Breast cancer is most common cancer in American women and is the second-leading cause of cancer death in women. The most common subtype is hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative breast cancer, which accounts for nearly 65 percent of all breast cancers.
Endocrine therapy (ET) is an important strategy of treatment for women with HR-positive, ERBB2-negative metastatic breast cancer. ET is associated with a significant increase in both progression-free survival (PFS) and overall survival (OS). However, approximately 20 percent will develop a recurrence either locally in the breast or elsewhere in the body over the first 10 years of treatment.
A better understanding of disease biology has led to the addition of new agents to the backbone of ET. Specifically, the recent development of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) is perhaps one of the most clinically important discoveries for patients living with HR-positive, ERBB2-negative metastatic breast cancer.
CDK4/6 proteins, which are found both in healthy cells and cancer cells, control how quickly cells grow and divide. Tumor cell proliferation in many breast cancers is driven by the hyperactivity of the cyclin D-CDK4/6 pathway. Currently, there are three FDA-approved available CDK4/6 inhibitors: abemaciclib, palbociclib, and ribociclib.
Importantly, in the National Comprehensive Cancer Network guidelines for the treatment of breast cancer, it is noted that the newest regimens, including mostly combination therapy approaches with CDK4/6 inhibitors, are those with the highest level of recommendation for use in patients with HR-positive disease.
In this update, we review some of the recent advancements achieved in the breast cancer treatment paradigm utilizing CDK4/6 inhibitors.
Treatment With CDK4/6 Inhibitors + ET
In a new study published in JAMA Network Open, Li and colleagues performed a meta-analysis of nine published randomized clinical trials that compared treatment with ET alone versus treatment with ET plus CDK4/6 inhibitors (2020; doi:10.1001/jamanetworkopen.2020.20312). Eight Phase III clinical trials were included, as well as one randomized Phase II study.
The researchers sought to analyze the potential benefit of a CDK4/6 inhibitors (ribociclib, palbociclib, or abemaciclib) to ET regarding OS, PFS, overall response rate, and development of adverse events (AEs). Across all nine trials, a total of 5,043 patients with HR-positive, ERBB2-negative breast cancer was included in the analysis.
In regard to OS, six trials were considered to have adequate OS reporting for inclusion: MONALEESA-2, MONALEESA-3, MONALEESA-7, PALOMA-1, PALOMA-3, and MONARCH-2, which included a total of enrolled 1,391 patients in the ET arm and 2,030 patients in the CDK4/6 inhibitors plus ET arm. Analysis of OS data from the six trials demonstrated a significant benefit for patients who did receive versus who did not receive a CDK4/6 inhibitor alongside ET, with a hazard ratio (HR) for survival of 1.33 (95% CI, 1.19-1.48; P <.001).
The above-mentioned six studies, along with PALOMA-2, MONARCH-3, and MONARCHplus, were included in the analysis for the additional points of interest. Compared with ET alone, the addition of CDK4/6 inhibitors was associated with a significant OS benefit regardless of whether participants were premenopausal (HR=1.32) or postmenopausal (HR=1.34), had visceral (HR=1.31) or bone-only (HR=1.22) metastases, were aged at least 65 years (HR=1.38) or were younger (HR=1.25), or received treatment in the first-line (HR=1.35) or second-line (HR=1.30). The addition of CDK4/6 inhibitors to ET was also associated with significant PFS benefit (HR, 1.84; 95% CI, 1.70-1.98; P < .001) and objective response rate benefit (odds ratio, 2.02; 95% CI, 1.61-2.53; P < .001).
Regarding safety, grade 3 or 4 AEs were noted to be higher for participants who received a CDK4/6 inhibitor. The three CDK4/6 inhibitors had differing AE profiles, such that abemaciclib was primarily associated with diarrhea and fatigue, while palbociclib and ribociclib were primarily associated with hematologic toxicity. Li and colleagues noted these "grade 3/4 AEs may be controlled through experience, medication, or dose adjustment."
Overall, these data support the current clinical practice of discussing the potential benefits of CDK4/6 inhibitors with nearly all patients living with HR-positive, ERBB2-negative metastatic cancer.
CDK4/6 Inhibitor + Adjuvant Endocrine
In a separate study, abemaciclib plus ET in the adjuvant setting was explored-based on its efficacy and safety in the metastatic setting-in adult patients with high-risk, early-stage, HR-positive, ERBB2-negative invasive breast cancer (J Clin Oncol 2020; doi: 10.1200/JCO.20.02514).
This study was an open-label Phase III trial (monarchE) in which patients were randomly assigned in a 1:1 ratio to receive adjuvant ET either alone or in combination with abemaciclib, with the latter agent given for 2 years following completion of primary therapy. The study included 5,637 patients, median patient age was 51 years, more than 99 percent of patients were female, and nearly 95 percent had received either neoadjuvant or adjuvant chemotherapy at baseline. The primary study endpoint was invasive disease-free survival, with secondary study endpoints including distant relapse-free survival, OS, and safety.
The findings revealed that administration of abemaciclib, in combination with standard ET to patients following completion of primary treatment was associated with an approximately 25 percent reduction in the risk of developing a recurrence of invasive disease. Most of the reductions occurred in sites of distant metastases, especially to liver and bone. Moreover, this benefit was seen across all prespecified subgroups, including whether patients had received prior chemotherapy or not, and whether they were classified as pre- or postmenopausal.
Regarding safety, no new safety signals were associated with administration of abemaciclib in the adjuvant setting compared with its FDA-approved use in combination with ET in patients with advanced HR-positive, ERBB2-negative breast cancer.
Future Directions
A decade ago, we may have seen a series of monotherapy regimens. These studies demonstrate that compared with ET alone, the use of CDK4/6 inhibitors plus ET was associated with significant improvements in PFS, ORR, and OS among patients with HR-positive, ERBB2-negative metastatic breast cancer. The data regarding the use of CDK4/6 inhibitors after progression is evolving with trials that are ongoing.
Dibash Kumar Das is a contributing writer.