Ribociclib Both Active and Safe in Elderly Patients With HR+/HER2- Breast Cancer

Gabe S. Sonke MD, PhD

Ribociclib, an orally bioavailable, selective cyclin-dependent kinase 4/6 inhibitor, demonstrated similar clinical benefits and safety profiles for both elderly and younger patients with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, according to findings from a pre-planned subgroup analysis of data from the MONALEESA-2 trial.

These data point to a shift in paradigm for the future management of these patients, from the current standard of care, letrozole (Femara), to a combination regimen of letrozole plus ribociclib. These results were presented at the 19th European Cancer Congress (ECCO 2017).

"At some point, all breast cancers become resistant to endocrine therapy. The addition of targeted agents may extend the treatment benefit derived from endocrine therapy and delay disease progression,” according to Gabe S. Sonke MD, PhD, of the Netherlands Cancer Institute and BOOG Study Center in the Netherlands.

MONALEESA-2 is a randomized international, double blind phase III trial of ribociclib plus the aromatase inhibitor letrozole. The study demonstrated improved progression-free survival (PFS) over letrozole alone in treatment-naïve post-menopausal women with advanced HR+ metastatic breast cancer.

In the overall population of patients, a 44% improvement in PFS was demonstrated with ribociclib plus letrozole as a frontline therapy over placebo/letrozole. The median PFS was not reached in the study arm at data cutoff, compared to 14.7 months in the placebo arm. In patients with measurable disease who received ribociclib, the overall response rate (ORR) was 52.7%, compared to 37.1% in those receiving letrozole alone.

In the subgroup of 295 MONALEESA-2 patients aged 65 or more years having a median age of 71 years (range, 65-91), 150 patients received 2.5 mg daily of ribociclib plus 2.5 mg daily of letrozole and 145 patients received placebo plus 2.5 mg daily of letrozole (n = 145). PFS by RESIST was the primary endpoint.

The subgroup analysis showed that the elderly cohort demonstrated similar responses and tolerability to the overall population.

At data cutoff on January 29, 2016, treatment was ongoing in 90 (60%) patients receiving ribociclib/letrozole and in 77 (53%) patients on placebo/letrozole. Median PFS was not reached (95%CI, 19.3 months — NR) with ribociclib/letrozole versus 18.4 months (95%CI, 15.0 months – NR) with placebo/letrozole, HR = 0.608 (95%CI, 0.394 – 0.937). The ORR in the elderly receiving ribociclib/letrozole versus placebo/letrozole was 37% versus 31%, respectively.

The median duration of study treatment exposure in elderly patients was 13.1 with ribociclib/letrozole and 12.5 months with placebo/letrozole. In the elderly cohort, 40% versus 47% of patients receiving ribociclib/letrozole versus placebo/letrozole, respectively, discontinued treatment. The most common reasons for discontinuation were disease progression in 33 (22%) versus 51 (35%) patients and adverse events (AEs) in 13 (9%) versus 5 (3%) patients in the ribociclib/letrozole versus placebo/letrozole arms, respectively. One death occurred in the ribociclib combination arm.

“The elderly patients had a slower rate of disease progression in both treatment arms, representing more stabilization of disease,” said Sonke. He also noted in his presentation that over 40% of patients diagnosed with breast cancer are aged 65 years or older, and physiologic functioning, comorbidities, or concomitant medications may impact their tolerability of combination regimens.

The rates of AEs in elderly patients were similar to those experienced by the younger patients; AEs that occurred more than 10% more frequently with ribociclib/letrozole than with sole letrozole included neutropenia (74% percent versus 5%), leukopenia (31% versus 4%), fatigue ( 37% versus 24%), alopecia (33% versus 17%), diarrhea (41% versus 26%), and vomiting (35% versus 19%).

“The rates of dose reduction or interruption due to an AE were similar in both treatment arms in elderly and younger patients, despite a higher proportion of elderly patients with ECOG performance status 1,” Sonke pointed out.

Most AEs could be managed through dose interruption; dose interruptions due to an AE occurred in 13% versus 13% in the ribociclib/letrozole versus placebo/letrozole arms, respectively, and no dose reductions due to an AE were made in either arm.

The Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for ribociclib in August 2016 and has also accepted a New Drug Application (NDA) and granted priority review for ribociclib as firstline treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer in combination with letrozole. The NDA was based in part on results of the MONALEESA-2 trial, which was presented at the European Society for Medical Oncology (ESMO) 2016 Congress and published simultaneously in the New England Journal of Medicine.

Sonke, G.S.,Hart, L.L., Campone M, et al. Efficacy and safety of ribociclib (LEE011) + letrozole in elderly patients with hormone receptor-positive (HR+), HER2-negative (HER2˗) advanced breast cancer (ABC) in MONALEESA-2. Abstract presented at: 2017 European Cancer Congress; January 27-30, 2017; Amsterdam. Abstract 2LBA.