Elias, Anthony

506 Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. [Table: see text]

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. Pertuzumab (P) has established survival benefit in the metastatic setting, and received accelerated approval in the neoadjuvant setting when combined with trastuzumab (H) and docetaxel(D) as part of a complete treatment regimen for early breast cancer. We tested its ability, when combined with standard therapy (paclitaxel, T, and H) to improve pCR (ypT0ypN0) over TH in the adaptively randomized, phase II, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive BC ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to control (TH, qwk x 12) or THP (P, q3wk x 4) followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. To compare THP to TH we utilized all 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 experimental arms was based on current Bayesian probabilities of superiority over control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a 2-arm, N = 300 phase III randomized 1:1 trial of THP vs. TH with pCR endpoint. Results: THP met the predictive probability criterion and graduated in 3 signatures: all HER2+, HER2+/HR+, and HER2+/HR- (See Table 1). Final accrual: 44 THP and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial efficiently evaluates agents in biomarker-defined pt subsets. THP -> AC substantially improves pCR rates over standard TH -> AC in all 3 HER2+ signatures, including HR+ and HR- subsets. APHINITY, a trial of adjuvant pertuzumab with a primary outcome of invasive disease-free survival, is ongoing. Table 1Signature*Estimated pCR Rate (95% probability interval)Signature*THPControl (TH)Probability THP Is Superior to ControlPredictive Probability of Success in Phase IIIHER2+54% (38%-70%)22% (5%-39%)99.8%96%HER2+/HR+44% (24%-63%)17% (0%-34%)99%91%HER2+/HR-74% (53%-95%)33% (6%-59%)99.8%98%*HR = Hormone Receptor Citation Format: Meredith Buxton, Angela M. DeMichele, Stephen Chia, Laura van't Veer, Jo Chien, Anne Wallace, Henry Kaplan, Julie Lang, Douglas Yee, Claudine Isaacs, Stacy Moulder, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Susan Minton, Andres Forero, Rita Nanda, Anthony Elias, Larissa Korde, Rebecca Viscuzi, Hope Rugo, Richard Schwab, Fraser Symmans, Melissa Paoloni, Nola Hylton, Michael Hogarth, Julia Lyandres, Jane Perlmutter, Ashish Sanil, Christina Yau, Laura Esserman, Don Berry, I-SPY 2 TRIAL Investigators. Efficacy of pertuzumab/trastuzumab/paclitaxel over standard trastuzumab/paclitaxel 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 CT106.

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) -> AC substantially improves pCR rates over standard TH -> 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.

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 <-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->AC). HER2- patients were randomized to receive N+T- >AC vs. T->AC. For HER2+ patients, neratinib was administered in place of trastuzumab (N+T->AC vs. H+T->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 < 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.

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 <-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 < 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.

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->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->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

AbstractThe 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.

Purpose Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (nonstandard) regimen including both an anthracycline and a taxane. Patients and Methods Participants in this phase III randomized study had operable breast cancer involving four or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery. Patients were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide followed by HDC with AHPCS or to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide. The primary end point of this study was disease-free survival (DFS). Results Among 536 eligible patients, there was no significant difference between the two arms for DFS or overall survival (OS). Estimated five-year DFS was 80% (95% CI, 76% to 85%) for dose-dense therapy and 75% (95% CI, 69% to 80%) for transplantation. Estimated 5-year OS was 88% (95% CI, 84% to 92%) for dose-dense therapy and 84% (95% CI, 79% to 88%) for transplantation. Conclusion There is no evidence that transplantation was superior to dose-dense dose-escalated therapy. Transplantation was associated with an increase in toxicity and a possibly inferior outcome, although the hazard ratios were not significantly different from 1.