The invited discussant of monarchE,1 Aditya Bardia, MD, MPH, Director, Breast Cancer Research, and Associate Professor of Medicine, Harvard Medical School, commented: “Based on a hazard ratio of 0.69 for invasive disease–free survival, the results are statistically significant and clinically meaningful…. It’s reassuring to see the stability of the hazard ratio and the reduced risk of distant metastases. Nevertheless, additional follow-up is needed, as recurrences in hormone receptor–positive breast cancer can occur beyond 3 years.”
Will the significant results persist with longer follow-up? Only longer follow-up will tell, according to Dr. Bardia. The risk of recurrence continues beyond 3 years, and only a minority of patients have reached even the 5-year mark. It is also unclear what will happen once abemaciclib is stopped.
Aditya Bardia, MD, MPH
Why do the results differ from the negative findings of adjuvant trials of palbociclib? One potential reason, noted Dr. Bardia, is that monarchE enrolled higher-risk patients who would be more likely to experience benefit from treatment, though subset analyses of the PALLAS trial do not support this.2 Treatment discontinuations in PALLAS were also higher, but no differences were seen in that study based on dose exposure to palbociclib, he added.
Could the studies’ outcome difference be due to the drugs themselves? Yes, Dr. Bardia said. Drugs that appear similar can have kinome differences that may make them behave differently, particularly in the primary endocrine resistance setting. Abemaciclib may be more effective when tackling primary endocrine resistance: It has single-agent activity in these patients and has been shown to provide a survival advantage. However, the idea of molecular differences determining efficacy is solely hypothesis-generating, and further validation is needed, Dr. Bardia cautioned.
Patient Selection in Clinical Practice
How will the results impact clinical practice, and should all patients with hormone receptor–positive, HER2-negative early breast cancer receive abemaciclib along with their endocrine therapy? Dr. Bardia said he would balance the potential benefits against the potential risks, primarily toxicity, which includes diarrhea for most patients and the “rare but serious” occurrence of interstitial lung disease. Financial toxicity and compliance in the real-world adjuvant setting are also considerations, he added.
“The question is whether we can further identify patients who are most likely to benefit from escalation to abemaciclib,” he continued. Based on the monarchE data, the benefit is strong in patients with a high Ki67 index, since CDK4/6 inhibitors clearly impact proliferating cells. The achievement of a 7% absolute improvement in invasive disease–free survival makes such patients strong candidates for abemaciclib. On the other hand, patients with a low Ki67 index did benefit (hazard ratio = 0.70), but the number of events was low and the upper limit of the confidence interval was 0.979—close to 1; therefore, this group, in particular, requires further follow-up, he said.
“Ki67 as a biomarker to identify patients at ‘high-high risk’ is a start. However, we need more refined static as well as dynamic biomarkers to further identify patients most likely to benefit,” Dr. Bardia commented.
Meanwhile, there are also practical issues in using the Ki67 index. Since the Ki67 index is a continuous variable, is a cutoff of 20% optimal? How should clinicians deal with analytic variability among labs? Although these issues are being worked out, Dr. Bardia suggested more research into using genomic profiles (such as Oncotype DX or MammaPrint) or PAM50 subtypes that have lower analytic variability.
Future Studies
Dynamic studies using Ki67 to identify endocrine therapy resistance (eg, the POETIC trial) and those incorporating treatment monitoring with circulating tumor DNA should provide some clarity regarding the best use of CDK4/6 inhibitors for treatment escalation. Other studies (eg, the NATALEE trial) may help to determine the optimal treatment duration in the adjuvant setting.
“More than 10,000 patients have participated in adjuvant CDK4/6 inhibitor trials, and robust translational interrogation from the completed studies is critical to guide the next generation of adjuvant clinical trials,” Dr. Bardia said.
DISCLOSURE: Dr. Bardia has served as a consultant or advisor to Genentech/Roche, Immunomedics/Gilead, Novartis, Pfizer, Merck, Radius Health, Foundation Medicine, Sanofi, AstraZeneca, Daiichi Sankyo, and Eli Lilly; and has received institutional research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Eli Lilly, and Natera.
REFERENCES
1. O’Shaughnessy J, et al: Adjuvant abemaciclib combined with endocrine therapy: Updated results from monarchE. ESMO Virtual Plenary Session. Presented October 14, 2021.
2. Mayer EL, et al: Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): Interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 22:212-222, 2021.
