New Approval in Early Breast Cancer: First Advance in 20 Years

Zosia Chustecka


October 13, 2021

The CDK4/6 inhibitor abemaciclib (Verzenio) has been approved for use in early breast cancer for certain patients. One expert has described the drug as the first advance for this patient population in 20 years.

Abemaciclib had already been approved for use in the treatment of HR+, HER2- advanced or metastatic breast cancer.

Now it is also approved for use in HR+, HER2- early breast cancer for patients who have high-risk, node-positive disease and whose tumors have a Ki-67 score of ≥20%, as determined by a US Food and Drug Administration (FDA)–approved test.

The FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay for use as a companion diagnostic test.

This is the first CDK4/6 inhibitor to be approved for use in this patient population.

Approximately 70% of all breast cancers are of the HR+, HER2- subtype.

The approval is based on some of the results from the monarchE study, which was presented last year at the annual meeting of the European Society of Medical Oncology (ESMO) and was simultaneously published in the Journal of Clinical Oncology.

The results showed that the addition of abemaciclib to endocrine therapy (tamoxifen or aromatase inhibitors) significantly improved invasive disease-free survival (IDFS), which was defined on the basis of the length of time before breast cancer comes back, any new cancer develops, or death.

The 2-year IDFS rates were 92.2% with the combination vs 88.7% for endocrine therapy alone for the overall patient population.

"This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer," lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom, said at the meeting, as reported at the time by Medscape Medical News.

Reacting to the findings, Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, said, "This is a very important trial and the findings will change practice."

He predicted that once the drug is approved for use in high-risk HR+, HER2- early breast cancer, "the new standard of care for these patients will be to add 2 years of abemaciclib to endocrine therapy."

In a press release about the new approval from the manufacturer (Lilly), another investigator on the monarchE study, Sara M. Tolaney, MD, MPH, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts, agreed that the results are practice changing. She said that the combination of abemaciclib and endocrine therapy is a potential new standard of care for this patient population. "We are encouraged by the marked reduction in the risk of recurrence even beyond the two-year treatment period in these patients, and I'm grateful to be able to offer this as a treatment option to my patients," she said.

On Twitter, she commented that restricting the indication to patients who show Ki67 ≥20% is "interesting," inasmuch as benefits were seen in patients with both low and high Ki67.

Hal Burstein, MD, from Dana-Farber, also found this detail "interesting, as Ki67 testing remains a very controversial topic and difficult to standardize."

Replying, Pedro Exman, MD, from the Hospital Alemão Oswaldo Cruz, in São Paulo, Brazil. said: "Does it make sense to approve only in a subset of patients based in a positive subgroup analysis of a positive ITT study that was not even described in the JCO publication?"

Other experts said they were eagerly awaiting further results, particularly on overall survival, from the monarchE trial. New data are due to be presented on October 14 at an ESMO virtual plenary session.

Commenting late last year about these results, George W. Sledge, Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, California, said that the median follow-up time "is still quite short for a study of ER+ adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies."

Consequently, "we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early stage ER+ breast cancer, particularly on late recurrences," he told Medscape Medical News at the time.

Agreed, said C. Kent Osborne, MD, co-director of the San Antonio Breast Cancer Symposium and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Texas. The results are "very encouraging, especially in the subgroup of tumors with high proliferation" (identified by the K1-67 score).

However, Osborne also urged caution in the interpretation of the results, "given the still rather short follow-up, given that that ER+ disease is known for its persistent recurrence rate, even past 10 years."

He also noted that "this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells." Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once patients stop taking the drug.

Study Details

The monarchE trial involved patients with HR+, HER2-, high-risk early breast cancer who had undergone surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes or one to three nodes and either tumors of size ≥5 cm, histologic grade 3, or central Ki-67 ≥20% were eligible; 5637 patients were randomly assigned in a 1:1 ratio to receive standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years).

A preplanned interim analysis was carried out after 323 IDFS events were observed in the intent-to-treat population. The results, as published last year in the Journal of Clinical Oncology, show that abemaciclib plus ET yielded superior IDFS in comparison with ET alone (P = .01; hazard ratio [HR], 0.75; 95% CI, 0.60 – 0.93), with 2-year IDFS rates of 92.2% vs 88.7%.

In the press release announcing the approval of the new indication, the manufacturer notes that the approval was based on the results from a subgroup of 2003 patients whose tumors had a Ki-67 score of ≥20% and who were also at high risk for recurrence (≥4 positive axillary lymph nodes [ALN], or one to three positive ALN with grade 3 disease and/or tumor size ≥5 cm).

There was a statistically significant improvement in IDFS for this prespecified subgroup of patients (HR = 0.643; 95% CI, 0.475 – 0.872; P = .0042).

With additional follow-up, conducted post hoc, the results showed a 37% decrease in the risk for breast cancer recurrence or death compared to ET alone (HR, 0.626; 95% CI, 0.49 – 0.80) and an absolute benefit in IDFS event rate of 7.1% at 3 years. IDFS was 86.1% for abemaciclib plus ET vs 79.0% for ET alone.

Adverse reactions from monarchE were consistent with the known safety profile for abemaciclib, the company noted. Safety and tolerability were evaluated in 5591 patients. The most common adverse reactions reported (≥10%) with abemaciclib plus ET vs ET alone were diarrhea (84% vs 9%), infections (51% vs 39%), neutropenia (46% vs 6%), fatigue (41% vs 18%), leukopenia (38% vs 7%), nausea (30% vs 9%), anemia (24% vs 4%), headache (20% vs 15%), vomiting (18% vs 4.6%), stomatitis (14% vs 5%), lymphopenia (14% vs 3%), thrombocytopenia (13% vs 2%), decreased appetite (12% vs 2.4%), increased ALT (12% vs 6%), increased AST (12% vs 5%), dizziness (11% vs 7%), rash (11% vs 4.5%), and alopecia (11% vs 2.7 %).

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