Wilson, Amy

Abstract Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility (<10% probability of success), maximum sample size accrual (10% <probability of success <85%), or safety as recommended by the independent DSMB. Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-02.

PURPOSEThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.PATIENTS AND METHODSI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.RESULTSMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).CONCLUSIONThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Abstract Background: I-SPY2 is a multicenter, Phase II trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk at least T2N0 breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify regimens that have ≥ 85% Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) and HER2 status, and MammaPrint (MP). Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or as recommended by the independent DSMB. For HER2- subjects the control arm is weekly paclitaxel x12 then doxorubicin & cyclophosphamide (AC) q2-3 weeks x4. For this arm, paclitaxel was omitted and replaced with maximum tolerated dose PARPi talazoparib with synergy dosed irinotecan (25mg/m2). Paclitaxel could be given adjuvantly for these subjects and non-responding subjects could be taken off of experimental therapy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 cycles after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Talazoparib was given at 1mg daily with 25mg/m2 irinotecan q2wks. Analysis was intention to treat. Subjects who switched to non-protocol therapy count as non-pCR. Subjects on experimental therapy at time of arm closure are non-evaluable. Talazoparib/irinotecan (TI) was open only to HER2- tumors and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-/HER2-. Results: TI did not meet criteria for graduation and was stopped at the recommendation of the DSMB based on expectations of limited activity beyond that seen with standard treatment. Maximum sample size had been reached at the time of this recommendation and subjects currently receiving TI were allowed to continue or change to standard therapy. Exploratory “as treated” analysis for response in gBRCA mutation carriers showed 6/10 gBRCA carriers attained a pCR in the TI arm. Except for 1 patient these gBRCA pCR subjects had >90% tumor reduction by MRI after TI and prior to AC (range: 68-96%). In the TI arm pCR rates were also higher in subjects with a PARPi7-High/MP2 gene expression signature (0.344 vs 0.146). Expected differences in toxicity were seen between arms including g3/4 peripheral neuropathy on control therapy which included paclitaxel (2.6% vs none) and g3/4 neutropenia with TI (30.2% vs 8.2%). Notably gBRCA mutation carriers receiving TI had higher rates of g3/4 neutropenia (60% vs 25.9%). Conclusion: The I-SPY2 study finds the probability that investigational regimens will be successful in a Phase III neoadjuvant trial; TI did not reach the efficacy threshold of 85% probability of success in Phase III in any of the 3 signatures. However by adding talazoparib with synergy dosed irinotecan we were able to omit paclitaxel and observe similar estimated pCR rates. This informs current work to evolve the I-SPY2 trial design to reduce toxicity without compromising outcomes and develop successful combinations targeted to biology, including DNA repair deficiency. Citation Format: Richard Schwab, Amy S. Clark, Christina Yau, Nola Hylton, Wen Li, Denise Wolfe, A Jo Chien, Anne M. Wallace, Andres Forero-Torres, Erica Stringer-Reasor, Rita Nanda, Nora Jaskowiak, Judy Boughey, Tufia Haddad, Heather S. Han, Catherine Lee, Kathy Albain, Claudine Isaacs, Anthony D. Elias, Erin D. Ellis, Payal Shah, Julie E. Lang, Janice Lu, Debasish Tripathy, Kathleen Kemmer, Douglas Yee, Barbara Haley, Melanie Majure, Erin Roesch, Christos Vaklavas, Cheryl Ewing, Teresa Helsten, W Fraser Symmans, Jane Perlmutter, Hope S. Rugo, Michelle Melisko, Amy Wilson, Ruby Singhrao, Laura van 't Veer, Angela DeMichele, Smita Asare, Don Berry, Laura J. Esserman. Evaluation of talazoparib in combination with irinotecan in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT136.