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Abstract BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

Abstract BACKGROUND EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

Abstract Introduction Non-vitamin-K oral anticoagulants (NOACs) were recommended in preference to oral vitamin K antagonists (VKAs) in the 2020 updated guidelines for stroke prevention in atrial fibrillation (AF), from the European Society of Cardiology (ESC). Rivaroxaban is a NOAC that is approved in many countries worldwide for reducing the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Purpose To explore the baseline characteristics, dosing and 2-year outcomes of patients with AF treated with rivaroxaban. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international, multicenter registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Results A total of 5043 patients were enrolled into RIVER between January 2015 and June 2017. Mean (SD) age at diagnosis was 69.5 (11.0) years and 55.7% were males. Caucasian patients represented the largest proportion of patients in RIVER (80.3%), followed by Asians (5.5%) and hispanic/latino (3.7%). Almost all patients (98.5%) were prescribed a single daily dose of rivaroxaban, most commonly 20 mg (77.3%) and 15 mg (20.4%), while a 10 mg dose was prescribed in only 2.3% of patients. During the 2-year follow-up, the rates (95% CI) of all-cause mortality, stroke/SE, and major bleeding were 2.75 (2.43 to 3.12), 0.89 (0.72; 1.11), and 1.26 (1.05 to 1.52) per 100 person years, respectively (Figure 1). The most common cardiovascular cause of death was congestive heart failure (30.4%) and myocardial infarction (11.4%). Leading non-cardiovascular causes of death were malignancy (27.4%), respiratory failure (18.9%) and infections/sepsis (13.2%). Over 2 years, 710 (14.1%) of patients discontinued rivaroxaban. The corresponding proportions at 6 months and 1 year were 7.8% and 10.8%, respectively. Out of all the patients who discontinued, 62 (8.7%) restarted rivaroxaban during their follow-up (Table 1). Conclusion During 2 years of follow up in the international, prospective RIVER registry, rivaroxaban treatment for AF was associated with low rates of stroke or major bleeding. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Abstract Introduction Rivaroxaban is recommended as an option for anticoagulation in patients with nonvalvular atrial fibrillation (AF) with one or more risk factors for stroke. The approved/recommended rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is solely based on renal function: 20 mg once daily (od) for patients with a creatinine clearance [CrCl] ≥50 ml/min and 15 mg od in patients with CrCl 15–49 mL/min). Purpose To assess the patterns of rivaroxaban prescription as per the creatinine clearances levels and to assess the impact of the rivaroxaban dosing on the rate of events at 2-year follow-up in patients with AF. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Adjusted hazard ratios (HRs) were obtained through Cox proportional-hazard model. Results Among 3402 patients with normal renal function (CrCl ≥50 mL/min), 82.1% were prescribed the recommended rivaroxaban dose of 20 mg (od) at baseline. Among 524 patients with moderate or severe renal impairment (CrCl 15–50 mL/min), 55.3% patients received rivaroxaban 15 mg (od), 39.9% received 20 mg (od) and 4.2% 10 mg (od). Non-recommended dosing was rare in patients younger than 70 (13.5%) but more frequent in older patients (28.8%). Non-recommended low dosing was more frequent in Asians (38.9%), compared to non-Asian patients (13.8%). Regarding clinical outcomes, adjusted hazards ratios (HR, presented with 95% confidence intervals) showed that the non-recommended low dosing (<20 mg od) was associated with higher risk of non-cardiovascular mortality (HR 2.09 (1.16–3.77)) in patients with normal renal function. The non-recommended high dosing (>15 mg od) was associated with lower risk of all-cause mortality (HR 0.63 (0.42–0.93)) and cardiovascular mortality (HR 0.32 (0.13–0.77)) and higher risk of major bleeding (HR 2.86 (1.49–5.50)) in patients with moderate to severe renal impairment (figure 1 and 2). Conclusion In patients with normal renal function, non-recommended low dose rivaroxaban was associated with increased cardiovascular mortality without reducing the risk of major bleeding compared to recommended dosing. In patients with CrCl <50 ml/min, non-recommended high dose rivaroxaban was associated with reduced cardiovascular mortality but at the cost of increased major bleeding. These observational data largely support the reduction of rivaroxaban dosing according to renal function but educational strategies are needed to ensure that rivaroxaban is used appropriately. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the RIVER registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

