Citations

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, 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, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [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 P2-20-02.

7059 Background: Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ~6-7 mos median OS in relapsed/refractory (r/r) setting. Splenomegaly is a poor prognostic factor and potential target in CMML. CD123 is detected on blasts, monocytes, and neoplastic microenvironmental plasmacytoid dendritic cell (pDC) infiltrates part of the CMML malignant clone (Solary, et al). Tagraxofusp, a novel CD123 targeted therapy, demonstrated high levels of activity in BPDCN, an aggressive hematologic malignancy derived from CD123-expressing pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel approach in CMML. Methods: Multicenter, 2-stage Ph1/2 enrolling patients (pts) with r/r CMML. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed on days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing), pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 20 pts (12 CMML-1; 8 CMML-2) enrolled. 18 pts 2nd-line (2 pts in 1L), HMAs most common prior therapy. Median age 69 (43-80); 81% male. 11 (52%) had baseline splenomegaly (spleen palpable below left costal margin by physical exam) of 2-27 cm. Most common TRAEs: hypoalbuminaemia (35%), thrombocytopenia (35%), nausea (30%), vomiting (30%), and fatigue (20%). Most common ≥Gr3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome in 3 pts (15%; all Gr1&2). 100% (10/10) of pts with splenomegaly had spleen response: 80% (8/10) had reductions ≥50% and 67% (4/6) with spleen size ≥5 cm had reductions ≥50%. 3 pts achieved bone marrow complete responses, including 1 pt bridged to SCT in remission. Conclusions: Tagraxofusp demonstrated single agent activity in CMML as 80% of pts showed ≥50% reduction in splenomegaly by palpation. Splenomegaly in CMML, as in myelofibrosis, is a major cause of morbidity and associated with poor prognosis and impaired QoL. Targeting splenomegaly in myeloid neoplasms with proliferative features may be an important therapeutic goal. Given CD123 expression on CMML blasts, monocytes, and malignant pDCs, tagraxofusp may offer a targeted approach, especially in pts with splenomegaly. Updated safety and efficacy data to be presented. Registrational trial planned. Clinical trial information: NCT02268253.

7058 Background: Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. CD123 is expressed on a variety of malignancies, including MF. CD123+ plasmacytoid dendritic cells (pDCs), in the MPN microenvironment, including chronic myelomonocytic leukemia and MF, may be tumor-promoting. Monocytosis in MF associated with rapid disease progression and short survival, suggesting an accelerated disease phase. Notably, monocytes share a common precursor with CD123+ pDCs. Tagraxofusp, a novel CD123 targeted therapy, demonstrated high activity in patients with BPDCN, an aggressive hematologic malignancy derived from CD123+ pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel therapeutic approach in MF. Methods: Multicenter, 2-stage Ph 1/2 trial enrolling patients (pts) with MF relapsed, refractory, or intolerant to JAKi. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed daily days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing): pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 23 r/r pts treated. Median age 69 (55-81); 57% female. DIPSS Plus: 4% INT-1, 55% INT-2, 41% high. Baseline platelets: median 59 K/uL (15-579); 70% (16/23) <100 K/uL, 8 pts <50 K/uL. 87% (20/23) baseline splenomegaly (palpable ≥5 cm below left costal margin by physical exam). Most common TRAEs: headache (22%), hypoalbuminaemia (22%), ALT incr. (17%) and thrombocytopenia (17%). Most common ≥Gr3 TRAE thrombocytopenia (2%). Capillary leak syndrome in 1 pt (4%; Gr3). 57% (8/14) of pts with baseline spleen ≥5cm BCM spleen responses: 43% (6/14) had ≥29% and 21% (3/14) had ≥45% reduction. 100% of pts with baseline spleen ≥5cm and monocytosis splenomegaly reductions: 80% (4/5) had ≥29% and 40% (2/5) had ≥45%. 6 pts (3 monocytosis pts and 5 pts platelets <100 K/uL) had 6 mos+ duration, 9 pts ongoing. Conclusions: Tagraxofusp demonstrated single agent activity (reduction in splenomegaly) and manageable safety in R/R MF, including pts with monocytosis, an unmet medical need. Given the presence of CD123+ pDCs, tagraxofusp may offer a novel targeted approach in MF. Updated data to be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253.

