Kim, Mi‐Ok

Background: MARVEL-HCM is a US multicenter study assessing the safety and effectiveness of mavacamten in real-world academic and community practices. Mavacamten is a first-in-class cardiac myosin inhibitor (CMI) and the only CMI currently approved in over 50 countries for use in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Modest evidence exists describing the effectiveness and safety of mavacamten monotherapy. Aims: To describe the real-world outcomes of patients using mavacamten as monotherapy for oHCM. Methods: Patient-level data from medical records at 5 sites were analyzed to describe mavacamten monotherapy, defined as monotherapy at baseline or after background HCM therapy (beta-blockers [BB], calcium channel blockers [CCB], disopyramide) discontinuation within 12 weeks(wks) of mavacamten initiation and without reinitiation, up to 60 wks. A minimum of 12 wks follow-up was required for inclusion. Patient characteristics, echocardiographic data, and safety are reported at baseline and follow-up visits. Results: The monotherapy cohort comprised 13.4% (32/239) of patients: 24 were on mavacamten monotherapy at initiation, and 8 discontinued background therapy. Baseline characteristics included: NYHA Class II (46.9%) and III (53.1%), female (66%), hypertension (50%), and atrial fibrillation (AF) (18%) (Table 1). Median follow-up and duration of mavacamten monotherapy were 48 wks (range 12-60 wks) and 57 wks (range 14-60 wks), respectively. Resting left ventricular outflow tract gradient (LVOTg) was ≤ 30 mmHg in 93%, 91% and 100% of patients at Wk 24, 36, and 60. Valsalva LVOTg was ≤ 30 mmHg in 61%, 77% and 86% of patients at Wk 24, 36, and 60 (Fig 1). No patients were in NYHA Class III at wk 60, and ~50% of patients were NYHA Class I by wk 48 (Fig 2). Mean reduction in LVEF was 4.8% over 60 wks. One patient had LVEF < 50% at Wk 20, resulting in a dose reduction (10 to 7.5 mg). Safety events included 3 hospitalizations due to AF ablation (n=1), viral gastrointestinal illness (n=1) and heart failure (n=1). Demographic, clinical characteristics, and outcomes were similar across the mavacamten monotherapy cohort, mavacamten in combination with background HCM therapy (n=207), and the overall cohort of MARVEL-HCM (N=239). Conclusions: Mavacamten monotherapy was effective, safe, and consistent with the overall MARVEL cohort, as well as previously reported monotherapy cohorts from pivotal, long-term, and real-world evidence.

Background: Mavacamten was approved by the US Food and Drug Administration (FDA) in April 2022 for the treatment of adults with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (HCM). Few studies have reported on the long-term real-world effectiveness and safety of mavacamten. We evaluated clinical outcomes in patients on mavacamten in multiple health centers across the United States. Research Questions: This study assessed the real-world effectiveness and safety of mavacamten in patients with symptomatic obstructive HCM. Methods: In this multi-center observational study, we evaluated patient characteristics at baseline, NYHA class, left ventricular outflow tract gradients (LVOTg) at rest and Valsalva, and left ventricular ejection fraction (LVEF) in patients with symptomatic obstructive HCM treated with mavacamten for up to 72 weeks. Results: Mavacamten was initiated in 172 patients across 4 US centers (UCSF, Mayo Arizona, Stanford, and Atlantic Health System/Morristown Medical Center). Baseline characteristics included: 56% female, mean age 64 (standard deviation ±13) years, 47% NYHA class III, mean resting LVOTg of 47 mmHg and mean Valsalva LVOTg of 89 mmHg, and 23% non-White. Comorbidities included hypertension (56%) and atrial fibrillation (25%) at baseline (Table). Patients experienced a notable early response to mavacamten in resting and Valsalva gradients by week 4, which was sustained through week 72 (Figure A). No patients were NYHA class III at week 72, compared to 47% at baseline (Figure B). Mean LVEF did not change substantially between baseline and week 72. No patients experienced an LVEF of <40% and 2% experienced an LVEF of <50%. Conclusions: This is the largest observational study to date demonstrating the effectiveness and safety of mavacamten with substantial sustained reductions in resting and Valsalva LVOTg, and progressive improvements in NYHA class without considerable changes in mean LVEF up to 72 weeks.

