Controversy Swirls Around the Use of CDK4/6 Inhibitors as Adjuvant Breast Cancer Therapy
CDK4/6 inhibitors like abemaciclib and ribociclib improve invasive disease-free survival in breast cancer trials, but controversy surrounds study designs, bias, and cost-effectiveness, raising critical questions about their clinical benefit.
THE CDK4/6 INHIBITORS palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) slow the progression of cancer cells by inhibiting key molecules involved in regulating the cell cycle. In the phase 3 monarchE trial (NCT03155997), patients with hormone receptor–positive, HER2-negative breast cancer were randomly assigned to a control arm of endocrine therapy alone or to an investigational arm of endocrine therapy plus 2 years of abemaciclib.1 The trial investigators reported an improvement in invasive disease-free survival (iDFS) in the abemaciclib arm. As a result, in October 2021 the FDA approved abemaciclib for adjuvant therapy in select patients. More recently, in the phase 3 NATALEE trial (NCT03701334), similar (though not identical) patients were randomly assigned to a control arm of aromatase inhibitor alone or to an investigational arm of aromatase inhibitor plus 3 years of ribociclib.2 As in the monarchE trial, the addition of the CDK4/6 inhibitor improved iDFS, leading to an FDA approval.
So what’s the controversy? In a 2023 Lancet Oncology article authors argued that the efficacy results of monarchE should be called into question because of the potential for the same informative censoring bias I discussed in my November 2024 column.3,4 They conclude, “Adjuvant abemaciclib should not be prescribed to women with high-risk, estrogen receptor–positive breast cancer.”
In a 2024 European Journal of Cancer article a different set of investigators leveled a similar list of criticisms at both studies, pointing to the studies’ open-label design and informative censoring as being sources of error that could lead to false efficacy results.5 Based on NATALEE results, they estimated 30 patients would need to be treated to prevent 1 iDFS event. In addition, they calculated that, with the cost of a 3-year course of ribociclib being approximately $550,000, the health care system would need to spend approximately $11 million to prevent 1 iDFS event.
In a response to a letter to the editor in the New England Journal of Medicine, the NATALEE authors state that sensitivity analyses to assess the effect of censoring did not show any major effect on results and argue that their results demonstrate a “substantial magnitude of clinical benefit.”6
All I can say is that we must get this issue figured out and get it right. We cannot afford to be spending that kind of money without providing real benefit to patients. Even more importantly, our patients have no interest in us putting them through pain without gain.
References
Johnston SRD, Toi M, O’Shaughnessy J, et al; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomized, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. doi:10.1016/S1470-2045(22)00694-5
Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi:10.1056/NEJMoa2305488
Meirson T, Goldstein DA, Gyawali B, Tannock IF. Review of the monarchE trial suggests no evidence to support use of adjuvant abemaciclib in women with breast cancer. Lancet Oncol. 2023;24(6):589-593. doi:10.1016/S1470-2045(23)00165-1
Burke JM. Addressing informative censoring bias in clinical trials. Targeted Therapies in Oncology. 2024;13(14):7.
Haslam A, Ranganathan S, Prasad V, Olivier T. CDK4/6 inhibitors as adjuvant therapy in early breast cancer? uncertain benefits, guaranteed harms. Eur J Cancer. 2024;207:114192. doi:10.1016/j.ejca.2024.114192
Slamon D, Yardley DA, Hortobagyi G. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(13):2221-2222. doi:10.1056/NEJMc2404917
Durability and Intracranial Efficacy Observed With T-DXd in HER2+ MBC
January 13th 2025During a Case-Based Roundtable® event, Ian Krop, MD, and participants discussed how the outcomes of the DESTINY-Breast03 and other trials impact treatment of metastatic HER2-positive breast cancer in the second article of a 2-part series.
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