Survival Benefit Observed With Ribociclib Plus Endocrine Therapy in Advanced HR+/HER2– Breast Cancer With Visceral Metastases

According to findings from a pooled exploratory analysis of the phase 3 MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), and MONALEESA-7 (NCT02278120) trials, ribociclib (Kisqali) plus endocrine therapy elicited statistically significant progression-free survival (PFS) and overall survival (OS) benefits vs placebo plus endocrine therapy in patients with hormone receptor–positive, HER2-negative advanced breast cancer with visceral metastases, including those with liver metastases and multiple metastatic sites.

Findings presented at the 2022 European Society for Medical Oncology Congress (ESMO)showed that patients with visceral metastases treated with ribociclib in the first- or second-line setting (n = 640) achieved a median PFS of 22.1 months vs 12.7 months with placebo (n = 484), resulting in a 39% relative reduction in the risk of disease progression or death (HR, 0.61; 95% CI, 0.53-0.70). Ribociclib also elicited a median OS of 49.0 months vs 46.5 months with placebo, resulting in a 19% relative reduction in the risk of death (HR, 0.81; 95% CI, 0.69-0.94).

“Patients with visceral metastases experienced a clinically meaningful survival benefit with ribociclib plus endocrine therapy over endocrine therapy alone, with a 1-year improvement in median OS in patients receiving first-line therapy, making it an effective therapeutic option in this patient population,” lead study author, Denise A. Yardley, MD, of the Sarah Cannon Research Institute at Tennessee Oncology, and colleagues, wrote.

Patients with HR-positive/HER2-negative advanced breast cancer with visceral metastases typically have a more aggressive cancer that responds less to treatment and progresses quickly. Those with liver metastases or multiple metastatic sites have particularly poor survival.

The MONALEESA-3 and MONALEESA-7 trials previously revealed a median PFS and median OS benefit of ribociclib plus endocrine therapy over endocrine therapy alone in patients with visceral metastases, including liver metastases.

MONALEESA-2 and MONALEESA-3 included postmenopausal patients. MONALEESA-7 included premenopausal patients.

In this exploratory analysis, median PFS and median OS were evaluated in a pooled dataset of the 3 trials in all patients with visceral metastases, liver metastases, and visceral metastases with at least 3 metastatic sites of any type. These same analyses were conducted separately in patients treated in the first-line setting.

Patients treated in the first-line setting were defined as those with de novo disease with no prior exposure to endocrine therapy, and those who had late relapse, defined as relapse more than 12 months after the end of neoadjuvant or adjuvant endocrine therapy. Patients who had early relapse, defined as relapse within 12 months of the end of neoadjuvant or adjuvant endocrine therapy, were excluded from the first-line subgroup, as their disease behavior was more similar to that of second-line patients. Data from the second-line population were not analyzed separately.

In MONALEESA-2, 668 patients were randomly assigned 1:1 to receive either oral ribociclib at 600 mg daily for 3 weeks on and 1 week off plus letrozole at 2.5 mg daily or placebo for 3 weeks on and 1 week off plus letrozole at 2.5 mg daily.

In MONALEESA-3, 726 patients were randomly assigned 2:1 to receive either oral ribociclib at 600 mg daily for 3 weeks on and 1 week off or placebo for 3 weeks on and 1 week off, plus intramuscular fulvestrant (Faslodex) at 500 mg on days 1 and 15 of cycle 1 and day 1 of every subsequent 28-day cycle.

In MONALEESA-7, 672 patients were randomly assigned 1:1 to receive either oral ribociclib at 600 mg or placebo daily for 3 weeks on and 1 week off, plus tamoxifen at 20 mg daily, anastrozole at 1 mg daily, or letrozole at 2.5 mg daily, plus goserelin at 3.6 mg every 28 days.

Of the 1889 patients in the 3 MONALEESA trials and the 1229 patients in the first-line populations, 59.5% (n = 1124) and 57.7% (n = 709), respectively, had visceral metastases. In the visceral metastases group, the median time between randomization and cutoff date was 71.26 months in the ribociclib arm and 72.23 months in the placebo arm. At data cutoff, 12.5% and 6.8% of patients with visceral metastases in the ribociclib and placebo arms, respectively, were still receiving treatment. Of the visceral metastases group, 65.9% of the ribociclib arm and 78.5% of the placebo arm discontinued treatment because of progressive disease.

Across all 3 trial populations, 26.4% (n = 498) of patients had liver metastases. Of these patients, 89.5% (n = 247) and 95.5% (n = 212) in the ribociclib and placebo arms, respectively, had discontinued treatment by data cutoff. Additionally, 20.8% (n = 256) of the patients in the first-line group had liver metastases.

