Citations

Abstract Purpose: We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor–positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503). Experimental Design: Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. Results: Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12–1.97] and OS (HR, 2.08; 95% CI, 1.49–2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58–3.07) and death (HR, 3.4; 95% CI, 2.36–4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54–3.47) and OS (HR, 2.6; 95% CI, 1.59–4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. Conclusions: CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

TPS1114 Background: Immunotherapy combined with chemotherapy is being studied in metastatic breast cancer, and may have durable outcomes. Chest wall recurrence represents a difficult to treat subtype of breast cancer with a poor prognosis, with lymphovascular invasion in the primary tumor a significant risk factor. Given the inflammatory nature of this disease and the association of programmed cell death 1 (PD-1) expression with lymphovascular invasion, we hypothesized that the combination of pembrolizumab, an anti-PD-1 antibody, with carboplatin may be effective as treatment for breast cancer chest wall recurrences. Methods: This randomized phase II study is enrolling 84 patients with breast cancer involving the chest wall, who may also have distant metastases. Patients receive treatment with pembrolizumab 200 mg and carboplatin AUC 5 every 3 weeks for 6 cycles (Arm A, n = 56) followed by maintenance pembrolizumab +/- carboplatin (Arm Ax), or carboplatin AUC 5 every 3 weeks for 6 cycles (Arm B, n = 28) with an option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Patients with all disease subtypes, triple-negative, hormone receptor positive/HER2- after 2 prior lines of hormone therapy, and HER2+ disease (with the option to continue trastuzumab) are eligible, with no limit on the number of prior therapies. Prior platinum chemotherapy is allowed in the absence of overt disease progression. Patients undergo clinical assessment with every cycle of treatment including chest wall photography, scans (CT chest, abdomen, and pelvis) every 2 cycles, and have peripheral blood and chest wall biopsies collected at baseline and the start of cycle 3 for correlative studies. The primary endpoint is the disease control rate in the chest wall and distant sites at 18 weeks of treatment based on RECIST 1.1. The study is powered to determine a 20% difference in disease control between arms (hazard ratio 0.52, α = 0.10, β = 0.20). Additional endpoints include response by tumor programmed death ligand 1 (PD-L1) status and irRECIST, progression-free survival, and toxicity. Chest wall tumor samples will be analyzed for changes in tumor immune composition, and PD-L1 and MYC oncogene expression, based on preclinical data to suggest that PD-L1 may be upregulated by MYC. Peripheral blood samples will be evaluated for changes in PD-L1 expression, cell-free DNA, and circulating tumor cells with treatment. The study is enrolling patients at 7 sites within the Translational Breast Cancer Research Consortium (TBCRC), with current enrollment of 38/84 patients. Clinical trial information: NCT03095352 .

PURPOSE To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer. METHODS A systematic review of the literature collected evidence regarding nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment. RECOMMENDATIONS Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Abstract Purpose In breast MRI, contrast enhancement of normal fibroglandular tissue is referred to as background parenchymal enhancement (BPE). Hormonal status significantly affects the degree of BPE, potentially due to the association with mammary vascularity and activity1-5. Studies have shown that BPE may be associated with breast cancer survival6, treatment response to neoadjuvant chemotherapy (NAC)7,8 and