tbuckley/cabot-search huggingface dataset:
Treatment trends with immune checkpoint inhibitor (ICI) therapy in older adults with lung cancer.
Authors: Christine Marie Walko, Allison Dickey, Alison A. Motsinger-Reif, Elizabeth Scholl, Howard L. McLeod, Robert Sean Hauser, G J. Van Londen, Harpreet Singh, Jody Simon
Journal: Journal of Clinical Oncology (2020)

e24016 Background: ICI therapy has become the standard of care for the treatment of most types of advanced lung cancer with an average age at diagnosis of 70 years old (yo). The objectives of this study were to describe the demographics and practice patterns of real-world ICI usage in lung cancer patients &gt; 70 yo. Methods: We conducted a retrospective, observational cohort study utilizing statistically deidentified data sourced from CancerLinQ Discovery® ( www.cancerlinq.org/solutions/researchers ): Lung Cancer (2014-2019), October, 2018 data set release, American Society of Clinical Oncology’s (ASCO’s) CancerLinQ LLC. Of the 1632 patients in this data release, only those patients who received a single agent ICI of nivolumab, pembrolizumab or atezolizumab and had a known birthdate were included in the analyses. Results: The majority of the 1632 patients in the data set were male (46.9%) and Caucasian (43.4%), although a substantial percentage of patient Gender and Race data was not known (14.5% and 43.1% respectively). The majority of the patients were treated in the southern part of the United States (52.6%) and the median ages for adenocarcinoma and squamous cell carcinoma histologies were 66 and 70, respectively, with interquartile ranges of 59-74 and 63-76. In the analyses, the major delineator was age at 70 yo, where age is based on when a patient received their first ICI dose. For patients &lt; 70 yo, the mean (max) number of cycles in patients who received atezolizumab, nivolumab and pembrolizumab was 5.4 (24), 8.7 (62) and 7.7 (32), respectively and for patients &gt; 70 yo was 4.6 (30), 8.1 (64) and 6.5 (23), respectively. The median overall survival for patients &lt; 70 yo who received atezolizumab, nivolumab and pembrolizumab was 24, 12 and 24 months, respectively and for patients &gt; 70 yo was 24, 12 and 18 months, respectively. Conclusions: The number of cycles and overall survival reported in this real-world dataset were similar between patients older and younger than 70 yo with lung cancer treated with ICI. Limitations included decreased power for multivariate analysis due to suppressed data elements which has been improved in more recent data releases.
Single-institution outcomes with less than two-year anti-PD-1 antibody therapy in metastatic melanoma.
Authors: Tsering G. Lama Tamang, John P. Fruehauf, Samuel Ejadi
Journal: Journal of Clinical Oncology (2020)

e22001 Background: Optimal duration of anti-PD-1 antibody therapy remains undefined. Currently, treatment is given up to two years in metastatic melanoma based on clinical trials. However, recent observations suggest that anti-PD-1 antibodies may work as well if given for shorter time periods. To better understand duration of anti-PD-1 antibody treatment, we reviewed outcomes for patients who discontinued immunotherapy earlier than 2 years in our Cancer Center. Methods: This is a retrospective, single-institution review of metastatic melanoma patients who received anti-PD-1 antibodies from January 2010 to December 2019. We further identified the patients discontinuing treatment before completion of 2 years for reasons other than disease progression. Duration was categorized into three groups: &lt; 6 months (A), 6-12 months (B) and &gt; 12 months (C) and outcomes were analyzed. Progression free survival (PFS) was defined as the time from the initiation of anti-PD1-therapy to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Results: 25 patients with mean age 69 years (49-91; N = 19 &gt; 60yo) were identified. Number of patients who received anti-PD-1 antibodies were N = 8, N = 9 and N = 8 in in groups A, B and C respectively. 44% of patients discontinued treatment after achieving either partial or near complete remission, whereas the remaining 66% of patients discontinued treatment due to adverse events. Majority of patients who stopped treatment due to adverse events were older than 60 (71.4%). In 29 months of median follow up (range 11-54), none of patients who received treatment in group B progressed, whereas in groups A and C, 25% percentage progressed in each group with 80% PFS at 12.8 months and 88% PFS at 26 months respectively. 12.5% of patients in group A had progression at 12 months follow up, where no progression was noticed in groups B and C during the same time period. Conclusions: Retrospective analysis of our experience supports other retrospective findings that treatment with anti-PD-1 antibodies more than 12 months might not add further benefit in responding or non-progressing older patients though further study with longer follow up is required.
INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors.
Authors: Erminia Massarelli, Ani Sarkis Balmanoukian, Maria Vieito, Christophe Le Tourneau, Tatiana Hernandez-Guerrero, Jose Manuel Trigo, Raid Aljumaily, Michael Jon Chisamore, Debra Rogan, Ruby Sung, Courtney Henry, David Turner, Sapna Yadavilli, Sonia Franco, Catherine Elizabeth Ellis, Marc S. Ballas, Axel Hoos, Danny Rischin
Journal: Journal of Clinical Oncology (2020)

