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MIAMI BEACH -- After a bumpy start, CDK4/6 inhibitors have started to gain traction in early hormone receptor (HR)-positive/HER2-negative breast cancer, according to recent data.

Two negative phase III trials of palbociclib (Ibrance) questioned whether the transformative impact of CDK4/6 inhibition in advanced HR+/HER2- breast cancer would carry over into early disease. More recently, the phase III monarchE trial with abemaciclib (Verzenio) showed statistically significant improvement in invasive disease-free survival (IDFS) in patients with high-risk early breast cancer. A recent update to the trial showed a persistence of the IDFS benefit and a reduction in the risk of distant relapse, but no improvement in overall survival (OS).

The data suggest the adjuvant abemaciclib should be considered for patients who meet the monarchE trial eligibility criteria, said Sara Tolaney, MD, of Dana-Farber Cancer Institute in Boston, at the Miami Breast Cancer Conference.

"Adjuvant abemaciclib clearly does reduce the risk of recurrence for our high-risk, hormone receptor-positive breast cancer patients," she said. "Really, I think, quite a milestone in development of agents in the early-stage setting. To date, we've really just had endocrine therapies, but now we have an oral targeted agent that can help our patients."

"In general, I would recommend it for patients who have four or more positive lymph nodes, or one to three positive lymph nodes with a tumor five centimeters or larger or high grade -- and we can consider it irrespective of Ki-67 -- given that the benefit was seen in both the low- and high-Ki-67 patients," Tolaney stated.

Data from her own institution on 4,500 patients with HR+/HER2- breast cancer suggested that 11.1% of patients met monarchE criteria. The unpublished data also showed that patients eligible for abemaciclib were more likely to be premenopausal (52% vs 30%), be BRCA2 mutation carriers (11% vs 3%), have lobular tumors (21% vs 14%), and have high 21-gene risk scores (31% vs 14%).

The recommendations come with notable qualifiers. In October 2021, the for women with high-risk, node-positive HR+/HER2- early breast cancer associated with a Ki-67 score ≥20 as determined by an FDA-approved test. In monarchE, 60% of the patients had four or more involved lymph nodes, and a majority of those patients had low Ki-67 scores, Tolaney noted.

"Taking all of this into account, both [American Society of Clinical Oncology] and NCCN [National Comprehensive Cancer Network] did end up recommending abemaciclib irrespective of Ki-67 level, recommending it for use in the monarchE overall ITT [intention to treat] population," she said. "I think this is the general way I have been practicing, recommending it at the bedside for anyone who would have met eligibility for monarchE."

A second qualifier pertains to patients with germline BRCA mutations. The phase III, placebo-controlled OlympiA trial of patients with early BRCA-mutant showed a 42% reduction in the risk of IDFS with adjuvant olaparib (Lynparza), a PARP inhibitor. About 18% of the trial participants had HR+ tumors, but the benefit in that subgroup was consistent with the overall population, said Tolaney.

Moreover, a study showed that patients with metastatic HR+ breast cancer and BRCA2 mutations had significantly worse progression-free survival when treated with a CDK4/6 inhibitor.

"We don't have data from monarchE to look at outcome differences for germline BRCA versus wild-type patients, but we do have some suggestions in the metastatic setting that patients who have germline BRCA mutations tend to have less benefit from CDK4/6 administration than patients who have wild-type disease," said Tolaney.

The endocrine agent paired with abemaciclib also may affect outcomes. A recent analysis of safety data from monarchE showed patients who received tamoxifen had more than double the risk of as compared with patients who received abemaciclib and an aromatase inhibitor (AI).

"In my general practice, I've been recommending abemaciclib more with an aromatase inhibitor and more cautiously with tamoxifen," said Tolaney. "That being said, most of these high-risk patients are patients we're going to end up offering aromatase inhibitors -- premenopausal patients -- usually using ovarian suppression with an AI, again in a high-risk population."

Following a presentation of at a 2021 European Society of Medical Oncology (ESMO) Virtual Plenary, ESMO invited discussant Aditya Bardia, MD, of Mass General Cancer Center in Boston, suggested that monarchE raised several questions about adjuvant CDK4/6 inhibition.

The negative results of and PENELOPE-B require further study, but both trials had shorter treatment durations with palbociclib as compared with abemaciclib in monarchE. The optimal duration of adjuvant therapy remains to be determined, said Bardia. Whether the three approved CDK4/6 inhibitors, including ribociclib (Kisqali) have differing activity in different clinical settings also remains unresolved. Finally, is Ki-67 the best biomarker for identifying patients who should receive a CDK4/6 inhibitor?

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