Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 May 3;29(5):e622-e634.
doi: 10.1093/oncolo/oyad337.

CDK4/6-Inhibitors Versus Chemotherapy in Advanced HR+/HER2-Negative Breast Cancer: Results and Correlative Biomarker Analyses of the KENDO Randomized Phase II Trial

Francesco Schettini  1   2   3 , Michela Palleschi  4 , Francesca Mannozzi  5 , Fara Brasó-Maristany  1 , Lorenzo Cecconetto  4 , Patricia Galván  1 , Marita Mariotti  4 , Alessia Ferrari  6 , Emanuela Scarpi  5 , Anna Miserocchi  5 , Oriana Nanni  5 , Esther Sanfeliu  2   7 , Aleix Prat  1   3   8   9   10 , Andrea Rocca  11 , Ugo De Giorgi  4
Affiliations
Clinical Trial

CDK4/6-Inhibitors Versus Chemotherapy in Advanced HR+/HER2-Negative Breast Cancer: Results and Correlative Biomarker Analyses of the KENDO Randomized Phase II Trial

Francesco Schettini et al. Oncologist. .

Abstract

Background: The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.

Materials and methods: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.

Results: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.

Conclusions: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.

Keywords: CDK4/6-inhibitors; breast cancer; chemotherapy; hormone receptors; intrinsic subtypes; tertiary lymphoid structures.

PubMed Disclaimer

Conflict of interest statement

Francesco Schettini reports honoraria from Novartis, Gilead and Daiichy-Sankyo for educational events/materials and travel expenses from Novartis, Gilead and Daiichy-Sankyo. Michela Palleschi reports honoraria for educational events/materials from Novartis, Daiichy-Sankyo, Gilead and travel, accommodations, and/or expenses from Grant from Novartis. Ugo De Giorgi reports a consulting or advisory role for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, and PharmaMar; research funding (institution) from AstraZeneca, Roche, and Sanofi; and travel, accommodations, and/or expenses from Ipsen and Pfizer. Aleix Prat has received grants or contracts from Boehringer Ingelheim, Novartis, Roche, NanoString Technologies, Medica Scientia Innovation Research, Celgene, Astellas, and Pfizer; has received grants or contracts paid to his institution from Boehringer Ingelheim, Lilly, Roche, Novartis, Amgen, Daiichi Sankyo, and AstraZeneca; has received consulting fees from Roche, Pfizer, Novartis, Amgen, Bristol Myers Squibb, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc, Lilly, Daiichi Sankyo, and AstraZeneca; has received payment or honoraria from Roche, Pfizer, Novartis, Amgen, Bristol Myers Squibb, NanoString Technologies, and Daiichi Sankyo; has received payment or honoraria paid to his institution from NanoString Technologies; has participated on a data safety monitoring board or advisory board for Oncolytics Biotech, Lilly, AstraZeneca, Novartis, Peptomyc, and Roche; has served in a leadership or fiduciary role for Reveal Genomics and IOB Quironsalud; has stock ownership in Reveal Genomics, IOB Quironsalud, and Oncolytics Biotech; has served on the executive board for Reveal Genomics and SOLTI Cooperative Group; has served on the patronage committee for the SOLTI Foundation and Actitud Frente al Cáncer Foundation; and their institution has patents for HER2DX (pending), ERBB2 (issued), WO2018/103834A1, and CES WO/2018/096191. The other authors have nothing to declare.

Figures

Figure 1.
Figure 1.
PFS and OS according to treatment arm. Abbreviations: PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval; arm A: CDK4/6i + ET; arm B: chemotherapy +/− concomitant or maintenance ET.
Figure 2.
Figure 2.
PFS and OS according to PAM50 IS and ROR-P. Abbreviations: A, PFS and OS in arm A and B based on PAM50 IS; B, PFS and OS in arm A, according to ROR-P category; PFS, progression-free survival; OS, overall survival; IS, intrinsic subtypes; ET, endocrine therapy; ROR, risk-of-relapse score.
Figure 3.
Figure 3.
Significant associations with survival outcomes of selected PAM50 and BC360 signatures in arm A. The cut-offs were calculated using the Maximally Selected Rank Statistics method. Abbreviations: PFS, progression-free survival; OS, overall survival; ER, estrogen receptor.
Figure 4.
Figure 4.
Significant associations with PFS/OS of TILs and immune signatures. The cut-offs were calculated using the Maximally Selected Rank Statistics method. Abbreviations: PFS, progression-free survival; OS, overall survival; TILs, tumor-infiltrating lymphocytes.
Figure 5.
Figure 5.
Survival trends according to TLS presence and treatment arm. (A) Representative images of TILs infiltration without TLS, with TLS and GC or without GC, at hematoxylin and eosin staining. All pathology images in these panels are magnified at 10×. (B) Exploratory Kaplan-Meier curves of PFS and OS according to study population, based on presence/absence of TLS. The “TLS present” category included TLS with/without clearly visible GC. Abbreviations: TILs, tumor-infiltrating lymphocytes; TLS, tertiary lymphoid structures, including every lymphoid aggregates more or less organized; w/o, without; GC, germinal center; m, median; PFS, progression-free survival; OS, overall survival; CI, confidence interval; NR, not reached; NA, not assessable.
Figure 6.
Figure 6.
Survival trends according to immune pattern and treatment arm. (A) Representative images of different immune infiltration patterns at hematoxylin and eosin staining. All pathology images in these panels are magnified at 10X. (B) Exploratory Kaplan-Meier curves of PFS and OS according to study population, based on immune infiltration pattern. Abbreviations: m, median; PFS, progression-free survival; OS, overall survival; CI, confidence interval; NR, not reached; NA, not assessable.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Schettini F, Giuliano M, Giudici F, et al.. Endocrine-based treatments in clinically-relevant subgroups of hormone receptor-positive/HER2-negative metastatic breast cancer: systematic review and meta-analysis. Cancers (Basel). 2021;13(6):1458. 10.3390/cancers13061458 - DOI - PMC - PubMed
    1. Giuliano M, Schettini F, Rognoni C, et al.. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20(10):1360-1369. 10.1016/S1470-2045(19)30420-6 - DOI - PubMed
    1. Gao JJ, Cheng J, Bloomquist E, et al.. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2020;21(2):250-260. 10.1016/S1470-2045(19)30804-6 - DOI - PubMed
    1. Schettini F, Giudici F, Giuliano M, et al.. Overall survival of CDK4/6-inhibitors-based treatments in clinically relevant subgroups of metastatic breast cancer: systematic review and meta-analysis. J Natl Cancer Inst. 2020;112(11):1089-1097. 10.1093/jnci/djaa071 - DOI - PMC - PubMed
    1. Gennari A, André F, Barrios CH, et al.; ESMO Guidelines Committee. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475-1495. 10.1016/j.annonc.2021.09.019 - DOI - PubMed

Publication types

MeSH terms