tbuckley/cabot-search huggingface dataset:
Effect of PD1/PD-L1 checkpoint blockade on efficacy of anti-GD2 antibody ch14.18/CHO in neuroblastoma.
Authors: Holger N. Lode, Maxi Zumpe, Madlen Juettner, Sascha Troschke-Meurer, Hans Loibner, Nikolai Siebert
Journal: Journal of Clinical Oncology (2017)

10548 Background: Immunotherapy (IT) with anti-GD 2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients mainly due to induction of GD 2 -specific Ab-dependent cellular cytotoxicity (ADCC). Methods to further enhance the effect are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± scIL-2. Programmed death-1 (PD-1) is an inhibitory receptor expressed by activated T- and NK-cells, and cancer cells express PD-1 ligand. Here, we report for the first time effect and mechanism of PD-1/PD-L1 blockade in the context of ch14.18/CHO-based IT in preclinical models. Methods: Expression of PD-L1 and PD-1 on NB cells and leukocytes was analyzed by RT-PCR and flow cytometry in the presence of ch14.18/CHO or IL-2. Mechanism of PD-L1 induction was analyzed with anti-CD11b Ab. The effect of PD-1/PD-L1 blockade on ch14.18/CHO-mediated anti-NB immune response was evaluated using anti-PD-1 Ab both in vitro (Nivolumab) and in the syngeneic GD 2 + NB NXS2 mouse model (anti-mouse PD-1). Mice (n = 10) were treated with ch14.18/CHO (5x300 µg, i.p.) in combination with anti-PD-1 (8x250 µg, i.p.), and compared to controls. Results: Culture of LA-N-1 (low PD-L1 baseline expression) in the presence of leukocytes and subtherapeutic ch14.18/CHO concentrations for 24h induced strong upregulation of PD-L1 resulting in complete inhibition of ADCC mediated by ch14.18/CHO. Co-incubation with anti-CD11b Ab abrogated this PD-L1 upregulation. Importantly, blockade with Nivolumab reversed the PD-L1-dependent inhibition of ADCC. Mice treated with ch14.18/CHO in combination with PD-1 blockade showed a strong reduction of tumor growth and prolonged survival as well as the highest level of NB cell lysis mediated by serum and leukocytes compared to controls. Conclusions: Ch14.18/CHO-mediated effects upregulate the inhibitory checkpoint PD-1/PD-L1 and combination of ch14.18/CHO with PD-1/PD-L1 blockade results in synergistic treatment effects in mice. This concept will be evaluated in a clinical trial.
A personalized, web-based prognostic tool for resectable gastric cancer.
Authors: Brice Jabo, John W. Morgan, Mayada A. Aljehani, Matthew J Selleck, Albert Y. Lin
Journal: Journal of Clinical Oncology (2017)

