tbuckley/cabot-search huggingface dataset:
Quantification of dose dependence and frequency of checkpoint inhibitor immune-mediated adverse events: A Bayesian model-based meta-analysis.
Authors: Boris Shulgin, Yuri Kosinsky, Alexandra Smirnova, Gabriel Helmlinger, Kirill Peskov
Journal: Journal of Clinical Oncology (2020)

83 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis to quantify dose dependence and compare imAE frequencies for PD-1, PD-L1 and CTLA-4 inhibitor monotherapies and their combinations. Methods: We searched PubMed, TrialTrove, ASCO and ESMO databases and retrieved relevant ICI safety data. In order to quantitatively compare safety across doses and drugs against a given target, we converted the various dose regimens used into drug exposures derived from pharmacokinetic models; we also normalized exposures by the corresponding drug potency. We performed a Bayesian meta-analysis for Grades 3&amp;4 of treatment related (trAE) and immune-mediated (imAE) adverse events. Results: A total of 149 articles were identified, covering 35,559 patients in 197 dosing cohorts treated with ICI therapies. For PD-1 and PD-L1 inhibitor monotherapies, no dose dependence of AEs was found; Grades 3&amp;4 trAE rates for anti PD-L1 vs. anti PD-1 were, respectively, 12% and 15%. The AE rates for the different ICI drugs and organ classes were estimated. Dose dependence was found for anti CTLA-4 monotherapies, for total trAEs of Grades 3/4, gastrointestinal and hepatic imAEs. Dose dependence was found and quantified for anti CTLA-4 in combination with anti PD-1 with respect to total trAEs of Grades 3/4 trAEs and imAEs per gastrointestinal and hepatic organ groups. We found that combination of anti PD-L1 agents with anti CTLA-4 exhibited lower AE rates, as compared to anti PD-1 combined with anti CTLA-4. Conclusions: We introduced a novel meta-analysis methodology and used it to quantify and compare AE rates across ICI agents. Significant AE rate dose dependencies were observed for CTLA-4 inhibitors, either as monotherapy or used in combinations. Patients naive to anti-cancer therapies exhibited higher AE rates vs. previously treated patients. AE rates for CTLA-4 + PD-1 inhibitor combination regimens were supra-additive vs. the respective monotherapies. AE rates for anti PD-L1 agents were lower vs. anti PD-1, both in monotherapy and combinations with CTLA-4.
A novel gene signature for predicting response to chemoradiotherapy in esophageal adenocarcinoma.
Authors: Souvik Ghatak, Ashten N. Omstead, Blair A Jobe, Rachael Kreft, Anastasia Gorbunova, Madison Salvitti, Ronan Joseph Kelly, Ali Hussainy Zaidi, Ajay Goel
Journal: Journal of Clinical Oncology (2020)

445 Background: While neoadjuvant chemoradiotherapy (CRT) has emerged as an important treatment modality in patients with locally advanced esophageal adenocarcinoma (EAC), ~60%-70% of patients do not respond to such treatments; but are exposed to their toxicity nonetheless. This highlights the clinical need for the development of biomarkers that can robustly predict response to CRT and spare others from the toxicity and expense associated with these treatments. Herein, we systematically identified a biomarker signature that predicts response to CRT in EAC patients. Methods: Using a clinical-trial driven cohort of 25 EAC patients treated with 5- fluorouracil plus carboplatin and concurrent radiation therapy, we performed whole-exome sequencing (WES) in paired biopsy specimens obtained at baseline and 3-6 weeks post-treatment. In addition, we also analyzed the predictive potential of a panel of immune-related genes (TIM3, LAG3, IDO1 and CXCL9) in these matched tissues. Results: In our cohort, based upon RECIST criteria, 14 EAC patients were categorized as non-responders, while 11 were deemed as responders to CRT. Among responders, the most frequently mutated genes were NOTCH1, NOTCH2, NOTCH3, and MLL2; and the overall tumor mutation burden (TMB) was significantly reduced for these genes in post-treatment specimens (P&lt;0.001). In contrast, in non-responders, NFE2L2, KEAP1, FAT1, FAT2, FAT3 and PIK3CA, harbored frequent mutations. Similarly, all four immune-related genes were significantly up-regulated in post-treatment specimens (p&lt;0.05-0.001). Interestingly, the progression-free survival was significantly greater in patients with lower TMB (64.1%, p=0.04) and increased immunogenic scoring (62.7%, p=0.01). We finally constructed a risk-stratification model that comprised of mutational scores from 10 most frequently mutated genes, together with 4 immune-related genes, which achieved an AUC of 0.83 in predicting response to CRT in EAC patients. Conclusions: Using a systematic biomarker discovery approach, we have developed a novel biomarker signature that robustly predicts response to CRT in EAC patients and has a significant potential for personalized management of EAC patients.
Treatment efficacy of ramucirumab-based chemotherapy in patients with alpha-fetoprotein producing gastric cancer (AFPGC).
Authors: Daisaku Kamiimabeppu, Takeru Wakatsuki, Daisuke Takahari, Naoki Fukuda, Hiroki Osumi, Izuma Nakayama, Mariko Ogura, Tarou Sato, Akira Ooki, Eiji Shinozaki, Mitsukuni Suenaga, Keisho Chin, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2020)

