 70.2% of patients who received the combination were alive versus 46% of patients who received endocrine therapy alone, which translated to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.54-0.95; P = .0097).1

Additionally, results of the SOLAR-1 trial showed that the addition of the PI3K inhibitor alpelisib (Piqray) to fulvestrant (Faslodex) improved progression-free survival (PFS) compared with fulvestrant alone for postmenopausal patients with HR-positive, HER2-negative breast cancer and harbor PIK3CA mutations. The median PFS was 11.0 months versus 5.7 months with fulvestrant alone at a median follow-up of 20 months, which led to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.50-0.85; P = .00065).2

“We have been making progress,” said Varella, a medical oncologist and professor of medicine at Weill Cornell Medicine. “We now have many more agents for patients with metastatic HR-positive, HER2-negative disease.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Varella discussed the progression of these available treatments in HR-positive, HER2-negative metastatic breast cancer.

OncLive: What are your thoughts on the recently updated findings of the MONALEESA-7 trial?

Varella: The MONALEESA-7 trial was a very interesting phase III study, because it involved premenopausal and perimenopausal women with HR-positive, HER2-negative metastatic breast cancer. The patients were randomized to receive endocrine therapy with ovarian suppression versus endocrine therapy with ovarian suppression plus ribociclib. We already saw data demonstrating a significant improvement in PFS [with ribociclib]. Then, at the 2019 ASCO Annual Meeting, the MONALEESA-7 OS data were presented, and it was the first time that we had a significant improvement in OS with CDK4/6 inhibitors in this setting.

What has been the impact of the FDA approval of alpelisib for patients with PIK3CA mutations and its impact on the landscape?

The SOLAR-1 trial involved patients with advanced breast cancer who had received prior endocrine therapy with an aromatase inhibitor, and were randomized to receive fulvestrant with placebo or fulvestrant with alpelisib. The patient population with PIK3CA mutations had a significant improvement in PFS, and the data from this trial led to FDA approval of alpelisib in this setting for patients with PIK3CA mutations in May 2019. Now, this is one more drug available as standard therapy for patients with advanced HR-positive, HER2-negative disease—still in the endocrine therapy phase, before receiving chemotherapy.

What is the prevalence of PIK3CA mutations in HR-positive, HER2-negative breast cancer?

We have data showing that approximately 40% of patients with metastatic HR-positive, HER2-negative breast cancer have a mutation in PIK3CA. The SOLAR-1 trial had the biggest benefit in PFS for this patient population when alpelisib was combined with fulvestrant.

Regarding the available CDK4/6 inhibitors, how will physicians choose which of the 3 to use?

The 3 CDK4/6 inhibitors palbociclib (Ibrance), ribociclib, and abemaciclib (Verzenio), have not been compared head to head. They have all been compared in combination with an aromatase inhibitor or with fulvestrant versus placebo. In clinical practice, we tend to choose based on toxicity profile because the adverse events are different between the drugs. Sometimes, the dosing schedule plays a [factor].

What advice can you give for your colleagues regarding treatment of patients with metastatic breast cancer?

One of the things we're going to get more data on in the near future is how to sequence these patients. The alpelisib trial included 6% of patients who have received CDK4/6 inhibitors prior to enrollment on the trial. The question now is, “How do you sequence?” We have more agents than we've had in the past. There are several trials that involve CDK4/6 inhibitors and alpelisib in patients with PIK3CA mutations. We don’t know the ideal sequence, yet. However, we continue to learn more from these big clinical trials.


  1. Hurvitz SA, Im SA, Lu YS, 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; abstr LBA1008). doi: 10.1200/JCO.2019.37.18_suppl.LBA1008.
  2. Andre&#769; F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol. 2018;29(suppl 8, abstr LBA3_PR). doi: 10.1093/annonc/mdy424.010.