tbuckley/cabot-search huggingface dataset:
New drug approvals and their effect on performance for participants in the Oncology Care Model.
Authors: Larry Edward Bilbrey, Stephen Matthew Schleicher, Basit Iqbal Chaudhry, Andrew Yue, L. Johnetta Blakely
Journal: Journal of Clinical Oncology (2021)

e13525 Background: The Oncology Care Model (OCM) is an oncology-specific value-based care model that holds participating practices accountable for all costs of care. Medicare implements quantitative adjustments to model target costs in OCM, including a trend factor to reflect aggregate cost growth and a novel therapy adjustment for new indications. However, it is unclear how well these adjustments account for the emergence of new therapies that are evidence based and influence standard of care for an individual cancer type. We sought to investigate this by studying the impact that FDA approval for brentuximab vedotin (BV) in the first line setting in March 2018 had on OCM practice performance in Hodgkin’s Lymphoma (HL). Methods: We identified all HL OCM episodes attributed to Tennessee Oncology (TO), a large community oncology network of over 90 oncologists, during performance periods (PP) 3 through 6. HL episodes within the lymphoma bundle were identified through the use of individual ICD-10 coded diagnoses on claims for antineoplastic infusions and E&amp;M visits. Using OCM performance data, our electronic health record, and claims data analytics software, we calculated average episode target costs, drug spending by drug type, and hospitalization costs to determine key determinants of OCM performance. Results: During the study period, there were 577 episodes of lymphoma attributed to TO, of which 28 were for patients with HL. TO’s OCM performance in HL was significantly under target in PP4 (under target by $13.5K) and significantly over target in PP5 (over target by $32.1K) after the updated BV FDA approval. Average episode spending on BV increased by over $45K during this timeframe, while OCM target cost increased only by approximately $19K. Despite the change in OCM performance, hospitalization costs and hospice utilization remained relatively stable. Conclusions: In the OCM, despite quantitative payment factors that in principle are intended to adjust target prices to reflect changing cost dynamics, significant gaps exist. These gaps can inappropriately shift risk to providers for the appropriate use of new indications, including those that change standard of care. The example of brentuximab vedotin in HL illustrates the difficulty in reaching performance benchmarks due to dynamics associated with the rising cost of drugs. Further methodological changes are needed in future oncology value-based care models to ensure accurate prediction of rapidly changing treatment costs for appropriate therapies. Hodgkin’s lymphoma OCM payment period cost and utilization comparison data.[Table: see text]
Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.
Authors: Jeffrey Sum Lung Wong, Gin Wai Kwok, Vikki Tang, Bryan Li, Roland Ching-Yu Leung, Joanne Wing Yan Chiu, Ka Wing Ma, Wong-Hoi She, Wing Yan Josephine Tsang, Tan To Cheung, Thomas Yau
Journal: Journal of Clinical Oncology (2021)

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.
Gender bias in academia: A lifetime problem that needs solutions
Authors: Anaïs Llorens, Athina Tzovara, Ludovic Bellier, Ilina Bhaya-Grossman, Aurélie Bidet-Caulet, William K. Chang, Zachariah R. Cross, Rosa Dominguez-Faus, Adeen Flinker, Yvonne Fonken, Mark A. Gorenstein, Chris Holdgraf, Colin W. Hoy, Maria V. Ivanova, Richard T. Jimenez, Soyeon Jun, Julia W.Y. Kam, Celeste Kidd, Enitan Marcelle, Deborah Marciano, Stephanie Martin, Nicholas E. Myers, Karita Ojala, Anat Perry, Pedro Pinheiro-Chagas, Stephanie K. Riès, Ignacio Saez, Ivan Skelin, Katarina Slama, Brooke Staveland, Danielle S. Bassett, Elizabeth A. Buffalo, Adrienne L. Fairhall, Nancy J. Kopell, Laura J. Kray, Jack J. Lin, Anna C. Nobre, Dylan Riley, Anne-Kristin Solbakk, Joni D. Wallis, Xiao-Jing Wang, Shlomit Yuval-Greenberg, Sabine Kastner, Robert T. Knight, Nina F. Dronkers
Journal: Neuron (2021)
Meant to B: B cells as a therapeutic target in systemic lupus erythematosus
Authors: Yemil Atisha-Fregoso, Bahtiyar Toz, Betty Diamond
Journal: Journal of Clinical Investigation (2021)

