Abstract MS1-2: Targeting CDK 4/6 in breast cancer

Abstract

Abstract For decades, cyclin-dependent kianses (CDKs) have been known to be critical regulators of cell cycle progression leading to the Nobel Prize in 2001 for their identification and characterization. Subsequently, alteration in these and associated proteins have been implicated in cancer. In breast cancer, they have been associated with various molecular subtypes, prognosis, and response to therapy. The concept of blocking CDKs has been around for some time but only recently have they seen clinical success. First generation CDK inhibitors did not demonstrate significant clinical activity and had unacceptable toxicity. In addition to having an appropriate compound, as with other molecular targeted agents, identification of a patient population most likely to benefit is critical to successful clinical development. Palbociclib (PD-0332991, Pfizer) is a first-in-class CDK 4/6 specific inhibitor. Pre-clinical studies identified that ER+ breast cancer models were most sensitive to growth inhibition with palbociclib and identified a synergistic interaction in inhibiting proliferation in combination with anti-estrogens (Finn et al 2009). These data served as a hypotheses for the Phase II Paloma-1/ TRIO 18 study of palbociclib +letrozole vs letrozole alone (Finn et al Lancet Oncolog 2015). Results of this study demonstrated a significant improvement in PFS with the combination and served as the basis for the expedited approval of palbociclib +letrozole as first line therapy for advanced post-menopausal ER+ breast cancer. Most common toxicities were neutropenia, leukopenia and fatigue. Subsequently, a consistent benefit was seen in combination with fulvestrant in more advanced settings (Turner et al NEJM 2015) with a similar toxicity profile. Currently there are several other CDK 4/6 inhibitors in development in breast cancer and other malignancies including abemaciclib (LY2835219, EliLilly) and ribociclib (LEE011, Novartis). In the presentation we will review the rationale for CDK 4/6 inhibition in breast cancer as well as clinical efficacy and toxicity data and the ongoing development of this new class of agent in breast cancer. Citation Format: Finn R. Targeting CDK 4/6 in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr MS1-2.