tbuckley/cabot-search huggingface dataset:
Long-term (LT) disease control in patients (pts) with hormone receptor-positive (HR+), <i>PIK3CA</i>-altered advanced breast cancer (ABC) treated with alpelisib (ALP) + fulvestrant (FUL).
Authors: Dejan Juric, Fabrice Andre, Udaiveer Panwar, Filip Janku, Yen-Shen Lu, Howard A. Burris III, Josefina Cruz Jurado, Zsuzsanna Papai, Salomon M. Stemmer, Josep Tabernero, Johan Ahlgren, Marianne Leheurteur, Ines Lorenzo, Dragana Jankovic, Cornelia Quadt, Huilin Hu, Xueying Chen, Hope S. Rugo
Journal: Journal of Clinical Oncology (2021)

1054 Background: PIK3CA mutations, present in ̃40% of HR+, HER2– ABC, are associated with therapeutic resistance and shorter survival. Alpelisib (ALP) + fulvestrant (FUL) demonstrated efficacy in this population for which achieving long-term (LT) disease control is challenging. Here, we report on pts with HR+, PIK3CA-altered ABC who achieved LT disease control with ALP + FUL. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or placebo) + FUL in HR+, HER2– ABC that progressed on/after an aromatase inhibitor. CBYL719X2101 (X2101) was a phase 1, open-label study of escalating ALP doses ± FUL in advanced solid tumors that progressed on/after anti-estrogen therapy (ET) or relapsed after adjuvant anti-ET. A cut-off ≥ median (progression-free survival [PFS] + 2 SE) was chosen based on Kaplan-Meier curves from SOLAR-1 to define LT disease control as PFS (SOLAR-1) or time on treatment (X2101) ≥18 mo. Results: In SOLAR-1, 51 of 169 pts (30.2%) randomized to ALP + FUL achieved LT disease control with a median PFS of 33.5 mo (95% CI, 27.4 mo-not reached). Baseline characteristics of pts in SOLAR-1 are in the table below. In pts with LT disease control, adverse events (AEs) of special interest (combined preferred terms) of GI toxicity were observed in 47 pts (92.2%; grade ≥3: 11.8%, n=6), of hyperglycemia in 41 pts (80.4%; grade ≥3: 39.2%, n=20), and of rash in 28 pts (54.9%; grade ≥3: 19.6%, n=10). Median ALP relative dose intensity was 79.9% and 82.1% for pts with LT disease control (n=51) and the overall population (n=168), respectively. In X2101, 7 of 52 pts (13.5%) with ABC who received ALP+FUL achieved LT disease control up to 47.8 mo. Conclusions: In this subset of pts with hard-to-treat, endocrine-resistant disease, LT disease control ≥18 mo is meaningful considering median PFS of 4.6-9.3 mo or 9.5-16.4 mo with FUL alone or with cyclin-dependent kinase 4/6 inhibitors, respectively. Here, LT disease control was observed in 2 studies of HR+, PIK3CA-altered ABC, including in pts with poor prognosis, diabetes/pre-diabetes at baseline, and heavy pre-treatment. AE profile was consistent with prior reports and did not preclude LT disease control. Further work is needed to better understand factors influencing LT disease control. Clinical trial information: NCT01219699, NCT02437318 .[Table: see text]
TrilynX: A phase 3 trial of xevinapant and concurrent chemoradiation for locally advanced head and neck cancer.
Authors: Jean Bourhis, Barbara Burtness, Lisa F. Licitra, Christopher Nutting, Jonathan D. Schoenfeld, Rafik Ait Sarkouh, Florilene Bouisset, Heidi Nauwelaerts, Yulia Urfer, Claudio Zanna, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2021)

TPS6091 Background: Concurrent chemoradiotherapy (CRT) is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinomas of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements of xevinapant versus placebo in addition to standard chemoradiation (CRT) for locoregional control (LRC) rate at 18 months, PFS and OS. The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. Methods: TrilynX is a multinational, Phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-HNSCC. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharynx, larynx and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ̃90% power to detect the expected hazard ratio benefit of 0.73. Secondary end-points include OS, PFS, LRC, ORR, HRQL, and safety. Data driven design, patients will be followed up for a minimum of 60-months. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and it is ongoing. References: [1] X. Sun et. al, Lancet Oncol; 21(9): 1173-1187, 2020. [2] J. Bourhis et al., Ann Oncol; 31 (suppl 4): LBA39, 2020. Clinical trial information: NCT04459715.