Background: Marked septal hypertrophy is considered a requirement for effective myectomy in obstructive hypertrophic cardiomyopathy (HCM), with mitral valve replacement recommended as the alternative strategy in patients with minimal hypertrophy. However, it remains uncertain whether relief of obstruction can be effectively abolished without mitral valve replacement in patients with minimal septal wall thickening. Methods: Of 500 patients who underwent surgical myectomy from 2004 to January 2014, 21 (4.2%) were identified with a maximum LV wall thickness ≤ 15mm and constitute the study cohort. Results: All 21 patients (56 ± 10 years old; 62% male) were followed for advanced heart failure symptoms refractory to drug therapy with a maximal septal wall thickness of 13.6 ± 1.7 mm (range: 10-15 mm; ≤ 12 mm in 5 patients). Outflow obstruction ≥ 30 mmHg due to mitral valve-septal contact was present after exercise in 17 of 21 patients (range: 50-150 mmHg), and under resting conditions in 4 patients (range: 30-65 mmHg). In all patients, surgical relief of obstruction consisted of muscular resection of the basal septum with revision of abnormal and apically displaced papillary muscles, which were judged intraoperatively to be contributing to obstruction. In addition, in 10 patients (47%) myectomy alone was not sufficient to relieve obstruction due to the limited opportunity for septal reduction and adjunctive mitral valve repair was performed to shorten an elongated anterior leaflet. No patient required mitral valve replacement or incurred a ventricular septal defect. Post-operatively, 4 patients developed complete heart block requiring permanent pacemaker (1 patient with pre-operative right bundle branch block) and 1 had a cerebrovascular event. At most recent follow up 18 ± 19 months post-myectomy, septal thickness was reduced to 10 ± 2 mm, no patient had an outflow gradient at rest or with provocation, and all patients were alive with the majority asymptomatic (class I: n=13; 62% and class II n=8; 38%). Conclusion: In patients with minimal septal hypertrophy, outflow obstruction can be effectively abolished with surgical myectomy and adjunctive mitral valve repair with a small increased risk of heart block, but without the need for mitral valve replacement.