389 Background: AFPGC is an aggressive subgroup of gastric cancer and is associated with a worsened survival because of a high incidence of liver metastasis. Ramucirumab-based chemotherapy is the standard treatment as a second line in advanced gastric cancer. Recently ramucirumab has showed survival benefit in hepatocellular carcinoma, but only those with higher AFP levels. However, the efficacy of ramucirumab in AFPGC is unknown. Methods: We retrospectively assessed 283 patients who received paclitaxel or nab-paclitaxel combined with ramucirumab between July 2015 and December 2018. AFPGC was defined when serum AFP levels were elevated and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal when diagnosed. Other patients were excluded. Patients’ demographics, progression-free survival (PFS), overall survival (OS) and objective response rates (ORR) were compared between the two groups. Results: Among the 283 patients, 24 patients were AFPGC and 189 patients were non-AFPGC. AFPGC was associated with high incidences of intestinal histology (46%) and liver metastasis (63%), while AFPGC was associated with a low incidence of peritoneal metastasis (21%), compared with non-AFPGC. There was no significant difference in PFS and OS between the two groups. Median PFS were 5.4 (95%CI 3.6-6.7) months in AFPGC and 4.1 (3.7-5.1) months in non-AFPGC (HR 0.93 95%CI 0.60-1.46, p = 0.788), respectively. Median OS were 19.0 (95%CI 13.2-NA) months in AFPGC and 19.3 (17.9-20.1) months in non-AFPGC (HR 1.21 95%CI 0.70-2.10, p = 0.494), respectively. Regarding with ORR, AFPGC showed higher ORR with 52.6% (95%CI 30.2-75.1), while 37.3% (95%CI 26.4-48.3) in non-AFPGC (p = 0.296), although this was not statistically significant. Conclusions: Ramucirumab showed comparable survival and higher ORR in AFPGC than in non-AFPGC. Considering the generally poor prognosis of AFPGC, it is speculated that ramucirumab may have compensated for disadvantage in survival.
Usefulness of laparoscopic narrow-band imaging for the evaluation of therapeutic effects on peritoneal metastasis in gastric cancer.
Authors: Hirotoshi Kikuchi, Wataru Soneda, Sanshiro Kawata, Amane Hirotsu, Tomohiro Matsumoto, Yoshihiro Hiramatsu, Kinji Kamiya, Yoshifumi Morita, Takanori Sakaguchi, HIROYA TAKEUCHI
Journal: Journal of Clinical Oncology (2020)

