Citations

4007 Background: Biliary tract cancer (BTC) is an aggressive malignancy with a poor prognosis, and current treatment options for advanced BTC are limited, with second-line therapy, FOLFOX and S-1 offering an objective response rate (ORR) of 5.0% and 7.5%, respectively. Up to 20% of BTCs overexpress human epidermal growth factor receptor 2 (HER2). Tucatinib (TUC) is a highly selective HER2-directed TKI approved for HER2-positive (HER2+) metastatic breast and colorectal cancer. Discussed here are the efficacy and safety results of TUC combined with Trastuzumab (Tras) in pts with previously treated HER2+ metastatic BTC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with HER2-altered solid tumors. Pts in the BTC cohort had been previously treated with and progressed after ≥1 line of systemic therapy for metastatic disease. Eligible pts had locally determined HER2+ (defined as HER2 overexpression determined by immunohistochemistry [IHC] 3+ or HER2 amplification determined by in situ hybridization assay or next-generation sequencing) metastatic BTC. Pts were treated on a 21-day cycle with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is confirmed objective response rate (cORR) per investigator assessment. Secondary endpoints include overall survival (OS), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. Results: Thirty pts were enrolled in the BTC cohort as of data cutoff date of 30 Nov 2022. The median duration of follow-up was 8.3 months. cORR was 46.7% (90% CI, 30.8, 63.0), with 14 responses including 1 complete and 13 partial responses. Median DOR was 6.0 months (90% CI, 5.5, not estimable). DCR was 76.7% (n=23; 90% CI, 60.6, 88.5), and median PFS was 5.5 months (90% CI, 3.9, 8.1). At data cutoff, 13 (43.3%) patients had died, and the 12-months OS rate was 53.8% (90% CI, 35.2, 69.1%). Overall, the most common treatment-emergent adverse events (TEAEs) reported were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 (60.0%) of 30 pts; however, only 6 (20.0%) and 2 (6.7%) of these pts had Grade ≥3 TEAEs related to TUC and Tras, respectively. Two (6.7%) pts discontinued TUC due to TEAEs, cholangitis and liver disorder. No deaths were due to TEAEs. Conclusions: The combination of TUC and Tras was well tolerated in pts with previously treated HER2+ metastatic BTC. The observed antitumor activity supports the combination of TUC and Tras as a future chemotherapy-free treatment option for this population with historically poor outcomes. Clinical trial information: NCT04579380 .

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed > 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

Abstract Objectives We aimed to explore current practice and interregional differences in the treatment of idiopathic inflammatory myopathies (IIMs). We triangulated these observations considering countries' gross national income (GNI), disease subtypes, and symptoms using patient-reported information. Methods A cross-sectional ancillary analysis of the ‘COVID-19 vaccination in auto-immune disease’ (COVAD) e-survey containing demographic characteristics, IIM subtypes (DM, PM, IBM, anti-synthetase syndrome [ASSD], immune-mediated necrotizing myopathy [IMNM], overlap myopathies [OM]), current symptoms (surrogate for organ involvement) and treatments (corticosteroids [CS], immunomodulators [IM], i.e. antimalarials, immunosuppressants [IS], IVIG, biologic treatments and targeted-synthetic small molecules). Treatments were presented descriptively according to continents, GNI, IIM and organ involvement, and associated factors were analysed using multivariable binary logistic regressions. Results Of 18 851 respondents from 94 countries, 1418 with IIM were analysed (age 61 years, 62.5% females). DM (32.4%), IBM (24.5%) and OM (15.8%) were the most common subtypes. Treatment categories included IS (49.4%), CS (38.5%), IM (13.8%) and IVIG (9.4%). Notably, treatments varied across regions, GNI categories (IS mostly used in higher-middle income, IM in lower-middle income, IVIG and biologics largely limited to high-income countries), IIM subtypes (IS and CS associated with ASSD, IM with OM and DM, IVIG with IMNM, and biologic treatments with OM and ASSD) and disease manifestations (IS and CS with dyspnoea). Most inter-regional treatment disparities persisted after multivariable analysis. Conclusion We identified marked regional treatment disparities in a global cohort of IIM. These observations highlight the need for international consensus-driven management guidelines considering patient-centred care and available resources.

