tbuckley/cabot-search huggingface dataset:
A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors.
Authors: Emiliano Calvo, Victor Moreno, Ruth Perets, Tamar Yablonski-Peretz, Nele Fourneau, Suzette Girgis, Yue Guo, Peter Hellemans, David Hokey, Natalia Pendas Franco, Qi Xia, Ravit Geva
Journal: Journal of Clinical Oncology (2019)

2527 Background: JNJ-64457107 (JNJ-107) is an agonistic human monoclonal (IgG1) antibody targeting CD40, a novel target for anti-tumor immunotherapy with a central role in adaptive and innate immunity. Methods: JNJ-107 was administered intravenously Q2W in treatment cycles of 28 days. Dose escalation was pursued with (w) and without (wo) pre-infusion steroids for mitigation of infusion related reactions (IRRs). Dose-limiting toxicity (DLT), safety, PK, PD and antitumor activity were evaluated. Results: 95 pts of age 18-80 years (median 59) were enrolled in 7 cohorts (n = 50, 75µg/kg – 2000 µg/kg) w/steroids and 5 cohorts (n = 45, 75 µg/kg – 1200 µg/kg) wo/steroids and received 1-26 (median 3) cycles of JNJ-107. Two DLTs occurred: Grade (G) 3 headache lasting 5 days at 1200 µg/kg w/steroids and G3 ALT/AST + G2 bilirubin increase at 1200 µg/kg wo/steroids. Most frequent adverse events (≥20%) were pyrexia (41%), fatigue (39%), pruritus (39%), headache (26%), chills (26%), nausea (22%) and rash (21%). IRRs were reported in 51% of pts (G1-G2 50%, G3 1%). Most commonly reported IRRs (≥10%) were pruritus (31%), rash (15%), chills (13%) and flushing (12%). Cetirizine and Montelukast premedication during dose escalation wo/steroids significantly reduced IRRs. Preliminary PK of JNJ-107 suggest target mediated drug disposition with rapid decline in serum concentrations (half-life of ~13h at 600 µg/kg and ~ 24h at doses ≥1200 µg/kg). Dose proportional increase in C max and AUC(last) was observed at doses ≥1200 µg/kg and more than dose proportional increase was seen at lower doses. PD of JNJ-107 demonstrated dose-independent reduction in peripheral blood B cells recovering in a dose-dependent manner. MCP-1, IP-10, MIP-1a, and MIP-1b cytokines showed high-level responses with cytokine/chemokine secretion kinetics consistent, but not confirmatory, for activation of antigen presenting cells. IFNg, TNF, and IL-8 showed moderate responses reflecting downstream T cell activation. Other tested cytokines were at low levels. A partial response lasting 9.2 months was observed in 1 pt with renal cell cancer. 13 (14%) and 10 (11%) pts showed stable disease lasting ≥3 months and ≥ 6 months, respectively. Conclusions: The CD40 agonist JNJ-107 has a manageable safety profile with favorable PK and PD properties. Future clinical development will require combination with either chemotherapy, or other immunotherapies such as antitumor vaccines or checkpoint inhibitors. Clinical trial information: NCT02829099.
Health-related quality of life (HRQoL) of pembrolizumab (pembro) versus physician choice single-agent paclitaxel, docetaxel, or irinotecan in subjects with advanced/metastatic adenocarcinoma (ACC) or squamous cell carcinoma (SCC) of the esophagus that has progressed after first-line standard therapy (KEYNOTE-181).
Authors: Antoine Adenis, Amit Kulkarni, Gustavo Colagiovanni Girotto, Christelle De La Fouchardiere, Helene Senellart, Hanneke W.M. Van Laarhoven, Daniel Hochhauser, Wasat Mansoor, Raed Al-Rajabi, Josephine Norquist, Shailaja Suryawanshi, Pooja Bhagia, Jean-Philippe Metges
Journal: Journal of Clinical Oncology (2019)