B cells have a prominent role in the pathogenesis of systemic lupus erythematosus (SLE). They are mediators of inflammation through the production of pathogenic antibodies that augment inflammation and cause direct tissue and cell damage. Multiple therapeutic agents targeting B cells have been successfully used in mouse models of SLE; however, these preclinical studies have led to approval of only one new agent to treat patients with SLE: belimumab, a monoclonal antibody targeting B cell-activating factor (BAFF). Integrating the experience acquired from previous clinical trials with the knowledge generated by new studies about mechanisms of B cell contributions to SLE in specific groups of patients is critical to the development of new treatment strategies that will help to improve outcomes in patients with SLE. In particular, a sharper focus on B cell differentiation to plasma cells is warranted.
Improving feedback for hematologists and oncologists in training.
Authors: Ilana Schlam, Sarah Sewaralthahab, Monica Peravali, Calvin Chou, Timothy D. Gilligan, Irina Veytsman, Aarthi G. Shenoy
Journal: Journal of Clinical Oncology (2021)

11025 Background: Feedback is an integral part of the learning process, allowing learners to remain on course in reaching competence in clinical, research, and interpersonal skills. However, the impact of teaching feedback during hematology-oncology training has not been studied. We aimed to identify barriers in delivering and receiving high-quality feedback in our fellowship program and to create a curriculum aimed at teaching fellows and faculty how to engage in more effective feedback conversations. Methods: This pilot study aimed at determining and addressing perceived barriers to high-quality feedback in the hematology-oncology fellowship program. A pre-intervention questionnaire, consisting of Likert scale and open-ended questions, was administered to identify barriers to giving feedback and to assess satisfaction with the quality of feedback received in our fellowship program. The results of the baseline questionnaire were utilized to build a virtual interactive three-session workshop provided by the ASCO Quality Training Program in which the importance of feedback and methods of providing effective feedback were taught. Topics included feedback set-up, low-inference observation, and a structured approach to reinforcing and modifying feedback. One month after the intervention the participants completed a follow up questionnaire. This project was developed through the ASH Medical Educators Institute. Results: Each questionnaire was completed by 11 participants. The two main barriers to high-quality feedback identified were the discomfort with both giving and receiving feedback, and the lack of protected time. At baseline only 54% of the participants reported they were comfortable giving feedback, increasing to 81% post- intervention. Pre-intervention, 81% of participants reported they did not have protected time for feedback, decreasing to 64% after the intervention and institution of weekly protected time for feedback. Half of the participants reported that the feedback was not actionable in the initial questionnaire, decreasing to 10% post-intervention. Overall, fellows reported that their feedback was mostly focused on notes, followed by presentations and interpersonal skills. Faculty reported that most of the feedback they received was about time management and patient care. Conclusions: This pilot study helped address a major barrier to improvement and growth within our training program and confirmed that feedback skills must be taught and practiced. A 6-hour virtual workshop showed tangible results in the satisfaction with and quality of feedback given to both fellows and faculty. Our findings are salient as we completed the intervention during the COVID pandemic. Limitations of the study include its single-institutional design and sample size. A major challenge anticipated is sustainability, which will be addressed by maintaining periodic lectures and assigning protected time for feedback.
Phase I study of the aurora kinase A inhibitor alisertib in combination with osimertinib in EGFR-mutant lung cancer.
Authors: Collin M. Blakely, Matthew A. Gubens, Gregory M. Allen, Shrusti Shah, Matthew Jereza, Bianca Bacaltos, Sourav Bandyopadhyay
Journal: Journal of Clinical Oncology (2021)

9074 Background: The 3rd generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutant (mt) lung adenocarcinoma (LUAD). However, tumor resistance to osimertinib monotherapy invariably occurs. Activation of Aurora Kinase A (AURKA) drives resistance to osimertinib treatment in preclinical models of EGFR-mutant LUAD and is associated with TKI resistance in patients. Alisertib is a selective AURKA inhibitor with an acceptable safety profile established in early phase clinical trials. Methods: We performed a single institution phase Ia clinical trial of alisertib in combination with the 3rd generation EGFR inhibitor osimertinib in patients with metastatic EGFR-mutant LUAD who had experienced disease progression on osimertinib monotherapy (NCT04085315). The primary objective of the study was to determine the safety and tolerability of alisertib in combination with osimertinib in order to define the maximum tolerated dose (MTD) and to identify a recommended phase 2 dose (RP2D). Secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Utilizing a 3+3 trial design, patients receiving osimertinib 80 mg daily were treated with alisertib using an intermittent dosing strategy of 20-50 mg twice daily (BID) oral alisertib on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle. Results: A total of 10 patients were treated with osimertinib 80 mg and received at least one dose of alisertib. 6 patients were treated at the 30 mg BID and 4 patients at the 40 mg BID intermittent dosing schedule of alisertib. The most commonly reported adverse events (AEs) were diarrhea (70%), fatigue (60%), alopecia (50%) and neutropenia (50%). All AEs, except neutropenia, were grade 1 or 2. Two patients (20%) experienced grade 3 or grade 4 neutropenia; both patients were treated at the 40 mg BID intermittent dose of alisertib. Intermittent alisertib 30 mg BID was identified as the MTD and RP2D in combination with osimertinib 80 mg daily. The ORR was 10% (1/10) and DCR 70% (7/10), with the majority of patients, 60% (6/10), achieving stable disease (SD). 30% (3/10) experienced progressive disease (PD) as their best response. The median PFS was 9.4 months (2.0 months - N.R.). Conclusions: Intermittent dosing of alisertib 30 mg BID on d1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily demonstrates an acceptable toxicity profile. Preliminary efficacy analysis suggests that alisertib + osimertinib may result in clinically meaningful disease control in EGFR-mt LUAD patients whose disease is resistant to osimertinib monotherapy. Clinical trial information: NCT04085315.
One-stop-shop for cancer screening: A model for the future.
Authors: Ezra Bernstein, Shiran Shapira, Shahar Lev-Ari, Ari Leshno, Udi A. Sommer, Lior Galazan, Humaid O. Al-Shamsi, Ido Wolf, Meital Shaked, Mori Hay Levy, Miri Sror, Menachem Moshkowitz, Ori A. Segal, Eyal Gur, Alfred I. Neugut, Nadir Arber
Journal: Journal of Clinical Oncology (2021)

