Pooled OS by intrinsic subtype | KISQALI® (ribociclib) Professional Site

For Healthcare Professionals Outside the US
KISQALI is indicated for the treatment of women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)—negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre‑ or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone‑releasing hormone (LHRH) agonist.

It looks like you are using an older version of Internet Explorer which is not supported. We advise that you update your browser to the latest version of Microsoft Edge, or consider using other browsers such as Chrome, Firefox or Safari.

Click below for educational background on intrinsic subtypes

Intrinsic subtypes and patient outcomes

Intrinsic subtypes in HR+/HER2- aBC are associated with different outcomes for patients

While it is known that breast cancer is a heterogeneous disease, advancements in gene-expression profiling have uncovered that even within the classically defined HR+/HER2– subgroup, heterogeneity continues to exist. This diversity is driven by intrinsic subtypes, and may lead to different prognoses and response to treatment in patients with HR+/HER2– aBC.^1,2

Intrinsic subtypes provide clinically relevant information beyond current pathology-based classifications to help clinicians better understand prognoses and guide treatment selection.^1,2

How does tumor biology impact outcomes for patients?

These 4 main subtypes vary in their prevalence and impact on patients’ survival and response to treatment in HR+/HER2– aBC.

7423_L02_Global_Tumor_biology_outcomes_Table

Intrinsic subtypes and overall survival

Intrinsic subtype is prognostic for overall survival

Pooled exploratory analysis of tumor samples from patients in the placebo arms of the MONALEESA trials¹¹

OVERALL SURVIVAL | PLACEBO + ET¹¹

7423_Placebo_BarChart_frm_KM

Median OS differed by subtype, with luminal cancers seeing better outcomes and HER2E cancers seeing worse outcomes¹¹

Pooled MONALEESA exploratory analysis study design

Intrinsic subtypes across the MONALEESA clinical trial program

Analysis background:
The MONALEESA clinical trial program in HR+/HER2− aBC includes 3 phase III trials studying KISQALI in combination with various ET partners and in different lines of therapy and patient populations, including:

KISQALI + AI in 1L postmenopausal patients (MONALEESA-2)¹²
KISQALI + ET in 1L premenopausal patients (MONALEESA-7)¹³
KISQALI + fulvestrant in 1L/2L postmenopausal patients (MONALEESA-3)¹⁴

A pooled exploratory analysis of these 3 trials (N=2066) was conducted to analyze the correlation between intrinsic subtype and OS.¹¹

997 tumor samples (71% primary) from patients enrolled in the MONALEESA-2 (n=318), MONALEESA-3 (n=414), and MONALEESA-7 (n=265) trials underwent subtyping¹¹
Subtype distribution was consistent across treatment arms (KISQALI arm, n=585; placebo arm, n=412)^4,11

SUBTYPE DISTRIBUTION IN THE POOLED MONALEESA DATASET¹¹

7423_pieChart_Desktop

The OS benefit achieved with KISQALI + ET included patients with HER2E-classified tumor subtypes¹¹

The greatest relative reduction in risk of death was observed in the HER2E subtype, which is commonly associated with endocrine resistance and a very poor prognosis compared with luminal disease⁴
Intrinsic subtype was prognostic for and predictive of OS outcomes in both the KISQALI and placebo arms⁴

OVERALL SURVIVAL BY INTRINSIC SUBTYPE | KISQALI + ET⁴

7423_barChart_Mobile_Desktop-M

Data from the univariable analysis.

The only subtype in which an OS benefit was not observed was the basal-like subtype
- The investigators warned the results should be interpreted with caution due to small sample size (3% in each arm)¹¹
- From a clinical and biological perspective, the basal-like subtype is more similar to triple-negative breast cancer than to HR+/HER2– breast cancer, including its association with poor outcomes⁵

The most common intrinsic subtypes in HR+/HER2– aBC are luminal A, luminal B, and HER2E.¹

Aleix Prat, MD, PhD
Barcelona, Spain
Dr Aleix Prat discusses results from the latest OS data from the whole MONALEESA program, analyzed by intrinsic subtypes as presented at SABCS 2021, and how these results may differentiate ribociclib from other CDK4/inhibitors.

Wolfgang Janni, MD, PhD
Ulm, Germany
Dr Wolfgang Janni speaks about how the latest OS data by intrinsic subtypes from KISQALI^® (ribociclib) provides molecular rationale for KISQALI’s consistent OS across three phase 3 trials.