6544 Background: The KEYNOTE-048 study (Burtness, at al. Lancet 2019;394:1915–28) led to approval of PE in combination with 5-FU/plat for first-line (1L) treatment of head and neck squamous cell carcinoma (HNSCC). The Phase I INDUCE-1 study (NCT02723955) has shown that GSK609±PE has a manageable safety profile in patients (pts) with advanced solid tumors (Hansen, at al. Annals of Oncology 2018;29[suppl_8]:viii404) and that GSK609 combined with PE has anti-tumor activity in pts with anti-PD-1/L1-naïve HNSCC (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). To evaluate the safety of GSK609±PE in combination with 5-FU/plat, we initiated additional safety cohorts. Methods: Pts eligible for GSK609+5-FU/plat had a diagnosis of advanced selected solid tumors and ≤5 prior lines of systemic therapy. Pts eligible for GSK609+PE+5-FU/plat had a diagnosis of recurrent or metastatic 1L HNSCC deemed incurable by local therapies. 5-FU/plat was administered every 3 weeks (Q3W) for 4-6 cycles (Burtness, at al. Lancet 2019;394:1915–28); GSK609 24 or 80 mg ±PE 200 mg were administered Q3W for up to 2 years/35 cycles or until disease progression or unacceptable toxicity. Results: Twenty-nine pts were enrolled in the 5-FU/plat safety cohorts: 10 pts in the GSK609+5-FU/plat cohort and 19 pts in the GSK609+PE+5-FU/plat cohort. With GSK609+5-FU/plat, 9/10 (90%) pts experienced ≥ 1 adverse event (AE). Of 32 AEs of any grade, 9 were Grade ≥3 and 3 were serious AEs (SAEs). Two of the 3 SAEs were related to study treatment (oral mucositis and febrile pancytopenia). With GSK609+PE+5-FU/plat, 18/19 (94.7%) pts experienced ≥ 1 AE. Of 119 AEs of any grade, 24 were Grade ≥3 and 15 were SAEs. Of the 15 SAEs, 11 were related to study treatment (febrile neutropenia [n=4], colitis [n=2], diarrhea [n=1], vomiting [n=1], acute kidney injury [n=1], cardiac chest pain [n=1] and lung infection [n=1]). For all cohorts, no Grade 5 AEs were observed. For 10 pts evaluable for confirmed best overall response in all cohorts, 2 pts had partial response, 6 pts had stable disease and 2 pts were nonevaluable. No difference in GSK609 exposure was observed relative to GSK609 monotherapy. Conclusions: The safety profile of GSK609 in combination with 5-FU/plat±PE is manageable. Most AEs were Grades 1 or 2 and consistent with PE and chemotherapy toxicities. Continued follow-up to investigate long-term safety and efficacy of this combination is warranted. Clinical trial information: NCT02723955 .
Cost effectiveness of combination ipilimumab-nivolumab in advanced non-small-cell lung cancer.
Authors: Patrick T Courtney, Anthony T Yip, Daniel R Cherry, Mia A Salans, Abhishek Kumar, James Don Murphy
Journal: Journal of Clinical Oncology (2020)

