Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206: Graduation results from the I-SPY 2 Trial.

Tripathy, Debu; Chien, Amy Jo; Hylton, Nola M.; Buxton, Meredith; Ewing, CA; Wallace, Anne M.; Forero, Andres; Kaplan, Henry G.; Nanda, Rita; Albain, Kathy S.; Moulder, Stacy L.; Haley, Barbara; DeMichele, Angela; Symmans, W. Fraser; Veer, Laura van ‘t; Paoloni, Melissa; Esserman, Laura J.; Berry, Donald A.; Yee, Douglas

doi:10.1200/jco.2015.33.15_suppl.524

Cited by 29 publications

(14 citation statements)

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“…© 2019 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from REVIEW 9 months versus 4.9 months in the placebo plus paclitaxel group, suggesting that the pathway may drive oncogenesis in a subset of patients with TNBC and providing the rationale for the ongoing randomized phase III IPATunity130 trial assessing the combination in preselected patients with activation of the PI3K pathway (NCT03337724). In addition, results from I-SPY 2, an adaptive-design trial testing novel agents in the neoadjuvant setting, showed an improvement in pCR with the addition of an allosteric AKT inhibitor, MK-2206, to standard chemotherapy in TNBC (40.2% vs. 22.4% in the control group), with a predicted 75.9% probability of success in a phase III trial (45).…”

Section: ) Genomic Alteration (Frequency %)mentioning

confidence: 99%

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

2019

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Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specifi c molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profi ling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratifi cation of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.Signifi cance: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identifi cation of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population. TNBC AND INTRINSIC BREAST CANCER SUBTYPESEarly transcriptomic profi ling of breast cancer using microarrays classifi ed tumors into fi ve intrinsic subtypes: luminal-A, luminal-B, HER2-enriched, basal-like, and a normal breast-like group ( 5,6 ). Although all intrinsic subtypes can be found within immunohistochemically defi ned triplenegative disease, basal-like tumors exhibit the greatest overlap with TNBC. Between 50% and 75% of TNBC have basal phenotype, and approximately 80% of basal-like tumors are ER-negative/HER2-negative ( Fig. 2 ; refs. 7, 8 ). Characterization Research.on August 1, 2020.

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Section: ) Genomic Alteration (Frequency %)mentioning

confidence: 99%

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

2019

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“…The addition of the MK-2206 restored sensitivity to these AIs [Vilquin et al, 2013]. The ISPY-2 neoadjuvant study (NCT 01042379), assesses the combination of paclitaxel, trastuzumab, and MK-2206, and reported a signifiantly higher estimated pathologically complete RR compared to paclitaxel and trastuzumab alone, in patients with early-stage HER2-overexpressing BC [Tripathy et al, 2015]. Oral MK-2206 (135 mg/week) in combination with paclitaxel (80 mg/m 2 weekly) and trastuzumab (2 mg/kg) is well tolerated in HER2-upregulating trastuzumab-refractory BC and appears to have promising antitumor activity in these patients [Chien et al, 2016].…”

Section: Akt Inhibitors In Bcmentioning

confidence: 99%

The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress

Bahrami

Khazaei

Hassanian

et al. 2017

J of Cellular Biochemistry

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Breast cancer (BC) is the most commonly diagnosed cancer in women. The PI3K/AKT/mTOR pathway is among the most frequently dysregulated pathways in patients with BC. The activation of this pathway is associated with increased cell growth and clinical outcome, and its overexpression is associated with a poor prognosis. It has been proposed that it may be of importance as a potential therapeutic target in the treatment of BC. The aim of current review is to provide an overview of the potential utility of PI3K/Akt/mTOR inhibitors in patients with BC, with particular emphasis on recent preclinical and clinical studies.

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“…I-SPY 2 investigators have also described results of the graduated veliparib/carboplatin arm and MK-2206. 3,4 Evaluations of other experimental arms have been completed or are ongoing in I-SPY 2.…”

Section: Introductionmentioning

confidence: 99%

Adaptive Randomization of Neratinib in Early Breast Cancer

Liu²,

et al. 2016

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Background I-SPY2, a standing, multicenter, adaptive phase 2 neoadjuvant trial ongoing in high-risk clinical stage II/III breast cancer, is designed to evaluate multiple, novel experimental agents added to standard chemotherapy for their ability to improve the rate of pathologic complete response (pCR). Experimental therapies are compared against a common control arm. We report efficacy for the tyrosine kinase inhibitor neratinib. Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR), and MammaPrint. Neratinib was evaluated for 10 signatures (prospectively defined subtype combinations), with primary endpoint pCR. MR volume changes inform likelihood of pCR for each patient prior to surgery. Adaptive assignment to experimental arms within disease subtype was based on current Bayesian probabilities of superiority over control. Accrual to experimental arm stop at any time for futility or graduation within a particular signature based on Bayesian predictive probability of success in a confirmatory trial. The maximum sample size in any experimental arm is 120 patients, Results With 115 patients and 78 concurrently randomized controls, neratinib graduated in the HER2+/HR− signature, with mean pCR rate 56% (95% PI: 37 to 73%) vs 33% for controls (11 to 54%). Final predictive probability of success, updated when all pathology data were available, was 79%. Conclusion Adaptive, multi-armed trials can efficiently identify responding tumor subtypes. Neratinib added to standard therapy is highly likely to improve pCR rates in HER2+/HR2212; breast cancer. Confirmation in I-SPY 3, a phase 3 neoadjuvant registration trial, is planned.

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Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206: Graduation results from the I-SPY 2 Trial.

Cited by 29 publications

References 0 publications

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress

Adaptive Randomization of Neratinib in Early Breast Cancer

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