MIAMI BEACH — After a bumpy start, CDK4/6 inhibitors have begun to gain traction in hormone receptor (HR)-positive/HER2-negative early breast cancer, according to recent data.
Two negative phase III trials of palbociclib (Ibrance) questioned whether the transformative impact of CDK4/6 inhibition in HR+/HER2- advanced breast cancer would carry over to the early stages of the disease. More recently, the phase III monarchE trial with abemaciclib (Verzenio) showed a statistically significant improvement in invasive disease-free survival (IDFS) in patients with high-risk early breast cancer. A recent trial update showed persistence of IDFS benefit and reduced risk of distant relapse, but no improvement in overall survival (OS).
Data suggest adjuvant abemaciclib should be considered for patients who meet eligibility criteria for the monarchE trial, said Sara Tolaney, MD, of the Dana-Farber Cancer Institute in Boston, at the Miami Breast Cancer Conference .
“Adjuvant abemaciclib clearly reduces the risk of recurrence in our patients with high-risk, hormone receptor-positive breast cancer,” she said. “Really, I think, a big step in the development of early-stage agents. To date, we’ve really only had endocrine therapies, but now we have an oral targeted agent that can help our patients. “
“In general, I would recommend it to patients who have four or more positive lymph nodes, or one to three positive lymph nodes with a tumor that is five centimeters or larger or high grade – and we can consider this regardless of Ki-67 – since the benefit was seen in both low and high Ki-67 patients,” Tolaney said.
Data from his own institution on 4,500 patients with HR+/HER2- breast cancer suggested that 11.1% of patients met the monarchE criteria. Unpublished data also showed that patients eligible for abemaciclib were more likely to be premenopausal (52% versus 30%), be BRCA2 carriers of the mutation (11% versus 3%), have lobular tumors (21% versus 14%) and have high risk scores for gene 21 (31% versus 14%).
The recommendations are accompanied by notable qualifiers. In October 2021, the Abemaciclib adjuvant approved by the FDA for women with high-risk HR+/HER2- early breast cancer with nodal involvement associated with a Ki-67 score ≥20 as determined by an FDA-approved test. In monarchE, 60% of patients had four or more lymph nodes involved, and the majority of those patients had low Ki-67 scores, Tolaney noted.
“Given all this, both ASCO [American Society of Clinical Oncology] and NCCN [National Comprehensive Cancer Network] ended up recommending abemaciclib regardless of Ki-67 level, recommending it for use in the overall monarchE ITT [intention to treat] population,” she said. “I think that’s the general way I’ve practiced, recommending it bedside to anyone who has met the eligibility requirements for monarchE.”
A second qualifier relates to patients with germ line BRCA mutations. The phase III, placebo-controlled trial, Olympia in patients with BRCA-mutant showed a 42% reduction in the risk of IDFS with adjuvant olaparib (Lynparza), a PARP inhibitor. About 18% of trial participants had HR+ tumors, but the benefit in this subgroup was consistent with the overall population, Tolaney said.
Moreover, a study reported at San Antonio Breast Cancer Symposium 2021 showed that patients with HR+ metastatic 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 examine differences in germline outcomes BRCA compared to wild-type patients, but we have some suggestions in the metastatic setting that patients who have a germline BRCA mutations tend to benefit less from CDK4/6 administration than patients with wild-type disease,” Tolaney said.
The endocrine agent associated with abemaciclib may also affect results. A recent analysis of safety data from monarchE showed that patients who received tamoxifen had more than double the risk of venous thromboembolism compared to patients who received abemaciclib and an aromatase inhibitor (AI).
“In my general practice, I recommend abemaciclib more with an aromatase inhibitor and more cautiously with tamoxifen,” Tolaney said. “That being said, most of these high-risk patients are patients that we’re going to end up offering aromatase inhibitors to – premenopausal patients – typically using ovarian suppression with AI, again in a high-risk population. risk.”
Following a presentation by monarchE data updated During a virtual plenary of the European Society for Medical Oncology (ESMO) in 2021, Aditya Bardia, MD, discussant invited by ESMO, of the Mass General Cancer Center in Boston, suggested that monarch raises several questions about the adjuvant inhibition of CDK4/6.
The negative results of PALLAS and PENELOPE-B require further study, but both trials had shorter treatment durations with palbociclib compared to abemaciclib in monarE. The optimal duration of adjuvant therapy remains to be determined, Bardia said. Whether the three approved CDK4/6 inhibitors, including ribociclib (Kisqali) have different activity in different clinical settings, also remains unresolved. Finally, is Ki-67 the best biomarker to identify patients who should receive a CDK4/6 inhibitor?
Tolaney disclosed relationships with Genentech, Lilly, Novartis, NanoString, AstraZeneca, Merck, Pfizer, Nektar, Exelixis, Bristol Myers Squibb, Eisai, Cyclacel, Immunomedics/Gilead, Odonate, Seattle Genetics, Sanofi, Puma, Daiichi Sankyo, Athenix, OncoPep, Samsung, Bioepis, Kyowa, Kirin, CytomX, Certara, Mersana Therapeutics, OncoSec, Ellipses Pharma, 4D Pharma, Chugai Pharma, Infinity Therapeutics, BeyondSpring Pharmaceuticals, Zymeworks, Zentalis, G1 Therapeutics, Reveal Genomics and Blueprint Medicines.