e19387 Background: The combination of nivolumab and ipilimumab was found to improve overall survival compared to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the Checkmate 227 trial. However, nivolumab and ipilimumab are significantly more expensive than chemotherapy, and given the high incidence of advanced lung cancer, incorporating dual checkpoint inhibitors into the standard of care could have substantial economic consequences. In this study, we evaluated the cost effectiveness of combination ipilimumab and nivolumab for the treatment of advanced NSCLC. Methods: We designed a Markov model simulating the three treatment arms of the Checkmate 227 trial: nivolumab plus ipilimumab, nivolumab monotherapy, and chemotherapy. Transition probabilities, such as disease progression, survival, and treatment toxicities, were derived from trial data. Costs (in 2019 United States dollars) and health utilities were estimated from published literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated, with results less than $100,000/QALY considered cost-effective from a healthcare payer perspective. We assessed model uncertainty with one-way and probabilistic sensitivity analyses. Results: In our base-case model, nivolumab and ipilimumab combination therapy increased overall cost by $227,700 and improved effectiveness by 0.55 QALY compared to chemotherapy, resulting in an ICER of $413,400/QALY. Nivolumab monotherapy increased overall cost by $98,500 and improved effectiveness by 0.05 QALY compared to chemotherapy, resulting in an ICER of $1,885,400/QALY. Our model was most sensitive to both the cost and duration of dual immunotherapy. Combination immunotherapy became cost effective at an ICER under $100,000/QALY if monthly costs of treatment were reduced from $26,586 to $8,844 (a 67% reduction) or if maximum allowed duration of immunotherapy was reduced from 24 to 4 months. The model was not sensitive to assumptions about survival differences between the study arms. Probabilistic sensitivity analysis showed that at a willingness-to-pay threshold of $100,000/QALY, dual immunotherapy was less cost-effective than chemotherapy 99.99% of the time. Conclusions: Combination nivolumab and ipilimumab immunotherapy is not cost-effective at current prices despite increasing overall survival for patients with advanced NSCLC.
Genomic architecture of gallbladder cancer: Results of a first prospective study.
Authors: Amol Patel, H P Singh, Suresh Pandalanghat, Manish Kumar, Bhupesh Guleria, Shivashankara Swamy Mathighatta Shivarudraiah
Journal: Journal of Clinical Oncology (2020)

e16628 Background: Rarity in western countries precluded Gallbladder cancer (GBC) from prospective research. Comprehensive Genomic profiling carries potential to determine oncogenic pathways, driver mutations and possible resistance mechanisms. This study is evaluating the role of comprehensive genomic profiling and role of targeted therapies therein. Methods: This is a single center, prospective, study conducted from Aug2018-Dec2019. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture based comprehensive genomic profiling was performed by Foundation Medicine CDx. Microsatellite instability and PDL1 expression were studied. Results: Median age was 56 years (range:26-83) with male to female ratio of 1:1.6. NGS information was available for 50 patients. ERBB pathway was aberrated in 44% of patients. ERBB2 &amp; ERBB3 amplification was seen in 9(18%) and 2(4%) patients respectively. ERBB2 mutations were present concurrently with amplification in 3 patients. MET amplification was present in 3 (6%) PIK3CA mutations were seen in 14% of cases. PIK3CA mutations were independent of ERBB aberrations. FGFR2 mutation, FGFR2 and FGFR3 amplification was present in one patient each. NF1 and NF2 mutations were seen in three and two patients respectively. Median TMB (n = 39) was 5 mut/Mb with range of 1-14 mut/Mb. PDL1 (n = 31) of ≥ 1% was present in 32% of cases and it ranged from 1-100%. MSI (n = 39) was stable in all cases. Other somatic mutations and/or amplifications are shown in Table. Conclusions: GBC is enriched in 28% of patients with ERBB2 &amp; ERBB3 amplifications and/or mutations. FGFR2 mutation is rare in GBC. PIK3CA aberrations are common. Phase 2 trial of frontline Trastuzumab combined with chemotherapy is ongoing. [Table: see text]
Investigation of immune repertoires in thymoma.
Authors: Priyadarshini Pathak, Mary Cox, Utpal P. Dave, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2020)