10554 Background: Cancer is the second leading cause of death globally. Early detection will often greatly reduce mortality for many cancers, increase treatment effectiveness, and improve the quality of life for cancer patients, and, by implementing evidence-based prevention strategies, 30–50% of cancers can be prevented. Screening for different cancer types separately is inefficient. A solution is the Integrated Cancer Prevention Center (ICPC), a program with specialists in each discipline who test for multiple cancers during one visit. Methods: This is a prospective cohort study of 17,104 self-referred, asymptomatic patients who visited the Integrative Cancer Prevention Center (ICPC) between January 1, 2006, and December 31, 2019. Clinical, laboratory, and epidemiological data were recorded by multiple specialists. Patients were given follow-up recommendations and diagnoses when appropriate. The primary measure was the detection and staging of new malignant lesions. Secondary measures included cost-benefit and mortality benefit. Results: We screened 8618 men and 8486 women with an average age of 47.11 ± 11.71 years. Of 259 cancers detected through the ICPC, 49 (18.9%) were stage 0, 115 (44.4%) were stage I, 31 (12%) were stage II, 25 (9.7%) were stage III, and 32 (12.4%) were stage IV. Seventeen cancers were missed, only six of which were within the scope of the ICPC, and 189 cancers developed &gt; one year after the last visit to the ICPC. Compared to the stage of detection for cancers in the US, all cancers except for colon were detected at an earlier stage at the ICPC. Lung was the most significant with 86.7% of cancers detected at stage 0, I, or II at the ICPC compared to only 49.3% caught at those stages in the US. Conclusions: This is a proof of concept for a one-stop-shop approach to asymptomatic cancer screening in a multidisciplinary outpatient clinic. It offers evidence that this screening framework can and should be replicated in other healthcare settings and on a national policy level as it saves lives and money. The encouraging results presented here should further the conversation about the utility of screening and add momentum to the movement for increased screening.[Table: see text]
Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics
Authors: Ramón Cacabelos, Iván Carrera, Olaia Martínez, Ramón Alejo, Lucía Fernández‐Novoa, Pablo Cacabelos, Lola Corzo, Susana Rodríguez, Margarita Alcaraz, Laura Nebril, Iván Tellado, Natalia Cacabelos, Rocío Pego, Vinogran Naidoo, Juan C. Carril
Journal: Medicinal Research Reviews (2021)

Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic (SNCA, NUCKS1, ITGA8, GPNMB, GCH1, BCKDK, APOE, LRRK2, ACMSD), mechanistic (DRD2), metabolic (CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, NAT2), transporter (ABCB1, SLC6A2, SLC6A3, SLC6A4) and pleiotropic genes (APOE) influence the DA response to Atremorine and its psychomotor and brain effects. Atremorine enhances DNA methylation and displays epigenetic activity via modulation of the pharmacoepigenetic network. Atremorine is a novel neuroprotective agent for dopaminergic neurons with potential prophylactic and therapeutic activity in PD.
Back to the well: Can patients with advanced non-small cell lung cancer benefit from changing PD-1/PD-L1 inhibitors after progression?
Authors: James Newman, Chung-Shien Lee, Kerri McGovern, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2021)

