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Adding a CDK4/6 inhibitor to adjuvant endocrine therapy significantly improved invasive disease-free survival (IDFS) and decreased the risk of distant relapse in early hormone receptor (HR)-positive/HER2-negative breast cancer, according to updated results from a randomized trial.

The addition of abemaciclib (Verzenio) was associated with an IDFS hazard of 0.696 (95% CI 0.588-0.823, P<0.0001) and a hazard of 0.687 for distant relapse-free survival (DRFS, 95% CI 0.571-0.826, P<0.0001). These persisted over time from interim to primary and updated analyses. The 3-year IDFS was 86.8% with abemaciclib and 83.4% with endocrine therapy alone.

The phase III, multicenter, randomized monarchE trial also confirmed the value of the Ki-67 proliferation factor as a prognostically useful biomarker, although patients benefited from the addition of abemaciclib regardless of their tumors' Ki-67 status, reported Joyce O'Shaughnessy, MD, of Texas Oncology and Baylor University Medical Center in Dallas, at a European Society for Medical Oncology (ESMO) virtual . The findings were published simultaneously in .

"With additional follow-up, adjuvant abemaciclib, combined with endocrine therapy, continued to demonstrate clinically meaningful benefit for patients with HR-positive/HER2-negative, node-positive, high-risk early breast cancer," said O'Shaughnessy. "A robust invasive disease-free survival and distant relapse-free survival benefit was maintained beyond the 2-year treatment period of abemaciclib."

"The safety dataset is mature, with 90% of patients off study treatment period. The data are consistent with the known safety profile of abemaciclib and considered acceptable in high-risk early breast cancer," she stated, adding that follow-up will continue to a final assessment of overall survival (OS).

The findings from a median follow-up of 27 months are consistent with the interim analysis, which showed statistically significant IDFS after a median follow-up of 15-16 months.

'Story Continues'

The monarchE trial demonstrated statistically and clinically meaningful improvement in IDFS in a high-risk population, agreed ESMO invited discussant Aditya Bardia, MD, MPH, of Massachusetts General Hospital Cancer Center in Boston. The results provided the basis for recent FDA approval of abemaciclib in the adjuvant setting for early, high-risk HR-positive/HER2-negative breast cancer, the first new approval in the adjuvant setting for HR-positive breast cancer in more than 15 years.

However, he said the study raised a number of questions that require further study to clarify the findings and implications:

• The results differed from the PENELOPE-B and adjuvant trials with palbociclib (Ibrance), neither of which showed improvement in IDFS but had shorter durations of anti-CDK4/6 treatment.
• Do the three approved CDK4/6 inhibitors behave differently in different clinical settings?
• The optimal duration of anti-CDK4/6 therapy remains undetermined.
• How do clinicians balance the potential benefits and the potential risks, including drug-related toxicity (diarrhea and interstitial lung disease), financial toxicity, and adherence?
• Can Ki-67 be used as a biomarker for therapy selection? Can tumor genomics or other biomarkers better support treatment decisions?

The favorable results from monarchE notwithstanding, "the story continues," said Bardia.

CDK4/6 inhibitors transformed the treatment of advanced HR-positive breast cancer, achieving significant improvement in clinical outcomes when added to standard endocrine therapy. Whether the benefits would carry over into early disease remained unclear. To address the issue, monarchE investigators enrolled 5,637 patients with high-risk, node-positive, HR-positive/HER2-negative breast cancer. The trial comprised two cohorts: one that defined high risk on the basis of clinicopathologic features and the other on the basis of Ki-67 expression (high/low cutoff ≥20%).

Patients in both cohorts were randomized to receive standard-of-care adjuvant endocrine therapy with or without abemaciclib. Patients allocated to abemaciclib continued the CDK4/6 inhibitor for 2 years. Adjuvant endocrine therapy lasted 5-10 years as clinically indicated.

Benefits Persist Over Time

The patients had a median age of 51, 84%-85% were younger than 65, and 57% were postmenopausal. About half the patients had tumors 2-5 cm and 27% had smaller tumors. About 60% of the patients had four or more positive lymph nodes. Half the patients had grade 2 disease and 38% had grade 3 cancer. About a third of the patients had low Ki-67 expression, 44% had ≥20% expression, and the rest had unknown Ki-67 status.

The treatment effect of abemaciclib trended toward improvement over time, said O'Shaughnessy. During the first year of follow-up, the IDFS and DRFS hazards were 0.795 and 0.732 in favor of treatment with the CDK4/6 inhibitors. The hazard values from 1-2 years were 0.681 and 0.675, and beyond 2 years, the IDFS hazard was 0.596 and the DRFS hazard was 0.692. All were statistically significant with the exception of the DRFS hazard beyond 3 years.

A planned analysis by Ki-67 expression showed better outcomes in the Ki-67-low population, as expected, but patients randomized to abemaciclib had significantly better IDFS, irrespective of Ki-67 status. For example, patients at high risk as a result of clinicopathologic features, and with a high Ki-67 expression, had a 3-year IDFS of 86.1% with abemaciclib and 79.0% without. In the Ki-67-low subgroup, 3-year IDFS values were 91.7% and 87.2%, respectively.

No new or unexpected adverse events (AEs) occurred with longer follow-up, said O'Shaughnessy. Most AEs were grade 1/2 severity. The most common AE in abemaciclib-treated patients was diarrhea, followed by neutropenia, fatigue, leukopenia, abdominal pain, nausea, and anemia, all of which occurred more often with with CDK4/6 inhibitor.

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