CDK4/6 Inhibitors: Their Role in Breast Cancer
Sara A. Hurvitz, MD
The robust progression-free survival benefits achieved with the use of the CDK4/6 inhibitors palbociclib or ribociclib in the metastatic setting provided the impetus to study these agents in early-stage breast cancer. Adjuvant studies are underway, but they take time to mature. For evaluating promising new drugs, neoadjuvant trials are increasingly used, according to Sara A. Hurvitz, MD, Associate Professor of Medicine at the University of California, Los Angeles, and Director of the Breast Cancer Clinical Research Program at the David Geffen School of Medicine.
At the 2017 Miami Breast Cancer Conference, Dr. Hurvitz described how cyclin-dependent kinase (CDK) 4/6 inhibitors are being evaluated in the neoadjuvant treatment setting and how response is being evaluated using the proliferation marker Ki67. She also envisioned the use of these drugs beyond the hormone receptor–positive, HER2-negative subset.
The achievement of a pathologic complete response to neoadjuvant therapy and its association with event-free and overall survival are meaningful in the treatment of breast cancer. Neoadjuvant therapy allows researchers to perform in vivo analysis to capture molecular changes that occur during treatment and which might predict for longer-term responses or treatment resistance.
However, the prognostic effect of pathologic complete response is fairly weak in the hormone receptor–positive, HER2-negative subset. “We still see an association between pathologic complete response and long-term outcomes, but the chance of achieving a pathologic complete response is quite low in this group,” Dr. Hurvitz pointed out. “In these patients, could there be a better way to get a snapshot of what’s happening in the tumor?”
Based on data from the IMPACT study, Ki67 can serve as this marker.1 In patients receiving preoperative tamoxifen, anastrozole, or both, change in Ki67 from baseline to 2 weeks posttreatment was associated with relapse-free survival. “From this, we began to appreciate that change in Ki67 may be a better way to evaluate hormonally targeted therapies in this disease subset,” she commented.
Dr. Hurvitz described the use of the Ki67 assay in two small neoadjuvant studies of palbociclib and ribociclib and in a larger trial of abemaciclib.
Ma et al applied Ki67 in a phase II study of anastrozole plus palbociclib, followed by surgery, in 43 patients.2 The proportion of patients who achieved complete cell-cycle arrest (Ki67 < 2.7% at biopsy) was achieved 1 month after treatment initiation in 60% of patients on the combination therapy, compared with 26% of patients on anastrozole alone. Patients who stopped palbociclib 4 weeks before surgery experienced a rebound in Ki67 level, whereas in those continuing the drug until surgery, this rebound was mitigated.
The Ki67 assessment was also applied to ribociclib (plus letrozole) in a neoadjuvant study of 13 patients led by Dr. Hurvitz.3 A drop in the Ki67 level was achieved by > 92% of ribociclib-treated patients, vs 69% of those on letrozole alone. Phosphorylated retinoblastoma was also decreased in patients on ribociclib, whereas it increased with letrozole alone. “This is not clinically useful information at this point, but it does give insights into what is happening molecularly with this CDK4/6 inhibitor,” she commented.
The larger phase II neoMONARCH study evaluated change in Ki67 level in 223 hormone receptor–positive HER2-negative patients receiving abemaciclib, anastrozole, or both. Patients randomized to receive abemaciclib or the combination had a significantly greater reduction in Ki67, and significantly more achieved complete cell-cycle arrest at day 15. Dr. Hurvitz reported these findings at the 2016 San Antonio Breast Cancer Symposium.4
Mean reduction in Ki67 level was 92.6% with the combination, 90.6% with abemaciclib alone, and 63.2% with anastrozole (P < .001). Complete cell-cycle arrest was observed in 58.8%, 66.1%, and 14.8%, respectively (P < .001). Radiologic responses were observed in 54.7% of the combination arm.
As one component of the study, researchers examined the tumor microenvironment, specifically looking for T-cell infiltration across the treatment course. With abemaciclib, they observed an increase in tumor differentiation and an increase in total CD3-positive T cells and CD8-positive cytotoxic T cells, without upregulation of immunosuppressive T regulatory cells. The fact that CDK4/6 inhibitors might be stimulating immune infiltration could render them partners for immunotherapies. This concept is now being tested. ■
References
1. Dowsett M, et al: J Natl Cancer Inst Monogr 120-123, 2011.
2. Ma CX, et al: 2015 San Antonio Breast Cancer Symposium. Abstract S6-05. Presented December 11, 2015.
3. Curigliano G, et al: Breast 28:191-198, 2016.