4048 Background: KEYNOTE-181 (NCT02564263) is an open-label, randomized, phase 3 trial in ACC and SCC of the esophagus that evaluated IV pembro 200 mg Q3W for up to 2 years vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (control). Pembro was superior to control for OS in patients with PD-L1 CPS ≥10 (N = 222; median 9.3 vs 6.7 months; P= 0.0074). Here we present results of prespecified HRQoL analyses in this population. Methods: The EORTC QLQ-C30 and EORTC QLQ-OES18 were administered at baseline; weeks 2, 3, 4, 6, 9, 12, 18; every 9 weeks up to 1 year/end of treatment; and 30-day safety follow-up visit. Data from patients receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were analyzed. Least squares mean (LSM) score change from baseline to week 9, 95% CI, and nominal P values were calculated. Time to deterioration (TTD) (≥10-point decline from baseline) was assessed by Kaplan-Meier method and Cox regression model. HRs, 95% CIs, and nominal P values are provided. Results: The HRQoL population included 218 PD-L1 CPS ≥10 patients (107 pembro, 111 control). QLQ-C30 compliance at week 9 was 88.9% for pembro and 83.9% for control. There was no significant difference in LSM between arms (3.68; 95% CI –2.28, 9.64; P= 0.2248) in global health status (GHS)/QoL score. Week 9 QLQ-OES18 compliance was 88.4% for pembro and 83.3% for control. QLQ-OES18 scores were not significantly different between arms. TTD for pain (HR 1.02; 95% CI 0.58, 1.81; P= 0.5282), reflux (HR 1.69; 95% CI 0.83, 3.47; P= 0.9254), and dysphagia (HR 1.81; 95% CI 0.97, 3.37; P= 0.9693) subscales were not significantly different between arms. Conclusions: Over 9 weeks, patients treated with pembro had stable GHS/QoL scores similar to those of patients treated with single-agent docetaxel/paclitaxel/irinotecan. Combined with the superior OS and lower rate of treatment-related AEs seen with pembro, these data support clinically meaningful benefit of pembro in esophageal cancer patients with PD-L1 CPS ≥10. Clinical trial information: NCT02564263.
Development of imjSCORE for early prediction of response to nivolumab among patients with advanced cancer.
Authors: Milos Josef Janicek, Diana Cirstea, Gerald V Denis, Adam Lerner
Journal: Journal of Clinical Oncology (2019)

e14169 Background: Cross-sectional Imaging (CI) plays an essential role in early assessment of patients on immune checkpoint inhibitors (ICIs), yet often remains inconclusive in the setting of advanced disease, prior cancer treatment, toxicity, and cancer unrelated findings. Best timing of scans is also uncertain and may affect interpretation. We propose here a robust, reproducible imjScore based on measurable tumor response on the first two re-staging scans and their ratios that may predict treatment impact. Our approach incorporates the prognostic aspect of early imaging, time lag of ICIs effect, and alternative measures of treatment impact. Methods: Retrospective review of CI studies was performed in 92 patients with advanced stage solid tumors treated with Nivolumab during 6/2015-8/2018 at Boston Medical Center utilizing standard clinical protocols. Time on therapy (TOTx) was used as a surrogate marker of therapy impact. Modified imRECIST score utilizing Σ of 4 discrete cancer lesions at baseline (&lt; 1 month before Nivolumab), 1st, and 2nd CI since initiation of Nivolumab were adjusted for TOTx. Our imjSCORE averages "predicted days on therapy" calculated from best fit function of tumor change/day [%] at each time point vs. TOTx and ratios between 1st and 2nd scan. Results: Median TOTx was 70 days (range from 1 to 1029). Differences in imRECIST scores derived from two early restaging CI studies adjusted for TOTx were able to identify with high statistical significance two groups of "SHORT" vs "LONG" sojourn on Nivolumab based on Median of 70 days. Early progression curve was associated with shorter benefit of Nivolumab; subset with pseudo-progression curve showed still significantly shorter sojourn on Nivolumab compared to initial regression or stable score curves (P &lt; .002). Conclusions: The development of imjScore may differentiate with high likelihood patients with short versus long sojourn on Nivolumab. Our CI-based evaluation using the imjSCORE suggests a clear benefit from early imaging with a response curve and standardized point analysis of the 1st and 2nd post-treatment scans. If validated with other ICIs, this scoring tool may allow early prediction of ICIs treatment response and clinical outcome. Further correlation of imjSCORE with clinical biomarkers may be useful to build predictive nomograms of "short" versus "long" treatment impact.
Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study.
Authors: Brian I. Rini, Elizabeth R. Plimack, Viktor Stus, Rustem Gafanov, Robert Hawkins, Dmitry Nosov, Frederic Pouliot, Denis Soulieres, Bohuslav Melichar, Ihor Vynnychenko, Sergio Jobim Azevedo, Delphine Borchiellini, Raymond S. McDermott, Jens Bedke, Satoshi Tamada, Shuyan Wan, Rodolfo F. Perini, Mei Chen, Michael B. Atkins, Thomas Powles
Journal: Journal of Clinical Oncology (2019)

