Kemmer, KA

Abstract Background: In women with breast cancer receiving neoadjuvant chemotherapy, residual cancer burden (RCB) predicts distant recurrence and survival. In those with high risk tumors, locoregional recurrence (LRR) remains a concern, and has been associated with type of local therapy received. We evaluated the impact of local therapy on LRR in the ISPY-2 TRIAL. Methods: Data were analyzed in Stata 14.2, using Chi2 test, log rank test, and a Cox proportional hazards model. RCB was considered a categorical variable (0/1 versus 2/3), as described in prior publications. Breast surgery categories were lumpectomy +/- radiotherapy, or mastectomy +/- radiotherapy. Axillary surgery was defined as sentinel lymph node (SLN) surgery (≤6 nodes removed) or axillary dissection (>6 nodes). Results: Follow up data from the I-SPY2 TRIAL were available for 630 patients (median follow up 2.76 yrs, range 0.4-7.2). Type of local therapy was significantly associated with clinical stage at presentation, with stage III patients most frequently undergoing mastectomy + radiation (p<0.001). Women with higher RCB were more likely to undergo mastectomy than those with lower RCB (61.3% vs 48.8% mastectomy rate, p=0.002), and more likely to receive adjuvant radiotherapy (62.0% vs 53.9%, p=0.048). There was no association between clinical stage, type of surgery, or radiotherapy and LRR (Table). Higher RCB was significantly associated with LRR, with 3 year locoregional recurrence free rate of 95.1% in RCB 0/1 versus 89.9% in RCB 2/3 (p=0.003). In a Cox model adjusting for clinical stage, tumor subtype, surgical therapy, RCB status, nodal radiation, and age, significant predictors for LRR were tumor subtype and RCB status. Hazard ratio (HR) for LRR in those with RCB 0/1 was 0.39 compared to those with RCB 2/3 (95% CI 0.17-0.87, p=0.021). There was no difference in LRR between breast conservation and mastectomy; within the breast conservation group, those who had lumpectomy alone had higher hazard of LRR compared to those having lumpectomy + radiation (HR 3.1, 95% CI 1.1-9.2, p=0.043). Conclusions: Extent of surgical therapy was not associated with local tumor control, regardless of advanced tumor stage at presentation. Rather, tumor biology and response to therapy were the best predictors of LRR. These data highlight the opportunity to minimize the morbidity of extensive surgical therapy for patients with excellent response to systemic therapy. LRR rates by clinical features and treatment status FrequencyLRR RateP valueClinical Stage 0.5I240 (47.5%)5.8% II185 (36.6%)8.7% III80 (15.8%)6.3% Tumor Subtype 0.014ER+PR+Her2-161 (26.4%)3.1% ER+PR-Her2-56 (9.2%)3.6% Her2+176 (28.9%)6.3% Triple negative216 (35.5%)11.1% Local therapy 0.169Lumpectomy85 (13.5%)11.8% Lumpectomy with radiation198 (31.4%)5.6% Mastectomy173 (27.5%)5.2% Mastectomy with radiation174 (27.6%)8.6% Axillary surgery 0.23None5 (0.8%)20% SLN329 (52.2%)5.8% ALND296 (47%)8.5% Axillary radiation 0.535Yes42 (6.7%)9.5% No588 (93.3%)7.0% Axillary management 0.2No surgery or radiation5 (0.8%)20.0% SLN312 (50%)5.3% SLN+Axillary radiation17 (2.7%)8.3% ALND271 (43%)10.3% ALND+Axillary radiation25 (4%)5.4% RCB 0.0020/1293 (50.1%)3.8% 2/3292 (49.9%)10.3% Citation Format: Silverstein J, Suleiman L, Yau C, Price ER, Singhrao R, Yee D, DeMichele A, Isaacs C, Albain KS, Chien AJ, Forero-Torres A, Wallace AM, Pusztai L, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Leyland-Jones B, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, I-SPY 2 TRIAL Consortium, Berry DA, Asare SM, Esserman LJ, Boughey JC, Mukhtar RA. The impact of local therapy on locoregional recurrence in women with high risk breast cancer in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-01.