287 Background: As recent advances in chemotherapy improved prognosis of gastric cancer (GC) patients with peritoneal metastasis (PM), accurate diagnosis of PM has become more important. However, the sensitivity of conventional imaging modalities such as CT or PET is not satisfactory. Staging laparoscopy (SL) is often used to diagnose PM in advanced GC patients, but accurate detection of PM can be difficult. In this study, we evaluate the usefulness of laparoscopic narrow-band imaging (NBI) versus conventional laparoscopic white-light imaging (WLI) for the diagnosis of PM and for the evaluation of therapeutic effect of chemotherapy. Methods: We excised 54 white nodules from the parietal peritoneum of 40 GC patients. Among them, 9 patients received chemotherapy for advanced or recurrent GC before SL, and 31 did not receive chemotherapy except for adjuvant chemotherapy with S-1. The WLI and NBI findings were compared with the pathological findings. Results: Intranodular vessels were evaluated by WLI and NBI for dilatation, tortuousness, heterogeneity, and brown spots. Detection of any one abnormal finding on NBI plus clear demarcation of the peritoneal nodules on WLI more properly diagnosed 42 peritoneal nodules of 31 patients who did not receive chemotherapy (sensitivity, 100%; specificity, 88.9%; accuracy, 95.2%). In contrast, diagnosis ability was poor for 12 peritoneal nodules of 9 patients who received chemotherapy before SL (sensitivity, 66.7%; specificity, 33.3%; accuracy, 58.3%). Conclusions: Laparoscopic NBI is a useful tool for the diagnosis of PM in advanced GC before chemotherapy, and disappearance of dilated vessels on laparoscopic NBI could be useful to evaluate the therapeutic effect.
Pattern of recurrence after curative resection of stage I-III duodenal adenocarcinoma.
Authors: Andreina Colina, Kanwal Pratap Singh Raghav, Matthew H. G. Katz, Prajnan Das, Naruhiko Ikoma, Eugene Jon Koay, Jane V Thomas, Ching-Wei David Tzeng, Robert A. Wolff, Michael J. Overman
Journal: Journal of Clinical Oncology (2020)

794 Background: Duodenal adenocarcinoma (DA) is a rare cancer with limited data regarding the pattern of disease recurrence following resection. Methods: A retrospective review of 115 patients with Stage I-III DA from 3/1994 to 6/2018, at a single high-volume cancer center was conducted. Only patients (pts) who underwent a potentially curative surgical resection (R0/R1 margins) and had a postoperative follow-up radiographic evaluation were included. Periampullary adenocarcinomas were excluded. Clinicopathologic features and patterns of recurrence were compared across cohorts. Results: Of 76 patients who met inclusion criteria, 7 (9%) were stage I, 25 (33%) stage II, and 44 (57%) stage III. Histologic grade was moderate in 58% and poor in 38%. Median age was 63 years (range, 29-84), 38% were female, and R0 resection was 97%. Neoadjuvant therapy was given to 14% and adjuvant therapy to 61%. Radiation therapy (XRT) as either adjuvant/neoadjuvant therapy was used in 27%. Median follow-up was 44 (6-293) months. Median time to recurrence was 11mo, with 84% of recurrences occurring within 2 years. Median time to local recurrence (LR) vs. distant recurrence (DR) was 11mo vs. 12mo, respectively, p = 0.42. Stage impacted recurrence rate: 0% in stage 1 vs. 50% stage 2 vs. 71% stage 3 (p = 0.002). Median time to recurrence was 16mo for stage II and 11mo for stage III (p = 0.04). In total, 4 (5%) pts had LR only, 8 (10%) had LR concurrent with DR, and 32 (42%) had DR only. Recurrence distribution was similar across stage II (LR 8%, LR+DR 15%, DR 77%) and stage III (LR 10%, LR+DR 19%, DR 71%). LR was similar in patients that received XRT (10%) compared to those who did not (9%). Most common sites of DR were peritoneal (38%), liver (33%), distant lymph nodes (12%), and lung (10%). Conclusions: The recurrence pattern for resected DA is predominantly distant metastatic disease with the majority of recurrences occurring within the first two years. Future therapies should focus on improved systemic therapy, and surveillance should be most intensive in the first two years.
Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial
Authors: Punnee Pitisuttithum, Sorachai Nitayaphan, Suwat Chariyalertsak, Jaranit Kaewkungwal, Peter Dawson, Jittima Dhitavat, Benjaluck Phonrat, Siriwat Akapirat, Nicos Karasavvas, Lindsay Wieczorek, Victoria Polonis, Michael A Eller, Poonam Pegu, Dohoon Kim, Alexandra Schuetz, Surat Jongrakthaitae, Yingjun Zhou, Faruk Sinangil, Sanjay Phogat, Carlos A Diazgranados, James Tartaglia, Elizabeth Heger, Kirsten Smith, Nelson L Michael, Jean-Louis Excler, Merlin L Robb, Jerome H Kim, Robert J O'Connell, Sandhya Vasan, Arom Pitisuthitham, Yupa Sabmee, Narongrid Sirisopana, Chirapa Eamsila, Prapaporn Savaraj, Wanlaya Labwech, Siriluck Teerachia, Nuntisa Chotirosniramit, Taweewat Supindham, Boonlure Pruenglampoo, Patcharaphan Sugandhavesa, Natthapol Kosashunhanan, Oranitcha Kaewthip, Piyathida Sroysuwan, Pawinee Jarujareet, Silvia Ratto-Kim, Sebastian Molnar, Jesse Schoen, Nampueng Churikanont, Saowanit Getchalarat, Nongluck Sangnoi, Bessara Nuntapinit, Anant Phramtong, Pornsuk V. Grandin, Sirinan Madnote, Surawach Rittiroongrad, Boot Kaewboon, Rapee Trichavaroj, Jiraporn Puangkaew, Somsak Chantakulkij, Phiromrat Rakyat, Pornchanok Panjapornsuk, Nipattra Tragonlugsana, Weerawan Chuenarom, Mark de Souza, Viseth Ngauy, Nittaya Phanuphak, Nitiya Chomchey, Puttachard Saengtawan, Nipat Teeratakulpisarn, Rungsun Rerknimitr, Eugene Kroon, Carter A. Lee, Suchada Chinaworapong
Journal: The Lancet HIV (2020)
Fifteen-week window for recurrent muscle strains in football: a prospective cohort of 3600 muscle strains over 23 years in professional Australian rules football
Authors: John W Orchard, Mohammad Chaker Jomaa, Jessica J Orchard, Katherine Rae, Daniel Tyler Hoffman, Tom Reddin, Tim Driscoll
Journal: British Journal of Sports Medicine (2020)

