Maintained Survival Benefit Supports Frontline Ribociclib/Fulvestrant Combo in Advanced HR+ Breast Cancer

The addition of ribociclib (Kisqali) to fulvestrant (Faslodex) continued to significantly prolong overall survival (OS), delayed time to second disease progression (PFS2), and improved chemotherapy-free survival (CFS) vs placebo plus fulvestrant in the first-line treatment of patients with advanced hormone receptor–positive, HER2-negative breast cancer, according to updated data from an exploratory analysis of the phase 3 MONALEESA-3 trial (NCT02422615).^1,2

Data presented during the 2022 ESMO Breast Cancer Congress showed that at a median follow-up of 70.8 months, patients who received ribociclib/fulvestrant experienced a median OS of 67.6 months vs 51.8 months in those who were given fulvestrant/placebo (HR, 0.67; 95% CI, 0.50-0.90). The 5-year OS rate was 56.5% in the investigative arm compared with 42.1% in the control arm.

In this subgroup of patients who received treatment in the first-line setting, the median second PFS2 was 50.7 months in the ribociclib arm vs 34.6 months in the placebo arm (HR, 0.64; 95% CI, 0.49-0.84). The median CFS was 49.2 months in the investigative arm vs 29.0 months in the control arm (HR, 0.62; 95% CI, 0.48-0.81). The addition of ribociclib to fulvestrant also delayed the time to first subsequent chemotherapy (HR, 0.57; 95% CI, 0.42-0.79).

“MONALEESA-3 results continue to demonstrate the survival benefit of treatment with ribociclib for postmenopausal women with advanced breast cancer,” Dennis J. Slamon, MD, the director of Clinical/Translational Research at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, stated in a press release. “Whether partnered with fulvestrant or an aromatase inhibitor in the first-line setting, ribociclib offers oncologists a CDK4/6 inhibitor with consistent benefit in providing women with hormone receptor–positive/HER2-negative advanced breast cancer more quality time, regardless of their disease characteristics.”

MONALEESA-3 enrolled 726 men and postmenopausal women with advanced hormone receptor–positive/HER2-negative breast cancer who did not receive chemotherapy for advanced disease. Patients received no more than 1 prior line of endocrine therapy for advanced disease.

Patients were randomized 2:1 to receive ribociclib at 600 mg daily as part of a 3-weeks-on/1-week-off schedule (n = 484) or a matching placebo (n = 242). All patients received 500 mg of fulvestrant on day 1 of each 28-day cycle, with an additional dose on day 15 of cycle 1. Patients were stratified by presence or absence of liver or lung metastases prior to endocrine therapy.

The primary end point of the trial was progression-free survival (PFS) per local radiological assessment. Secondary end points included OS, overall response rate, clinical benefit rate, time to treatment response, duration of response, health-related quality of life (QOL), safety, and tolerability.

Previously, data from the final protocol-specified OS analysis showed that at a median follow-up of 39.4 months, ribociclib plus fulvestrant demonstrated a statistically significant improvement in OS compared with placebo/fulvestrant when given to patients in the first- and second-line settings (HR, 0.72; 95% CI, 0.57-0.92; P = .00455).³

Additionally, findings from a prior exploratory OS analysis, which had a median follow-up of 56.3 months, confirmed the OS benefit with the combination over fulvestrant alone in the intent-to-treat population (HR, 0.73; 95% CI, 0.59-0.90). However, the median OS was not yet reached for those treated with ribociclib plus fulvestrant in the first-line setting.⁴

The data from the exploratory analysis presented during the ESMO Breast Cancer Congress shed additional light on the OS benefit derived from the subgroup of patients who received treatment in the first-line setting.

Additional findings indicated that 83.5% of patients who received ribociclib plus fulvestrant have discontinued study treatment compared with 91.4% of those who were given placebo plus fulvestrant. Moreover, 81.8% and 89.7% of patients in the investigative arm and control arm, respectively, received their first subsequent antineoplastic therapy. Subsequent therapies included chemotherapy alone (12.6% vs 16.2%, respectively), chemotherapy plus a hormonal or other therapy (8.1% and 12.8%), hormonal therapy alone (35.9% and 25.6%), hormonal therapy plus targeted or other therapy (22.7% and 34.2%), and targeted therapy alone or other therapy (2.5% and 0.9%).

Notably, post-discontinuation treatment with a CDK4/6 inhibitor was higher in the control arm vs the investigational arm, at 35.0% vs 16.7%, respectively. Subsequent CDK4/6 inhibitors received in the investigative and control arms, respectively, included palbociclib (8.6% vs 27.4%), ribociclib (6.6% vs 6.0%), and abemaciclib (Verzenio; 3.0% vs 2.6%).

No new safety signals were identified with extended follow-up. The frequency of adverse effects (AEs) remained generally consistent with prior analyses of MONALEESA-3. Any-grade AEs of special interest reported in the ribociclib and placebo arms, respectively, included neutropenia (73.8% vs 4.7%), leukopenia (32.5% vs 1.6%), hepatobiliary toxicity (26.6% vs 17.2%), prolonged QT interval (10.5% vs 0.8%), and interstitial lung disease or pneumonitis (3.4% vs 0.8%).

Study authors stated that these data further support the use of ribociclib in advanced hormone receptor–positive, HER2-negative breast cancer.

“It is a tremendous achievement to see such remarkable, consistent OS results from the MONALEESA clinical trial program, demonstrating how Novartis is transforming care for people with breast cancer as we continue to work toward cures,” Jeff Legos, the executive vice president and global head of Oncology & Hematology Development at Novartis, added in the press release. “The unique profile of [ribociclib] continues to be reinforced, with results from MONALEESA-3 pushing the boundaries of how using a [ribociclib] combination treatment regimen can extend lives of postmenopausal women living with hormone receptor–positive, HER2-negative advanced breast cancer without compromising QOL.”

References

1. Neven P, Fasching PA, Chia S, et al. Updated overall survival results from the first-line population in the phase III MONALEESA-3 trial of postmenopausal patients with HR+/HER2- advanced breast cancer treated with ribociclib + fulvestrant. Presented at: 2022 ESMO Breast Cancer Congress; May 3-5, 2022; Berlin, Germany. Abstract LBA4.
2. New Novartis data demonstrate only Kisqali offers more life in the first-line setting for postmenopausal HR+/HER2- advanced breast cancer patients. News release. Novartis. May 4, 2022. Accessed May 4, 2022. https://bit.ly/3FdBXXI
3. Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) + ribociclib (rib). Ann Oncol. 2019;30(suppl 5):V856-V857. doi:10.1093/annonc/mdz394.007
4. Slamon DJ, Neven P, Chia SKL, et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) +/- ribociclib (RIB). J Clin Oncol. 2021;39(suppl 15):1001. doi:10.1200/JCO.2021.39.15_suppl.1001