Genome-wide association study to reveal novel germline markers of melanoma survival.
Authors: Vylyny Chat, Robert Ferguson, Leah Morales, Una Moran, Min Jae Kim, Matija Snuderl, Iman Osman, Jeffrey S. Weber, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2021)

9581 Background: Cutaneous melanoma (CM) is the most invasive form of skin cancer accounting for ̃80% of all skin cancer related deaths. While tumor staging (based on recent AJCC classification) is routinely used in prognostic assessment, a large fraction of the outcomes is not explained by AJCC staging system. This urges for the discovery of a more personalized prognostic surrogates. Growing evidence highlights the role of germline genetics in CM progression; yet, to date no systematic prognostic germline study has been conducted in melanoma. We performed the first genome-wide association analysis (GWAS) to identify germline variants associated with melanoma survival. Methods: A cases/case GWAS was performed using the Infinium global screening array (GSA v3.0) to genotype 1,117 stage 0-III melanoma patients with no history of immunotherapy treatments ascertained at New York University Langone Health (NYULH). We randomly divided the study cohort into a discovery (N=630) and a validation (N=487) sets and tested the association of &gt; 5 million imputed germline variants with melanoma overall survival (OS) by fitting Cox-proportional hazard ratio (HR) regression in an additive genetic model adjusting for sex, age at diagnosis, AJCC 8th staging, tumor anatomic sites, and top 3 principal components. Results: We found 151 independent variants associated with melanoma OS (p&lt; 5×10 −5 ) in the discovery cohort. Two of these associations validated in the independent replication set ( Bonferroni threshold for 151 tests: p &lt; 0.003) with enhanced clinical and statistical significance in the pooled meta-analysis: rs4128212 [HR =2.47(1.75-3.48); p=2.2× 10 −7 ], and rs13212644 [HR =2.59 (1.72-3.88); p=4.2× 10 −6 ]. We further tested the combined effect of these two variants and found the presence of at least one risk allele of the variants associated with a substantially increased risk of death, surpassing GWAS level of significance (HR=3.74 (2.43-5.74); p=1.5×10 −9 ). Conclusions: We present the results of first GWAS testing an association of germline variation with melanoma OS. Stemming from a unique patient population with extensive clinical follow-up data, we identified two prognostic germline loci with large HR effect size &gt;2.5 that were independently validated. The observed association is independent of established histopathologic markers. While rs4128212 was mapped to a putative cancer prognostic gene locus (PLPP4: phospholipid phosphatase 4), rs13212644 was an eQTL (expression quantitative trait loci) for GCLC (Glutamate-Cysteine Ligase Catalytic Subunit), a key regulator in glutathione synthesis previously linked with favorable melanoma survival. The significantly enhanced combined effect of these two loci (HR &gt;3.5; p&lt;5×10 −9 ) indicates a great promise for their clinical utility as independent personalized predictive markers of melanoma progression.
Relative bioavailability of H3B-6545 tablets versus capsules and drug-drug interaction between H3B-6545 and pantoprazole.