Abstract Introduction: The irreversible pan-HER inhibitor NER showed modest single agent activity for HER2mut MBC in Part I of MutHER trial. In Part II, we hypothesized that (1) N+F would improve activity in estrogen receptor positive (ER+) HER2mut MBC due to ER-HER2 crosstalk and (2) dual HER2 blockade by adding trastuzumab at disease progression (PD) could overcome resistance. Methods: Pts with ER+HER2mut MBC were enrolled to 2 cohorts (FUL treated or naive) to receive N+F with diarrhea prophylaxis. ER- pts received NER in an exploratory ER- cohort. Trastuzumab was added at PD if approved by insurance. Simon's Minimax 2-stage phase II design with the primary endpoint of clinical benefit rate (CBR: rates of complete/partial response [CR/PR] plus stable disease [SD] >24 weeks [wks]), with anticipated vs null hypothesis being CBR of 55% vs 35% (FUL treated) or 65% vs 40% (FUL naïve) with 80% power, 1 sided 0.05 alpha, was used. Secondary endpoints included progression free survival (PFS) and adverse events (AEs). Serial blood samples were analyzed for circulating tumor DNA (ctDNA) by Guardant360 for concomitant mutations, HER2mut variant allele frequency (VAF) dynamics, and resistance mechanisms. Results: Between Sep. 2015 and Oct. 2020, 40 pts with HER2mut MBC were enrolled, completing the 1st stage of each ER+ cohort. 35 pts (21 FUL treated, 10 FUL naïve, 4 ER-) were evaluable for response, with median age 63 (35-82) years, 3 (0-12) prior MBC regimen, lobular BC in 13 (37%) and visceral mets in 32 (91%) pts. 21 (68%) ER+ pts had prior CDK4/6 inhibitor. All but 1 pt has come off study due to PD. Table 1 shows the efficacy by cohort. Further enrollment is closed per protocol. Adding trastuzumab at PD induced CB in 4 (3 PR, 1 SD≥24 wks) of 5 pts (1 ER-, 4 ER+), with PFS 28 (95% CI 18~NA) wks. Common AEs across cohorts were diarrhea (G3 21%) and fatigue (G3 5%). No G4 AEs. ctDNA HER2mut was detected in 72% (23/32) baseline (BL) samples tested. In pts with paired samples, HER2mut VAF decreased at C1D15/C2D1 from BL in 75% (15/20) and rose in 89% (16/18) at PD. Acquired HER2mut, including the T798I gatekeeper mutation, were detected in 2 pts at PD. Mutations in TP53 (53%), PIK3CA (43%), and CDH1 (35%) were common, but none significantly associated with PFS in all or ER+ pts. Conclusions: NER, or N+F, is active for HER2mut MBC with good tolerability. Adding trastuzumab at PD induced further response, supporting dual HER2 blockade for HER2mut MBC. Table 1.EfficacyCohortFUL treatedFUL naïveER-Best Response, n evaluablen = 21n = 10n = 4CR, n100PR, n431SD (≥ 24 wks), n300SD (< 24 wks), n1030PD, n343CBR, n with CB/total n evaluable, % (95% CI)8 of 20*, 40% (19~64%)3 of 10, 30% (7~65%)1 of 4, 25% (0.6~81%)mPFS (95% CI), wks, ITT (n)24 (16~31) wks, (n = 24)20 (8~NA) wks, (n = 11)8.5 (8~NA) wks, (n = 5)*20 of 21 pts are evaluable for CBR in the FUL treated Cohort as 1 pt had SD as best response and treatment is still ongoing. ITT (intent to treat) population is used for mPFS estimate. Citation Format: Cynthia X. Ma, Jingqin Luo, Rachel A. Freedman, Timothy Pluard, Julie Nangia, Janice Lu, Frances Valdez-Albini, Melody Cobleigh, Jason Jones, Nancy U. Lin, Eric Winer, P. Kelly Marcom, Shana Thomas, Jill Anderson, Brittney Haas, Kimberly M. Hamann, Richard Bryce, Alshad S. Lalani, Lisa Carey, Matthew Goetz, Feng Gao, Gretchen Kimmick, Mark Pegram, Matthew J. Ellis, Ron Bose. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT026.

Functional renal oxygen consumption, V r O 2 is due to tubular reabsorption of sodium (T Na ) in the proximal and distal nephrons, resulting in compartments (cortex/medulla) with distinct V r O 2 /T Na relationships. Compartmental divisions promote non‐invasive imaging strategies like MRI, to indirectly assess tissue oxygenation, (P t O 2 ). However, the extent to which these regional P t O 2 differences are affected by successive T Na are not fully understood. The objective is to determine V r O 2 and intra‐renal regional alterations in P t O 2 directly and indirectly during successive T Na inhibition. It is hypothesized successive T Na inhibition is accompanied by intra‐renal regional changes in P t O 2 . Pigs (n=6) underwent MRI scans at baseline, furosemide and acetazolamide. Five days later, the right kidney was instrumented with P t O 2 sensors (cortex/medulla). P t O 2 was measured during drug infusions (identical to MRI exam). There was a decrease in V r O 2 , and a 40% and 30% increase in medullary and cortical P t O 2 following drug infusions. There was ~25% medullary and ~20–30% cortical decrease in BOLD signal with furosemide and acetazolamide administration, respectively. This study suggests successive inhibition of T Na is accompanied by intra‐renal regional P t O 2 changes and these changes are detectable with BOLD‐MRI, a non‐invasive imaging modality. Funding provided by NIH Grant (HL16496‐32), 2007 APS Porter Physiology Fellowship and the Mayo Foundation.