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent(I) +paclitaxel(T) qwk, doxorubicin & cyclophosphamide(AC) q2-3 wk x 4 vs. T/AC (control arm). The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Regimens may also leave the trial for futility (< 10% probability of success) or following accrual of maximum sample size (10%< probability of success <85%). We report the results for experimental arm Ganitumab, a type I insulin-like growth factor receptor (IGF1R) inhibitor. IGF1R inhibitors are known to induce insulin resistance and all patients assigned to Ganitumab received metformin. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ and HER2+ tumors were ineligible for randomization. Hemoglobin A1C≥ 8.0% were ineligible. MRI scans (baseline, 3 cycles after start of therapy, at completion of weekly T and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganitumab was given at 12mg/kg q2 weeks and metformin at 850mg PO BID, while receiving ganitumab. Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. Ganitumab/metformin was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Results: Ganitumab/metformin did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual to this arm stopped. Ganitumab/metformin was assigned to 106 patients; there were 128 controls. We report probabilities of superiority for Ganitumab/metformin over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganitumab/metformin and control, for each of the 3 biomarker signatures, using the final pathological response data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganitumab/ Metformin Is Superior to ControlPredictive Probability of Success in Phase 3 Ganitumab/ Metformin N = 106Control N = 128 All HER2-22% (13%-31%)16% (10%-23%)89%33%HR+/HER2-14% (4%-24%)12% (4%-19%)66%21%HR-/HER2-32% (17%-46%)21% (11%-32%)91%51% Conclusion: The I-SPY 2 adaptive randomization study estimates the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. The value of I-SPY 2 is to give insight about the performance of an investigational agent's likelihood of achieving pCR. For Ganitumab/metformin, no subtype came close to the efficacy threshold of 85% likelihood of success in phase 3, and this regimen does not appear to impact upfront reduction of tumor burden. Our data do not support its continued development for the neoadjuvant treatment of breast cancer. Citation Format: Yee D, Paoloni M, van't Veer L, Sanil A, Yau C, Forero A, Chien AJ, Wallace AM, Moulder S, Albain KS, Kaplan HG, Elias AD, Haley BB, Boughey JC, Kemmer KA, Korde LA, Isaacs C, Minton S, Nanda R, DeMichele A, Lang JE, Buxton MB, Hylton NM, Symmans WF, Lyandres J, Hogarth M, Perlmutter J, Esserman LJ, Berry DA. The evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-04.

Abstract Background:Pathologic complete response(pCR) after neoadjuvant therapy is an established prognostic biomarker for high-risk breast cancer(BC). Improving pCR rates may identify new therapies that improve survival. I-SPY 2 uses response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer; the goal is to identify regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint (MP). We report the results for Ganetespib, a selective inhibitor of Hsp90 that induces the degradation/deactivation of key drivers of tumor initiation, progression, angiogenesis, and metastasis.Ganetespib + taxanes previously have resulted in a superior therapeutic response compared to monotherapy in multiple solid tumor models including BC. Methods:Women with tumors ≥2.5cm were eligible for screening and participation. MP low/HR+ tumors were ineligible for randomization. QTcF >470msec and HbA1C >8.0% were ineligible. MRI scans (baseline, +3 cycles, following weekly paclitaxel, T, and pre-surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganetespib was given with weekly T at 150 mg/m2 IV weekly (3 weeks on, 1 off). Patients were premedicated (dexamethasone 10mg and diphenhydramine HCl 25-50 mg, or therapeutic equivalents). Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. The Ganetespib regimen was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2- and HR-/HER2-. Results:Ganetespib did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual stopped. Ganetespib was assigned to 93 patients; there were 140 controls. We report probabilities of superiority for Ganetespib over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganetespib and control, for the 3 biomarker signatures, using the final pCR data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganetespib Is Superior to ControlPredictive Probability of Ganetespib Success in a Phase 3 Trial Ganetespib N = 93Control N = 140 All HER2-26% (16%-37%)18% (8%-28%)91%47%HR+/HER2-15% (4%-27%)14% (4%-24%)60%19%HR-/HER2-38% (23%-53%)22% (9%-35%)96%72% Conclusion:The I-SPY 2 adaptive randomization model efficiently evaluates investigational agents in the setting of neoadjuvant BC. The value of I-SPY 2 is that it provides insight as to the regimen's likelihood of success in a phase 3 neoadjuvant study. Although no signature reached the efficacy threshold of 85% likelihood of success in phase 3, we observed the most impact in HR-/HER2- patients, with a 16% improvement in pCR rate. While our data do not support the continued development of Ganetespib alone for neoadjuvant BC, combinations with Ganetespib, which could potentiate its effect, may be worth pursuing in I-SPY 2 or similar trials. Citation Format: Forero A, Yee D, Buxton MB, Symmans WF, Chien AJ, Boughey JC, Elias AD, DeMichele A, Moulder S, Minton S, Kaplan HG, Albain KS, Wallace AM, Haley BB, Isaacs C, Korde LA, Nanda R, Lang JE, Kemmer KA, Hylton NM, Paoloni M, van't Veer L, Lyandres J, Perlmutter J, Hogarth M, Yau C, Sanil A, Berry DA, Esserman LJ. Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-02.