OBR Daily Commentary - Breast

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FDA Approves First PI3K inhibitor for Breast Cancer

(FDA.gov) May 24, 2019 - Today, the U.S. Food and Drug Administration approved Piqray (alpelisib) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen. The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by the therascreen test using the liquid biopsy should undergo tumor biopsy for PIK3CA mutation testing.

Debu Tripathy, MD (Posted: May 30, 2019)

quotesThe PI3 kinase pathway is difficult to target as it is the superhighway to essential functions including cell growth, metabolic activity and even immunity. These pathways converge, diverge and exhibit “short circuits” that can be adapted to bypass pharmacological blockade. Yet there is now doubt that this pathway is dysregulated in cancer with numerous activating mutations as well as a loss of function alterations in the dampening components of this pathway. Many of these adaptive changes are not even occurring at the genomic level and are being uncovered though more sophisticated assays that reveal epigenetic or post-translational mechanisms. This is evident in the recent approval of the first mutation-directed therapy for breast cancer. The study did meet its pre-specified endpoint of improving progression-free survival by over 5 months (HR 0.65). Both the efficacy and reciprocal side effects demonstrate challenges in targeting this pathway. The inability to fully isolate the oncogenic from the normal function signals result in incomplete effects as well as “off target” and “on target” toxicities, which are clearly of greater extent in general compared to CDK 4/6 inhibition. The alpha isoform-selective PI3K inhibitor alpelisib is relevant to hormone receptor-positive and HER2-negative breast cancer, where activating mutations in the alpha catalytic subunit (PIK3CA) are common. Using an selective drugs in patients with demonstrated mechanisms of activation of PI3K pathway is an important step forward, and had been clearly demonstrated in the SOLAR-1 trial. Combinations with other endocrine therapies is underway, and methods to mitigate toxicities, particularly hyperglycemia and gastrointestinal symptoms are being evaluated. This field will clearly grow, as innovations refine the approach and improve the therapeutic index. quotes

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MacroGenics Thrives Following Positive Breast Cancer Results

(BioSpace) May 16, 2019 - The trial evaluated margetuximab in patients with HER2-positive metastastic breast cancer who had already been treated with anti-HER2-targeted therapies.

(Posted: May 17, 2019)

quotesTrastuzumab deruxtecan makes Margetixumab clinically irrelevant quotes

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Trastuzumab Deruxtecan Demonstrated Clinically-Meaningful Response In Patients With Refractory HER2-positive Metastatic Breast Cancer, A Population With High Unmet Need

(AstraZeneca) May 8, 2019 - AstraZeneca and Daiichi Sankyo Company, Limited today announced positive top-line results for the pivotal Phase II DESTINY-Breast01 trial of trastuzumab deruxtecan (DS-8201). The HER2-targeting antibody drug conjugate (ADC) and potential new medicine was evaluated in patients with HER2-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine.

Debu Tripathy, MD (Posted: May 08, 2019)

quotesThe development of testing of new antibody-drug conjugates (ADCs, also known as immunoconjugates) is rapidly growing as these agents allow for more cancer cell-specific drug delivery and the use of more potent cytotoxic drugs than can be given by conventional administration. Every such drug has its own "operating characteristics" depending on the antibody/antigen system used, the nature of the linker attaching the antibody to the active drug and the cytotoxic "payload". In the case of trastuzumab deruxtecan, impressive response rates were shown in pretreated patients with HER2+ breast cancer the Phase I setting. Responses nearing 50% were even shown in a separate cohort of patients who had lower HER2 expression in the negative range by conventional definitions. While the results of the Phase II trial have not yet been made public, there is significant enthusiasm as the Phase III registration trials for both HER2+ and HER2-low get off the ground.quotes

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Tomasz M. Beer, MD, FACP

Professor of Medicine, Division of Hematology/Medical O...

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Dean Gesme, MD

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Debu Tripathy, MD

Professor and Chair, Department of Breast Medical Oncol...

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H. Jack West, MD

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