e15575 Background: Gastric cancer (GC) mortality remains high, with a 5-year survival of 30 percent. For patients with resectable GC, mortality varies depending on both patient and tumor characteristics. The current study sought to develop a web-based prognostic model to assist patients and health care providers in decision making regarding either surgery-only or adjuvant chemoradiotherapy (CRT). Methods: California SEER data was used and records, including demographic, pathologic, and treatment information, for 2,583 patients diagnosed with stage IB to III GC and treated with either surgery only or adjuvant CRT from 2006 to 2013 were retrieved. Purposeful selection using Cox regression model was used to identify important mortality predictors. Additionally, with simple random sampling, 70% of the data were assigned to the training set and the remaining 30% were assigned to the test set. Furthermore, generalized boosted classification model was trained using the training set and validated using the test set. Area under the curve (AUC) of the receiver operating characteristic (ROC), sensitivity, specificity and accuracy were determined for 5- and 10-year mortality. Results: The median survival was 33 months for patients in the training set, and 32 for the test set. Predictors included in the model were age, ethnicity (Asian/other, Hispanic, non-Hispanic black and non-Hispanic white), T-stage, histology (intestinal, diffuse and other), presence of signet ring (yes/no), proximal location (yes/no), lymph node ratio, and CRT following surgery (yes/no). Validation of the model on the test set showed as follows: AUC, sensitivity, specificity and accuracy of 0.78(95%CI = 0.75,0.82), 0.75, 0.65 and 0.70 for 5-year survival and 0.77(95%CI = 0.74,0.80), 0.79, 0.55 and 0.70 for 10-year survival. Conclusions: The proposed web-based prognostic tool using readily available patient and tumor characteristic provides validated and personalized prognostic information to aide clinicians and patients in GC adjuvant treatment decision process. [Table: see text]
Cardiovascular disease (CVD) risk factors and health behaviors after cisplatin-based chemotherapy (CHEM): A multi-institutional study of testicular cancer survivors (TCS) in the Platinum study.
Authors: Mohammad Issam Abu Zaid, Chunkit Fung, AnnaLynn Williams, Howard D. Sesso, Sarah L. Kerns, Shirin Ardeshir-Rouhani-Fard, Darren R. Feldman, Robert James Hamilton, David J. Vaughn, Clair Beard, Patrick Monahan, Sophie D. Fossa, Lawrence H. Einhorn, Lois B. Travis
Journal: Journal of Clinical Oncology (2016)

10087 Background: TCS are at increased risk of CVD. Few clinical studies have comprehensively evaluated CVD risk factors through physical exams, lipid panels, and health behaviors in North American TCS. Methods: Eligible TCS were < 50 y at diagnosis and treated with only first line CHEM. TCS underwent physical exams, had fasting lipid panels, and completed questionnaires regarding comorbidities and health behaviors. Age, race, and educational status-matched controls (1:1) were chosen from the general population using the 2011-2012 National Health and Nutrition Examination Survey. Odds ratios (OR) of outcomes among TCS vs. controls were estimated using logistic regression models. Results: We evaluated the first 680 enrolled TCS (fasting = 114). Median age at diagnosis was 31 y (range, 15-49) and at clinical evaluation 39 y (range, 19-68). Median time since CHEM was 4 y (range, 1-30). Compared to normative controls, TCS were more likely to be overweight (OR = 1.65; 95% CI 1.26-2.16), have total cholesterol ≥ 240 mg/dL (OR = 2.47; 95% CI 1.29-4.70) and LDL ≥ 160 mg/dL (OR = 3.39; 95% CI 1.18-9.73), and report alcohol use > 2 days/week (OR = 2.12; 95% CI 1.63-2.76). In contrast, they were less likely to have a waist circumference > 40 inches (OR = 0.75; 95% CI 0.59-0.95) or currently smoke (OR = 0.32; 95% CI 0.23-0.45); and more likely to engage in vigorous (OR = 4.21; 95% CI 3.36-5.29) or moderate (OR = 17.0; 95% CI 11.5-24.9) physical activity. TCS were about 3 times more likely to report excellent, very good, or good health compared to controls (P < 0.05). No significant differences were seen comparing HDL, triglycerides, or self-reported hypertension (P > 0.05). Conclusions: Although North American TCS appear more likely to exercise and abstain from smoking compared to normative controls, a greater proportion are overweight and have higher fasting total cholesterol and LDL levels. Health care providers should screen TCS for CVD risk factors, and encourage practices consistent with a healthy lifestyle. Future research should elucidate mechanisms of increased CVD risk and ultimately develop customized prevention and intervention strategies.
Assessment of the clinical utility of chip-based digital PCR for HER2 assessment in formalin fixed paraffin-embedded breast carcinoma tissue.
Authors: Parth Shah, Shiva Murarka, Jacob Sands, Bhavna Mehta, Anupam Joshi, Khushbu Patel, Vipal Parmar
Journal: Journal of Clinical Oncology (2017)