future breast cancer risk9. In most patients undergoing NAC, BPE is suppressed by the nonspecific anti-proliferative effects of chemotherapy on normal breast and/or ovary5,10. However, some patients exhibit equivalent or even stronger BPE post-NAC compared to pre-NAC. We hypothesized that non-suppressed BPE in post-NAC MRI may be associated with inferior treatment response. This study aimed to investigate the association between BPE suppression and treatment response as defined by pathologic complete response (pCR). Methods This study included patients with stage II/III breast cancer enrolled in the I-SPY 2 TRIAL being treated with standard NAC with or without investigational agents. The whole cohort was split into two subgroups based on hormone receptor status (HR+, n= 536; HR-, n=452). Patients underwent dynamic contrast enhanced MRIs at four time points during NAC: baseline (T0), after 3 weeks of the first regimen (T1), inter-regimen (T2), and pre-surgery (T3). Using in-house software, the contralateral breast parenchyma was automatically segmented for the entire breast volume. Quantitative BPE (qBPE) was calculated as the mean early (~150s post-contrast injection) percent enhancement of the central 50% of the axial slices. A breast radiologist reviewed all exams and excluded those where automated segmentation failed to accurately define tissue. For T1, T2 and T3, BPE was categorized based on the change from T0 as suppressed (qBPE < qBPE[T0]) or non-suppressed (qBPE ≥ qBPE[T0]). Chi-squared test was used to examine the association between BPE suppression and pCR, with p<0.05 considered statistically significant. Results HR+ cohort: pCR rates were lower for patients with non-suppressed BPE than those with suppressed BPE at every visit (T1-T3) (Table 1). The difference was statistically significant at T2 (p=0.04) and T3 (p=0.01). Table 1: HR+ cohortpCR rate (%)No. of pCR patientsNo. of non-pCR patientsTotal number of patientsP valueOverall22.8122414536BPE at T1suppressed23.6822663480.45non-suppressed20.532124156BPE at T2suppressed25.7972803770.04*non-suppressed16.01789106BPE at T3suppressed25.7982833810.01*non-suppressed12.5128496 HR- cohort: pCR rates were slightly lower for the non-suppressed BPE group, but no statistically significant association was found (Table 2). Table 2: HR- cohortpCR rate (%)No. of pCR patientsNo. of non-pCR patientsTotal number of patientsP valueOverall44.7202250452BPE at T1suppressed46.81411603010.66non-suppressed44.45265117BPE at T2suppressed48.81441512950.79non-suppressed47.3434891BPE at T3suppressed49.31461502960.94non-suppressed48.9434588 Conclusion In HR+ breast cancer, lack of BPE suppression may indicate inferior treatment response. The contrasting results in HR+ and HR- cohorts are noteworthy in terms of the possible relationship between suppression of normal mammary and ovarian activity and treatment response in HR+ cancer. Reference Radiographics 2014; 34: 234-47. Radiology 1997; 203: 137-44. Radiology 1997; 203: 145-9. Breast J 2005; 11: 236-41. AJR Am J Roentgenol 2015; 204: 669-73. Eur Radiol 2018; 28: 4705-16. Eur Radiol 2016; 26: 1590-6. Transl Oncol 2015; 8: 204-9. J Clin Oncol 2019; : JCO1800378. Radiology 2015; 277: 687-96. Citation Format: Natsuko Onishi, Wen Li, David C. Newitt, Roy Harnish, Jessica Gibbs, Ella F. Jones, Alex Nguyen, Lisa Wilmes, Bonnie N. Joe, Michael J. Campbell, Amrita Basu, Laura J. van’t Veer, Angela DiMichele, Douglas Yee, Donald A. Berry, Kathy S. Albain, Judy C. Boughey, A. Jo Chien, Amy S. Clark, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, W. Fraser Symmans, Smita M. Asare, Julie E. Yau, Christina Yau, Laura J. Esserman, Nola M. Hylton. Lack of background parenchymal enhancement suppression in breast MRI during neoadjuvant chemotherapy may be associated with inferior treatment response in hormone receptor positive breast cancer [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 PD9-05.