To determine the rates of muscle strain injury recurrence over time after return to play in Australian football and to quantify risk factors.
Efficacy and safety of regorafenib in combination with chemotherapy as second-line therapy in patients with metastatic colorectal cancer: A network meta-analysis.
Authors: Xiaoyu Xie, Jianwei Zhang, Huabin Hu, Yue Cai, Zehua Wu, Jiayu Ling, Weiwei Li, Yanhong Deng
Journal: Journal of Clinical Oncology (2020)

115 Background: Recent studies have shown efficacy of chemotherapy (CTX) in combination with different biological agents including regorafenib (REG) in second-line treatment of metastatic colorectal cancer (mCRC). As there is no evidence on the relative efficacy and safety of REG as compared to other biological agents in combination with CTX, we evaluated the same in this network meta-analysis (NMA). Methods: Randomized controlled trials (RCTs) comparing efficacy and safety of biological agents + CTX against CTX alone as second-line treatment of mCRC were retrieved from PubMed, EMBASE and Cochrane databases. Progression free survival (PFS) was the primary outcome, while objective response rate (ORR), overall survival (OS) and safety were secondary outcomes. Outcomes were compared by random/mixed-effects NMA using Bayesian (R software, Gemtc package) and frequentist (R software, netmeta package) approaches. Results: Twelve RCTs comparing 9 different treatment regimens with a total of 6805 patients were included for analysis. Hazard ratios (HR)/ odds ratio (OR)/ relative risk (RR) and 95% confidence intervals (CI) for PFS, ORR and grade&gt; 3 adverse events (AE) of selected comparisons from the results of the NMA are shown in table. Conclusions: REG combined with CTX might be a potential alternative to conventional therapeutic options and could be considered as the best option for treating KRAS and BRAF mutated mCRC patients. Future RCTs are needed to confirm our results. [Table: see text]
Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.
Authors: Philippa Gail Corrie, David Chao, Ruth Board, Lawton Sarah, Rebecca Smittenaar
Journal: Journal of Clinical Oncology (2020)

