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
. 2025 Mar 12:15:1555921.
doi: 10.3389/fonc.2025.1555921. eCollection 2025.

Abemaciclib in combination with therapies for patients with metastatic breast cancer: a phase 1b study

Sara M Tolaney  1 , Komal Jhaveri  2 , Teresa Helsten  3 , Shannon L Puhalla  4 , Alison Conlin  5 , E Claire Dees  6 , Muralidhar Beeram  7 , Sonya C Chapman  8 , Andrew Lithio  8 , Lacey M Litchfield  8 , Matthew P Goetz  9
Affiliations

Abemaciclib in combination with therapies for patients with metastatic breast cancer: a phase 1b study

Sara M Tolaney et al. Front Oncol. .

Abstract

Background: The oral, selective, and potent small molecule cyclin-dependent kinases (CDK) 4/6 inhibitor (CDK4/6i) abemaciclib has demonstrated efficacy in advanced breast cancer and high-risk early breast cancer. This Phase 1b study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapies (Parts A-D), exemestane + everolimus (Part E), or fulvestrant + LY3023414 (a PI3K/mTOR inhibitor; Part G) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), or trastuzumab (Part F), or trastuzumab + pertuzumab (Part H) in patients with HER2-positive (HER2+) MBC.

Patients and methods: This study enrolled women aged ≥18 years old with either HR+, HER2- (Parts E and G), or HER2+ (Parts F and H) MBC. Additional requirements included measurable disease or non-measurable but evaluable bone disease (Parts E and F), or measurable disease (Parts G and H), an Eastern Cooperative Oncology Group performance status of 0-1, and no prior treatment with CDK4/6i (Parts E, F, and H). Adverse events were graded, and tumor response was assessed.

Results: Nineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane + everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant + LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab + pertuzumab (with prophylactic loperamide). The most common treatment-emergent adverse events (TEAEs) were diarrhea, fatigue, neutropenia, and nausea. Grade ≥3 TEAEs were reported in 16, 18, 10, and 4 patients in Parts E-H, respectively. Abemaciclib had no effect on the pharmacokinetics of the combination study drugs. The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E-H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F.

Conclusions: Overall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC.

Keywords: CDK4; CDK6; abemaciclib; everolimus; exemestane; fulvestrant; metastatic breast cancer; trastuzumab.