Abstract Background: In an adaptive randomized trial, when new treatment combinations are being tested, it is important to be able to identify patients who are progressing on treatment so that they can be changed to a different therapeutic regimen. We know that even within the molecularly high risk patients in I-SPY 2, there is considerable variation in biology. In this study, we will present results of using MRI-calculated functional tumor volume (FTV) to identify tumor progression for each breast cancer subtype. Methods: Patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Four MRI exams were performed for each patient: pre-NAC (T0), after 3 weeks of NAC (T1), between regimens (T2), and post-NAC (T3). Functional tumor volume (FTV) was calculated at each exam by summing voxels meeting enhancement thresholds. Tumor progression at T1, T2 or T3 was identified by a positive FTV change relative to T0. Visual inspection was used to exclude false progression due to strong background parenchymal enhancement post-contrast, prominent vessels, motion, or insufficient image quality. pCR was defined as no invasive disease in the breast and lymph nodes. Negative predictive value for pCR was defined as:NPV=number of true non-pCRs / number of patients with MRI assessed tumor progressions, where “true non-pCRs” referred to patients who were non-pCRs at surgery and were assessed as progressors by MRI. The analysis was performed in the full cohort and in sub-cohorts defined by HR and HER2 statuses. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Total and non-pCR numbers for each subtype, number of patients with tumor progression assessed by MRI at T1, T2, and T3, and NPVs, are shown in Table 1. In the full cohort, the NPV increased consistently over treatment, from T1 (NPV=83%) to T2 (93%), and to T3 (100%). The HER2+ cancer subtypes showed fewer MRI-assessed tumor progressions than HER2- subtypes: e.g. 10/209 (5%) vs. 108/669 (16%) at T1. NPV was 100% for HER2+ subtypes at T1 and T2 except for a single misclassification of a HR- tumor at T1. Only 6 tumor progressors, all HER2- were identified at T3, and all were confirmed at surgery as non-pCRs (NPV=100%). For HR+/HER2-, the NPV increased slightly from 89% at T1 to 91% at T2, while triple negative subtype had a more substantial increase, from 78% to 92%. Conclusions: Our study showed strong association between tumor progressors assessed by MRI with true non-pCRs after NAC. For HER2+ tumors, although MRI progressors are rare, they strongly indicate non-pCR at all treatment time points, while HER2- subtypes show more accurate results later in treatment. We are evaluating MRI change at 6 weeks to determine if that time point is sufficient to predict progressors. Table 1 MRI assessed tumor progression at different treatment time pointN/non-pCRs/%non-pCRMRI assessed tumor progressionT1 (after 3 weeks)T2 (inter-regimen)T3 (post-NAC)NNPV (%)NNPV (%)NNPV (%)Full cohort878/572/65%11883.14192.76100%HR+/HER2-344/280/81%4588.91190.93100%HR+/HER2+134/85/63%610021000N/AHR-/HER2+75/23/31%47521000N/Atriple negative325/184/57%6377.82692.33100% Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Jessica Gibbs, Lisa J Wilmes, Ella F Jones, Bonnie N Joe, Laura S Sit, Christina Yau, A. Jo Chien, Elissa Price, Kathy S Albain, Theresa Kuritza, Kevin Morley, Judy C Boughey, Kathy Brandt, Sadia Choudhery, Amy S Clark, Mark Rosen, Elizabeth S McDonald, Anthony D Elias, Dulcy Wolverton, Kelly Fountain, David M Euhus, Heather S Han, Bethany Niell, Jennifer Drukteinis, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Smita M Asare, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Donald A Berry, Angela DeMichele, Hiroyuki Abe, Deepa Sheth, Kirsten K Edmiston, Erin D Ellis, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Michael Nelson, An Church, Claudine Isaacs, Qamar J Khan, Karen Y Oh, Neda Jafarian, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Pulin Sheth, Linda Hovanessian-Larsen, Mohammad Eghtedari, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Sally Goudreau, Thelma Brown, Laura J Esserman, Nola M Hylton. Breast cancer subtype specific association of pCR with MRI assessed tumor volume progression during NAC in 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 PD9-04.