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. We have previously observed in the I-SPY 2 TRIAL that while metastatic events outside the central nervous system (CNS) were dramatically reduced in the setting of pCR, the incidence of CNS metastasis remained similar across RCB classes, raising the possibility that these CNS events may be independent of response in the breast. In this study, we evaluate the type and sites of recurrences by RCB in a large pooled dataset, which allows for analysis within subtype, to validate these findings. Methods: 5161 patients pooled across 12 institutions/trials with available RCB and event-free survival (EFS) data were included in this analysis. EFS was calculated as the interval between treatment initiation, and locoregional recurrence, distant recurrence or death from any cause; patients without event are censored at time of last follow-up. The median follow-up is 4.6 years. We summarized the EFS event type, further sub-dividing the distant recurrence events (DR) by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We used a competing risk (Fine-Gray) model to assess which of these site-specific relapses differ between RCB classes and estimated the cumulative incidence of CNS-only and non-CNS events at 5 years. Analyses were performed across the entire study population and within HR/HER2 defined subtypes. Results: Among the 5161 subjects, there were 1164 EFS events, including 92 (7.9%) local recurrences (without distant recurrence and/or death) and 1072 distant recurrence-free survival (DRFS) events. Among the DRFS events, 158 patients died without a distant recurrence. 914 experienced distant recurrences, including 90 (9.8%) with CNS-only, 145 (15.9%) with CNS and other sites, 664 (72.6%) with non-CNS distant recurrence; 15 (1.6%) patients had missing recurrence site information. Table 1 summarizes the cumulative incidence of CNS-only and non-CNS recurrence at 5 years and the proportion of CNS-only recurrences among DR events by RCB class overall and within each HR/HER2 subtypes. The incidence of CNS-only recurrences was low and similar across RCB classes. In contrast, the incidence of non-CNS recurrences increases with increasing RCB. As a result, CNS-only recurrences are proportionally higher within the RCB-0 and RCB-I than in the RCB-II and RCB-III groups, largely because of the low DR event rate and relative low frequency of non-CNS recurrence events within the RCB-0 and RCB-I classes. Overall, 27% of the recurrences in the setting of pCR (RCB-0) are due to CNS-only recurrences.Conclusions: Consistent with previous studies, our large pooled analysis confirmed that 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 suggest that inclusion of CNS-only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcomes in the context of current therapies. Novel therapies that cross the blood brain barrier will be needed to impact CNS recurrence rates. Table 1: Cumulative Incidence of CNS Only and non-CNS Distant Recurrences at 5 years and proportion of CNS-only events among DR eventsRCB Class0IIIIIIpOverall (5161)N16766622017806Cum. Inc. CNS Only2%2%2%1%0.627Cum. Inc. Non-CNS3%6%16%27%&lt;0.001# CNS-Only / # DR events (%)26/96 (27%)14/74 (19%)39/443 (9%)11/301 (4%)HR-HER2- (1774)N770212590202Cum. Inc. CNS Only2%3%2%4%0.298Cum. Inc. Non-CNS4%11%19%42%&lt;0.001# CNS-Only / # DR events (%)13/50 (26%)6/32 (19%)13/148 (9%)8/111 (7%)HR-HER2+ (572)N3766710029Cum. Inc. CNS Only1%5%5%0%0.022Cum. Inc. Non-CNS2%5%18%38%&lt;0.001# CNS-Only / # DR events (%)4/17 (24%)3/10 (30%)6/31 (19%)0/13 (0%)HR+HER2+ (858)N31317229182Cum. Inc. CNS Only1%1%2%0%0.37Cum. Inc. Non-CNS2%3%15%26%&lt;0.001# CNS-Only / # DR events (%)3/10 (30%)2/16 (12%)7/68 (10%)0/29 (0%)HR+HER2- (1957)N2172111036493Cum. Inc. CNS Only3%2%1%0.2%0.087Cum. Inc. Non-CNS5%4%13%20%&lt;0.001# CNS-Only / # DR events (%)6/19 (32%)3/16 (19%)13/196 (7%)3/148 (2%) Citation Format: Sonal Shad, Marieke van der Noordaa, Marie Osdoit, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Miguel Martin, María Del Monte-Millán, Sara López-Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Gabe Sonke, Tessa G Steenbruggen, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephen Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fan Fang, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberly Cole, Lajos Pusztai, Laura Van't Veer, Fraser Symmans, Laura Esserman, Christina Yau. Site of recurrence after neoadjuvant therapy: A multi-center pooled analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-02.