Abstract Funding Acknowledgements Type of funding sources: None. Background Falls are the leading cause of injury-related morbidity and mortality among older adults in the United States, including those with cardiovascular disease. Cardiac rehabilitation (CR) helps to optimize functional capacity, strength, and balance in patients with cardiovascular disease and, in theory, may reduce the risk of falls. However, little evidence has been published in this regard. Purpose The purpose of this study was to assess the association between CR participation and risk of falls in a community-based sample of individuals 65 years of age and older with cardiovascular disease who were eligible for CR participation. Methods Individuals from Southeastern MN and Western WI, USA, 65 years of age and older who had experienced a cardiovascular event that qualified them for CR (MI, PCI, CABG, Valve Surgery, Transplant) between January 1, 2000, and December 31, 2018, were included in this study. Participation in CR (≥1 sessions, CR-group) and subsequent falls (moderate or severe, using the Campbell classification system) were ascertained using the Rochester Epidemiology Project records-linkage system. Logistic model to create propensity weighting were used to test the association between CR participation and falls after adjustment for potentially confounding factors. Results A total of 5004 individuals met inclusion criteria for the study, with 2183 (44%) included in the CR group and 2821 (56%) in the non-CR group (CR was indicated, but the individual did not participate). Overall, 1122 patients experienced a fall within the first 5 years (16% of those in the CR-group, 23% of those in the non-CR group). After adjustment, CR participation was not associated with falls, but older individuals, females, and those with a history of falls were more likely to have had a fall, compared to young individuals, males, and those without a history of a fall. Conclusions While CR is beneficial for patients with cardiovascular disease, our study did not find evidence of an association between CR participation and fall risk in individuals 65 years of age and older who have cardiovascular disease. Additional research is needed to evaluate the role of CR components that may potentially reduce modifiable risk factors for falls and thereby reduce the risk of falls.

Abstract Purpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-“addicted” tumors who may benefit from a chemotherapy-sparing strategy. Experimental Design: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor–positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.

ObjectiveWe aimed to develop readily measurable digital quality measure statements for clinical care in systemic lupus erythematosus (SLE) using a multistep process guided by consensus methods.MethodsUsing a modified Delphi process, an American College of Rheumatology (ACR) workgroup of SLE experts reviewed all North American and European guidelines from 2000 to 2020 on treatment, monitoring, and phenotyping of patients with lupus. Workgroup members extracted quality constructs from guidelines, rated these by importance and feasibility, and generated evidence‐based quality measure statements. The ACR Rheumatology Informatics System for Effectiveness (RISE) Registry was queried for measurement data availability. In 3 consecutive Delphi sessions, a multidisciplinary Delphi panel voted on the importance and feasibility of each statement. Proposed measures with consensus on feasibility and importance were ranked to identify the top 3 measures.ResultsReview of guidelines and distillation of 57 quality constructs resulted in 15 quality measure statements. Among these, 5 met high consensus for importance and feasibility, including 2 on treatment and 3 on laboratory monitoring measures. The 3 highest‐ranked statements were recommended for further measure specification as SLE digital quality measures: 1) hydroxychloroquine use, 2) limiting glucocorticoid use >7.5 mg/day to <6 months, and 3) end‐organ monitoring of kidney function and urine protein excretion at least every 6 months.ConclusionThe Delphi process selected 3 quality measures for SLE care on hydroxychloroquine, glucocorticoid reduction, and kidney monitoring. Next, measures will undergo specification and validity testing in RISE and US rheumatology practices as the foundation for national implementation and use in quality improvement programs.image

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality.

Abstract Background Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort. Methods Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. Results Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non–MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non–MBL-Ec was 62% (95% CI: 48.2–74.3%). Among infected patients, non–MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec. Conclusions Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non–MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.

Purpose Identifying actionable oncogenic mutations have changed the therapeutic landscape in different types of tumors. This study investigated the utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) assay, in clinical practice in a developing country. Methods In this retrospective cohort study, CGP was performed on clinical samples from patients with different solid tumors recruited between December 2016 and November 2020, using hybrid capture-based genomic profiling, at the individual treating physicians’ request in the clinical care for therapy decisions. Kaplan–Meier survival curves were estimated to characterize the time-to-event variables. Results Patients median age was 61 years (range: 14–87 years), and 64.7% were female. The most common histological diagnosis was lung primary tumors, with 90 patients corresponding to 52.9% of the samples (95% CI 45.4-60.4%). Actionable mutations with FDA-approved medications for specific alterations correspondent to tumoral histology were identified in 58 cases (46.4%), whereas other alterations were detected in 47 different samples (37.6%). The median overall survival was 15.5 months (95% CI 11.7 months-NR). Patients who were subjected to genomic evaluation at diagnosis reached a median overall survival of 18.3 months (95% CI 14.9 months-NR) compared to 14.1 months (95% CI 11.1 months-NR) in patients who obtained genomic evaluation after tumor progression and during standard treatment ( P = .7). Conclusion CGP of different types of tumors identifies clinically relevant genomic alterations that have benefited from targeted therapy and improve cancer care in a developing country to guide personalized treatment to beneficial outcomes of cancer patients.