Authors: Jianjun Alan Xiao, Hugh A Coleman, Tarek Sahmoud, Lei Gao, Weili Chong, Sonja McAuley, Catherine Scholz, Antonio Gualberto
Journal: Journal of Clinical Oncology (2021)

e13022 Background: H3B-6545 is a selective, orally available, small molecule antagonist of the estrogen receptor (ER), covalently binding to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated preliminary clinical antitumor activity in breasts cancer patients in phase 1b/2. Methods: This was an open-label phase 1 study to evaluate the relative bioavailability of H3B-6545 from a tablet formulation compared to capsules, and the effect of pantoprazole on the pharmacokinetics of H3B-6545, in healthy post-menopausal women. Subjects were randomized (1:1 ratio) to a combined crossover and fixed sequence 3 periods treatment: A single oral dose (SOD) of 450 mg H3B-6545 fasted on day 1 (capsules or tablets), followed by a 4-day washout; A SOD of 450 mg H3B-6545 fasted on day 5 (crossover formulation from the first period), followed by a 4-day washout; daily oral doses of 40 mg pantoprazole on days 9 to 15 with coadministration of a SOD of 450 mg H3B-6545 (tablets) on day 15. Results: A total of 16 subjects were enrolled and received at least one dose of H3B-6545 and 15 subjects completed all 3 periods. One subject assigned to the tablet/capsule treatment sequence withdrew from the study due to subject decision on day 13 (Period 3), following completion of Period 1 (H3B-6545 tablet) and Period 2 (H3B-6545 capsule). Following a SOD of H3B-6545 capsules alone, tablets alone, or tablets at steady-state QD of pantoprazole, H3B-6545 geometric mean Cmax was about 1070, 1120 and 1330 ng/mL, respectively, AUC was about 16600, 17500 and 18300 ng.h/mL, respectively, half-life was about 11.0, 11.0 and 10.2 hours, respectively, and the median Tmax was about 3.0, 4.0, and 2.0 hours post dose, respectively. The ratio (capsule/tablet) of Cmax and AUC was both about 0.95; steady-state pantoprazole QD increased H3B-6545 Cmax by 20% with no change in AUC. Nine subjects (56.3%) reported at least 1 TEAE during the study with constipation being the most common (43.8%); all TEAEs were mild in severity. There were no SAEs reported. Conclusions: Plasma PK of H3B-6545 is similar between tablets and capsules, and in the absence or presence of pantoprazole. Concurrent use of gastric acid reducers had a minimal effect on H3B-6545 exposure and was not considered clinically meaningful.
Adolescents’ Experiences, Emotions, and Coping Strategies Associated With Exposure to Media-Based Vicarious Racism
Authors: Nia Heard-Garris, Patricia O. Ekwueme, Shawnese Gilpin, Kaitlyn Ann Sacotte, Leishla Perez-Cardona, Megan Wong, Alyssa Cohen
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Adolescents frequently encounter racism vicariously through online news and social media and may experience negative emotional responses due to these exposures. To mitigate potential adverse health impacts, including negative emotional health, it is important to understand how adolescents cope with these exposures. <h3>Objectives</h3> To examine adolescents' responses to online and media-based vicarious racism exposure and to explore coping strategies, particularly positive coping strategies, that may be used to combat negative emotions. <h3>Design, Setting, and Participants</h3> This qualitative study rooted in phenomenological research methods conducted 4 semistructured focus groups, with 3 to 6 English-speaking adolescents (aged 13-19 years) in each group, between November 2018 and April 2019. Focus groups were facilitated by 2 research team members. The study was conducted at community sites and youth organizations in the greater Chicago, Illinois, area. Interview transcripts were analyzed thematically. <h3>Exposures</h3> Lived experiences of media-based vicarious racism. <h3>Main Outcomes and Measures</h3> Focus group participants shared their experiences with media-based vicarious racism online, including their responses to exposure and the coping strategies used. <h3>Results</h3> Four focus group sessions were conducted with a total of 18 adolescents. Participants had a mean (SD) age of 16.4 (1.6) years. Overall, 7 participants (39%) self-identified as Black/African American, 8 (44%) as Hispanic/Latinx, and 3 (17%) as White individuals; 7 (39%) were in grades 7 to 9, 8 (44%) in grades 10 to 12 grade, and 3 (17%) at the college or university level. Central themes emerged related to adolescents' experiences, including their emotional and coping responses to media-based vicarious racism. Many participants reported helplessness as a major negative emotion associated with these exposures. Activism was endorsed as a key positive coping strategy that participants used, including online and in-person modalities. <h3>Conclusions and Relevance</h3> The findings from this qualitative study suggest adolescents may experience helplessness as a primary negative emotion after exposure to media-based vicarious racism and activism may serve as a coping mechanism. Activism may represent an important and constructive means by which adolescents cope with and combat structural racism, mitigate negative emotions, and potentially prevent adverse health effects.