Click below for information on the ongoing HARMONIA trial

HARMONIA trial in patients classified as HER2E

The HARMONIA trial will test whether KISQALI can uniquely change tumor biology from HER2E to luminal subtypes in HR+/HER2- aBC^15,16

HARMONIA will evaluate whether KISQALI may improve the course of disease for patients with HR+/HER2– aBC by positively altering tumor biology, inducing a switch from HER2E to luminal subtypes, enabling a better response to ET^15,16
- The HARMONIA trial is an international, randomized, phase III, multicenter, open-label, head-to-head study of KISQALI vs palbociclib, both in combination with ET, and in patients with the HER2E intrinsic subtype¹⁵
  - The HER2E subtype is commonly associated with endocrine resistance and a very poor prognosis compared with luminal disease⁴
- The HARMONIA trial is the first trial to directly compare 2 CDK4/6 inhibitors in patients with HR+/HER2– aBC¹⁵
- HARMONIA is the first prospective phase III trial to enroll patients selected by RNA-based molecular subtyping of their tumors¹⁵
- HARMONIA is expected to be complete January 1, 2026

HARMONIA has the opportunity to provide further evidence distinguishing KISQALI as a unique CDK4/6 inhibitor

PAM50 was the genetic microarray used in the pooled exploratory analysis to identify subtypes by analyzing the expression of 50 genes.^1,4
The prognostic and/or predictive relationship between PAM50-based subtypes and OS was evaluated using univariable and multivariable Cox proportional hazards models, which were adjusted for known clinical prognostic factors, including age, prior chemotherapy, prior ET, ECOG performance status, visceral disease (presence of liver/lung metastases), bone-only metastases, histological grade, number of metastatic sites, tumor type, and de novo metastatic disease.⁴

1L, first line; 2L, second line; aBC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; HER2E, human epidermal growth factor receptor 2–enriched; HR, hazard ratio; NR, not reached; OS, overall survival; PAM50, 50 Prosigna Breast Cancer Prognostic Gene Signature Assay; RNA, ribonucleic acid.

References: 1. Cejalvo JM, Pascual T, Fernández-Martínez A, et al. Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer. Cancer Treat Rev. 2018;67:63-70. doi:10.1016/j.ctrv.2018.04.015 2. Cejalvo JM, Martínez de Dueñas E, Galván P, et al. Intrinsic subtypes and gene expression profiles in primary and metastatic breast cancer. Cancer Res. 2017;77(9):2213-2221. doi:10.1158/0008-5472.CAN-16-2717 3. Molecular subtypes of breast cancer. Breastcancer.org. Updated April 7, 2021. Accessed December 19, 2021. https://www.breastcancer.org/symptoms/types/molecular-subtypes 4. Carey LA, Solovieff N, André F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Abstract presented at: San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. 5. Prat A, Chaudhury A, Solovieff N, et al. Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA phase III studies. J Clin Oncol. 2021;39(13):1458-1467. doi:10.1200/JCO.20.02977 6. Badowska-Kozakiewicz AM, Budzik MP. Immunohistochemical characteristics of basal-like breast cancer. Contemp Oncol (Pozn). 2016;20(6):436-443. doi:10.5114/wo.2016.56938 7. Eroles P, Bosch A, Pérez-Fidalgo JA, Lluch A. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012;38(6):698-707. doi:10.1016/j.ctrv.2011.11.005 8. Prat A, Cheang MCU, Galván P, et al. Prognostic value of intrinsic subtypes in hormone receptor-positive metastatic breast cancer treated with letrozole with or without lapatinib. JAMA Oncol. 2016;2(10):1287-1294. doi:10.1001/jamaoncol.2016.0922 9. Cejalvo JM, Pascual T, Fernández-Martínez A, et al. Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer. Supplement Fig S1. Intrinsic subtype distribution in advanced or metastatic breast cancer (A) in HR+/HER2-negative, and (B) HR+/HER2-positive. Cancer Treat Rev. 2018;67:63-70. Accessed December 19, 2021. https://www.cancertreatmentreviews.com/cms/10.1016/j.ctrv.2018.04.015/attachment/710ed0fa-4544-490a-a410-ef90481cb13d/mmc2.pdf 10. Yersal O, Barutca S. Biological subtypes of breast cancer: prognostic and therapeutic implications. World J Clin Oncol. 2014;5(3):412-424. doi:10.5306/wjco.v5.i3.412 11. Carey LA, Solovieff N, André F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. 12. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival results from the phase III MONALEESA-2 trial of postmenopausal patients with HR+/HER2− advanced breast cancer treated with endocrine therapy ± ribociclib. Presented at: European Society of Medical Oncology; September 16-21, 2021. 13. Tripathy D, Im S-A, 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 14. Slamon DJ, Neven P, Chia S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021;32(8):1015-1024. doi:10.1016/j.annonc.2021.05.353 15. Novartis announces collaboration on HARMONIA, a Phase III, head-to-head trial evaluating Kisqali® vs. Ibrance®* in patients with HR+/HER2-advanced breast cancer. News release. Novartis. September 19, 2021. Accessed December 19, 2021. https://www.novartis.com/news/media-releases/novartis-announces-collaboration-harmonia-phase-iii-head-head-trial-evaluating-kisqali-vs-ibrance-patients-hrher2-advanced-breast-cancer 16. Data on file. Novartis Pharma AG.