Ribociclib Improves Survival in Postmenopausal Women With Advanced Breast Cancer

Susanne Schaffert, PhD, President, Novartis Oncology

Susanne Schaffert, PhD

Adding the CDK4/6 inhibitor ribociclib (Kisqali) to fulvestrant (Faslodex) significantly improved overall survival (OS) as a first- or second-line treatment for postmenopausal women with hormone receptor (HR)—positive/HER2-negative breast cancer, according to findings from a preplanned interim analysis of the phase III MONALEESA-3 trial.

This is the second phase III trial in which a ribociclib regimen has led to a statistically significant OS benefit in women with HR+/HER2- breast cancer. Previously reported findings showed that adding the CDK4/6 inhibitor to endocrine therapy reduced the risk of death by 29% (HR, 0.71; 95% CI, 0.54-0.95; P = .00973) in peri or premenopausal women with advanced breast cancer.^1,2

Novartis, the manufacturer of ribociclib, reported in a press release that findings from MONALEESA-3 will be presented at an upcoming medical meeting and submitted to global regulatory authorities. The company also noted that no new safety signals emerged since the initial reporting of progression-free survival (PFS) and other data from the trial.

“We are thrilled that Kisqali combination therapy again has demonstrated improved overall survival for patients with HR+/HER2- advanced breast cancer — first in premenopausal and perimenopausal women in MONALEESA-7, and now in postmenopausal women in MONALEESA-3,” Susanne Schaffert, PhD, President, Novartis Oncology, said in the press release. “We will continue to reimagine cancer to help patients live longer, and also improve quality of life as we work towards finding a cure for this incurable disease.”

MONALEESA-3

Previous data from MONALEESA-3 reported at the 2018 ASCO Annual Meeting showed a median PFS of 20.5 months in patients randomized to ribociclib plus fulvestrant compared with 12.8 months in those randomized to fulvestrant plus placebo, representing a 41% reduction in the risk of disease progression (P = .00000041).³

The study included a total of 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer were randomized 2:1 to ribociclib, 600 mg/day in a 3-weeks-on/1-week-off schedule plus fulvestrant, 500 mg/day, or placebo. The primary objective was investigator-assessed PFS.

Baseline patient characteristics were balanced between arms. The median patient age was 63 years. Approximately 60% of patients had visceral disease and 21% had bone-only metastasis. Half of the patients received treatment in the first-line setting and half in the second-line setting. About 60% of patients received prior endocrine therapy in the neoadjuvant setting and 16.5% (placebo arm) and 22.7% (ribociclib arm) in the adjuvant setting.

The median duration from randomization to data cut-off was 20.4 months. At the time of the analysis, treatment was ongoing in 42.1% of those randomized to ribociclib and 31.4% of those in the placebo arm. Treatment was discontinued in 57.6% and 68.2% of patients, respectively. The primary reason for treatment discontinuation was disease progression in 39.9% of patients in the ribociclib arm and 58.7% of patients in the placebo arm.

In addition to investigator assessment, PFS by a blinded Independent Review Committee was assessed in 290 patients as a supportive analysis, which demonstrated that median PFS was not reached in the ribociclib arm and was 10.9 months in the placebo arm. Corresponding to a 51% reduction in the risk of progression with ribociclib (HR, 0.492; 95% CI, 0.345-0.703).

The PFS benefit with ribociclib was equally apparent in all subgroups, including those defined by prior line of endocrine therapy, metastatic site and number of metastatic sites, prior tamoxifen therapy, prior aromatase inhibitor therapy, age, race, and performance status. When ribociclib was given as first-line therapy, the median PFS was not reached in the ribociclib arm and was 18.3 months in the placebo arm (HR, 0.577; 95% CI, 0.415-0802). When used in the second-line setting, median PFS was 14.8 months in the ribociclib arm and 9.1 months in the placebo arm (HR, 0.565; 95% CI, 0.428-0.744).

