The results of the MONALEESA-3 trial include the first data reported for the combination of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor plus fulvestrant as initial endocrine therapy (ET) in postmenopausal women with HR+, HER2- advanced breast cancer (ABC) (J Clin Oncol 2018;36(24):2465-2472). Previous phase III trials of CDK4/6 inhibitors such as PALOMA 3 (palbociclib plus fulvestrant) and MONARCH 2 (abemaciclib plus fulvestrant) showed a progression-free survival (PFS) benefit of CDK4/6 inhibitors in combination with fulvestrant in patients with progression following ET (N Engl J Med 2015;373(3):209-219, J Clin Oncol 2017;35(25):2875-2884). However, no study has previously evaluated the efficacy of a CDK4/6 inhibitor plus fulvestrant as initial ET for ABC.
In the MONALEESA-3 trial, a total of 726 women with HR+, HER2- ABC were randomized to treatment with ribociclib plus fulvestrant or placebo plus fulvestrant. Patients were stratified according to prior ET for ABC. Patients with no prior ET included patients with de novo ABC and patients who had recurrence >12 months after completing (neo)adjuvant ET. Patients with one line of treatment for ABC included patients with ABC at diagnosis who progressed on or after ET for ABC, patients who had recurrence within 12 months of completing (neo)adjuvant ET with no subsequent treatment for ABC, and patients who had recurrence >12 months after completing (neo)adjuvant ET with progression on or after ET for ABC (J Clin Oncol 2018;36(24):2465-2472).
In the overall study population, ribociclib plus fulvestrant significantly improved PFS versus placebo plus fulvestrant, with a median PFS of 20.5 months (95% CI, 18.5-23.5 months) versus 12.8 months (95% CI, 10.9-16.3 months) and a hazard ratio of 0.593 (95% CI, 0.480-0.732; p<0.001). The PFS benefit was consistent between the subgroup of patients without prior ET and the subgroup with one line of prior ET. The PFS hazard ratio was 0.577 (95% CI, 0.415-0.802) in patients without prior ET for advanced disease and 0.565 (95% CI, 0.428-0.744) in patients with up to one line of ET for advanced disease. The median PFS in patients without prior ET for advanced disease was not reached in patients receiving ribociclib plus fulvestrant and was 18.3 months in those receiving fulvestrant plus placebo, corresponding to a 42 percent reduction in risk of disease progression in patients without prior ET who received ribociclib plus fulvestrant.
Patients receiving up to one line of prior ET for advanced disease also had a greater PFS benefit with ribociclib plus fulvestrant than placebo plus fulvestrant (median PFS of 14.6 months vs. 9.1 months) and a 43 percent reduction in risk of progression (J Clin Oncol 2018;36(24):2465-2472). This is similar to results in previous phase III studies where a CDK4/6 inhibitor plus fulvestrant treatment following progression after prior ET prolonged PFS compared with fulvestrant alone and further confirms the clinical usefulness of such combinations in patients whose disease progressed following prior ET (N Engl J Med 2015;373(3):209-219, J Clin Oncol 2017;35(25):2875-2884).
In addition to the PFS benefits, the MONALEESA-3 trial results also demonstrated significantly improved tumor response rates (objective response rate [ORR] and clinical benefit rate) in the overall population with ribociclib plus fulvestrant than with placebo plus fulvestrant. In the full study population, the ORR was 32.4 percent and 21.5 percent for the ribociclib plus fulvestrant and placebo plus fulvestrant arms, respectively (p<0.001). In patients with measurable disease at baseline, the ORR was 40.9 percent and 28.7 percent, respectively (p=0.003) (J Clin Oncol 2018;36(24):2465-2472).
The safety profile of ribociclib plus fulvestrant in MONALEESA-3 was consistent with that of other trials of ribociclib (N Engl J Med 2016;375(18):1738-1748, Lancet Oncol 2018;19(7):904-915). The most common all-grade adverse events (AEs) reported in >30 percent of patients in either arm were neutropenia, nausea, and fatigue. AEs were generally manageable with dose modifications, with rates of discontinuation due to AEs of 8.5 percent for ribociclib plus fulvestrant versus 4.1 percent for placebo plus fulvestrant. On the basis of electrocardiographic assessments, a postbaseline corrected QT interval (Fridericia's formula) >480 ms occurred in 5.6 percent of patients in the ribociclib plus fulvestrant group and 2.5 percent of patients in the placebo plus fulvestrant group (J Clin Oncol 2018;36(24):2465-2472).
