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  • American Association for Cancer Research (AACR)  (13)
  • 1
    Online Resource
    Online Resource
    The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 13 ( 2015-07-01), p. 2911-2915
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 13 ( 2015-07-01), p. 2911-2915
    Abstract: The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-1760
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
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    Abstract P3-06-15: Evaluation of HER family protein signaling network as a predictive biomarker for pCR for breast cancer patients treated with neratinib in the I-SPY 2 trial
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-15-P3-06-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-15-P3-06-15
    Abstract: Background: We hypothesize that response to the pan-ERBB inhibitor, neratinib (N), may be predicted by pre-treatment HER2-EGFR signaling. In the I-SPY 2 TRIAL, N graduated in the HR-/HER2+ signature. All patients received at least standard chemotherapy. For HER2+ patients, N was administered in place of trastuzumab. We evaluated 18 HER family signaling proteins as biomarkers of N response using reverse phase protein microarray (RPMA) data from pre-treatment LCM purified tumor epithelium. Methods: 168 patients (N: 106, concurrent controls: 62) had RPMA and pCR data. 18 biomarkers relating to HER family signaling were evaluated: AKT S473, AKT T308, EGFR, EGFR Y1068, EGFR Y1148, EGFR Y1173, EGFR Y992, ERBB2, ERBB2 Y1248, ERBB3 total, ERBB3 Y1289, ERK1/2 T202/Y204, Heregulin, mTOR, mTOR S2448, PI3K p85 Y458/p55 Y199, PTEN S380, and SHC Y317. We assessed association between biomarker and response in the N and control arms alone (likelihood ratio test), and relative performance between arms (biomarker x treatment interaction) using a logistic model. Analysis was also performed adjusting for HR/HER2 status. In an exploratory analysis, we selected the marker with the greatest interaction (phosphorylated EGFR (Y1173)) to dichotomize patients optimally based on the data and assessed it in the context of the graduating signature by adding the EGFR Y1173-High patients to the HR-/HER2+ subtype and evaluating the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data and does not account for multiplicities. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Results: 7 HER pathway markers (EGFR Y1068, EGFR Y1173, EGFR Y992, ERBB2 total, ERBB2 Y1248, ERBB3 Y1289, SHC Y317) are associated with response in the N but not the control arm. However, the difference in performance between arms did not reach significance by permutation testing. Adjusting for HR/HER2 status, EGFR Y1173 shows a significant biomarker x treatment interaction (p = 0.049). In an exploratory analysis, we dichotomized patients by their EGFR Y1173 levels and evaluated the distribution of pCR rates (Table 1). Neratinib (n=106)Control (n=62)EGFR Y1173 Low (n=31)EGFR Y1173 High (n=75)EGFR Y1173 Low (n=29)EGFR Y1173 High (n=33)HR-/HER2+ (n=28)0 / 412 / 181 / 11 / 5Not HR-/HER2+ (n=140)3 / 2724 / 575 / 285 / 28Table 1 OR between EGFR Y1173 groups in the N relative to control arm is 10.1. When EGFR Y1173 High patients are added to the graduating HR-/HER2+ subset, the OR associated with treatment is 3.2 and is comparable to that in the HR-/HER2+ signature (OR: 2.1), while increasing the prevalence of biomarker-positive patients by ∼50%. Evaluation of EGFR Y1173 under the I-SPY 2 Bayesian model is pending. Conclusion: Our sample size is too small to draw definitive conclusions. Our exploratory analysis reveals that HER family phosphoproteins associate with response to N, but only phosphorylated EGFR Y1173 appears to add value to the graduating signature. Given that this biomarker would expand the patient population that may benefit, it merits evaluation in other ongoing trials of neratinib. Citation Format: Julia D Wulfkuhle, Christina Yau, Denise M Wolf, Rosa I Gallagher, Ashish Sanil, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, I-SPY 2 TRIAL Investigators, Meredith Buxton, Angela DeMichele, Nola Hylton, William F Symmans, Laura van't Veer, Douglas Yee, Melissa Paoloni, Laura Esserman, Donald Berry, Minetta C Liu, John W Park, Emanuel F Petricoin III. Evaluation of HER family protein signaling network as a predictive biomarker for pCR for breast cancer patients treated with neratinib in the I-SPY 2 trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P3-06-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Abstract 859: Gene and pathway differences between MammaPrint High1/High2 risk classes: results from the I-SPY 2 TRIAL in breast cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 859-859