e23120 Background: 15%-25% of breast cancer neoplasms exhibit Human epidermal growth factor receptor-2(HER2) amplification, as the driver mutation.Techniques to identify HER2 amplification include Immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH). Digital PCR (dPCR) has been increasingly explored in determining HER2 status in cases of indeterminate results on IHC, mainly in archived samples. In this study, we aim to demonstrate the clinical utility of the Quantstudio 3D Digital PCR system to evaluate HER2 levels from Formalin Fixed Paraffin Embedded (FFPE) tissue with RNaseP as a control target. Methods: 61 tissue samples were analyzed by IHC and dPCR in parallel in a double blinded manner. IHC equivocal samples were reflexed to FISH and compared to the results obtained from dPCR. Samples suboptimal for IHC or FISH were satisfactorily processed by dPCR. dPCR results were analyzed on the Thermofisher Cloud platform. The general turnaround time(TAT) was about 2 and 3 days for IHC and FISH respectively with that of dPCR being 24 hours. Results: All 9 IHC positive and 35 negative samples had similar results on dPCR using an amplification ratio threshold for a positive result of 1.8. Of 17 IHC-equivocal samples, 5 resulted as positive, 10 negative and 2 as equivocal by dPCR. There was 100% concordance between the dPCR and FISH results. Two IHC equivocal samples that were unanalyzable by FISH were negative on dPCR Conclusions: Our results demonstrate that the chip based dPCR was non-inferior for HER2 detection in FFPE samples in a clinical setting. Superior TAT's and objective results were obtained compared to more subjective techniques like FISH and IHC even with low sample input. dPCR requires controls but no standards for calibration as it gives absolute copy numbers. Further study is needed to understand dPCR interpretation in cases of chromosomal aneuploidy. [Table: see text]
MicroRNA-330-3p as a putative promoter of brain metastasis in non-small cell lung cancer.
Authors: Chunhua Wei, Qian Cai, Xican Gao, Xiaorong Dong
Journal: Journal of Clinical Oncology (2018)

e14007 Background: Brain metastasis (BM) is the leading cause of poor prognosis, recurrence, and death in non-small-cell lung cancer (NSCLC) patients. The median overall survival (OS) of NSCLC patients with BM is only 4-6 months. Thus it is important to identify risk factors of BM in patients with NSCLC. MicroRNAs (miRNAs) are a class of conserved small non-coding RNAs of 18-25 nucleotides. Studies reported that some miRNAs were associated with BM of NSCLC. Methods: Study subjects were 122 patients with histologically confirmed NSCLC using AJCC criteria, blood and tissue samples were collected prior to any treatment. Patients without BM upon diagnosis (n = 60) received whole brain CT scan after every two cycles of chemotherapy to identify potential development of BM. The expression of candidate miRNAs (miR-325, miR-328, miR-330-3p, miR-500-3p, miR-326, and miR-370), which were reported high expression in NSCLC BM samples, were examined in a cohort of 122 NSCLC patients, 60 without BM and the remaining 62 with BM upon diagnosis. Results: Our study confirmed several previously reported risk factors for BM: the female gender, age under 60 years, adenocarcinoma, N2 or N3 lymph node metastases, and mutation at EGFR19 exon. Moreover, serum miR-328 (P = 0.05) and miR-330-3p (P = 0.02) were significantly higher in BM+ patients, whereas serum miR-325, miR-326 and miR-370 did not differ between the BM+ and BM- groups. PCR revealed higher miR-330-3p in the primary lung lesions in subjects with BM than in subjects without BM upon diagnosis (n = 30 each, P = 0.003). Among the 60 patients without BM upon diagnosis, 23 developed BM during the follow-up period (the median follow-up time was 17 months); the percentage of the patients who developed BM was higher in patients with high (above sample median) circulating miR-330-3p (P = 0.02 vs. subjects with low circulating miR-330-3p). A Kaplan-Meier analysis revealed shorter time to BM development with higher miR-330-3p. Conclusions: miR-330-3p may act as an independent risk factor for BM of NSCLC, and targeting miR-330-3p can provide a potential therapeutic strategy for metastatic NSCLC.
Burden of febrile neutropenia hospitalizations (FNH) in U.S. clinical practice, by use and patterns of colony-stimulating factor prophylaxis (CP).
Authors: Derek Weycker, Xiaoyan Li, Spiros Tzivelekis, Mark Atwood, Jacob Garcia, Yanli Li, Maureen Reiner, Gary H. Lyman
Journal: Journal of Clinical Oncology (2016)

