tbuckley/cabot-search huggingface dataset:
Clinical features and response to immune checkpoint inhibitors (ICIs) in pregnancy-associated melanoma (PAM).
Authors: Daniel Ying Wang, Carina N. Owen, David James Palmieri, Justine Vanessa Cohen, Zeynep Eroglu, Georgina V. Long, Ryan J. Sullivan, Justin M. Balko, Matteo S. Carlino, Alexander M. Menzies, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2019)

9564 Background: Melanoma is one of the most common malignancies diagnosed during pregnancy. Little is known about the clinical outcomes of PAM, in particular, response to ICIs. We performed a retrospective study to assess this issue. Methods: A multicenter retrospective study was performed at 4 large melanoma centers. Patients (pts) with PAM treated with ICIs were identified and examined. Clinical data and molecular data (RNA sequencing, IHC) were explored. PAM was defined as development of advanced melanoma during pregnancy or within 2 years post-partum. Results: 19 pts with PAM were treated with ICIs. Median follow-up was 11.7 months (range 1.4 – 41.9 months). Median age was 29 years (range 16-36). Most pts had a cutaneous primary (N = 17, 89%) including the extremity (N = 8) or trunk (N = 7), and 5% were occult. 11 pts (58%) had a BRAF V600E mutation and 6 (32%) pts received BRAF/MEK targeted therapy. Most pts had prior primary melanoma (N = 12, 63%) and presented with advanced melanoma in the post-partum setting (N = 11, 58%). At advanced presentation, 6 (32%) pts were stage III/M1a and 13 (68%) pts were stage M1b/c/d; 7 (41%) pts had elevated LDH and 13 (68%) had visceral involvement. Among 11 patients treated with combination ipilimumab + anti-PD-1 therapy, 7 (64%) had objective responses (OR) with a 1-year progression free survival (PFS) of 40% and 1-year overall survival (OS) of 100%. By contrast, ICI monotherapy (3 with anti-PD-1/L1 and 4 with ipilimumab) was associated with poorer outcomes (OR in 25% and 33% for ipilimumab and anti-PD-1/L1, respectively). Molecular features (RNA sequencing, immunohistochemistry) will be presented. Conclusions: Patients with PAM represent a unique population and may particularly benefit with combination ICI therapy compared with ICI monotherapy (in a limited sample size). Molecular underpinnings of PAM biology are still being elucidated.
Randomized, double-blind phase III study of pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy: A trial of the ECOG-ACRIN cancer research group (E2810).
Authors: Leonard Joseph Appleman, Maneka Puligandla, Sumanta K. Pal, Wayne Harris, Neeraj Agarwal, Brian Addis Costello, Christopher W. Ryan, Michael Pins, Jill Kolesar, Daniel A. Vaena, Rahul Atul Parikh, Mehmood Hashmi, Janice P. Dutcher, Robert S. DiPaola, Naomi B. Haas, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2019)

4502 Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. &gt; 1 site of resected disease, and by disease-free interval ≤ vs. &gt; 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.
IL-12p40 and MIP3a to predict clinical responses to anti-PD-1 therapy in patients with metastatic melanoma.
Authors: Jesus Vera Aguilera, Courtney L. Erskine, Vera J. Suman, Jonas Paludo, Robert R. McWilliams, Lisa A. Kottschade, Yiyi Yan, Roxana Stefania Dronca, Haidong Dong, Svetomir Markovic, Matthew Stephen Block
Journal: Journal of Clinical Oncology (2019)

9535 Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels &gt;15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.
Hyperprogressive disease in advanced triple-negative breast cancer (aTNBC) treated with immunotherapy (IO).
Authors: Tira Jing Ying Tan, David W. Cescon, Lisa Wang, Eitan Amir, Daniella Vieira, Kaitlyn Zammit, David Warr, Christine Elser, Marcus O. Butler, Albiruni Ryan Abdul Razak, Aaron Richard Hansen, Anna Spreafico, Lillian L. Siu, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2019)

