Ribociclib Therapy Is Informed by HR+/HER2– Breast Cancer Intrinsic Subtype

A retrospective exploratory analysis of 3 trials of ribociclib in patients with hormone receptor–positive, HER2-negative advanced breast cancer confirmed the prognostic value of intrinsic tumor subtype for efficacy outcomes with CDK4/6 inhibition.

A retrospective exploratory analysis of 3 trials of ribociclib (Kisqali) in patients with hormone receptor–positive, HER2-negative advanced breast cancer confirmed the prognostic value of intrinsic tumor subtype for efficacy outcomes with CDK4/6 inhibition, according to data presented by Aleix Prat, MD, PhD, at the 2020 San Antonio Breast Cancer Symposium.1

Patients with HER2 enriched and luminal A and B breast cancer subtypes all had consistent benefit in terms of progression-free survival (PFS) with the addition of ribociclib to endocrine therapy versus placebo and endocrine therapy in the MONALEESA phase 3 randomized trials.

“On one hand, these results confirm previous studies looking at the independent prognostic value of intrinsic subtypes,” Prat, who is an associate professor at the University of Barcelona and Medical Oncology Department head of the Hospital Clinic of Barcelona in Spain, said in a presentation of the data. “On the other hand, this study clearly shows that [most subtypes] exhibited a PFS benefit with ribociclib treatment, while patients with basal-like subtype did not.”

The phase 3 MONALEESA-2 (NCT01958021), -3 (NCT02422615), and -7 (NCT02278120) trials explored the combination of ribociclib and endocrine therapy versus different endocrine therapy controls in patients with hormone receptor–positive, HER2-negative advanced breast cancer. In all 3 trials, the experimental arm demonstrated superior PFS to endocrine therapy alone, supporting its use in this patient population.2-4

Samples across the 3 trials were pooled to increase the sample size (n = 1160) and statistical power of the analysis comparing the prognostic value of the 4 main intrinsic hormone receptor–positive, HER2-negative breast cancer subtypes—which are luminal A, luminal B, HER2 enriched, and basal like—on efficacy in patients treated with the CDK4/6 inhibitor.

Biopsies were assessed by Prediction Analysis of Microarray 50 (PAM50). PFS and tumor progression were evaluated by univariate and multivariable Cox proportional hazard models, with multivariable models used to adjust for known clinical prognostic factors, such as age, prior chemotherapy, prior endocrine therapy, ECOG performance status, histological grade, number of metastatic sites, and presence of de novo disease.

Baseline characteristics of patients whose samples were assessed in the pooled population were well balanced compared with the intention-to-treat population. The majority of patients had an ECOG performance status of 0, had no metastases in the liver or lung, and did not have de novo metastatic disease. The distributions of intrinsic subtype of the pooled samples were luminal A at 47%, luminal B at 24%, normal like at 14%, HER2 enriched at 13%, and basal like at 3%.

For patients with luminal A subtype, the median PFS was 29.60 months (95% CI, 23.03-not available [NA]) with ribociclib versus 19.48 months (95% CI, 15.61-24.80) for the placebo arm (HR, 0.63; P <.001).

In the luminal B groups, the median PFS was 22.21 months (95% CI, 18.79-NA) in those who received ribociclib versus 12.85 months (95% CI, 10.84-14.82) for those who received the placebo (HR, 0.52; P <.001).

In the HER2-enriched group, the median PFS was 16.39 months (95% CI, 12.71-24.6) versus 5.52 months (95% CI, 3.12-9.17) for the ribociclib and placebo arms, respectively (HR, 0.39; P <.001). This patient group showed the greatest degree of benefit with ribociclib versus placebo.

“Importantly, the HER2 enriched subtype, which represents 13% of all patients with breast cancer, had a very poor prognosis in the placebo arm [but] this group exhibited the greatest relative reduction in the risk of progression or death with ribociclib plus endocrine therapy,” Prat said.

Patients with basal-like subtype were the only ones who did not derive statistically significant benefit from ribociclib versus placebo, with a median PFS of 3.71 months (95% CI, 1.91-13.0) and 3.58 months (95% CI, 1.87-NA), respectively (HR, 1.15; P = .7672).

Rates of response were significantly higher with ribociclib versus placebo in the luminal B (51.94% vs 29.83%; P = .0002) and HER2 enriched (40.00% vs 9.61%; P <.0001) subtypes. Response differences were not statistically significant between the 2 treatment arms in the luminal A (39.37% with ribociclib vs 35.15% with placebo; P = .3) and basal-like groups (25.00% vs 28.57%, respectively; P = 1.0).

Using the luminal A group as a comparator, all other subtypes demonstrated a higher risk of tumor progression, regardless of therapy arm, with basal-like (P <.0001) and HER2 enriched (P <.0001) populations being at the highest risk. After adjusting for all other factors, intrinsic subtype was independently associated with PFS (P < .0001).

“Although this is an exploratory and retrospective analysis, further validation studies will be required to firmly establish the clinical utility of intrinsic subtypes in this particular context,” Prat concluded.


1. Prat A, Chaudhury A, Solovieff N, et al. Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA Phase III studies. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS1-04.

2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi:10.1056/NEJMoa1609709

3. DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi:10.1200/JCO.2018.78.9909

4. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi:10.1016/S1470-2045(18)30292-4