Use of biomarkers and imaging to evaluate the treatment effect of AUY922, an HSP90 inhibitor, in patients with HER2+ or ER+ metastatic breast cancer.

Schröder, Carolien P.; Pedersen, Jan; Chua, Sue; Swanton, Charles; Akimov, Mikhail; Ide, Shotaro; Fernandez-Ibarra, Cristina; Dzik-Jurasz, Andy; Vries, Ege de; Gaykema, Sietske B.M.; Banerji, Udai

doi:10.1200/jco.2011.29.15_suppl.e11024

Cited by 21 publications

(9 citation statements)

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“…Multiple phase II studies in molecularly prespecified cohorts such as HER2-amplified breast cancer and EGFR-mutated NSCLC were prospectively planned, and are ongoing, to specifically address the proof of concept that HSP90 inhibitors are effective in these subsets of patients. These trials have documented single-agent activity of AUY922 in HER-2 amplified breast cancer and EGFR-mutant and ALK-rearranged NSCLC (38,39). In conclusion, given the safety, pharmacologic, and pharmacodynamic profile, 70 mg/m 2 was recommended as the dose to be taken forward in phase Ib and phase II studies.…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

Sessa

Shapiro

Bhalla

et al. 2013

Clinical Cancer Research

137

142

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Purpose: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles.Patients and Methods: Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed doselimiting toxicities (DLT) in the first treatment cycle was used to guide dose-escalation decisions, with the established MTD to be used in phase II studies.Results: One hundred and one patients were enrolled and explored at doses in the range of 2 to 70 mg/m

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Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

Sessa

Shapiro

Bhalla

et al. 2013

Clinical Cancer Research

137

142

View full text Add to dashboard Cite

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“…Patients with HER2+ and ER+ disease underwent FDG-PET with trastuzumab and bevacizumab respectively at baseline and during treatment. Two HER2+ patients had partial metabolic response and 1 of these patients had confirmed PR by RECIST [105]. …”

Section: Clinical Studies With Hsp90 Inhibitors In Cancersmentioning

confidence: 99%

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Jhaveri

Taldone

Modi

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

401

426

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Hsp90 is an ATP dependent molecular chaperone protein which integrates multiple oncogenic pathways. As such, Hsp90 inhibition is a promising anti-cancer strategy. Several inhibitors that act on Hsp90 by binding to its N-terminal ATP pocket have entered clinical evaluation. Robust pre-clinical data suggested anti-tumor activity in multiple cancer types. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma. In breast cancer, proof-of-concept was demonstrated by first generation Hsp90 inhibitors in combination with trastuzumab mainly in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer. There are a multitude of second generation Hsp90 inhibitors currently under investigation. To date, however, there is no FDA approved Hsp90 inhibitor nor standardized assay to ascertain Hsp90 inhibition. This review summarizes the current status of both first and second generation Hsp90 inhibitors based on their chemical classification and stage of clinical development. It also discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors. Ultimately, these efforts will aid in maximizing the full potential of this class of agents.

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“…Although there were no objective responses, 16 patients developed SD and 9 also had a partial metabolic response on flurodeoxyglucose positron emission tomography (FDG-PET) scans [38]. A Phase II expansion trial in HER2-positive and estrogen receptor-positive breast cancer also reported two partial metabolic responses on FDG-PET and one of these was also a confirmed PR by RECIST [39]. A Phase II trial of monotherapy NVP-AUY922, conducted in patients with NSCLC progressing on two or more chemotherapy regimens (including patients with EGFR mutations who had progressed on EGFR TKI therapy), reported responses in patients with EGFR mutations (20% RR) and those with ALK rearrangements (32% RR) [40].…”

Section: Hsp90 Clinical Agents: Second Generationmentioning

confidence: 99%

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

Jhaveri

Ochiana

Dunphy

et al. 2014

Expert Opinion on Investigational Drugs

156

173

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Introduction Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

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Use of biomarkers and imaging to evaluate the treatment effect of AUY922, an HSP90 inhibitor, in patients with HER2+ or ER+ metastatic breast cancer.

Cited by 21 publications

References 0 publications

First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

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