Abstract Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with breast cancer is associated with improved survival. Further assessment of the extent of residual disease, using the pathological anatomic American Joint Committee on Cancer staging method (ypStage) or the Residual Cancer Burden (RCB) method, have been shown to add prognostic information for patients with residual disease. Neo-Bioscore, an alternate system to classify response to NAC, includes clinical stage at diagnosis and biology and defines eight prognostic groups. The goal of this study was to compared three scoring systems (anatomic ypStage (7th ed), RCB Class and Neo-Bioscore) and assess whether RCB Class and Neo-Bioscore provide additional prognostic value in the context above anatomic ypStage, the most commonly used method for post-neoadjuvant residual disease assessment. Methods: Data from 5161 patients treated with NAC was pooled from 12 sites. Patients without clinical and pathological staging were excluded, as were patients with HER2+ breast cancer who did not receive neoadjuvant HER2-targeted therapy, leaving 3730 for analysis. PCR was defined as no residual invasive tumor in breast and nodes, i.e. RCB-0 or ypT0/Tis and ypN0. Patients with discordant pCR status by RCB Class vs ypStage (n=9) were excluded. Associations between each scoring system and event-free survival (EFS) were evaluated using the log rank test. EFS at 5 years was estimated using the Kaplan Meier method. Associations between Neo-Bioscore and EFS were assessed in the pCR group. For patients with residual disease, we assessed RCB and Neo-Bioscore within each ypStage. Analysis was performed overall and within subtype. Subgroups with &lt;5 patients were excluded from the survival analyses. Results: ypAJCC staging, RCB class and Neo-Bioscore were all associated with EFS in the overall population and within each subtype (log rank p&lt;0.0001). Of note, 13 patients with a Neo-Bioscore of 7 all recurred or died within 19 months of follow-up. Overall, 34% (1264/3721) of patients achieved a pCR. Their Neo-Bioscore ranges from 0-5, where 3% (37/1264) has a Neo-Bioscore of 5 despite achieving pCR. The Neo-Bioscore was not associated with EFS in case of a pCR, with EFS estimates at 5 years of 95%, 94%, 92%, 93%, 90% and 92% for Neo-Bioscores 0-5 respectively. As HR and HER2 status are components of the score, the range of Neo-Bioscore in the pCR group differs by subtype. However, similar to the overall analysis, the Neo-Bioscore was not prognostic within subtypes in case of pCR. Overall, among the patients who did not achieve pCR, both RCB class and Neo-Bioscore were associated with EFS within ypStages I, II and III. However, the ypStage within which RCB and Neo-Bioscore are prognostic is different for each subtype. RCB class was prognostic in ypStage I in both HR+ subtypes: patients with ypStage-I/RCB-I had significantly improved survival compared to patients with ypStage-I/RCB-II (5-year EFS: 100% vs 83% in HR+HER2- and 95% vs 77% in HR+HER2+). In contrast, for patients with triple negative breast cancer, RCB class was prognostic within ypStage II and III. Analysis by clinical stage and the components of the three systems that contribute most to prognosis will be presented. Conclusions: The degree of response to NAC adds important information to pCR versus residual disease. The Neo-Bioscore was not prognostic among patients with pCR, suggesting that clinical stage (including subtype and grade) adds little information in the setting of a pCR. In contrast, both RCB and Neo-Bioscore provide additional prognostic information to the conventional ypAJCC staging among non-pCR patients, suggesting that clinical stage, tumor biology as well as extent of residual disease all contribute to prognosis in the setting of residual disease after NAC. Citation Format: Marieke EM van der Noordaa, Christina Yau, Sonal Shad, Marie Osdoit, Tessa G Steenbruggen, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Maria Del Monte-Millán, Miguel Martin, Sara Lopez Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew Goetz, Tanya Hoskin, Rebecca Gould, Vincent Valero, Gabe Sonke, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephan Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna MacKintosh, Fang Fan, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberley Cole, Lajos Pusztai, Laura van 't Veer, Fraser Symmans, Laura Esserman. Assessing prognosis after neoadjuvant therapy: A comparison between anatomic ypAJCC staging, residual cancer burden class and neo-bioscore [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-07.