6568 Background: Many cancer chemotherapy patients who are candidates for CP do not receive it, while others receive it inconsistent with established guidelines (e.g., on same day as chemotherapy). The objective of this study was to characterize episodes, outcomes, and costs of FNH among cancer chemotherapy patients for whom CP is recommended, by use and patterns of CP. Methods: From US private healthcare claims repositories (2005-13), study subjects included adults who received a chemotherapy course with an NCCN-listed high-risk regimen or intermediate-risk regimen (if ≥ 1 FN risk factor present) for non-metastatic breast cancer or non-Hodgkin’s lymphoma (NHL); each cycle within the chemotherapy course and each FNH episode within the cycles were identified. Outcomes included mortality (all-cause) and inpatient days during the FNH; FNH-related costs were expressed in US$2013. Use (yes/no) of CP and patterns (by agent, administration day/duration) of CP were evaluated within cycles in which FNH occurred. Results: 58,320 subjects received AC/AC-T, TAC, or TC for non-metastatic breast cancer or CHOP±R for NHL. Among all FNH episodes (n = 6,355; rate = 109 per 1,000 patients), 41% occurred in patients who did not receive CP in that cycle, and 9% occurred in those who received CP on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CP (2% of total CP use), 56% received < 7 days of CP during the cycle. Findings for FNH outcomes and costs were comparable. Conclusions: In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CP occurred among those who either did not receive it or received it inconsistent with established guidelines. Use/Patterns of CP % of FNH Episodes No Receipt 41% Receipt By Administration Day 59% Same Day as Chemotherapy 9% 2-4 Days from Chemotherapy 50%
Phase II trial of neoadjuvant S-1 and concurrent radiotherapy for borderline resectable pancreatic cancer: Interim results of JASPAC05.
Authors: Shinichiro Takahashi, Izumi Ohno, Masafumi Ikeda, Masaru Konishi, Tatsushi Kobayashi, Tetsuo Akimoto, Motohiro Kojima, Soichiro Morinaga, Yonson Ku, Yasuhiro Shimizu, Shoji Nakamori, Shoichi Hishinuma, Norihisa Takakura, Osamu Kainuma, Satoshi Hirano, Takehito Otsubo, Masato Nagino, Wataru Kimura, Yoichi Yamashita, Katsuhiko Uesaka
Journal: Journal of Clinical Oncology (2017)