1086 Background: Hyperprogression of disease (HPD), a rapid acceleration of tumor growth rate (TGR) has been reported with IO in other tumor types. Here, we explore HPD in aTNBC. Methods: A retrospective chart review identified aTNBC patients who consented for IO clinical trials at Princess Margaret Cancer Centre between June 2013 and June 2018. Demographic data, medical history, details of trial enrolment and RECIST 1.1 response to study treatment were recorded. Patients with RECIST 1.1 measurable disease on CT scans or physical examination before trial entry, at trial baseline and at protocol-defined interval following IO start were evaluable for TGR as defined by Champiat et al. Clin Cancer Res 2017. HPD defined as a ≥2-fold increase in TGR between baseline and on-trial restaging assessment. Univariable logistic regression used to identify variables [age, co-morbidity index, prognostic index, performance status, distant disease free interval (dDFI), lactate dehydrogenase, no. of metastatic sites, visceral disease and no. of prior treatment lines] associated with HPD. Overall survival (OS) curves were estimated with the Kaplan-Meier method and compared by the log-rank test. Results: 99 patients with aTNBC consented for 15 IO clinical trials, 60% IO monotherapy, 22% chemotherapy+/-IO and 18% IO combinations. Median age 52 (range 25-78), median no. of lines of prior systemic therapy for advanced disease 1 (range 0-8). 15% had de-novo metastatic disease, 58% recurred after a dDFI of &lt; 3 years and 25% after a dDFI of &gt; 3 years. 61% had &lt; 3 metastatic disease sites, and 71% had metastases involving the viscera. 66 received IO treatment, 40 patients (20 monotherapy, 7 IO combination, 13 chemotherapy+/-IO) were evaluable for TGR. Median TGR pre-IO was 74.3 (range -17 – 1680) and post-IO was 2.5 (-71.4 – 223). 4 patients (10%) met criteria for HPD. All 4 treated with monotherapy PD1 inhibitor and received at least 2 further lines of therapy post-trial; 1 patient treated with IO as first-line therapy, 3 in the second or later lines. There was no significant difference in the overall OS of patients with HPD and patients who did not meet definition for HPD HR 0.89, (95% CI: 0.26-3.01; p = 0.41). Univariable analysis did not identify factors associated with HPD. Conclusions: HPD was observed in 10% of aTNBC treated on IO clinical trials. HPD was not associated with worse survival outcomes or known prognostic factors in our analysis.
Artificial intelligence-based clinical decision-support system improves cancer treatment and patient satisfaction.
Authors: Zuochao Wang, Zhonghe Yu, Xuejing Zhang
Journal: Journal of Clinical Oncology (2019)

e18303 Background: Traditional diagnostic model for cancer heavily relies on physicians and their teams’ knowledge. However, under this diagnostic model, patients’ source of information is quite limited. Cancer patients usually fill with negative emotion. Lack of knowledge to the disease and treatment options further leads to less confidence to their treatment outcome. Methods: In order to improve their faith in getting proper treatment and the hope for surviving the deadly disease, we has introduced an artificial intelligence based clinical decision-support system, the Watson for Oncology (WFO), since May-2018. WFO is developed by IBM, it assesses information from a patient’s medical record, evaluates medical evidence, and displays potential treatment options. Our oncologist can then apply their own expertise to identify the most appropriate treatment options. We have generated a new 7-step consultation system with the help of WFO. That include 1: introduce the WFO to patients, 2: patients express their demands and expectations, 3: the oncologist presents patient’s medical condition, 4: discussion with other members in the consultation team, 5: input patients’ information into WFO system and review treatment options, 6: discuss and finalize treatment options with patients, 7: feedbacks form patients after consultation. 70 patients who were hospitalized from May-2018 to Dec-2018 were divided into two groups, 50 patients volunteered to be assigned to the new 7-step consultation system and 20 patients stayed with the traditional diagnostic method to find them treatment options. All patients were followed up by questionnaire. Results: The results showed that patients in the 7-step consultation group presented significantly higher satisfaction rate towards treatment options, confidence level to their health care workers, and willingness to follow the treatment option when compared to patients in the traditional diagnostic group. Conclusions: The WFO assisted 7-step consultation system not only provides a more efficient way to find treatment options, but also improves patients’ understanding to their disease and possible side effects towards the treatment. Most importantly, patients build stronger confidence with their health care team and are willing to believe they will benefit from the treatment plans.
On-treatment changes in tumor-infiltrating lymphocytes (TIL) during neoadjuvant HER2 therapy (NAT) and clinical outcome.
Authors: Stephen James Luen, Gaia Griguolo, Paolo Nuciforo, Christine Campbell, Roberta Fasani, Javier Cortes, Michael Untch, Suling Joyce Lin, Peter Savas, Stephen B. Fox, Serena Di Cosimo, Antonio Llombart Cussac, Evandro de Azambuja, Martine J. Piccart-Gebhart, Lajos Pusztai, Christos Sotiriou, Roberto Salgado, Aleix Prat, Sherene Loi
Journal: Journal of Clinical Oncology (2019)

