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New Combination Therapy That Increases Progression-Free Survival In Hormone-Receptor-Positive Breast Cancer Patients

Researchers from the Revlon/UCLA Women’s at UCLA’s () reported an encouraging increase in progression-free survival (PFS, the length of time a patients is on treatment without tumor growth) for patients with that was estrogen receptor positive (ER+), HER2-negative who were given a combination of the standard anti-estrogen treatment, letrozole, and a new experimental drug called PD 0332991. The drug, initially developed by for potential use in blood malignancies, was tested in the laboratory in models by the JCCC investigators. This new clinical study using PD 0332991 and conducted in collaboration with Pfizer, compared the combination to letrozole alone in ER+ patients.

Reported at the annual meeting of the American Association for Cancer Research/ San Antonio Breast Cancer Symposium in San Antonio, TX on Dec. 5, 2012, the two-part Phase II clinical trial was led by Dr. Richard S. Finn, Associate Professor of Medicine at UCLA and JCCC member. The study originated from the Translational Oncology Research Laboratory (TORL) directed by Dr. Dennis Slamon, Professor of Medicine at JCCC and director of the Revlon/UCLA Women’s Cancer Research Program.

In part 1of the study 66 patients were enrolled. Preliminary results showed significant improvement in median PFS of the patients who were given the new drug combination. Ninety-nine more patients were enrolled in part 2 of the study, which allowed only for patients whose tumors revealed selected biomarkers: CCND1 amplification and p16 loss. Retrospective analysis from part I suggested clinical benefit from PD-332991 regardless of status of the biomarkers. All other demographic features for the patients in the study were similar, so for final trial analysis the results of the two parts of the study were combined for the San Antonio Breast Cancer Symposium presentation.

With the results from the two parts added together, data analysis showed that the median PFS of patients on the combination arm was 26.1 months compared to 7.5 months among those given letrozole alone. Of patients with measurable disease, 45% of the women given the combination had confirmed responses, compared to 31% with letrozole alone, and the clinical benefit rates (tumor shrinkage and/or stable disease for a minimum of 6 months) were 70% and 44%, respectively.

“This drug combination demonstrated a dramatic and clinically meaningful effect on PFS in women with ER positive breast cancer,” Finn said, “These results confirm the preclinical work we began at TORL.”

Finn and colleagues published their initial preclinical data in 2009, which showed that PD 0332991 blocked important proteins in cancer cells called cyclin D kinases 4 and 6 (CDK 4/6), thus blocked the growth of ER+ and HER2-amplified cancer cells in the laboratory.

With the goal of identifying important targets of cancer therapy in the laboratory and promptly developing them into patient treatments using the translational paradigm, the investigators then conducted a Phase I clinical trial, again in collaboration with Pfizer, in which the safety of the drug was tested. Those results confirmed the safety of PD 0332991, which had manageable side effects and is taken as a pill, and prompted the Phase II trial that compared the combination of PD 0332991 and letrozole to the standard treatment for these patients of letrozole alone. Critical to the clinical studies was the synergistic interactions observed in the laboratory between PD 0332991 and standard breast cancer drugs tamoxifen and trastuzumab, which are used in ER+ and HER2+ , respectively.

“The results of this Phase II study validate the TORL approach,” said Slamon, who is the senior author on the study. He further stated that “by identifying these targets for treatment, we move forward with personalized oncology that greatly improves the chances for this group of patients. These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2+ breast cancers but represent a new approach for a different and larger subset of breast cancers, i.e. those that are ER+”

The core laboratory research for this project was supported primarily through the Revlon/UCLA Women’s Cancer Research Program and longtime philanthropic support from Ronald O. Perelman. Additional resources were provided by a grant from the Department of Defense Innovator Award W81XWH-05-1-0395 and the Noreen Frazier Foundation. The clinical trial itself was supported entirely by Pfizer, Inc.


Source: UCLA’s Jonsson Comprehensive Cancer Center