6108 Background: This pilot study evaluated whether providing clinicians with patient(pt) QOL results and symptom management pathways linked to QOL domains at the time of clinical appointment would result in improvement in QOL and treatment (tx) satisfaction. The objective was to obtain preliminary effect size estimates and logistical evidence for design of a larger, definitive trial. Methods: Oncology pts receiving 5-7 weeks of radiotherapy (RT) electronically completed QOL assessments (LASA) at baseline and biweekly prior to seeing clinicians. Was It Worth It (WIWI) and Interpersonal Patient-Provider Relationship (IPPRS) were measured at tx end. Pt endpoints (pro-rated primary endpoint LASA area under the curve (AUC), LASA changes from baseline, and WIWI responses) and clinician endpoints (IPPRS) were compared between the control group (Phase 1: no QOL feedback) and the intervention group (Phase 2: QOL feedback) via Wilcoxon, Chi-square and Fisher Exact tests. There was 80% power to detect a 10 point difference in average AUC. Results: 148 pts enrolled (79 Phase 1, 69 Phase 2) from 11/28/2008 to 09/20/2011 (sites GI (27%), Lung (22%) and Head and Neck (52%)). 68% received RT and chemo. There were consistently moderate effect sizes observed but no statistically significant differences in any AUC nor end of tx change from baseline scores. 20% fewer pts in phase 2 reported clinical deficits in overall QOL (pain). In pts receiving 7 weeks of RT, end of tx average overall QOL, mental well-being (WB), physical WB and pain severity were significantly better in Phase 2 pts. WIWI results showed 76% found participation worthwhile, 95% would participate again, and 92% would recommend the study to others. No differences between groups were found in communication between clinicians and pts (IPPRS). Conclusions: Preliminary estimates indicate potentially clinically significant improvements of moderate effect size in mental and physical WB and pain severity when clinicians received QOL real time with symptom management pathways. Further study is warranted in larger trial setting.

5577 Background: Perioperative red blood cell transfusion (PRBCT) may be a negative prognostic marker in surgical oncology. We assessed PRBCT as an independent risk factor for recurrence and death from epithelial ovarian cancer (EOC) in the largest cohort to date. Methods: Patient characteristics and process-of-care variables (NSQIP-defined, >130 variables) were retrospectively abstracted from 587 women who underwent primary staging and cytoreduction for EOC (1/1/03-12/29/08). Evaluated using propensity scoring with univariate logistic regression and odds ratios (OR) and Cox proportional hazards regression and hazard ratios (HR). Factors with p<0.1 used in multivariate models. Results: Rate of PRBCT was 77.0% (452/587). In univariable analysis, PRBCT was associated with older age (OR 1.25[95% CI 1.06, 1.48]/10yr increase), stage≥IIIa (4.66[3.04, 7.13]), splenectomy (26.63[3.67, 193.17]), higher surgical complexity (1.86[1.17, 2.95] score 2; 21.48 [7.37, 62.59] 3; referent 1), serous histology (2.36[1.57, 3.55]vs non-serous), longer operating time (1.58[1.36, 1.83]/hr increase), and residual disease (3.26[1.97, 5.41]≤1cm; 1.97[1.09, 3.56]>1cm), and lower preop hemoglobin (Hb) (1.89[1.59, 2.27]per 1g/dL decrease). In univariable analysis, PRBCT was associated with a higher risk of recurrence (HR 1.96[95% CI 1.43, 2.68]) and death (1.71[1.28, 2.28]). However, in multivariable analysis, stage≥IIIa (4.03[2.05, 6.49]), splenectomy (1.41[1.02, 1.95]), residual disease (1.86[1.41, 2.46]≤1cm; 2.91[2.02, 4.18]>1cm), and lower preop Hb (1.09[1.01, 1.19]) were associated with higher risk of recurrence. Older age (1.24[1.12, 1.37]), stage≥IIIa (3.07[1.93, 4.90]), albumin ≤3 g/dL (2.06[1.28, 3.31]), residual disease (1.63[1.22, 2.19]≤1cm; 3.03[2.19, 4.18]>1cm), and low Hb (1.08[1.00, 1.19]) were associated with higher risk of death. Serous histology (0.70[0.52, 0.95]) associated with lower risk of death. Conclusions: PRBCT does not appear to be directly associated with disease-free and overall survival in EOC. Lower preoperative Hb was associated with a higher risk of both recurrence and death. The need for PRBCT appears to be a stronger prognostic indicator than the receipt of PRBCT.