574 Background: Higher quantity of pretreatment TIL (PT) is associated with improved pCR and EFS in HER2+ early breast cancer (BC). The value of on-treatment TIL is unknown. Methods: The NeoALTTO trial randomized 455 women with HER2+ BC to 12 weeks NAT with trastuzumab, lapatinib or combination with paclitaxel, followed by FEC after surgery. In the PAMELA trial 151 women received 18 weeks NAT with lapatinib and trastuzumab (±hormonal therapy). TIL were quantified on PT and on-treatment (W2) biopsies using the published method on H&amp;E slides, and tested for associations with pCR (logistic regression), EFS and OS (Cox models) in univariate (UV) and multivariate (MV) analyses. The likelihood ratio test assessed added prognostic value to clinicopathological (CP) variables. pCR associations were validated in PAMELA. We investigated enrichment of immune cell subsets using previously published RNAseq data from NeoALTTO. Results: In NeoALTTO, PT and W2 TIL were evaluable in 277/455 (61%). We defined two groups: immune-poor (L+F) and immune-enriched (II+P), see Table. Immune-enriched (41%; 134) vs poor (59%; 164) patients had significantly higher pCR rates (40% vs 21%; UV OR 2.24; 95%CI 1.31-3.85; P = .003; MV P = .009), and added significant value to CP + PT TIL for prediction of pCR (P = .003). This was further confirmed in PAMELA (N = 94/151) (26% vs 6%; UV P = .021; MV P = .028). In NeoALTTO, the immune-enriched vs poor patients had significantly improved EFS (5 yr est 85% vs 60%; UV HR 0.31; 95%CI 0.18-0.54; P &lt; .001; MV P &lt; .001) and OS (5 yr est 91% vs 77%; UV HR 0.40; 95%CI 0.20-0.82; P = .012; MV P = 0.026), and provided significant added prognostic value beyond CP + pCR + PT TIL (EFS P &lt; .001) In NeoALTTO PT samples, II vs F patients had enrichment of DCs, NKs and CD8+ including tissue resident memory cells (P = .009) suggesting requirement of key immune subsets. Further validation by IHC is ongoing. Conclusions: On-treatment TIL identifies patients more likely to achieve pCR and have improved EFS in early-stage HER2+ BC, beyond CP + PT TIL. This information could aid future trial design. Clinical trial information: NCT00553358, NCT01973660. [Table: see text]
Prognostic neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in locally advanced oropharyngeal cancer: a retrospective experience of two institutions.
Authors: Vittoria G. Espeli, Francesco Martucci, Antonella Richetti, Alessia Pastore
Journal: Journal of Clinical Oncology (2019)

e17548 Background: the Neutrophil-to-Lymphocytes ratio (NLR) and the Platelet-to-Lymphocytes ratio (PLR) represent potential prognostic markers in different tumor types. The purpose of our study was to investigate the prognostic role of the pretreatment inflammatory markers NLR and PLR in patients with locally advanced squamous cell oropharyngeal cancer (OPSCC) treated with curative concomitant chemoradiotherapy (CRT). Methods: between 2004 and 2016, all patients with OPSCC diagnosed at the University Hospital of Varese and the Oncology Institute of Southern Switzerland were reviewed retrospectively. CRT consisted of Intensity-Modulated Radiation Therapy (IMRT) to a dose of 66-70 Gy concomitant to 3 doses of 3-weekly cisplatin. Pre-treatment NLR and PLR were registered from blood samples obtained within 14 days before treatment. 3-year disease free survival (DFS) was analyzed. Results: ninety-two patients were identified. Median follow-up was 39 months. Median NLR was 3 and median PLR was 153. The 3 year DFS was 82.9%. Univariate analysis showed that HPV status and PLR were statistically significant factors in determining 3-year DFS (p 0.01 and 0.04 respectively). Multivariate analysis showed that only HPV status was a statistically significant factor for 3-year DFS (p 0.009). High NLR and high PLR were correlated with lower DFS: patients with NLR &gt; 4 had a 3-years DFS of 50% versus 75%in the group with NLR ≤ 4(p = 0.04) and patients with PLR &gt; 150 had a 3-years DFS of 65% versus 82% in the group with PLR ≤ 150 (p = 0.04). Conclusions: in our case series, NLR and PLR were significantly associated with clinical outcome. Additional data are necessary to investigate the prognostic value of inflammatory markers and to identify the ideal cut-off of both markers.
Climate change: overpopulation is the elephant in the room
Authors: Gee Yen Shin
Journal: BMJ (2019)

There is very little to argue against in the editorial by Stott and colleagues.1 Apart from the climate denier fringe, it is received wisdom that climate change is a real phenomenon, it is caused by human activity, and it is an existential threat to almost all life on Earth.