e21117 Background: Paraneoplastic autoimmune manifestations are seen in 30 to 40% of thymoma cases. Thymus plays the main role in T- cell maturation with ‘negative selection’ of autoreactive T-cells. Due to reasons not well understood, this function is deranged in thymomas resulting in dysregulation of immune function, loss of ‘self-tolerance’ and autoreactivity. The low cost and high-throughput of next generation sequencing techniques now make it feasible to analyze extensive T-cell receptor(TCR) gene rearrangements in peripheral blood lymphocytes. Methods: 40 patients with thymoma were identified between December, 2010 and September, 2019 at Indiana University. Whole blood samples were collected after diagnosis of thymoma but prior to thymectomy. 20 patients developed paraneoplastic manifestations at some point during the disease course. Genomic DNA was isolated from whole blood samples and TCR analysis performed using a commercially available next generation sequencing assay. This was compared with the control population of 20 patients who did not demonstrate any paraneoplastic features during their disease course. Patients were matched based on age, clinical stage and WHO classification. Results: Paraneoplastic manifestations seen in the 20 patients included Myasthenia Gravis (n = 12), Good’s Syndrome (n = 2), immune mediated cytopenia (n = 3) including pure red cell aplasia, pure white cell aplasia and thrombocytopenia, neurologic manifestations such as encephalitis (n = 2), Autoimmune Autonomic Neuronopathy(n = 1) and Isaac’s Syndrome (n = 2). Some patients also demonstrated more than one paraneoplastic syndrome. The onset and course of these manifestations varied; onset prior to diagnosis of thymoma, onset after thymectomy and improving or worsening clinical features after thymectomy. Since the exact mechanism of autoimmunity is still unknown, we attempted to detect differences in TCR subsets between these two groups. Our study shows that it is technically feasible to interrogate the peripheral blood lymphocytes of thymoma patients for TCR gene clonality and diversity. Conclusions: Diverse autoimmune syndromes can be described in thymoma patients with varying clinical course and severity. Although our study is underpowered, TCR gene sequencing is efficient and may not only improve our understanding of these paraneoplastic syndromes but also identify biomarkers for their diagnosis. Our research could also potentially lead to development of targeted treatment options in the future based on TCR manipulation.
以病人为中心是21世纪医院发展的核心战略
Authors: 吴春容
Journal: BMJ (2004)

医疗服务主要针对病人,而不是躯体、系统、器官和疾病,所有的疾病都是人的疾病,因此,医疗服务必须以病人为中心,而不是以疾病为中心.由于医学院校只有关于躯体、心理、社会、疾病、健康等课程,而没有关于病人的课程,所以我们目前的医学毕业生们往往缺乏人文科学的知识,不能把病人看成整体的人,头痛医头,脚痛医脚,只会看病不会看人,只治病不治人,只有技术缺乏艺术.我们的临床医生也往往只会看病(躯体的病、心理的病等)而不会看人,只会治病而不会治人。
A phase I/II study of GB1275, a first-in-class oral CD11b modulator, alone, and combined with pembrolizumab in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36).
Authors: Drew W. Rasco, Johanna C. Bendell, Andrea Wang-Gillam, Wungki Park, Eileen Mary O'Reilly, Lei Zhou, Anna Galkin, Laura L Carter, David Nickle, Jack Li, Beatrice Ferguson, Marya F. Chaney, Jakob Dupont, Wells A. Messersmith
Journal: Journal of Clinical Oncology (2020)

3085 Background: GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. When combined with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models [Panni RZ, et al. Sci Transl Med. 2019 Jul 3;11(499)]. This ongoing first-in-human study consists of dose escalation of GB1275 monotherapy (Regimen A), GB1275 + pembrolizumab (Regimen B), and GB1275 + nab-paclitaxel + gemcitabine (Regimen C), followed by Phase 2 expansion in newly diagnosed metastatic pancreatic, MSS colorectal, and PD-L1-positive gastric/GEJ cancers. Here we report interim results of the dose escalation portion of the trial. Methods: The dose escalation phase is based on a standard oncology phase 1, 3+3 design. Cohorts of 3 to 6 patients (pts) with histologically confirmed locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, prostate, or breast cancer were sequentially assigned to ascending dose levels of GB1275 taken orally twice daily (BID) in 1 of 3 regimens: Regimen A was initiated first; Regimen B commenced after completion of the first two cohorts of Regimen A, and Regimen C will be initiated when Regimen A is completed. Dose escalation was based on assessment of safety including dose-limiting toxicity (DLT). Serial blood and tumor samples were collected for pharmacokinetic (PK) and biomarker analyses. Results: As of January 21, 2020, 13 pts were treated, with 3 each in Regimen A (GB1275 100mg, 200 mg and 400 mg BID) dose levels and 4 in Regimen B with GB1275 100 mg BID + pembrolizumab. No DLTs have been reported. GB1275 treatment-related adverse events were reported in 5 pts; all were Grade 1 in severity. Preliminary PK analyses showed a mean elimination half-life of ~7 hours. Reduction in peripheral MDSCs was observed in the majority of pts with serial samples. Biomarker analysis in serial tumor tissue is ongoing. Conclusions: Preliminary data show minimal treatment-related toxicities with the studied regimens. PK data support BID dosing. Dose escalation is ongoing. Updated data will be presented. Clinical trial information: NCT04060342 .
Determining the unmet survivorship needs in patients with head and neck cancer: A prospective, longitudinal study.
Authors: Meredith Elana Giuliani, Jessica Weiss, Jennifer M. Jones, Alexander Toulany, NaaKwarley Quartey, Janet Papadakos, Jolie Ringash
Journal: Journal of Clinical Oncology (2020)

