PD 0332991, which is being developed by Pfizer Inc., is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4/6, which prevents cellular DNA synthesis by blocking cell cycle progression, Finn said. Previously published preclinical data have suggested that CDK 4/6 inhibition may play a role in the treatment of some breast cancers.
In the first part of this two-part, phase II study, Finn and colleagues randomly assigned 66 postmenopausal women with metastatic estrogen receptor (ER)-positive breast cancer to either the combination of PD 0332991 and letrozole or to letrozole alone. The second part of the study involved 99 patients with ER-positive cancers determined by screening to have certain genomic alterations, specifically cyclin D1 amplification and/or p16 loss, according to Finn.
Results showed that progression-free survival was 26.1 months for those in the combination arm versus 7.5 months for patients treated with letrozole alone. There was also a 45 percent response rate with the combination treatment versus 31 percent with letrozole alone in patients with measurable disease. The clinical benefit rate was 70 percent with the combination treatment and 44 percent with letrozole alone.
The combination of PD 0332991 and letrozole was also well tolerated. The most common adverse events were neutropenia, leukopenia, anemia and fatigue. "Importantly, this was uncomplicated neutropenia," Finn said. "There was no evidence of febrile neutropenia."
Further, after retrospectively analyzing the biomarkers for cyclin D1 amplification or p16 loss, the researchers found that "ER positivity was the only biomarker we really needed to select patients who were most likely to benefit from PD 0332991," he said.
"If these results are verified in a large, phase III study this could establish PD 0332991 as an important new treatment option for advanced ER-positive breast cancer in a frontline setting."
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The mission of the 2012 CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR''s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit www.sabcs.org.
Abstract:
Publication Number: S1-6
Title: 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)
Richard S Finn1, John P Crown2, Istvan Lang3, Katalin Boer4, Igor M Bondarenko5, Surgiy O Kulyk6, Johannes Ettl7, Ravindranath Patel8, Tamas Pinter9, Marcus Schmidt10, Yaroslav Shparyk11, Anuradha R Thummala12, Nataliya L Voytko13, Aurora Breazna14, Sindy T Kim15, Sophia Randolph16 and Dennis J Slamon17. 1University of California, Los Angeles, Los Angeles, CA; 2Irish Cooperative Oncology Research Group, Dublin, Ireland; 3Orszagos Onkologiai Intezet, Budapest, Hungary; 4Onkologia, Szent Margit Korhaz, Budapest, Hungary; 5Dnipropetrovsk City Multiple-Discipline Clinical Hospital, Ukraine; 6Radiology Department, Municipal Treatment-and-Prophylactic Institution "Donetsk City Oncological Dispensary", Ukraine; 7Klinikum rechts der Isar, Technical University of Munich, Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA; 9Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary; 10University Hospital Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV; 13Kyiv City Clinical Oncology Center, Ukraine; 14Pfizer Oncology, New York, NY; 15Pfizer Oncology, San Diego, CA; 16Pfizer Oncology, San Diego, CA and 17University of California, Los Angeles, Los Angeles, CA.
Body: Background: PD 0332991, a selective inhibitor of CDK 4/6, prevents cellular DNA synthesis by blocking cell cycle progression. Preclinical studies in a BC cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 (Finn et al. 2009). Synergistic activity was also observed in vitro when combined with tamoxifen. After determination of the recommended phase 2 dose in combination with letrozole (letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1), a randomized phase 2 study comparing letrozole alone (L) to letrozole plus PD 0332991 (L+P) was initiated.
Methods: The phase 2 portion of the study was designed as a two-part study; Part 1 enrolled post- menopausal women with ER+/HER2- advanced BC; Part 2 in addition to ER+/HER2- as eligibility criteria, screened for CCND1 amplification and/or loss of p16 by FISH. The primary endpoint is progression-free survival (PFS); secondary endpoints include response rate, overall survival, safety, and correlative biomarker studies. In both parts, post-menopausal women with ER+/HER2- advanced BC were randomized 1:1 to receive letrozole either with or without PD 0332991. Pts continue on assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal, and are followed for tumor assessments every 2 months.
Results: 66 pts were randomized in Part 1 and 99 pts in Part 2. Preliminary results from Part 1 of this study have been previously reported (IMPAKT Breast Cancer Conference, Abstract #292, Finn et al. May 2012) demonstrating a significant improvement in median PFS in the L+P vs. L arm (HR=0.35; 95% CI, 0.17 to 0.72; p=0.006). With the additional 99 pts randomized in Part 2 (N=165), the statistically significant improvement in median PFS (26.2 vs. 7.5 months, respectively) continues to be observed with a HR=0.32 (95% CI, 0.19 to 0.56) with p
Conclusions: The combination of PD 0332991 and letrozole is well tolerated and shows encouraging clinical benefit, confirming the sensitivity of ER+ BC to PD 0332991 observed in preclinical models. A phase 3 trial in this setting will commence in 2013.
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