4500 Background: In KEYNOTE-426, pembro + axi significantly improved OS (HR 0.53, P &lt; .0001), PFS (HR 0.69, P = .0001), and ORR (59.3% vs 35.7%, P &lt; .0001) vs sunitinib and had manageable toxicity as first-line therapy for mRCC (NCT02853331). The pembro + axi benefit was observed across all IMDC risk groups and regardless of PD-L1 expression. We present data for the combined intermediate/poor risk group and for patients (pts) with sarcomatoid features. Methods: 861 eligible pts with clear-cell mRCC, no prior systemic therapy for mRCC, and KPS ≥70 were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID (N = 432) or sunitinib 50 mg orally QD (4-wk on/2-wk off) (N = 429). Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR (RECIST v1.1 by BICR) was the key secondary endpoint. The intermediate/poor risk group was prespecified; the sarcomatoid group was exploratory. HRs and their 95% CIs were calculated with a Cox proportional hazards model. None of the analyses were multiplicity-controlled. Results: 592 (68.8%) of all randomized pts were of IMDC intermediate/poor risk — 294 in the pembro + axi arm, 298 in the sunitinib arm. Pembro + axi improved OS (HR 0.52, 95% CI 0.37-0.74; 12-mo rate 87.3% vs 71.3%), PFS (HR 0.67, 95% CI 0.53-0.85; median 12.6 vs 8.2 mo), and ORR (55.8% [95% CI 49.9-61.5] vs 29.5% [24.4-35.1]) in pts with intermediate/poor risk; CR rates were 4.8% (95% CI 2.6-7.9) vs 0.7% (0.1-2.4). Of the 578 pts with known status, 105 (18.2%) had sarcomatoid features — 51 in the pembro + axi arm, 54 in the sunitinib arm. Pembro + axi improved OS (HR 0.58, 95% CI 0.21-1.59; 12-mo rate 83.4% vs 79.5%), PFS (HR 0.54, 95% CI 0.29-1.00; median not reached vs 8.4 mo), and ORR (58.8% [95% CI 44.2-72.4] vs 31.5% [19.5-45.6]) in pts with sarcomatoid features; CR rates were 11.8% (95% CI 4.4-23.9) vs 0% (0.0-6.6). Conclusions: Pembro + axi provides benefit in the combined population of pts with IMDC intermediate or poor risk and in pts whose tumors had sarcomatoid features. The observed benefits were consistent with those seen in the total population. Clinical trial information: NCT02853331.
PIPA: A phase Ib study of β-isoform sparing phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (T) plus palbociclib (P) and fulvestrant (FUL) in <i>PIK3CA</i>-mutant (mt) ER-positive and taselisib (T) plus palbociclib (P) in <i>PIK3CA</i>-mutant (mt) ER-negative advanced breast cancer.
Authors: Javier Pascual, Iain R. MacPherson, Anne Caroline Armstrong, Sarah Emily Ward, Mona Parmar, Alison Joanne Turner, Hannah Bye, Paula Proszek, Andrew Dodson, Isaac Garcia-Murillas, Jenny King, Emma Hall, Laura Finneran, Juanita Suzanne Lopez, Alicia Frances Clare Okines, Alistair E. Ring, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2019)

