Combining an inhibitor of cyclin dependent kinase 4/6 with letrozole demonstrates significant clinical benefit in estrogen receptor positive breast cancer

The combination of the investigational agent PD 0332991 and letrozole significantly improves median progression-free survival (PFS) in patients with advanced estrogen receptor-positive (ER+) breast cancer, according to phase II results presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS).

PD 0332991 is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4/6, which prevents cellular DNA synthesis by blocking cell cycle progression. Preclinical studies in breast cancer cell lines identified the luminal ER subtype, elevated expression of the cyclin D1 and the Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991. Furthermore, synergistic activity was observed in vitro when combining PD 0332991 with tamoxifen. After determination of the recommended phase II dose in combination with letrozole, a randomized phase II study comparing letrozole alone to letrozole plus PD 0332991 was initiated.

In the first part of this two-part, phase II study, 66 postmenopausal women with metastatic ER+ breast cancer were randomised to receive the combination of PD 0332991 and letrozole or letrozole alone. The second part of the study involved 99 patients with ER+ cancers determined by screening to have certain genomic alterations, specifically cyclin D1 amplification and/or p16 loss. The primary endpoint of the study was PFS, while secondary objectives included response rate, overall survival and safety.

Preliminary results from the first part of this study have been reported earlier this year at the 2012 IMPAKT meeting and demonstrated a significant improvement in median PFS in the combination arm vs. the letrozole alone arm (HR[95%CI]: 0.35[0.17-0.72]; p= 0.006). With the additional 99 patients randomised in part 2 (N=165), the statistically significant improvement in median PFS continued to be observed with a median PFS of 26.1 months for those in the combination arm vs. 7.5 months for patients treated with letrozole alone (HR[95%CI]= 0.37[0.21-0.63]; p<0.001). In addition to that a 45% objective response rate was reported with the combination treatment compared with 31% for patients treated with letrozole alone in patients with measurable disease. Furthermore, the clinical benefit rate was shown to be 70% vs. 44% with letrozole alone. The combination of PD 0332991 and letrozole was well tolerated with neutropenia, leukopenia, anemia and fatigue being the most common adverse events. Importantly, the observed neutropenia was uncomplicated and there was no evidence of febrile neutropenia.

After retrospectively analysing the biomarkers for cyclin D1 amplification or p16 loss, the researchers found that ER positivity was the only biomarker that was needed to select patients who were most likely to benefit from PD 0332991.

In summary, the combination of PD 0332991 and letrozole is well tolerated and shows encouraging clinical benefit, confirming the sensitivity of ER+ breast cancer to PD 0332991 observed in preclinical models. If these results are verified in a large, phase III study (commencing in 2013) this could establish PD 0332991 as an important new treatment option for advanced ER+ breast cancer.

Reference

R. Finn, J. Crown, I. Lang et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Presented at SABCS 2012; Abstract S1-6.