Functional renal oxygen consumption, V r O 2 is due to tubular reabsorption of sodium (T Na ) in the proximal (∼67%) and distal(∼30%) nephrons, resulting in compartments (cortex/medulla) with distinct V r O 2 /T Na relationships. A progressive drop in renal blood flow (RBF) with renal arterial stenosis (RAS), disrupts O 2 delivery, vital for reabsorption. The overall objective for the study is to determine the intra‐renal regional alterations in tissue oxygenation (P t O 2 ) and theV r O 2 /T Na relationship in acute RAS. The hypothesis is RAS is accompanied by intra‐renal regional changes in oxygenation. Unilateral acute RAS was induced in 8 pigs by an extra‐vascular balloon. RBF and P t O 2 were measured continuously with an ultrasound flow probe during baseline, RBF autoregulation and 3 sequential decreases in RBF, recovery, and furosemide administration. V r O 2 was determined using Fick arterio‐venous differences. There were concomitant decreases in V r O 2 , and P t O 2 throughout the occlusion periods. Medullary P t O 2 changes were 35% more pronounced than cortical. This study suggests medullary decreases in P t O 2 are more aggravated than cortical changes with reductions in RBF, accentuating the medulla's vulnerability to progressive RAS. Mild to moderately severe obstructions seem to preserve the tubular transport costs. Funding provided by NIH Grant (HL16496‐32), 2007 APS Porter Physiology Fellowship and the Mayo Foundation.

11040 Background: Although women outnumber men in US medical school enrollment, women constitute < 50% of faculty in academic oncology. This study aimed to determine factors affecting women oncologists’ decisions to pursue academic versus non-academic oncology in Hematology/Oncology (HO), Pediatric Oncology (PO), Radiation Oncology (RO), and Surgical Oncology (SO), and to characterize the challenges women oncologists face. Methods: A survey was designed to collect cross-sectional data on factors affecting career choices among US women oncologists. The survey was distributed via email and social media. Data were collected anonymously and analyzed using t-tests for continuous variables and Chi-squared tests for categorical variables. Results: Six hundred sixty-seven women oncologists responded: 245 (45.3%) specialized in HO, 173 (25.9%) RO, 88 (13.2%) PO, 56 (8.4%) SO, and 48 (7.2%) other. Four-hundred twenty-two (63.2%) women identified as an academic oncologist (AO); 245 (36.8%) women identified as a non-academic oncologist (non-AO). Approximately ¼ of women oncologists reported their partner (156, 23.5%) or family (176, 26.4%) extremely or moderately impacted their decision whether to pursue academic practice. There was no difference in the timing of childbearing between AO and non-AO. AO perceived the biggest sacrifice of pursuing academics to be time with loved ones (181, 42.9%). Non-AO perceived the biggest sacrifice for AO to be pressure for academic promotion (102, 41.6%), which was the third most common response (44, 18.0%) among AO. Thirty-three (7.9%) AO and 5 (2.0%) non-AO reported feeling that they rarely or never have a sense of belonging in their work environment (p < 0.01). AO and non-AO had significantly different perceptions on how their gender impacted their ability to obtain a chosen job (p < 0.01), with 100 (23.8%) AO and 52 (21.2%) non-AO reporting a negative or somewhat negative impact, and 116 (27.6%) AO and 101 (41.2%) non-AO reporting a positive or somewhat positive impact. More than half of women surveyed (230 AO, 54.6%; 123 non-AO, 50.6%; p = 0.61) felt that they were somewhat or much less likely to be promoted compared to male colleagues. The majority of women reported they would choose the same career path again (71% of AO, 69% of non-AO); however, 92 (21.9%) of AO responded that they were likely or very likely to pursue a career outside academics in the next 5 years. Conclusions: While partners/family have a substantial impact on 1 in 4 women oncologists, this does not differ between AO and non-AO. Significantly more non-AO find their gender to have positively impacted their ability to obtain their chosen job. In contrast, a meaningful number of AO report a poor sense of belonging and perceived discrimination in obtaining jobs and being promoted; 1 in 5 are considering leaving academia. Academic oncology remains at high risk for continued gender inequality if the culture is not addressed.