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 859-859
    Abstract: BACKGROUND: Further stratification of the 70-gene MammaPrint(TM) prognostic signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), using a threshold predefined by the median cut-point of I-SPY 1 participants who fit the eligibility criteria for I-SPY 2. MP1/2 classification was added to HR and HER2 to define the subtypes used in the I-SPY 2 adaptive randomization engine. The first two experimental agents/combinations to graduate from I-SPY 2 were veliparib/carboplatin (V/C) in the TN subset, and neratinib (N) in the HR-HER2+ subset. MP2 was found to be a sensitivity marker for V/C but not N, whereas MP1 class appears associated with resistance to N within the HER2- subset. Despite these associations with response, it remains unclear whether MP1/MP2 classification represents differences in tumor biology. Here, we present exploratory analysis to elucidate the pathway differences between the MP classes. METHODS: 263 patients (V/C: 71, N: 115, and controls: 77) with pre-treatment Agilent 44K microarrays and MP1/2 class assessments were considered in this analysis. To identify signature genes associated with MP1 vs. MP2 class, we (1) apply a Wilcoxon rank sum test and (2) fit a logistic model. P-values are corrected for multiple comparisons using the Benjamini-Hochberg (BH) method, with a significance threshold of BH p & lt;0.05 from both tests. We then perform pathway enrichment analysis using DAVID. In addition, we perform multivariate analysis adjusting for receptor subtype. Our study is exploratory and does not adjust for multiplicities of other biomarkers in the trial but outside this study. RESULTS: 63% (165/263) of patients are MP1 class and 37% (98/263) MP2. MP1/2 class is associated with receptor subtype (Fisher's exact test: p & lt;2E-16), where 71% of TN patients are MP2 and 96% of HR+HER2+ patients are MP1. Of the 70 signature genes, 86% (60/70) differ in expression between MP1 and MP2, with 70% (42/60) expressed at a higher level in MP2, including CDCA7, MELK and CENPA. In a whole transcriptome analysis, 10,500 genes (of ∼30,000) appear differentially expressed. Following adjustment for HR and HER2 status, 4368 genes are significantly differentially expressed between MP1 and MP2. By DAVID enrichment analysis, the biggest pathway-level differences are found in cell cycle, proliferation, and DNA repair, with the MP2 set showing higher expression. CONCLUSION: MP2 class appears associated with higher expression of cell cycle & DNA repair genes. Association between MP2 class and response to V/C suggests that higher cell cycle activity may contribute to V/C sensitivity. Citation Format: Denise M. Wolf, Christina Yau, Lamorna Brown-Swigart, Gillian Hirst, Meredith Buxton, Melissa Paoloni, I-SPY 2 TRIAL Investigators, Olufunmilayo Olopade, Angela De Michele, Fraser Symmans, Hope Rugo, Don Berry, Laura Esserman, Laura van ‘t Veer. Gene and pathway differences between MammaPrint High1/High2 risk classes: results from the I-SPY 2 TRIAL in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 859.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-859
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Abstract P3-06-25: MammaPrint High1/High2 risk class as a biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-25-P3-06-25
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-25-P3-06-25