PubMed Disclaimer

Conflict of interest statement

At the time of the study SCC, AL, and LML were employees and shareholders of Eli Lilly and Company. ST received research grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Cyclacel, Eisai, Eli Lilly and Company outside submitted work, Exelixis, Genentech/Roche, Gilead, Merck, Nektar, Nanostring, Odonate, Pfizer, Puma, Sanofi; and personal fees from 4D Pharma, Athenex, BeyondSpring Pharma, Certara, Chugai Pharma, CytomX, Daiichi-Sankyo, Ellipses Pharma, G1 Therapeutics, Kyowa Kirin Pharmaceuticals, Mersana Therapeutics, OncoPep, OncoSec, OncXerna, Infinity Therapeutics, Samsung Bioepsis Inc., Seattle Genetics, Zentalis, and Zymeworks. ED acted in a consulting or advisory role for Novartis, Strata Oncology and G1 Therapeutics; received research funding from Novartis, Genentech/Roche, Pfizer, Merck, H3 Biomedicine, and Meryx Pharmaceuticals; and received reimbursement for travel expenses from G1 Therapeutics. MB received honoraria or research funding paid to the institution from Agios, Eli Lilly and Company, Genentech, Johnson & Johnson, Merck, Merrimack, Mersana, Puma Biotechnology, Phoenix Molecular Designs, and Zymerworks; Speaker’s Bureau paid to the institution from Bristol-Meyer-Squib, Genentech, and Merck; and travel expenses from Genentech and Merck. Consulting or advisory role payment was paid to an immediate family member from Bayer, Merck, Novartis, and Seattle Genetics. MG reports personal fees for CME activities from: AXIS, BroadcastMed, DAVA Oncology, IDEOlogy Health, MJH Life Sciences, PeerView, Physicians’ Education Resource, Research to Practice, Total Health Conferencing; consulting fees to Mayo Clinic from: AstraZeneca Pharmaceuticals LP, AstraZeneca UK Ltd., BeiGene USA, Biotheranostics, Biotheryx, eChinaHealth, EcoR1, Eli Lilly and Company, Engage Health Media, Genentech, Lilly, Laekna, Stemline Therapeutics, MJH Life Sciences, Novartis, Puma Biotechnology, RNA Diagnostics, Seattle Genetics, Sermonix Pharmaceuticals, TerSera Therapeutics/Amplity Health; grant funding to Mayo Clinic from: AstraZeneca, ATOSSA Therapeutics, Biotheryx, Lilly, Loxo, Pfizer, Sermonix, SimBioSys; travel support from: Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study design. Women aged ≥18 years diagnosed with HR+, HER2- or HER2+ MBC received abemaciclib orally every 12 hours and the assigned combination therapy. HER2-/HER2+, human epidermal growth factor receptor 2-negative/positive; HR+, hormone receptor positive; MBC, metastatic breast cancer; Q12H, every 12 hours. a: if dose level for Cohort 1 exceeds MTD of the combination MTD, then an additional Cohort 0 (100mg Q12H) could be enrolled b: Part H - cohort 2 not enrolled.
Figure 2
Figure 2
Treatment duration and best overall response. Treatment duration for patients receiving abemaciclib in combination with (A) exemestane and everolimus (Part E), (B) trastuzumab (Part F), (C) fulvestrant plus LY3023414 (Part G), and (D) trastuzumab plus pertuzumab (Part H). Best overall response is indicated as: star = complete response; filled circle = partial response; open circle = stable disease; filled triangle = progressive disease; diamond = not evaluable. The > sign indicates treatment ongoing at time of data cutoff.
Figure 3
Figure 3
Change in tumor size for patients with measurable disease. Best percent change in tumor size for patients for patients (with measurable disease and available post-baseline assessments) receiving abemaciclib in combination with (A) exemestane and everolimus (Part E), (B) trastuzumab (Part F), (C) fulvestrant plus LY3023414 (Part G), and (D) trastuzumab plus pertuzumab (Part H). Change in tumor size greater than 100% is truncated at 100%. Comparison among the study parts is not possible due to differences in patient and disease characteristics and because enrollment opened sequentially.
Figure 4
Figure 4
Mean plasma concentrations of abemaciclib following single and multiple doses. Abemaciclib mean plasma concentration versus time profiles for (A) Part E (150 mg or 200 mg abemaciclib plus everolimus and exemestane), (B) Part F (150 mg or 200 mg abemaciclib plus trastuzumab), (C) Part G (150 mg abemaciclib in combination with LY3023414 100 mg or 150 mg and fulvestrant), and (D) Part H (100 mg abemaciclib plus pertuzumab and trastuzumab).
See this image and copyright information in PMC

References

    1. Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. . Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. (2022) 66:15–23. doi: 10.1016/j.breast.2022.08.010 - DOI - PMC - PubMed
    1. Giaquinto AN, Sung H, Newman LA, Freedman RA, Smith RA, Star J, et al. . Breast cancer statistics 2024. CA Cancer J Clin. (2024) 74:477–95. doi: 10.3322/caac.21863 - DOI - PubMed
    1. Miranda F, Prazeres H, Mendes F, Martins D, Schmitt F. Resistance to endocrine therapy in HR+ and/or HER2+ breast cancer: the most promising predictive biomarkers. Mol Biol Rep. (2022) 49:717–33. doi: 10.1007/s11033-021-06863-3 - DOI - PubMed
    1. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discovery. (2023) 22:101–26. doi: 10.1038/s41573-022-00579-0 - DOI - PMC - PubMed
    1. (2023). Available online at: https://seer.cancer.gov/statistics-network/explorer/ (Accessed 24 August 2023). Surveillance Research Program, National Cancer Institute SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Data Source(s): SEER Incidence Data, November 2022 Submission (1975–2020), SEER 22 Registries.

LinkOut - more resources