Survival time in urban center breast cancer patients with CNS metastasis with or without visceral metastasis.
Authors: Miriam Pearl Klahr, Junwen Deng, Jesus Del Santo Anampa Mesias
Journal: Journal of Clinical Oncology (2021)

1088 Background: There is limited data about the role of isolated central nervous system (CNS) metastasis (mets) in patients with breast cancer (BC), since prior studies evaluated BC patients with CNS plus visceral mets. Furthermore, though Black race is associated with worse BC outcomes, there are few studies on CNS mets that predominantly included racial and ethnic minorities in their cohorts. Our study compares overall survival (OS) in BC patients with CNS involvement with and without visceral mets in an underrepresented patient population. Methods: This is a retrospective case series study. We used Montefiore’s Clinical Looking Glass software to identify patients. Inclusion criteria were females age ≥18 years at our institution with the diagnosis of BC and CNS mets between 3/31/1997 to 3/31/2019. Chart review was conducted to obtain clinical-pathological features, including date of diagnosis, treatment, clinical course, and survival status. Patients with BC and CNS mets were divided into two cohorts, those with additional mets limited to bone and lymph nodes but without further visceral spread (CNS-NV), and those with CNS mets plus visceral mets (CNS-V). Kaplan-Meier methods were used to analyze the median OS. Results: Our study included a high proportion of underrepresented minorities (n=177); 46.3% were Black, 10.7% were White, and 34.5% were Other Race; besides, 28% were Hispanic. Mean age at diagnosis of CNS mets was 58 years (SD = 12.9). 62.1% were estrogen receptor (ER) and/or progesterone receptor (PR) positive, 27.1% were HER2 positive; and 19.8% were ER, PR and HER2 negative. Mean number of chemotherapy and endocrine therapy lines before CNS mets were 2 (IQR = 1-2) and 1 (IQR = 1-2), respectively. CNS-NV and CNS-V cohorts included 35 and 142 patients, respectively. Patients with CNS-NV had longer OS than CNS-V (2118 vs. 1120 days, p=0.02). Further subgroup analysis for group CNS-NV was performed based on treatment modality. In this cohort, OS was not significantly different between patients who did and did not receive chemotherapy (n =35, mean OS 1509 vs. 960 days, p = 0.49). In addition, OS was not significantly different between patients who received and did not receive endocrine therapy (n = 24, mean OS 857 vs. 1394 days, p = 0.4). Finally, OS did not significantly differ between patients who did and did not receive anti HER2 treatment (n = 11, 1753 vs. 849 days, p = 0.15). Conclusions: Minimal research has been conducted on breast cancer patients with CNS mets and distal involvement limited to the bones or lymph nodes. In a heterogenous racial and ethnic population, patients with BC and CNS mets have prolonged OS if the extent of distal involvement is limited to the bones or lymph nodes, compared to those with visceral mets. More research with larger sample sizes is needed to confirm our findings, which may help to de-escalate and tailor treatment for patients with CNS mets.
Characterizing advance care planning, palliative care utilization, and location of end-of-life for adult allogeneic hematopoietic stem cell transplant recipients.