    Abstract: Background: Further stratification of the 70-gene MammaPrintTM signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score & lt;-0.154. MP1/MP2 classification was added to HR and Her2 to define the cancer subtypes used in the I-SPY 2 adaptive randomization engine. HER2- patients were randomized to receive standard chemotherapy or the oral PARP inhibitor veliparib in combination with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) signature, where MP2 was not an eligible signature for graduation. Here, we assess the performance of MP1/MP2 class as a specific biomarker of response to V/C. Methods:115 HER2- patients (V/C: 71 and concurrent controls: 44) were considered in this analysis. We assess association between MP1/MP2 and response in the V/C and control arms alone using Fisher’s exact test, and relative performance between arms (biomarker x treatment interaction, likelihood ratio p & lt; 0.05) using a logistic model. This analysis is also performed adjusting for HR status as a covariate. To assess MP1/MP2 in the context of the graduating signature, we added the MP2 patients to the graduating TN subset and evaluated the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). This analysis does not adjust for multiplicities of other biomarkers in the trial but outside this study. Results: In the V/C arm vs. concurrent controls, there were 66 MP1 (V/C: 32, Control: 34) and 49 MP2 patients (V/C: 39, Control: 10), 78% of which are TN. The distribution of pCR rates among MP1/MP2 dichotomized groups are summarized in Table 1. V/C (n=71)Control (n=44)MP1 (n=32)MP2 (n=39)MP1 (n=34)MP2 (n=10)TN (n=59)3 / 819 / 303 / 132 / 8HR+HER2- (n=56)1 / 244 / 94 / 210 / 2 The OR between MP1/MP2 risk groups for predicting pCR is 9.71 in the V/C arm (p=6.63E-05), in comparison to an OR of 0.97 in the control arm (p=1). There is a significant biomarker x treatment interaction (p=0.023), which remains upon adjusting for HR status (p= 0.028). Based on the I-SPY 2 Bayesian model, a Phase III trial with 300 MP2 patients has a 95% predictive probability of success. When the MP2 patients are added to the graduating TN subset, the OR associated with V/C is 4.36, which is comparable to that of the TN signature (OR: 4.29), while increasing the prevalence of biomarker-positive patients by ∼10%. Conclusion: In our exploratory analysis, MP2 suggests higher sensitivity to V/C combination therapy relative to controls. This observation has prompted an investigation into the biological mechanisms distinguishing the MP1/MP2 subtype that may account for this specificity. Citation Format: Denise M Wolf, Christina Yau, Ashish Sanil, Jo Chien, Anne Wallace, Angela DeMichele, Hank Kaplan, Doug Yee, Claudine Isaacs, Kathy Albain, Rebecca Viscuzi, Judy Boughey, Stacey Moulder, Steven Chui, Qamar Khan, Toncred Styblo, Kirsten Edmiston, Donald Northfelt, Anthony Elias, Barbara Haley, Debu Tripathy, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, Meredith Buxton, Nola Hylton, Melissa Paoloni, Fraser Symmans, Laura Esserman, Don Berry, Hope Rugo, Olufunmilayo I. Olopade, Laura van 't Veer. MammaPrint High1/High2 risk class as a biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-25.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P3-06-25
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Abstract CT062: GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT062-CT062
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT062-CT062
    Abstract: Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that improve the overall survival in patients with newly diagnosed or recurrent GBM. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE has screened over 1300 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with 12 more sites anticipated to open across 3 countries in Europe. Expansion to Australia is in progress. Stratification of the newly diagnosed patients is based on methylation status per the MGMT assay provided by a central CLIA lab. Maintaining reasonable timelines for MGMT read out to support eligibility and screening requires ongoing operational oversight. In order to continue to improve MGMT testing times, the percentage discordance between results from central testing and local lab testing is being evaluated to assess if local lab testing can be utilized for randomization within GBM AGILE. Exploratory analyses are ongoing to expand knowledge of GBM. For example, information from imaging and clinical assessments will be used to build a longitudinal model, which may inform randomization by providing earlier and continuous information regarding how a given experimental arm is performing. Citation Format: Ingo K. Mellinghoff, Brian Alexander, Donald Berry, Nicholas Blondin, Meredith Buxton, Webster Cavenee, Howard Colman, John de Groot, Macarena I. de la Fuente, Benjamin Ellingson, Gary Gordon, Emma M.V. Hyddmark, Mustafa Khasraw, Andrew Lassman, Eudocia Lee, Wenbin Li, Michael Lim, Tom Mikkelsen, Apoorva Nelli, James Perry, Erik Sulman, Kirk Tanner, Michael Weller, Patrick Y. Wen, Timothy Cloughesy. GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT062.