4521 Background: Expression of PDL1 by RCC has been associated with aggressive histology and poor survival. Tissue obtained from the patients enrolled in the IL-2 Select Trial, a prospective, single arm, multicenter CWG study, was analyzed by IHC to determine if PDL1or PDL3 expression predicted for response to initial or subsequent therapy. Methods: Paraffin embedded tumor tissue was stained for PDL1 and PDL3 expression, and results were correlated with RECIST defined response to IL2 treatment. Tumor tissue was considered positive for PDL1 if >5% of the tumor membranes stained for the marker. A cutoff of 10% was used for PDL3. Duration of subsequent VEGFR/mTOR inhibitor therapy was also correlated with tissue PDL1/3 expression. Results: 120 eligible pts were enrolled; 115 had clear cell histology. The overall response rate (ORR) to IL2 was 25% (30/120) with a median OS of 40.6 months. 113 tumors were stained. 18 (16%) were PDL1+. ORR was 19% and 50% in the patients PDL1- and PDL1+ tumors, respectively (p=0.012). 85 (75%) tumors were PDL3+. ORR was 10.7% and 29.4% in the PDL3- and PDL3+ tumors, respectively (p=0.075). In the 17 patients who were positive for both PDL1 and PDL3, ORR was 52.9%. In the 27 pts who were negative for both PDL1 and PDL3, ORR was 11.1%. 69 patients received at least 1 dose of a VEGFR TKI as next therapy following IL2 treatment. 66 tumors were stained. Pts who were PDL1+/PDL3+ had a shorter duration on VEGFR TKI therapy compared to pts who were PDL1-/PDL3- (see Table). Conclusions: This small, retrospective analysis suggests that PDL1 and PDL3 tissue expression may predict for better response to IL2. PDL1 expression has been suggested as a possible predictor of response to anti-PD1 therapy. The current data suggests that its expression may predict for benefit to other immune therapies. PDL3 (+/- PDL1) expression appears to correlate to less benefit from subsequent VEGFR TKI therapy. Funded by NCI SPORE Grant # 5 P50 CA101942-08. [Table: see text]

8032 Background: Btk supports activation, survival, and proliferation of malignant B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 < 0.5nM), selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) with previously treated CLL or B-NHL were administered AVL-292 in escalating cohorts of 125, 250, or 400 mg po QD using a 3+3 design in continuous 28 day cycles until progressive disease (PD) or toxicity. Key objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 was assessed by covalent probe assay in peripheral blood mononuclear cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or grade 4 adverse events (AEs) have occurred and MTD has not been reached. Most frequent AEs reported include transient diarrhea, rash/skin infection, URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients have stable disease (SD) with median 28% decrease from baseline lymph node measurement (range 3-40% decrease). Six of 8 pts with CLL experienced increased ALC in cycle 1: median increase 89.5% (range 50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose levels ≥ 250 mg. Multiple dose PK exposure (AUClast) was linear with no accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was achieved with ≥ 250 mg QD and PK was predictable with no accumulation. Dose escalation is ongoing and MTD cohort expansion is planned.

AbstractBackgroundCurrent approaches in tracking Clostridioides difficile infection (CDI) and individualizing patient management are incompletely defined.MethodsWe recruited 468 subjects with CDI at Mayo Clinic Rochester between May and December 2016 and performed whole-genome sequencing (WGS) on C. difficile isolates from 397. WGS was also performed on isolates from a subset of the subjects at the time of a recurrence of infection. The sequence data were analyzed by determining core genome multilocus sequence type (cgMLST), with isolates grouped by allelic differences and the predicted ribotype.ResultsThere were no correlations between C. difficile isolates based either on cgMLST or ribotype groupings and CDI outcome. An epidemiologic assessment of hospitalized subjects harboring C. difficile isolates with ≤2 allelic differences, based on standard infection prevention and control assessment, revealed no evidence of person-to-person transmission. Interestingly, community-acquired CDI subjects in 40% of groups with ≤2 allelic differences resided within the same zip code. Among 18 subjects clinically classified as having recurrent CDI, WGS revealed 14 with initial and subsequent isolates differing by ≤2 allelic differences, suggesting a relapse of infection with the same initial strain, and 4 with isolates differing by &gt;50 allelic differences, suggesting reinfection. Among the 5 subjects classified as having a reinfection based on the timing of recurrence, 3 had isolates with ≤2 allelic differences between them, suggesting a relapse, and 2 had isolates differing by &gt;50 allelic differences, suggesting reinfection.ConclusionsOur findings point to potential transmission of C. difficile in the community. WGS better differentiates relapse from reinfection than do definitions based on the timing of recurrence.

