New Agent Significantly Improves Progression-Free Survival in Patients With Advanced ER+ Breast Cancer

Richard S. Finn, MD

Combining an investigational agent called PD 0332991 with letrozole as first-line therapy extended progression-free survival (PFS) in women with advanced estrogen-receptor positive (ER+) breast cancer in a phase II study presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

The combination achieved median PFS of 26.1 months compared with 7.5 months for letrozole alone (P=.006).

PD 0332991 is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4/6 that prevents cellular DNA synthesis by blocking tumor cell progression.

“The dramatic improvement in progression-free survival with the combination is very encouraging and clinically meaningful,” said Richard S. Finn, MD, associate professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA) and lead author of the study. “These data represent a potential major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.”

Finn said this study validates preclinical studies showing that the new compound has significant activity in breast cancer models and acts synergistically with hormonal therapy.

The phase II study had two parts. In both parts, postmenopausal women with ER+/HER2- advanced breast cancer were randomized 1:1 to receive letrozole plus PD 0332991 or letrozole alone. Part 1 enrolled 66 patients, while part 2 enrolled 99 patients using the same eligibility criteria but also screened tumors of CCND1 amplification and/or loss of p16 by FISH analysis. For both parts of the trial, the primary endpoint was PFS. Secondary endpoints included response rate, overall survival, safety, and correlative biomarker studies.

At the conference, pooled results from both part 1 and 2 of the trial were presented, based on a total of 165 patients. In this pooled analysis, median PFS was 26.1 months (95% confidence interval [CI], 12.7 — 26.1) with the combination versus 7.5 months (95% CI, 5.6 – 12.6) with letrozole alone, representing a 63% improvement in risk of progression (hazard ratio [HR]=0.37; 95% CI, 0.21 – 0.63, P < .001).

In patients with measurable disease, response rates were 45% for the combination versus 31% for letrozole alone. Clinical benefit rate (complete and partial response rates plus stable disease) was 70% versus 44%, respectively.

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Dr Richard Finn on PD 0332991 Plus Letrozole in Breast Cancer

The most commonly observed treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue.

“Importantly this was uncomplicated neutropenia,” Finn said. “There was no evidence of febrile neutropenia.”

A phase III trial of the investigational agent in this patient population will be mounted in 2013.

“The oncology community is looking forward to the further evaluation of PD 0332991 in the planned phase 3 trial and very interested in the potential for this novel CDK4/6 inhibitor to improve the treatment landscape for patients with advanced breast cancer,” Finn said.

Finn RS, Crown JP, Lang I, 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: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4 — 8, 2012; San Antonio, Texas. Abstract S1-6.

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