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT062
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract CT042: Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT042-CT042
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT042-CT042
    Abstract: Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. T-DM1 and pertuzumab have established benefits in metastatic HER2+ BC. We tested their ability when combined, without paclitaxel, to improve pCR rates (ypT0ypN0) over standard therapy in the randomized, phase 2, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive breast cancer ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to 12 wkly cycles of paclitaxel+trastuzumab (TH, control) or T-DM1+pertuzumab (T-DM1+P) without T, followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. We utilized all TH control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the various experimental arms in the trial was based on current Bayesian probabilities of superiority vs. control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a future 2-arm, N = 300 neoadjuvant Phase 3 randomized 1:1 trial of T-DM1+P vs. control with pCR endpoint. Results: T-DM1+P met the predictive probability criterion and graduated from I-SPY 2 in 3 signatures: all HER2+, HER2+/HR+, HER2+/HR- (Table 1). Final accrual: 52 T-DM1+P and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial mechanism efficiently evaluates agents in biomarker-defined pt subsets. T-DM1+P (w/o T) - & gt; AC substantially improves pCR rates over standard TH - & gt; AC in all 3 HER2+ signatures, including HR+ and HR- subsets. These findings warrant further investigation of these agents without paclitaxel in a neoadjuvant trial powered for survival endpoints. Table 1Signature*Estimated pCR Rate (95% probability interval)Probability T-DM1+P Is Superior to Control**Predictive Probability of Success in Phase 3T-DM1+PControl (TH)HER2+52% (36%-68%)22% (5%-39%)99.5%94%HER2+/HR+46% (26%-66%)17% (0% - 34%)99.1%93%HER2+/HR-64% (39%-88%)33% (6%-59%)98%90%*HR = Hormone Receptor Citation Format: Angela M. DeMichele, Stacy Moulder, Meredith Buxton, Douglas Yee, Anne Wallace, Jo Chien, Claudine Isaacs, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Julie Lang, Henry Kaplan, Susan Minton, Andres Forero, Anthony Elias, Rita Nanda, Larissa Korde, Richard Schwab, Michelle Melisko, Ashish Sanil, Michael Hogarth, Nola Hylton, Melissa Paoloni, Fraser Symmans, Jane Perlmutter, Julia Lyandres, Christina Yau, Don Berry, Laura Esserman, I-SPY 2 TRIAL Investigators. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT042.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-CT042
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Abstract P3-06-05: Evaluation of an in vitro derived signature of olaparib response (PARPi-7) as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-05-P3-06-05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-05-P3-06-05
    Abstract: Background: We developed a 7-gene DNA-repair deficiency signature (PARPi-7) that predicts breast cancer cell line sensitivity to the PARP inhibitor olaparib [PMID: 22875744]. We hypothesized that this signature would also predict response to other PARP inhibitors including veliparib. In the I-SPY 2 TRIAL, HER2- patients were randomized to receive standard chemotherapy or the oral PARP inhibitor veliparib in combination with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) signature. Here we assess the PARPi-7 as a specific biomarker of V/C response. Methods: 115 HER2- patients (V/C: 71 and concurrent controls: 44) were considered in this analysis. The PARPi-7 signature score is computed from Agilent 