10526 Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease > 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]

Abstract Background: Recent studies have demonstrated independent validation of the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. However, a pooled subject-level analysis of multiple cohorts is needed to determine estimates of long-term prognosis for each class of RCB in each phenotypic subtype of breast cancer (BC) to better inform on patient outcomes. Also, a pooled subject-level analysis allows more detailed analyses of generalizability of the prognostic meaning of RCB assessments in a broader experience of practice settings. Method: Subject-level RCB results, with relevant clinical and pathologic stage, tumor subtype and grade, demographic, treatment and follow-up data from 11 institutes/trials are being collected for combined analysis. The association between the continuous RCB index and event-free survival (EFS), and distant recurrence free survival (DRFS) were assessed using mixed effect Cox models with the incorporation of random RCB coefficients to account for between-study heterogeneity. We will also allow for differences in baseline hazard across biological BC subtypes and, if needed, across studies as well. In addition to this stratified mixed effect model, a multivariate analysis adjusting for age, T-category, nodal status and grade was performed within each subtype. In addition, mixed effect Cox models will be employed to evaluate association between RCB index with EFS and DRFS within each HR/HER2 subtype. Kaplan Meier estimates of EFS and DRFS at 5 and 10 years were computed for each RCB class within subtype. Results: We analyzed subject-level data from 9 institutes/trials representing 4077 patients currently available from an anticipated final total of 4,800 patients (to be presented at the meeting). There were 950 EFS and 876 DRFS events during follow up (median 65 months, IQR: 70 months). RCB index (continuous) was independently prognostic within each subtype: HR+/HER2- (EFS HR (per unit increase in RCB index) =1.64, 95%CI 1.48-1.82; DRFS HR=1.68, 1.51-1.87), HR+/HER2+ (EFS HR=1.80, 1.57-2.05; DRFS HR=1.93, 1.67-2.24), HR-/HER2+ (EFS HR=2.15, 1.76-2.62; DRFS HR=2.10, 1.77-2.50), and HR-/HER2- (EFS HR=2.05, 1.89-2.22; DRFS HR=2.16, 1.90-2.46); and remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis. Table 1 contains the response rate and estimated EFS at 5 years and 10 years for each RCB class within each HR/HER2 phenotype (DRFS results were similar). Conclusions: Long-term prognosis after pCR was similarly excellent in all phenotypic subtypes. RCB index and classification was independently and strongly prognostic in all subtypes, and generalizable to multiple practice settings. Prognostic differences by RCB class occurred within 5 years in HR- BC, but extended to 10 years in HR+ BC. RCB-I had slightly worse EFS than pCR in HR- BC and HR+/HER2+ BC (after 5 years), but the same EFS as pCR in HR+/HER2- BC. Complete analysis of all subjects, including neoadjuvant treatments, will be presented at the meeting. PhenotypeOutcomepCRRCB-IRCB-IIRCB-IIIHR+/HER2-Frequency (%)11%10%52%27%(N=1467)5 yr EFS (95% CI)91% (86-96)93% (89-98)82% (79-85)70% (65-75)10 yr EFS (95% CI)84% (75-93)88% (82-95)71% (67-75)52% (46-58)HR+/HER2+Frequency (%)38%18%35%9%(N=762)5 yr EFS (95% CI)94% (91-97)93% (88-98)78% (73-84)49% (37-65)10 yr EFS (95% CI)91% (86-96)79% (70-90)65% (59-73)42% (29-60)HR-/HER2+Frequency (%)66%11%18%5%(N=550)5 yr EFS (95% CI)93% (90-96)88% (79-97)60% (50-71)45% (30-69)10 yr EFS (95% CI)90% (86-94)84% (74-95)56% (46-68)45% (30-69)HR-/HER2-Frequency (%)41%13%33%13%(N=1293)5 yr EFS (95% CI)92% (90-94)85% (79-91)68% (63-72)28% (21-36)10 yr EFS (95% CI)87% (82-91)80% (72-88)63% (58-68)24% (18-33) Citation Format: Christina Yau, Marieke van der Noordaa, Jane Wei, Marie Osdoit, Fabien Reyal, Anne-Sophie Hamy, Marick Lae, Miguel Martin, Maria del Monte, I-SPY 2 TRIAL Consortium, Judy C Boughey, Rebekah Gould, Jelle Wesseling, Tessa Steenbruggen, Maartje van Seijen, Gabe Sonke, Stephen Edge, Stephen-John Sammut, Elena Provenzano, Jean Abraham, Peter Hall, Ashley Graham, Lorna Mackintosh, David Cameron, Alice Wang, Priyanka Sharma, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura van ‘t Veer, Laura Esserman, W. Fraser Symmans. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis [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 GS5-01.