MONALEESA-3 Data Highlight Ribociclib as Standard in HR+ Breast Cancer

Dennis J. Slamon, MD, PhD

Findings from the MONALEESA-3 trial dispelled the theory that a CDK4/6 inhibitor had to be reserved following recurrence on hormone therapy in postmenopausal patients with hormone receptor (HR)-positive, HER2-negative breast cancer, explained Dennis J. Slamon, MD, PhD.

In the phase III trial, postmenopausal patients with HR-positive, HER2-negative advanced disease who received up to 1 prior line of therapy were randomized 2:1 to ribociclib (Kisqali) plus fulvestrant (Faslodex) or placebo.

“In MONALEESA-3, all subgroups benefitted. [There was a] subgroup analysis of age, race, performance status, whether or not they had had prior hormonal therapy, whether or not they had prior chemotherapy, and whether or not it was bone-only disease or organs were involved,” said Slamon, who was the lead MONALEESA-3 investigator.

Results presented at the 2018 ASCO Annual Meeting showed an improvement in progression-free survival (PFS) with the combination. At the time of data cut-off in November 2017, the median PFS was 20.5 months with ribociclib/fulvestrant versus 12.8 months with placebo. This was associated with a 41% reduction in the risk of disease progression (HR, 0.593; 95% CI, 0.480-0.732; P = .00000041).

Based on the MONALEESA-3 data, the FDA expanded ribociclib’s approval in July 2018 for use in combination with fulvestrant for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy. Based on the phase III MONALEESA-7 trial, upfront ribociclib was simultaneously approved by the FDA for use in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer.

OncLive: Can you provide an overview of the MONALEESA-3 trial?

What were the results of this study?

How was the combination tolerated among patients?

What are the implications of these findings for patients and clinical practice?

What makes ribociclib stand out from the other available CDK4/6 inhibitors?

What other questions do we still have with ribociclib?

Are there any other studies looking at ribociclib in combination with other agents?

In an interview with OncLive, Slamon, director of Clinical/Translational Research, Revlon/University of California, Los Angeles (UCLA) Women's Cancer Research Program, Jonsson Comprehensive Cancer Center, and a 2014 Giant of Cancer Care^® in Breast Cancer, discussed how the MONALEESA-3 results have shifted the understanding of therapy placement in women with HR-positive, HER2-negative advanced breast cancer.Slamon: MONALEESA-3 was a trial conducted in nearly 730 women with HR-positive, HER2-negative, postmenopausal disease. What is unique about MONALEESA-3 is that patients who had not received prior endocrine therapy were eligible for the trial as well as patients who were in the first-line or second-line setting. It is unique among the CDK4/6 trials, in that patients were treated earlier in the advanced setting with the combination of ribociclib and fulvestrant.The results that we presented at the 2018 ASCO Annual Meeting were very exciting. There was a very significant improvement in PFS for patients who received the combination of ribociclib plus fulvestrant compared with best available hormonal therapy—fulvestrant. The control group received fulvestrant and placebo, whereas the experimental group received fulvestrant and ribociclib. It's very well tolerated. As a class, CDK4/6 inhibitors cause neutropenia, but it is different from the kind of neutropenia we see with chemotherapy. In general, the counts do not go as low with chemotherapy nor do they stay down as long. That is because the drug does not kill those normal bone marrow progenitor cells. It just causes a cell cycle arrest, so they stay alive. Patients in the trial receive the drugs for 3 weeks on/1 week off. In the 1 week off, the bone marrow tends to recover very nicely. The tumor cells that are dependent on this pathway seem to be very much affected. These results mean that patients early in the course of recurrent disease will benefit significantly from this combination. In general, these combinations have been tested later in the course of advanced breast cancer after failure of hormonal therapy. Patients in that group were included, but there was a large number of patients who were first receiving it in the frontline setting at first recurrence, and in patients who had not seen hormonal therapy before. They were randomized to standard hormonal therapy versus the combination and they benefited significantly. Ribociclib is the first of the CDK4/6 inhibitors that has been tested in this setting early on. People had felt that we should withhold these drugs until after we administer hormonal therapy—and then introduce them if the patient recurs. These data show that if you compare patients who get that approach versus the combination, there is a dramatic improvement in PFS in the patients who get the combination. That indicates a new standard for patients who recur with this type of HR-positive, HER2-negative breast cancer even if they have not had any hormonal therapy.The question that needs to be answered is what role ribociclib will play in the earliest-stage breast cancers—–in the adjuvant and neoadjuvant settings. That is going to be tested in clinical trials. It will be important to see whether these benefits carry into the various stages. When a patient is initially diagnosed, if her tumor contains the right biomarkers that indicate that she might benefit from this, adding that combination upfront might make a big impact and further improve cure rates.The CDK4/6 inhibitors, including and especially ribociclib, are being looked at in combination with a number of other standard therapies as well as novel targeted therapies based on strong preclinical rationale and data. There are several things that need to be looked at and evaluated in the clinic.

Slamon DJ, Neven P, Chia SKL, et al. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2—) advanced breast cancer (ABC): results from MONALEESA-3. J Clin Oncol. 2018;36(suppl; abstr 1000).