4107 Background: Borderline resectable pancreatic cancer (BRPC) has a high probability of a positive surgical margin and poor prognosis because the tumor interacts with surrounding arteries or veins. Chemoradiotherapy (CRT) with S-1 has shown favorable activity in locally advanced pancreatic cancer. This study was designed to assess S-1 and concurrent radiotherapy in a neoadjuvant setting to determine whether it increases R0 resection rate for BRPC. Methods: This was a multicenter, single-arm phase II study. Patients with BRPC received S-1 (40 mg/m 2 BID) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of superior mesenteric vein or portal vein; (2) tumor contact with superior mesenteric artery ≤180°; or (3) tumor contact with common hepatic artery or celiac axis ≤180°. Primary endpoint was R0 resection rate in BRPC confirmed by central review. At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and a threshold values for primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible between December 2012 and May 2016. CRT was completed in 50 patients (96%) and was safe, with mostly grade 1 or 2 adverse events. Protocol treatment was withdrawn before surgery in 12 patients because of progressive disease diagnosed by computed tomography, and in one because of treatment refusal. Ten patients received exploratory laparotomy, or palliative/noncurative resection. In the rest of 29, R0 resection was conducted in 27, and R1 and RX in 1 patient each. This gave an R0 resection rate of 52% in all 52 eligible patients. In the 41 cases of BRPC confirmed by central review, R0 was confirmed in 26 (63%). Destruction of &gt; 50% of tumor cells was confirmed pathologically in 10 (32%). Postoperative grade III/IV adverse events according to Clavien–Dindo classification were observed in 6 (15%). Conclusions: S-1 and concurrent radiotherapy were well tolerated and found to be effective in BRPC. A randomized controlled trial comparing neoadjuvant CRT and chemotherapy, including gemcitabine+nab-paclitaxel, for BRPC is under planning. Clinical trial information: NCT02459652.
What role does the patient perspective play in determining access to innovative therapies?
Authors: Clare Frances Jones, Juan Fernando Soto Barrientos, George Spentzouris, Claire Hunter-Lavin
Journal: Journal of Clinical Oncology (2018)

6608 Background: The 21st Century Cures Act 2016 (21st CCA) requires the FDA to do more to incorporate patient perspectives into their decision-making on products, particularly patients’ experience of disease and effects related to treatment. This experience may be captured using patient-reported outcome measures (PROMs). We sought to understand how patient-relevant outcomes beyond survival were considered in evaluations of oncology drugs by regulators, oncology societies, and payers (health technology assessment [HTA] agencies), and how this might change in future. Methods: We reviewed EMA summaries of product characteristics and FDA package inserts of products approved in 2017 plus documents from completed or ongoing assessments by national HTA agencies in England, France, and Germany for reference to PROMs, quality of life, or symptoms of disease. PubMed and Google were searched for published ASCO value framework or ESMO MCBS v1.1 scores. Clinicaltrials.gov was searched to identify PROMs included in Phase 2 or 3 industry-sponsored trials initiated between 2013-2017. Results: None of the 16 FDA labels included any mention of PROMs or patient-reported symptom measures (other than AEs). Of 13 products in Europe, 7 reported PROMs or symptom measures. Few HTAs have been completed; documentation for 7 products (NICE 4; TC 1; IQWiG 4; G-BA 2) referred to measures of interest. No systematic scoring of newly approved products using ASCO was identified; ESMO MCBS v1.1 scores are available within updated treatment guidelines. Of 70 industry-sponsored Phase 2 or 3 trials, 68 reported including a PROM, the most commonly used were EORTC-QLQ-C30 (24% of trials) and associated disease-specific modules. Other pan-tumor PROMs used in > 1 trial included EQ-5D (23%) and PROMIS (4%) or PRO-CTAE (4%) (and only since 2015). Results will be updated in May 2018 Conclusions: To date, the 21st CCA appears to have had no impact on FDA approvals. However, recent inclusion of PRO-CTCAE or PROMIS in trials may be related to 21st CCA. In Europe there is wider consideration of PROMs. The use of these instruments and other patient-relevant measures of benefit by stakeholders determining access to innovative therapies should be monitored and encouraged further.
A phase I dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors.
Authors: Kenji Hashimoto, Ayesh Perera, Naofumi Sugaya, Yoshitaka Ogita, Mikiko Nakamura, Sheila Rossi, Takahiro Ishiguro, Yuji Sano, Sumire Shimada, Werner Frings, Shun-ichiro Komatsu, Akihisa Kaneko, Masamichi Ueda, Junnosuke Matsushima, Shohei Kishishita, Athos Gianella-Borradori
Journal: Journal of Clinical Oncology (2017)

TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1 st and 2 nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1 st dose of ERY974 is fixed at the last dose level when &lt; G2 CRS was not seen, DE proceeds with the 2 nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1 st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with &gt; 1cm or &gt; 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.