I agree with the response …
HD204: Analytical biocomparability and clinical trial I progression of bevacizumab.
Authors: Jocelyn hii, Xavier Pivot, Lisa Soyeon Park, Michael Kim, Peggy Feyaerts, Kuo Wei Chan, Jeong-Hyeon Lee, Felicia Ang, Martin Demarchi, Pierre Coliat, Philippe Barthelemy, Meher Ben Abdelghani
Journal: Journal of Clinical Oncology (2019)

e15014 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar of the EU-approved and US-licensed Bevacizumab (Avastin) that is approved treatment for a variety of tumour types. Bevacizumab is a recombinant humanized monoclonal antibody (IgG1) that binds to soluble vascular endothelial growth factor (VEGF), thus prevent interaction with VEGF receptors. Due to heterogeneity nature of antibody drug, extensive characterization of antibody from physicochemical and biological properties using multiple bioanalytical assays is required. The development of HD204 from analytical biocomparability to clinical trial I are demonstrated. Methods: Analytical biocomparability in physiocochemical and biological properties of HD204 was compared to Avastin sourced from EU and US using multiple bioanalytical assays as below. Clinical phase I (SAMSON), a randomized, double-blind, single dose and 3-way parallel group was initiated recently to compare pharmacokinetic and to evaluate the safety, tolerability and immunogenicity of HD204, EU-Avastin and US-Avastin. Approximately 120 healthy human subjects (assigned to 3 treatment group) was administered with a single intravenous infusion of 1 mg/kg of either HD204, EU- and US-Avastin. Results: HD204 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. For phase I study, patient recruitment was completed with treatment for come patients initiated but still ongoing. Conclusions: HD204 was shown to be equivalent in all parameters in the analytical biocomparability testing. Clinical Phase 1 trial (SAMSON) is ongoing on and key data from SAMSON trial will be reported in ASCO meeting. [Table: see text]
Real-world effectiveness of approved anticancer agents among Medicare beneficiaries.
Authors: Angela Green, Michael A. Curry, Peter Bach, Sham Mailankody
Journal: Journal of Clinical Oncology (2019)

6589 Background: The overall survival (OS) among elderly patients (pts) treated with novel anticancer agents in the real world may be inferior to the OS reported in pivotal trials for drug approval. Pts ≥ 65 yrs old constitute 60% of cancer pts, yet only 40% of cancer clinical trial participants. Elderly pts have greater comorbidities and experience a higher risk of toxicity from cancer drugs. Using the Surveillance Epidemiology and End Results-Medicare database (SEER-Medicare), we compared the OS among elderly pts treated with FDA-approved cancer drugs for advanced solid tumors to the OS reported in the clinical trial. Methods: We identified cancer drugs FDA-approved for metastatic solid tumors between 1/1/08-12/31/12. In a retrospective analysis, for each indication we identified pts in SEER-Medicare meeting disease eligibility criteria (stage, histology, prior therapies) in the trial associated with approval. Pts were diagnosed with cancer from 2010-2013 with follow-up through 2014. Treatment (tx) was determined from national drug codes in Medicare Part B for intravenous (IV) drugs and Part D for oral drugs. Indications were included if ≥ 30 pts receiving tx met eligibility. Kaplan-Meier methods were used to calculate median OS and cancer-specific survival (CSS) in Medicare pts. Median duration of therapy (DOT) was estimated from date of the first through completion of the last prescription claim for oral drugs and number of cycles for IV drugs. Results: OS data were available and sample size parameters met for 14 drug indications. The median OS among SEER-Medicare pts was shorter than the reported trial OS of tx arms for 13 of 14 drug indications (median difference -7.6 mos, range +3.4 to -28.7 mos). CSS was similar to OS among Medicare pts. Median DOT among SEER-Medicare pts was shorter than the reported trial DOT of tx arms for 13 of 14 indications (median difference -2.9 mos, range 0 to -8.9 mos). Conclusions: The OS and DOT among SEER-Medicare pts treated with FDA-approved cancer drugs was inferior to the reported OS in pivotal clinical trials for nearly all indications analyzed. The shorter DOT among Medicare pts may explain survival differences. Trials leading to regulatory approval may not be generalizable to cancer pts ≥ 65 yrs.