The results of the MONALEESA-3 study confirm for the first time in a phase III study that ribociclib plus fulvestrant is efficacious and well-tolerated not only in patients with disease progression following ET, but also in patients without prior ET for advanced disease. The MONALEESA-3 trial results suggest that ribociclib plus fulvestrant may provide an important new treatment option for postmenopausal women without prior ET for ABC and led the FDA to approve ribociclib plus fulvestrant for use in this patient population.
CDK4/6 Inhibitor Plus Fulvestrant
Fulvestrant and the aromatase inhibitors anastrozole and letrozole are approved by the FDA as monotherapy for the treatment of HR+, HER2- ABC in patients without prior ET for advanced disease. The phase III FALCON trial enrolled postmenopausal women with HR+ ABC who had not received previous ET and demonstrated that fulvestrant improved PFS compared with anastrozole monotherapy (Lancet 2016;388(10063):2997-3005).
Fulvestrant is also approved by the FDA for use in combination with the CDK4/6 inhibitors palbociclib, abemaciclib, or ribociclib in patients with HR+, HER2- ABC who progressed on prior ET and is approved by the FDA for use in combination with ribociclib as an initial ET. The results of the FALCON trial demonstrating superiority of fulvestrant to an aromatase inhibitor as initial ET for advanced disease suggest that the combination of ribociclib plus fulvestrant may provide greater benefit than a CDK4/6 inhibitor plus aromatase inhibitor in patients without prior therapy for ABC. However, there are no head-to-head data and no studies currently planned to support this hypothesis.
The trials investigating the safety and efficacy of a CDK4/6 inhibitor plus fulvestrant in patients with ABC included differing patient populations. The PALOMA-3 (palbociclib plus fulvestrant) and MONARCH 2 (abemaciclib plus fulvestrant) trials demonstrated the efficacy and safety of CDK4/6 inhibitors plus fulvestrant in patients with progression following ET but not in patients without prior ET (N Engl J Med 2015;373(3):209-219, J Clin Oncol 2017;35(25):2875-2884).
Similar to PALOMA-3 and MONARCH 2, the MONALEESA-3 trial investigated safety and efficacy of ribociclib plus fulvestrant in patients who progressed on ET for advanced disease (J Clin Oncol 2018;36(24):2465-2472), but also included patients with de novo ABC and patients who relapsed >12 months after completing adjuvant ET for ABC, populations that were excluded in PALOMA-3 and MONARCH 2 (J Clin Oncol 2018;36(24):2465-2472, N Engl J Med 2015;373(3):209-219, J Clin Oncol 2017;35(25):2875-2884).
Although the FALCON trial included patients who did not receive prior (neo)adjuvant ET, patients who received <=1 line of chemotherapy for ABC were included (Lancet 2016;388(10063):2997-3005). Prior chemotherapy for ABC was not permitted in MONALEESA-3 (J Clin Oncol 2018;36(24):2465-2472). Thus, because different study populations were used across trials of CDK4/6 inhibitor plus fulvestrant therapies, direct cross-trial comparisons cannot be made.
Clinical Implications of MONALEESA-3
MONALEESA-3 is the first phase III trial combining fulvestrant and a CDK4/6 inhibitor not only as an ET option following disease progression, but also as an initial endocrine-based therapy in patients with advanced disease. While the FALCON trial demonstrated improvement of PFS with fulvestrant versus aromatase inhibitor monotherapy, MONALEESA-3 demonstrated that ribociclib plus fulvestrant improves PFS compared with fulvestrant alone (Lancet 2016;388(10063):2997-3005, J Clin Oncol 2018;36(24):2465-2472). This study supports the use of ribociclib plus fulvestrant as an alternative to a CDK4/6 inhibitor in combination with an aromatase inhibitor in postmenopausal women who received up to one line of prior ET for ABC.
Editorial assistance for this commentary was provided under the direction of the authors by Elizabeth Harvie, PhD, ELS, MedThink SciCom.
FRANCISCO J. ESTEVA, MD, PHD, is Professor of Medicine and Director of the Breast Medical Oncology program at Perlmutter Cancer Center, NYU Langone Health.