e24088 Background: Head and neck cancer patients commonly have unmet needs. Our purpose was to determine the number, type, and predictors of unmet survivorship needs in patients with head and neck cancer over their cancer journey. Methods: Patients with primary, non-metastatic head and neck cancer were prospectively enrolled prior to curative intent treatment (surgery, radiation and or systemic therapy in any combination). Patients completed baseline demographics, the Cancer Survivors' Unmet Needs Measure (CaSUN) and the FACT-HN and then again 3, and 6 months post-treatment. Mean unmet needs at each time point were calculated. Univariable and stepwise multivariable analyses of predictors for number of unmet needs were performed at each time point. Results: Among 187 participants, median age was 64 (31-88) and 148 (79%) were male. Education was beyond high school in 117 (63%) and 63 (41%) were working at diagnosis. Most patients had oropharynx (n = 84; 46%), hypopharynx/larynx (n = 40; 22%) or oral cavity (n = 28;15%) cancers. At least one unmet need was reported by 68%, 52%, and 56% at baseline, 3 and 6 months. The mean number of unmet needs was 7.5 ± 9.1 at baseline, 3.8 ± 6 at 3 months and 5.4 ± 8.5 at 6 months. Higher education level [3.24 (0.24,6.24); p = 0.035] and worse QOL [-0.14 (-0.22,-0.06); p &lt; 0.01] were associated with increased survivorship unmet needs on multivariable analysis at baseline. Worse QOL was associated with increased survivorship unmet needs on multivariable analysis at 3 [-0.21 (-0.31,-0.12); p &lt; 0.01] and 6 months [-0.27 (-0.49,-0.06); p &lt; 0.01]. Table describes the top unmet needs. Conclusions: A high proportion of patients with head and neck cancer have unmet needs, more commonly in patients with poorer quality of life. Post-treatment, unmet needs were more often related to treatment toxicities and their impact on quality of life. [Table: see text]
Modulation of radiation biomarkers in a randomized phase II study of <sup>131</sup>I-MIBG with or without radiation sensitizers for resistant/relapsed neuroblastoma.
Authors: Kevin M. Campbell, Susan Groshen, Araz Marachelian, Sharmistha Pal, Daphne A. Haas-Kogan, Mark Kellogg, Angela Clare Evans, Matthew A. Coleman, Julie R. Park, Meaghan Granger, Katherine K. Matthay, Steven G. DuBois
Journal: Journal of Clinical Oncology (2020)

e22514 Background: 131 I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical agent, has demonstrated efficacy as a single agent for patients with neuroblastoma. Recently, trials have focused on MIBG combination strategies, though little is known about impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline and 72 hours after MIBG infusion and determined plasma flt3 ligand, serum amylase, gamma-H2AX levels, and gene expression for key transcripts. We plotted relative change from baseline and evaluated association of marker modulation by treatment arm and clinical response using NANT response criteria. Results: The cohort included 65 patients who had at least one biomarker available for analysis (19 Arm A; 24 Arm B; 22 Arm C). Across all arms, plasma flt3 ligand and serum amylase were significantly positively modulated while BCLXL/BCL2L1 and BCL2 gene expression demonstrated significant negative modulation by 72 hours after MIBG infusion compared to baseline (p &lt; 0.001 for all markers). For patients randomized to Arm B, we observed significantly greater positive modulation of Flt3 ligand (geometric mean fold change 4.21 for Arm B vs. 2.22 and 2.08 for Arms A and C, respectively; p &lt; 0.001) and significantly greater negative modulation of BCLXL/BCL2L1 (geometric mean fold change 0.11 for Arm B vs. 0.55 and 0.43 for Arms A and C, respectively; p &lt; 0.001). There were no statistically significant associations of differential modulation of a specific biomarker with higher likelihood of response (partial response or better), though there was a trend to suggest that responders had greater gamma-H2AX modulation (p = 0.053). Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after MIBG treatment, with differential modulation when chemotherapy is combined with MIBG. Analysis of additional markers and additional samples is ongoing. Clinical trial information: NCT02035137.