Abstract Background: Strong background parenchymal enhancement (BPE) may cause overestimation in tumor volume measured from dynamic contrast-enhanced (DCE) MRI, which may adversely affect the ability of MR tumor volume to predict treatment outcome for patients undergoing neoadjuvant chemotherapy (NAC). Specifically, an overestimation of tumor volume can result in misclassification of patients with complete pathologic response (pCR) as non-responders, leading to less confidence in MRI prediction. As well, overestimation of extent of disease might lead to more aggressive surgical therapy than necessary. This study investigated whether high BPE in the contralateral breast influences the predictive performance of MRI-measured functional tumor volume (FTV) for patients with locally advanced breast cancer undergoing NAC. Methods: patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Each patient had 4 MRI exams: pre-NAC (T0), after 3 weeks of NAC (T1), between NAC regimens (T2), and post-NAC (T3). FTV was calculated at each MRI exam by summing voxels meeting enhancement thresholds. Background parenchymal enhancement (BPE) in the contralateral breast was calculated automatically as mean percentage enhancement on the early (nominal 150sec post-contrast) image in the fibroglandular tissue segmented from 5 continuous axial slices centered in the inferior-to-superior stack. For each treatment time point, patients having both FTV and BPE measurements were included in the analysis. The area under the ROC curve (AUC) was estimated as the association between FTV and pCR at T1, T2, and T3. The analysis was conducted in the full patient cohort and in sub-cohorts defined by hormone receptor (HR) and HER2 status. In each patient cohort, a cut-off BPE value was selected to classify patients with high vs. low BPE by testing AUCs estimated with low-BPE patients reached maximum when the cut-off value varied from median to maximum in steps of 10%. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Table 1 shows the number of patients, pCR rate, and AUC of FTV for predicting pCR using all patients available vs. a subset patients with low BPE (< BPE cut-off). In the full cohort, AUC increased slightly across all time points after patients with high BPE were removed. In the HR+/HER2- subtype, AUC increased at T1 after removal of cases with high BPE (0.65 vs. 0.71). For HR-/HER2+, AUC increased substantially after removal of high BPE cases (0.65 to 0.86 at T1, 0.71 to 0.87 at T2, and 0.71 to 0.89 at T3), with greater improvement at the early time point (T1) compared to later time points (T2 and T3). Only a slight improvement in the AUC was observed in the HR+/HER2+ and HR-/HER2- subtypes across all time points. Conclusions: High background parenchymal enhancement adversely affected the predictive performance of functional tumor volume measured by DCE-MRI, at early treatment time point for HR+/HER2- and across all time points for HR-/HER2+ cancer subtype. The adverse effect might be offset using subtype-optimized enhancement threshold in calculating functional tumor volume. Table 1 Effect of BPE on the prediction of pCR using FTV at various treatment time pointsT1T2T3npCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offFullAll64734%0.662762334%0.701761134%0.6925Subset45334%0.6831133%0.7230534%0.72HR+/HER2-All26218%0.651924918%0.718225518%0.7519Subset13118%0.7124818%0.7120419%0.76HR+/HER2+All10636%0.642110538%0.62269634%0.7120Subset5332%0.668438%0.665740%0.73HR-/HER2+All5175%0.65204774%0.71204973%0.7116Subset3073%0.862871%0.872475%0.89HR-/HER2-All22842%0.682822243%0.751821143%0.6916Subset15940%0.7111137%0.7810540%0.75 Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Roy Harnish, Ella F Jones, Lisa J Wilmes, Jessica Gibbs, Elissa Price, Bonnie N Joe, A. Jo Chien, Donald A Berry, Judy C Boughey, Kathy S Albain, Amy S Clark, Kirsten K Edmiston, Anthony D Elias, Erin D Ellis, David M Euhus, Heather S Han, Claudine Isaacs, Qamar J Khan, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Christina Yau, Smita M Asare, Angela DeMichele, Sally Goudreau, Hiroyuki Abe, Deepa Sheth, Dulcy Wolverton, Kelly Fountain, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Theresa Kuritza, Kevin Morley, Michael Nelson, An Church, Bethany Niell, Jennifer Drukteinis, Karen Y Oh, Neda Jafarian, Kathy Brandt, Sadia Choudhery, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Mohammad Eghedari, Pulin Sheth, Linda Hovanessian-Larsen, Mark Rosen, Elizabeth S McDonald, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Laura J Esserman, Nola M Hylton. The effect of background parenchymal enhancement on the predictive performance of functional tumor volume measured in MRI [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 P6-02-01.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal 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 pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant 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 P3-11-02.

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.