Authors: Stephanie Hoffman, Pavan Reddy, John Martin Magenau, Attaphol Pawarode, Brian Parkin, Sarah Marie Anand, Monalisa Ghosh, John Joseph Maciejewski, Darren Patrick King, Mary Riwes
Journal: Journal of Clinical Oncology (2021)

7034 Background: The impacts of advance care planning (ACP) on end-of-life (EOL) outcomes in allogeneic hematopoietic stem cell transplant (allo HCT) recipients are not well known. ACP includes advance directive (AD) completion, and palliative care (PC) consultation. Using these two components, we aimed to explore the current state of ACP and its impact on EOL outcomes in allo HCT recipients to provide the groundwork for future prospective studies. Methods: We performed a retrospective study of deceased adult patients who underwent allo HCT between December 2015-December 2019. We summarized patient characteristics, the rate of AD completion, PC consultation, and location of end-of-life (EOL). Univariate and multivariate analyses were performed to evaluate patient characteristics that may be associated with AD completion, PC consultation and assess the impact of these two factors on location of EOL. Results: See Table for summary of patient characteristics. Of the 125 patients included, we found that 66% (n = 82) completed ADs. All patients with ADs completed them prior to undergoing transplant and never modified them. The majority of patients (84%) with an AD expressed the desire to avoid life-sustaining treatment in the event of terminal illness or irreversible coma. PC was consulted for 46% (n = 58) of patients within 6 months prior to time of death (TOD). Regarding location of EOL, 30% of all patients died in the hospital (non-ICU), 20% in the ICU, 38% at home with hospice, and 10% in a hospice facility. Patients with ADs appeared more likely to die outside of the hospital compared to those without (53% vs. 44%, p = 0.4506). By multivariate analysis, there were no significant patient characteristics associated with the presence of an AD or PC consultation. After adjusting for age and comorbidity index, we found that patients with an AD were significantly more likely to die outside of the ICU (OR 3.0, 95% CI 1.2-7.5, p = 0.02), an effect that was further amplified in patients who both had an AD and received PC consultation at any point (n = 30, p = 0.0077). Conclusions: Our findings highlight the importance of ACP for EOL outcomes in the allo HCT population. While the rate of AD completion in our study population is higher than that of prior studies, future prospective studies aimed to improve the rate of ACP are needed.[Table: see text]
Healthcare utilization and costs in hepatocellular carcinoma (HCC) patients treated at a large referral center in Washington (WA) State.
Authors: Veena Shankaran, Shasank Chennupati, Hayley Sanchez, Qin Sun, Abdalla Aly, Healey Marcus, Brian S. Seal
Journal: Journal of Clinical Oncology (2021)

e16149 Background: Though the treatment landscape for HCC has changed significantly in the last several years with the refinement of liver-directed therapy techniques and the introduction of multiple new drugs, few studies have investigated the impact of the changing treatment landscape on lifetime treatment costs, particularly in Barcelona Clinic Liver Cancer (BCLC) stage C disease. We therefore sought to investigate real-world clinical characteristics, treatment patterns, healthcare use, and costs in patients with HCC treated at a single high-volume institution in WA. Methods: We conducted a retrospective cohort study of patients diagnosed with HCC between 2007 and 2018 at a single clinical cancer center using a database containing abstracted data from the electronic medical record (EMR) linked to cancer registry data and health claims from commercial insurance plans, Medicare, and Medicaid. We described clinical characteristics, including BCLC stage and Child Pugh score, and treatment patterns. We investigated the mean per patient lifetime treatment costs by BCLC stage using Kaplan-Meier cost estimator methods. Results: The final cohort included 215 patients, majority white (71%), male (68%), and with underlying hepatitis C (61%). Most patients had either Child Pugh A (76%) or B (20%) liver disease and BCLC A (45%), B (20%), or C (19%) stage HCC. Only 40% of BCLC C patients received systemic chemotherapy. Mean per patient lifetime costs were highest in BCLC A ($289,318) and BCLC C ($255,430) patients and lowest in BCLC D ($123,701) patients (Table). Surgical costs, hospital costs, imaging, and outpatient visits were the major contributors to total lifetime costs in BCLC A patients. Chemotherapy costs were highest in BCLC C patients, but still were not the predominant area of spending. Conclusions: In a WA state cohort of HCC patients, mean lifetime costs were highest in patients with BCLC A disease, largely driven by surgery and hospital costs. As utilization of newer and less toxic therapies in BCLC C patients increases, mean lifetime costs in this group may surpass other stages.[Table: see text]