1051 Background: PI3K and CDK4/6 inhibitors synergise in ER+ve and –ve PIK3CA-mt breast cancer (BC) models. Escalation phase of this study set recommended phase 2 dose (RP2D) at P 125mg on a 3/1 scheme plus T 2mg daily ( Lim, ASCO 2017). Here we present the results of expansion cohorts for PIK3CA-mt BC patients (pts). Methods: The primary objective was to assess the confirmed objective response rate (ORR) of the P + T + FUL triplet in pts with measurable PIK3CA-mt ER+ve HER2-ve advanced BC, with up to two prior lines of chemotherapy for advanced disease. PIK3CA mutation was assessed in tissue or plasma DNA analysis. Exploratory objectives included assessment of efficacy of P + T in a cohort of pts with PIK3CA-mt advanced ER-ve BC. Safety is reported overall for 44 patients including an additional cohort of 7 PIK3CA-unknown ER+ve BC pts treated with P + T + letrozole (LET). For the P + T + FUL triplet a Simon minmax design was used, with 6 responses in 25 patients required to declare efficacy. Results: We recruited 24 assessable patients with PIK3CA-mt ER+ve HER2-ve advanced BC, median age 57 (42-74), median 3 (1-9) prior therapy lines for advance disease, with 24 (100%) receiving prior endocrine therapy and 23 (96%) prior aromatase inhibitor. ORR was 33% (8/24, 95% CI 16-55%), with median progression free survival (PFS) 7.9m (95% CI 5.6-11.8). For the 11 assessable PIK3CA-mt ER-ve pts (8 HER2-ve, 3 HER2+ve) receiving P + T, ORR was 0% (0/11), clinical benefit rate (CBR) 27% (3/11) and median PFS 4.3m (95% CI 1.8-6.1). Most common AEs across all cohorts were neutropenia (80%), fatigue (50%), mucositis (50%) and thrombocytopenia (30%). Most common grade 3/4 AEs were neutropenia (57%) and rash (11%). Translational research is ongoing. Conclusions: The triplet of P + T + FUL has promising efficacy in pre-treated PIK3CA-mt ER+ve advanced BC. A subset of patients with PIK3CA-mt ER-ve advanced BC had clinical benefit from P + T. The combination of P + T +/- FUL/LET was well tolerated with anticipated AEs. Clinical trial information: NCT02389842.
High dose apatinib in the reversal of immunosuppressive tumor microenvironment for irradiation therapy in lung carcinoma.
Authors: Lijun Liang, Chenxi Hu, Yixuan Wen, Kaiyuan Hui, Xiaodong Jiang
Journal: Journal of Clinical Oncology (2019)

e14503 Background: The purpose of this study was to investigate the potential systemic anti-tumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma. Methods: Lewis lung cancer cells were injected into C57BL/6 mice in the right hindlimb (primary tumor; irradiated) and in the left flank (secondary tumor; nonirradiated). When both tumors grew to palpable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 100 mg/kg, 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy to the primary tumor or no radiotherapy. Further tumor growth/regression of mice was followed and observed. Results: For the single 15 Gy modality, delays in tumor growth could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growths could be observed, indicating that an abscopal effect had been induced. Mechanism analysis suggested that programmed death ligand-1 expression increased with SABR and was counteracted by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor-antigen-specific immune responses, and the mice were resistant to subsequent tumor rechallenge. Ultimately, long-term survival was improved. Conclusions: Our results suggested that the tumor microenvironment could be managed with high-dose of apatinib, which was effective in eliciting an abscopal effect induced by SABR.
Association of immune-related adverse events with immune checkpoint inhibitor efficacy in pancancer.
Authors: Qiyun Ou, Yunfang Yu, Haitao Zhong, Anlin Li, Yongjian Chen, HaiYu Zhou, Shaopeng Zheng, Luyu Huang, Herui Yao
Journal: Journal of Clinical Oncology (2019)

e14087 Background: Immune-related adverse events (irAEs) have been shown to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced cancer, but the reported effect sizes have varied greatly in previous trials. We did a meta-analysis to assess immune checkpoint inhibitors efficacy and further explored the correlation of irAEs with efficacy in cancer. Methods: We systematically searched database inception to January, 2019 for randomized trials of immune checkpoint inhibitor in patients with advanced cancer that had available data for overall survival (OS) and progression-free survival (PFS), and irAEs. We calculated the pooled hazard ratios (HRs) and 95% confidence intervals [CIs] using a random-effects model, and assessed the association between the irAEs and PFS or OS using coefficient of determination ( R²). The PROSPERO registry number is CRD42017075610. Results: Thirty eight trials with 19,521 patients were included. Compared with conventional therapy, anti-PD-1 or PD-L1 combined with conventional therapy significantly enhanced survival (HR = 0.62, 95% CI 0.53 to 0.72 for PFS; HR = 0.71, 95% CI 0.58 to 0.87 for OS), and anti-PD1 or PD-L1 combined with anti-CTLA4 (HR = 0.75, 95% CI 0.63 to 0.90 for PFS). Anti-CTLA4 plus conventional therapy prolonged PFS (HR = 0.80, 95% CI 0.72 to 0.89) and OS (HR = 0.80, 95% CI 0.66 to 0.96) than conventional therapy alone. Anti-PD1 or PD-L1 outperformed anti-CTLA4 on OS (HR = 0.68, 95% CI 0.57 to 0.81). Significant correlation between treatment efficacy and irAEs was only identified in pneumonitis ( R 2 0.59, P = 0.026 for PFS) and diarrhea ( R 2 0.22, P = 0.006 for OS). Conclusions: We recommended the concurrent use of immune checkpoint inhibitor and conventional therapy or dual immunotherapy as the most appropriate regimens for advanced cancer. Furthermore, development of pneumonitis and diarrhea were associated with survival outcome of immune checkpoint inhibitors in patients with advanced cancer.
Risk factors predicting colorectal cancer recurrence in a Latin American population.
Authors: Jorge Leon, Fernando Namuche, Paola Catherine Montenegro, Claudio J. Flores
Journal: Journal of Clinical Oncology (2019)