Background Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. High-expressing CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor-promoting role. Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor in patients with MF, associated with shortened overall survival. We hypothesized that tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, and in particular in patients with monocytosis. Aims To assess safety and evaluate efficacy of tagraxofusp in patients with MF who were relapsed, refractory, or unable to tolerate JAKi. Methods This multicenter, open-label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1-3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the recommended Phase 2 dose (12 mcg/kg). Results 27 patients with MF have been treated, including 14 patients who had previously received ≥ 3 lines of therapy. Median age was 69 years (range 54-81), 52% were female, and 26% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate-1, 16 patients (59%) with intermediate-2, and 9 patients (33%) with high-risk. At study entry, median platelet count was 59 K/uL; 67% of patients had baseline platelets &lt;100 K/uL, of which 10 patients had platelets &lt;50 K/uL. 74% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin). In terms of molecular mutations: JAK2 (n=18); CALR (n=3); and MPL (n=1), and additional molecular analysis showed ASXL1 (n=5). In terms of cytogenetics, 30% (8/27) of patients had an abnormal karyotype, mainly 20q- (n=3), -5/5q-, -7/7q-, and 12p- (each n=2). Most common treatment-related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, increased levels of alanine aminotransferase, thrombocytopenia, and anemia. Most common ≥ grade 3 TRAE's were thrombocytopenia (8%) and anemia (15%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 17 evaluable patients with baseline splenomegaly, 53% had spleen size reductions, of which 4 patients had reductions of &gt; 45%. In 5 patients with baseline splenomegaly and monocytosis (&gt;1x109/L monocytes), 80% (4/5) had spleen size reductions, of which 2 had reductions of &gt;45%. Five patients had treatment duration of 12 months or more, with two of those patients ongoing (13+,and 24+ months, respectively). Six patients with platelets &lt;100 K/uL had treatment duration of 6 months or more, including 3 patients with baseline monocytosis who had treatment duration of 12 months or more. 7 patients had objective responses (IWG-MRT 2013 responses), including Clinical improvement (CI) (n=5) and CI (Symptom) (n=2). 20 patients were evaluable for symptomatic assessment (MPN-SAF TSS). Symptom response rate was 45% (defined as ³50% reduction in TSS score). Reductions in both symptom score and spleen size was noted in 6/6 patients who had splenomegaly at baseline. Conclusions Tagraxofusp demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor and unmet medical need. Tagraxofusp may offer MF patients, and MF patients with monocytosis in particular, a novel treatment option. Enrollment continues, and updated trial data will be presented. This clinical trial is registered at clinicaltrials.gov: NCT02268253. Disclosures Pemmaraju: affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding. Yacoub:Dynavax: Equity Ownership; Cara: Equity Ownership; Ardelyx: Equity Ownership; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agios: Speakers Bureau; Hylapharm: Equity Ownership. Wang:Agios: Other: Advisory role; Amgen: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau. Lee:AstraZeneca Pharmaceuticals: Consultancy; Ai Therapeutics: Research Funding; Karyopharm Therapeutics: Consultancy; Roche Molecular Systems: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Helsinn: Consultancy. Schiller:Agios: Research Funding, Speakers Bureau; Karyopharm: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Poradosu:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Taparia:Novartis: Consultancy. Verstovsek:Protaganist Therapeutics: Research Funding; Ital Pharma: Research Funding; Astrazeneca: Research Funding; Pharma Essentia: Research Funding; Sierra Oncology: Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

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.