e21194 Background: Immune checkpoint inhibitors (ICIs) have transformed the standard of care of non-small cell lung cancer (NSCLC) and are capable of inducing a sustained response in a cohort of patients. For those who progress while on ICIs and do not have a targetable mutation, options are typically reduced to chemotherapeutic regimens which have a higher probability of toxicity. In patients with a suboptimal performance status or those who are opposed to receiving chemotherapy and are not eligible or interested in clinical trials, treatments are unfortunately limited. Patients who progress on one ICI do not receive a different ICI as part of standard care in subsequent lines of therapy. Data behind switching ICIs, particularly to those with a different mechanism of action (ie anti-PD-1 followed by anti-PD-L1 or vice versa), are lacking. We evaluated the efficacy of receiving a 2nd ICI in patients with NSCLC. Methods: A single-center, IRB-approved retrospective analysis was conducted of NSCLC patients treated with two different ICIs from March 2015 to July 2020. ICIs were given either in combination with chemotherapy or as monotherapy. Patient and tumoral characteristics, including PD-L1 status (if available) and sequence of ICIs, were captured. A positive PD-L1 was defined as PD-L1 expression &gt; 0%. Progression-free survival (PFS) of each ICI (defined as PFS1 and PFS2) were calculated in months (m) for each patient. Median PFS2 was compared between groups stratified by a cutoff median PFS1 of 3m, sequence of PD-1 and PD-L1 inhibitors, and PD-L1 positive and negative subsets. Mood’s median test was used to compare medians. Results: 26 patients were included in the final analysis. 19/26 patients had a PFS1 &gt; 3m. For this cohort, the median PFS2 was 2.5m (Range: 0.1-36.2) compared to median PFS2 of 1.6m (Range: 0.6-15.9) in patients with PFS1 &lt; 3m (p=0.1847). 15 patients received a PD-1 inhibitor followed by a PD-L1 inhibitor. In this subgroup, the median PFS2 was 1.2m (Range: 0.2-36.2). Alternatively, 7 patients received a PD-L1 inhibitor followed by a PD-1 inhibitor and the median PFS2 in this cohort was 2.3m (Range: 0.1-15.9) (p=0.6471). PD-L1 data was available for 19 patients. 8/19 patients with positive PD-L1 had a median PFS2 of 3.6m (Range: 0.2-13.3) compared to median PFS2 of 1.3m (Range: 0.1-36.2) in patients with negative PD-L1 (p=0.2599). Conclusions: Treatment with a 2nd ICI can potentially provide a modest benefit in patients with advanced NSCLC, and some may even experience a very prolonged response. PFS1, sequence of PD-1/PD-L1 inhibitors, and PD-L1 expression did not show any significant correlation with PFS2. Using a 2nd ICI should be considered for advanced NSCLC patients with diminished performance status or limited treatment options.
Integration of proteomic and clinical data for the prediction of response to immune checkpoint inhibitor therapy in non-small cell lung cancer.
Authors: Yuval Shaked, Michal Harel, Coren Lahav, Eyal Jacob, Itamar Sela, Galit Yahalom, Yehonatan Elon, Ofer Sharon, Iris Kamer, Haim Bar, Adam P. Dicker, Jair Bar, Rivka Katzenelson, Ido Wolf, Maya Gottfried, Mahmud Abu-Amana, Abed Agbarya, Hovav Nechushtan, Mor Tal Moskovitz, Alona Zer
Journal: Journal of Clinical Oncology (2021)

e21110 Background: Immune checkpoint inhibitor (ICI) therapy represents one of the most promising cancer treatments to date. However, despite unprecedented rates of durable response, only a small proportion of patients benefits from this approach. Major efforts are therefore required to characterize treatment resistance mechanisms, as well as to identify reliable biomarkers for response. We have previously shown that in response to various types of cancer therapy, including ICIs, the host may induce pro-tumorigenic processes that can promote therapy resistance. Here we examined systemic host-response proteomic profiles in non-small cell lung cancer (NSCLC) patients, aiming to discover biomarkers for response to ICI therapy and to unravel underlying resistance mechanisms. Methods: As part of our ongoing PROPHETIC clinical trial (NCT04056247), plasma samples were obtained at baseline (T0) and early-on treatment (T1; following the first treatment) from 120 NSCLC patients receiving ICI therapy. Proteomic profiling of the plasma samples was performed using proximity-extension assay (PEA) technology; validation was carried out for a fraction of the samples using ELISA-based arrays. To identify a proteomic signature that predicts clinical outcome, machine learning algorithms were applied following a random separation of the cohort into a discovery set and a validation set. Results: A proteomic signature predictive of response to treatment was identified and validated. Bioinformatic analysis identified potential mechanisms of resistance based on differentially expressed proteins associated with pro-tumorigenic biological processes. Statistical analysis of the clinical data identified multiple novel differential clinical parameters between responders and non-responders, either at baseline or by comparing T0 to T1, which may suggest host-mediated effects. Conclusions: Our study demonstrates the potential clinical utility of analyzing the host response to ICI therapy, in particular for the discovery of novel predictive biomarkers for NSCLC patient stratification. Clinical trial information: NCT04056247.