A total of 31.6% (n = 597) of patients across all 3 trials had visceral metastases and at least 3 metastatic sites of any type. Of these patients, 89.5% (n = 299) and 94.7% (n = 249) in the ribociclib and placebo arms, respectively, had discontinued treatment by data cutoff. In addition, 36.4% (n = 447) of the patients in the first-line group had at least 3 metastatic sites.

In the first-line population of patients with visceral metastases, ribociclib (n = 392) elicited a median PFS of 29.6 months vs 14.7 months with placebo (n = 392), resulting in a 44% relative reduction in the risk of disease progression (HR, 0.56; 95% CI, 0.47-0.67),. Patients administered first-line ribociclib had a median OS of 63.4 months vs 51.8 months with placebo, resulting in a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64-0.96).

In the overall population with liver metastases, the median PFS in the ribociclib arm (n = 276) was 13.4 months vs 5.7 months in the placebo arm (n = 222), resulting in a 48% relative reduction in the risk of disease progression or death (HR, 0.52; 95% CI, 0.42-0.65). The median OS was 39.6 months with ribociclib vs 35.4 months with placebo, resulting in a 29% relative reduction in the risk of death (HR, 0.71; 95% CI, 0.57-0.89).

In the first-line population of patients with liver metastases, ribociclib (n = 140) demonstrated a significantly longer median PFS of 16.7 months vs 9.8 months with placebo (n = 116; HR, 0.55; 95% CI, 0.41-0.74) and a numerically longer median OS of 44.2 months vs 38.1 months with placebo (HR, 0.77; 95% CI, 0.55-1.07).

In all patients with at least 3 metastatic sites, the ribociclib arm (n = 334) was associated with a significantly longer median PFS of 21.3 months vs 11.0 months in the placebo arm (n = 263; HR, 0.55; 95% CI, 0.46-0.67). Ribociclib also elicited a significantly longer median OS of 49.0 months vs 40.4 months with placebo (HR, 0.73; 95% CI, 0.60-0.90).

In the first-line population of patients with 3 or more metastatic sites, the ribociclib arm (n = 253) demonstrated a significantly longer median PFS of 24.8 months vs 14.5 months in the placebo arm (n = 194; HR, 0.59; 95% CI, 0.47-0.74) and a numerically longer median OS of 57.7 months vs 49.2 months with placebo (HR, 0.80; 95% CI, 0.62-1.03).

Regarding safety, adverse effects (AEs) were consistent across the patient populations receiving ribociclib, regardless of the presence of visceral metastases, and no new safety signals were observed. In particular, AEs occurring in at least 30% of the ribociclib arm of patients with visceral metastases (n = 639) included neutropenia (all-grade, 62.1%; grade 3 or 4, 50.1%), nausea (all-grade, 47.4%; grade 3 or 4, 2.3%), arthralgia (all-grade, 36.9%; grade 3 or 4, 1.1%), fatigue (all-grade, 33.3%; grade 3 or 4, 1.7%), and diarrhea (all-grade, 33.0%; grade 3 or 4, 2.0%).

AEs observed in at least 30% of the ribociclib arm without visceral metastases (n = 426) included neutropenia (all-grade, 58.5%; grade 3 or 4, 46.9%), nausea (all-grade, 45.5%; grade 3 or 4, 0.7%), arthralgia (all-grade, 38.0%; grade 3 or 4, 1.2%), fatigue (all-grade, 38.0%; grade 3 or 4, 2.8%), and diarrhea (all-grade, 34.3%; grade 3 or 4, 1.6%).

The rates of AEs of special interest were also consistent across the ribociclib arms. Specifically, all-grade AEs of special interest occurring in at least 20% of the ribociclib arms with and without visceral metastases included neutropenia (with, 77.2%; without, 73.5%), infections (with, 56.8%; without, 61.3%), leukopenia (with, 35.2%; without, 34.5%), hepatobiliary toxicity (with, 27.2%; without, 27.9%), and anemia (with, 21.4%; without, 21.4%).

The investigators also observed similar AE rates between patients with and without liver metastases who received ribociclib. Specifically, the rates of all-grade AEs in these populations included neutropenia (with, 59.3%; without, 64.3%), nausea (with, 45.1%; without, 49.2%), diarrhea (with, 33.8%; without, 32.4%), fatigue (with, 30.5%; without, 35.4%), and arthralgia (with, 30.2%; without, 42.0%). Additionally, the rates of grade 3 or 4 liver enzyme elevations were similar in patients with and without liver metastases who received ribociclib. The rates were 7.3% vs 9.9% for alanine aminotransferase elevations and 7.6% vs 5.5% for aspartate aminotransferase elevations, respectively.

Reference

Yardley DA, Yap YS, Azim HA, et al. Pooled exploratory analysis of survival in patients with HR+/HER2– advanced breast cancer and visceral metastases treated with ribociclib + endocrine therapy in the MONALEESA trials. Ann Oncol. 2022;33(suppl 7):205P. doi:10.1016/annonc/annonc1039