44K array data as published using expression levels of BRCA1, CHEK2, MAPKAPK2, MRE11A, NBN, TDG, and XPA. We assess association between PARPi-7 and response in the V/C and control arms alone (Wald p & lt; 0.05), and relative performance between arms (biomarker x treatment interaction, likelihood ratio p & lt; 0.05) using a logistic model. In an exploratory analysis, we dichotomized patients by the PARPi-7 score using the published in vitro derived cutpoint (0.037). To assess PARPi-7 in the context of the graduating signature, we added the PARPi-7 High patients to the graduating TN subset and evaluated the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Our analyses do not adjust for multiplicities of other biomarkers in the trial but outside this study. Results: The PARPi-7 signature associates with patient response in the V/C arm (OR = 3.9, p=0.00056) but not in the control arm (OR = 0.87, p=0.68). There is a significant biomarker x treatment interaction (OR in V/C arm relative to control arm = 4.48, p=0.0028), which remains significant upon adjusting for HR status (p=0.0018). In an exploratory analysis, PARPi-7 dichotomized using the published in vitro derived cutpoint yields 62 PARPi-7 Low and 53 PARPi-7 High patients. 26% of PARPi-7 High patients are not TN. The distribution of pCR rates among PARPi-7 dichotomized groups are in Table 1. V/C (n=71)Control (n=44)PARPi-7 Low (n=38)PARPi-7 High (n=33)PARPi-7 Low (n=24)PARPi-7 High (n=20)TN (n=59)5 / 1317 / 251 / 74 / 14HR+HER2- (n=56)2 / 253 / 84 / 170 / 6 When the PARPi-7 High patients are added to the graduating TN subset, the OR associated with V/C is 5.12, which is comparable to that of the TN signature (OR: 4.29), while increasing the prevalence of biomarker-positive patients by ∼12%. Evaluation of PARPi-7 in the context of the graduating signature under the I-SPY 2 Bayesian model is pending. Conclusion: Our sample size is small. Our pre-specified analysis suggests the PARPi-7 signature shows promise for predicting response to veliparib/carboplatin combination therapy relative to control. If verified in a larger trial, this cell-line derived signature may contribute to the selection criteria of PARP inhibitor trials in the future. Citation Format: Denise M Wolf, Christina Yau, Ashish Sanil, Anneleen Daemen, Laura Heiser, Joe Gray, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, I-SPY 2 TRIAL Investigators, Meredith Buxton, Angela DeMichele, Nola Hylton, Fraser Symmans, Doug Yee, Melissa Paoloni, Laura Esserman, Don Berry, Hope Rugo, Olufunmilayo Olopade, Laura van 't Veer. Evaluation of an in vitro derived signature of olaparib response (PARPi-7) as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P3-06-05
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 8
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    Abstract P3-06-29: MammaPrint High1/High2 risk class as a biomarker of response to neratinib plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-29-P3-06-29
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-29-P3-06-29
    Abstract: Background: Further stratification of the 70-gene MammaPrintTM signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score & lt;-0.154. MP1/MP2 classification was added to HR and HER2 to define the cancer subtypes used in the I-SPY 2 adaptive randomization engine. Neratinib (N), one of the experimental agents evaluated in I-SPY 2, graduated in the HR-HER2+ signature. All patients received at least standard chemotherapy (paclitaxel followed by doxorubicin/cyclophosphamide; T- & gt;AC). HER2- patients were randomized to receive N+T- & gt;AC vs. T- & gt;AC. For HER2+ patients, neratinib was administered in place of trastuzumab (N+T- & gt;AC vs. H+T- & gt;AC). Here, we assess the performance of MP1/MP2 class as a specific biomarker of neratinib response. Methods: 115 patients in the neratinib arm and 76 concurrently randomized controls had Agilent 44K microarrays and pCR data available for analysis. We assess association between MP1/MP2 and response in the neratinib and control arms alone using Fisher’s exact test, and relative performance between arms (biomarker x treatment interaction, likelihood ratio p & lt; 0.05) using a logistic model. This analysis is also performed adjusting for HR status as a covariate, and in receptor subsets. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Our analyses do not adjust for multiplicities of other biomarkers in the trial but outside this study. Results: There are 133 MP1 patients (neratinib: 74, Control: 59) and 58 MP2 patients (neratinib: 41, Control: 17), 84% (49) of which are Her2-. The distribution of pCR rates among MP1/MP2 dichotomized groups are summarized in Table 1.  Neratinib (n=115)Control (n=76)MP1 (n=74)MP2 (n=41)MP1 (n=59)MP2 (n=17)HER2- (n=105)0 / 1715 / 337 / 395 / 16HER2+ (n=86)22 / 574 / 85 / 200 / 1 MP2, one of the 10 eligible signatures, did not meet the graduation threshold; and MP1/MP2 did not show a significant biomarker x treatment interaction (OR in neratinib relative to control arm = 1.25). The MP1/MP2 x treatment interaction remains non-significant after adjustment for HR and HER2 status (p=0.54). In HER2- patients receiving neratinib, 45% (15/33) of MP2 patients achieved a pCR, compared to 0% (0/17) of MP1 patients. In the HER2- controls, there is a 31% pCR rate in MP2 (5/16) vs. 18% in MP1 (7/39) patients (OR=2.14). This difference in performance between treatment arms appears significant (p=0.041). 90% of HER2+ patients are MP1, thus MP1/MP2 status x treatment interaction within the HER2+ subtype cannot be evaluated. Conclusion: Within the I-SPY 2 population as a whole, MP1/MP2 stratification does not appear to be a specific biomarker of response to neratinib relative to the control arm. The number of HER2- patients is small and precludes any definitive conclusion, but these data motivate further investigation of the biological mechanisms distinguishing MP1 from MP2 to better understand chemotherapy and/or neratanib responsiveness. Citation Format: Christina Yau, Denise M Wolf, Ashish Sanil, Jo Chien, Anne Wallace, Judy Boughey, Doug Yee, Debu Tripathy, Angela DeMichele, Rita Nanda, Steven Chiu, Claudine Isaacs, Kathy Albain, Hank Kaplan, Stacey Moulder, Rebecca Viscusi, Donald Northfelt, Kirsten Edmiston, Anthony Elias, Toncred Styblo, Barbara Haley, Lamorna Brown-Swigart, Susan Flynn, Gillian L Hirst, Meredith Buxton, Nola Hylton, Melissa Paoloni, W Fraser Symmans, Laura Esserman, Don Berry, Minetta C Liu, John W Park, Laura van 't Veer. MammaPrint High1/High2 risk class as a biomarker of response to neratinib plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-29.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P3-06-29
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 9
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    Developing Safety Criteria for Introducing New Agents into Neoadjuvant Trials
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 11 ( 2013-06-01), p. 2817-2823
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 11 ( 2013-06-01), p. 2817-2823
    Abstract: New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety. Clin Cancer Res; 19(11); 2817–23. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-2620
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 10
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    Abstract CT227: Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. CT227-CT227
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. CT227-CT227
    Abstract: Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T- & gt;AC). HER2- pts were randomized to N+T- & gt;AC vs. T- & gt;AC and HER2+ pts to N+T- & gt;AC vs. trastuzumab+T- & gt;AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 2's standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib's further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. SignatureEstimated pCR Rate (95% probability interval)Probability NeratinibIs Superior to ControlPredictive Probability of Success in Phase IIINeratinibControlALL32% (28-36%)23% (19%-28%)92%44%HR+23% (18%-28%)17% (11%-22%)81%40%HR-43% (37%-49%)31% (24%-38%)89%53%HER2+39% (33%-45%)23% (15%-30%)95%73%HER2-26% (21%-32%)24% (18%-29%)63%20%MP+*45% (38%-53%)29% (20%-39%)91%66%HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 't Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-CT227
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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