CDK4/6 Inhibitors Changing Practice in Advanced Breast Cancer

Sibylle Loibl, MD, PhD

Inhibition of CDK4/6 results in improvements in progression-free survival (PFS) in women with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer whether it is endocrine sensitive or resistant, according to an overview presented at the 25th St. Gallen Breast Cancer Conference.

Cancer progression is earmarked by loss of control over the cell cycle. One of the critical elements of cell cycle control is the estrogen-dependent cyclin D1-CDK 4/6-retinoblastoma (Rb) pathway, which controls the checkpoint for entry into the S-Phase, according to Sibylle Loibl, MD, PhD, co-chair of the German Breast Group and associate professor at the University of Frankfurt in Frankfurt, Germany.

“CDK4/6 inhibition is the most well-advanced cell cycle targeting strategy to date,” commented Loibl. “I called my talk ‘targetable pathways on the horizon’, but some CDK 4/6 inhibitors are already at the horizon, since palbociclib and ribociclib have already been approved,” she said. A third selective CDK4/6 inhibitor, abemaciclib (LY2835219) is in clinical development.

Palbociclib (Ibrance) was the first CDK4/6 inhibitor to be tested in early stage breast cancer. It had been reported to inhibit proliferation in luminal ER-positive and HER-negative amplified human breast cancer cell lines in vitro, but is effective only where functional retinoblastoma protein (Rb) is present; sensitive cells express high levels of Rb and cyclin D1, and low levels of CDKN2A¹.

Clinical data from the phase II, randomized PALOMA 1/TRIO 18 trial of palbociclib plus letrozole showed that the addition of palbociclib improved progression-free survival (PFS) over letrozole in postmenopausal women with ER-positive, HER2- negative advanced breast cancer. Median PFS with palbociclib/letrozole was 26.1 versus 5.7 months with letrozole (P <.0001) in cohort 1 of women with ER-positive, HER2-negative breast cancer and 18.1 versus 11.1 months (P = .0046) in the respective treatment arms in cohort 2, which included women with ER-positive HER2-negative disease who also had amplification of CCND1, loss of p16, or both.²

Findings from the PALOMA 3 trial supported the FDA accelerated approval of palbociclib for the treatment of ER-positive HER2-negative metastatic breast cancer. PALOMA 3 demonstrated median PFS of 9.5 months with palbociclib/fulvestrant versus 4.6 months with placebo/fulvestrant (P = .0001).

“The beauty of PALOMA 3 is that it also included premenopausal women,” said Loibl. In this cohort, median PFS with palbociclib/fulvestrant was 9.5 versus 5.6 months (P = 0.013) compared to 9.9 months versus 3.9 months (P <.0001) with the respective treatments in the postmenopausal cohort.³

When the PALOMA 3 data were reevaluated according to PIK3CA mutation status, the analysis showed the PFS benefit with palbociclib was retained regardless of PIK3CA mutation status.

Ribociclib was granted FDA approval earlier this week based upon findings from the phase III MONALEESA 2 trial which demonstrated a 44% implement in PFS with ribociclib/letrozole over placebo/letrozole (P = .00001) in postmenopausal women with previously untreated ER-positive HER2-negative metastatic breast cancer. Adjuvant ribociclib (Kisqali) also demonstrated a mean decrease in Ki-67 protein from baseline of 96% versus 69% with letrozole.

Abemaciclib is the third CDK4/Cyclin D1 inhibitor in the pipeline that has the distinction of being less potent that palbociclib or ribociclib, which may have the important clinical implication of reduced toxicity. Thus far, phase I trial data has demonstrated that neutropenia is not a dose limiting toxicity, allowing for continuous dosing.⁴ Heavily pretreated patients with ER-positive HER2-negative metastatic breast cancer were treated with abemaciclib as monotherapy and showed a 19.7% overall response rate consisting of all partial response and stable disease lasting more than 6 months in 42.2% of patients. Median PFS was 6.0 months. The median time to response was 3.7 months, median overall survival was 17.7 months, and the median duration of response was 8.6 months.⁵

Abemaciclib is being further studied in combination with anastrozole in the neoMONARCH trial, wherein an expression change in Ki-67 levels of over 80% from baseline by week 2 at two dose levels compared to a 21% decrease with anastrozole monotherapy. The neoMONARCH study met the boundary for statistical significance (P <.01) at the interim analysis.⁶

Loibl outlined further studies of CDK 4/6 pathway inhibitors such as the NeoPalAna, which is evaluating the ability of palbociclib to achieve complete cell cycle arrest (primary endpoint), defined as Ki-67 ≤ 2.7%, and also by luminal A and B subtypes.⁷

The PADMA trial is investigating palbociclib plus endocrine therapy compared to physician’s choice of chemotherapy with and without endocrine therapy. The primary endpoint of PADMA is time to treatment failure and, to date, 160 women with HER+ HER2-negative metastatic breast cancer have been enrolled. The PATINA trial will investigate palbociclib plus endocrine therapy plus physicians choice of trastuzumab with or without pertuzumab compared to trastuzumab plus pertuzumab and endocrine therapy.

The PENELOPE study plans to enroll 1100 patients with HR-positive HER2-negative breast cancer to test palbociclib versus placebo both in combination with neoadjuvant chemotherapy followed by surgery with and without radiotherapy. “No biomarkers have been identified for patient selection have been identified and it is very clear that patient selection strategies will be important in determining the optimal benefit from CDK4/6 inhibition,” Loibl concluded.

References

1. Finn RS, Dreing J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.
2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3.
3. Loibl S, Turner NC, Ro J, et al. Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy-results from Paloma-3. Abstract presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 524.
4. Goetz MP, Beeram M, Beck T, et al. Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. Abstract presented at: 38th Annual San Antonio Breast Cancer Symposium; December 8-12; San Antonio, TX. Abstract P4-13-25.
5. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+?HER2- breast cancer, after chemotherapy for advanced disease. Abstract presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 510.
6. Hurvitz S, Martin M, Abad MF, et al. Biological and clinical effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+, HER2- breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10; San Antonio, TX. Abstract S4-06.
7. Ma CX X, Gao F, Northfelt D, et al. A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). Abstract presented at: 2015 San Antonio Breast Cancer Symposium; Demeber 8-12, 2015; San Antonio, TX. Abstract S6-05.
8. Loibl S. Targeting the CDK4/6 pathway from research to clinic. Presentation presented at: 15th St. Gallen International Breast Cancer Conference; March 15-18, 2017; Vienna, Austria.

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