e15180 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. In our population more than 80% of patients are stage I-III. Recurrence is one of the most important factors to consider in the survival of CRC patients. The aim of this study was to identify which factors influence in the recurrence of CRC in our population. Methods: We retrospectively reviewed the electronic medical records of 506 patients with stage I-III CRC from one specialized Peruvian cancer center between 2006 and 2016. Survival analysis (with recurrence as the event to evaluate) was performed with Kaplan Meier curves and Long-rank test. We use a preliminary univariate analysis to do the multivariate analysis with Cox regression. We performed a ROC curve analysis to determine an appropriate cut-off value for the tumor size (≥4.2). Results: In the univariate analysis we found that sidedness, tumor size (cut-off ≥4.2), CEA, lymph node involvement, stage, histological grade, LVI, PNI, and chemotherapy were statistically significant. In the multivariate model, tumor size [HR, 1.462; 95% CI, 1.065-2.217; p&lt;0.05], lymph node involvement [HR, 0.136; 95% CI,0.41-0.447; p&lt;0.001], and stage III [HR, 0.003; 95% CI, 0.263-0.758; p&lt;0.05] retained a significant association and were independent factors with relapse disease. Conclusions: In stage I-III CRC pts it is important to evaluate tumor size, lymph node involvement and clinical stage as they are possible prognostic factors that will help our diagnosis and treatment along with other standard features.
Auxiliary diagnosis of pulmonary nodules using liquid biopsy and deep learning/techniques.
Authors: Li Bai, Yanqing Zhou, Yaru Chen, Quanxing Liu, Dong Zhou, Hong Zheng, Jigang Dai
Journal: Journal of Clinical Oncology (2019)

e13154 Background: Many people harbor pulmonary nodules. Such nodules can be detected by low-dose computed tomography (LDCT) during regular physical examinations. If a pulmonary nodule is small (i.e. &lt; 10mm), it is very difficult to diagnose whether it is benign or malignant using CT images alone. To address this problem, we developed a method based on liquid biopsy and deep learning to improve diagnostic accuracy of pulmonary nodules. Methods: Thirty-eight patientsharboring one or more small pulmonary nodules were enrolled in this study. Twenty-nine patients were diagnosed as having cancer (stage I = 21, stage II = 1, stage III = 3, stage IV = 4) using tissue biopsy, while the other 9 patients were diagnosed as having benign tumors or lung diseases other than cancer. For each patient, a blood sample was obtained prior to biopsy, and the cell free DNA (cfDNA) was sequenced using a 451-gene panel to a depth of 20,000×. The unique molecular identifiers (UMI) technique was applied to reduce false positives. Seventeen patients also had full-resolution CT images available. A deep learning system primarily based on deep convolutional neural networks (CNN) was used to analyze these CT images. Results: Sequence analysis of blood samples revealed that 75.8% (22/29) of cancer patients had detectable cancer related mutations, and only 1 of 9 (11.1%) non-cancer patient was found to carry a TP53 mutation. The most frequent mutations seen in cancer patients involved genes TP53 (N = 11), EGFR (N = 7), and KRAS (N = 3) with mutant allele fractions varying from 0.08% to 74.77%. Deep learning analysis of the 17 available CT images correctly identified cancers in 88.2% (15/17) of patients. However, by combining the liquid biopsy and image analysis results, all 17 patients were correctly diagnosed. Conclusions: Deep learning-based analysis of CT images can be applied to early diagnosis of lung cancers; but the accuracy of image analysis, when used alone, is only moderate. Diagnostic accuracy can be greatly improved using liquid biopsy as an auxiliary method in patients with pulmonary nodules.