In all patients, the overall response rate (ORR) was 32.4% in the ribociclib arm versus 21.5% in the placebo arm (P = .000912) and in those with measurable disease, ORR was 40.9% and 28.7%, (P = .003), respectively. The clinical benefit rate was 70.2% for ribociclib versus 62.8% for placebo (P = .020) in the overall cohort, and 69.4% versus 59.7% (P = .015), respectively, in patients with measurable disease.

Median relative dose intensity (ribociclib or placebo) was 92.1% in the ribociclib arm and 100% in the placebo arm. Dose interruption due to adverse events was required in 68.5% of the ribociclib arm and 18.7% of the placebo arm.

Grade 3 neutropenia occurred in 46.6% of the ribociclib recipients versus 0% of the placebo recipients, and the corresponding rates of grade 4 neutropenia were 6.8% and 0%, respectively. Febrile neutropenia was observed in 5 (1.0%) patients in the ribociclib arm and none in the placebo arm. Post-baseline QTcF >480 ms occurred in 5.6% of patients in the ribociclib arm and 2.5% in the placebo arm. Grade 3 and 4 elevation in alanine transaminase and aspartate transaminase occurred in 6.6% of patients and 1.9% of the ribociclib arm, respectively, and in 4.8% and 1.2% of the placebo arm.

MONALEESA-7

Data from the MONALEESA-7 trial presented at the 2019 ASCO Annual Meeting showed that the estimated OS rate with ribociclib plus endocrine therapy was 70.2% at 42 months compared with 46.0% for placebo and endocrine therapy in peri or premenopausal women with HR+/HER2- advanced breast cancer. The 42-month PFS rate was 54.6% with ribociclib compared with 37.8% with placebo, representing a 31% (HR, 0.69; 95% CI, 0.55-0.87) reduction in the risk of progression or death with the combination.

The MONALEESA-7 trial enrolled 672 pre or perimenopausal women with advanced breast cancer to receive endocrine therapy with ribociclib (n = 335) or placebo (n = 337). Ribociclib was administered at a dose of 600 mg once daily for 21 days followed by 7 days without the CDK4/6 inhibitor. Endocrine therapy consisted of a nonsteroidal aromatase inhibitor (NSAI; n = 495) or tamoxifen (n = 177), based on the patient's previous adjuvant or neoadjuvant therapy or preference. The use of these therapies was evenly balanced across each arm. Subcutaneous goserelin was administered to patients in both groups at a dose of 3.6 mg on day 1 of each cycle.

At the 42-month analysis, median OS could not be estimated in the ribociclib arm compared with 40.9 months in the placebo group. The median PFS was 23.8 months with ribociclib compared with 13.0 months with placebo (HR, 0.55; 95% CI, 0.44-0.69; P <.0001).

The 42-month OS analysis reached a predefined efficacy stopping boundary, making these data the final OS analysis for the study. Prior OS analyses from the study showed an OS advantage for ribociclib beginning to emerge at 24 months. The 24-month OS rate was 82.7% in the ribociclib arm compared with 81.8% for placebo; however, by month 36 the Kaplan—Meier curves began to separate, with an OS rate of 71.9% in the ribociclib arm compared with 64.9% with placebo.

Ribociclib was initially approved by the FDA in 2017 in combination with an aromatase inhibitor for postmenopausal women with HR+/HER2- advanced breast cancer. In July 2018, the FDA expanded this indication to include pre and perimenopausal women with the disease. The expanded indication also included combined use with fulvestrant for postmenopausal women.

Ribociclib continues to be explored in earlier settings for patients with HR+/HER- breast cancer. The phase III NATALEE trial is currently examining the CDK 4/6 inhibitor as an adjuvant therapy in combination with endocrine therapy for patients with early breast cancer. The primary endpoint of the study is invasive disease-free survival, and the estimated primary completion date is December 2025 (NCT03701334).

References

1. Hurvitz SA, Im S-A, Lu Y-S, 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).
2. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019.
3. 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. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 1000.