55 Background: Population-based research provides real world information about prescribing trends, as well as benefits and harms associated with new interventions first evaluated in randomized clinical trials (RCTs). The national health service in England has comprehensive databases which we used to track prescribing of checkpoint inhibitors (CPIs) approved for 1st line use in metastatic melanoma and determine patient outcomes associated with survival and treatment toxicity. Methods: National Cancer Registration and Analysis Services (NCRAS) datasets were used to identify metastatic melanoma patients (pts) prescribed 1st line CPIs and calculate survival outcomes. The HES (Hospital Episode Statistics) database was used to identify emergency attendances and emergency hospital admissions. Results: 5465 melanoma pts were registered between April ‘14 and March ‘18. 2322 pts received 1st line CPIs: 1174 pembrolizumab (pem), 724 ipilimumab (ipi), 52 nivolumab (nivo), 372 ipinivo. Prescribing reflected national access, with ipi starting in July ‘14 and dropping rapidly on approval of pem in Nov ’15. Ipinivo prescriptions increased annually since July ’16. There was good 3yr OS concordance with RCT outcomes for ipinivo (56%), nivo (51%), pembro (40%) and ipi (32%). Pts treated with ipinivo were significantly younger (88% vs 49% &lt;70 years, P&lt;0.001) and fitter (60% vs 38% ECOG PS 0, P&lt;0.0001) than pts treated with antiPD1. 30-day mortality from last SACT was 3.8% for ipinivo, 9.1% for antiPD1 and 9.4% for ipi. 30-day rates of emergency hospital admissions/A&amp;E emergency attendances from the earliest SACT and last SACT treatment dates were significantly higher for ipinivo (37%/16% and 55%/19%) compared with antiPD1 (17%/8% and 29%/14%) and ipi (24%/9% and 40%/15%), P&lt;0.01. 25% of ipinivo-, 4% of antiPD1- and 15% of ipi-treated pts had a hospital admission for colitis. Conclusions: This largest real world dataset demonstrated rapid uptake of CPIs and survival outcomes similar to RCTs. Use of emergency services varied by regimen, with colitis dominating hospitalization after ipi+/-nivo. Pt selection appeared to differ for different regimens, the consequences of which warrant further research.
A randomized phase III study of mFOLFOX6/bevacizumab combination chemotherapy with or without atezolizumab or atezolizumab monotherapy in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC): Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study (NRG-GI004/SWOG-S1610).
Authors: Caio Max Sao Pedro Rocha Lima, Greg Yothers, Samuel A. Jacobs, Hanna Kelly Sanoff, Deirdre Jill Cohen, Katherine A Guthrie, Norah Lynn Henry, Patricia A. Ganz, Scott Kopetz, Peter C. Lucas, Charles David Blanke, Norman Wolmark, Howard S. Hochster, Thomas J. George, Michael J. Overman
Journal: Journal of Clinical Oncology (2020)

TPS260 Background: Deficient DNA mismatch repair (dMMR) colorectal cancer (CRC) is highly immunogenic. Preclinical data showed synergistic interactions among FOLFOX, anti-VEGF, and programmed cell death-1 (PD-1) pathway blockade. Prior phase I study of mFOLFOX6/ bevacizumab (bev) + atezolizumab (atezo) was well tolerated and enhanced intratumoral infiltration of CD8 + T cells. We hypothesize that the dMMR subset of CRC may be effectively targeted with combination of PD-1 pathway blockade and mFOLFOX6/bev. Methods: This is a prospective randomized phase III open-label trial. Pts (N=347) with mCRC dMMR will be randomized to three trial arms (1:1:1): mFOLFOX6/bev; atezo monotherapy; or mFOLFOX6/bev + atezo. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) assessed by study investigator of mFOLFOX6/bev/atezo and atezo monotherapy compared to mFOLFOX6/bev. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and PFS by retrospective central review. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2); availability of archived tumor tissue for central confirmation of dMMR status; and measurable disease per RECIST. Activated 11-7-17. As of 9-11-19, enrollment continues with 44/347 pts enrolled. Clinical trial: NCT02997228. Support:U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.
MT-5111: A novel HER2 targeting engineered toxin body in clinical development.
Authors: Roger J. Waltzman, Asis Sarkar, Eric T Williams, Aimee T. Iberg, Jack T. Higgins, Erin K. Willert
Journal: Journal of Clinical Oncology (2020)

433 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 binds an epitope on HER2 distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2 targeting agents. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration capability in solid tumor settings. Methods: HER2 expression and activity of MT-5111 was assessed in vitro by flow cytometry and cell viability assays. Serum exposure and tolerability of MT-5111 was measured in non-human primate (NHP) studies. Results: MT-5111 effectively kills 8/9 cell lines (2 gastric) with moderate to high HER2 surface expression, as well as two additional gastric cell lines with lower HER2 expression. No cytotoxicity is observed on multiple HER2- cell lines. As a protein, MT-5111 is not a substrate of drug efflux transporters that limit efficacy of ADCs. MT-5111 demonstrates effective cell-killing in vitro against cell lines expressing HER2 but resistant to trastuzumab (HCC1954) or T-DM1 (JIMT-1 and gastric SNU-216), highlighting the benefit of a novel mechanism of action to treat resistant disease. MT-5111 binds human and NHP HER2 protein. Based on serum exposure of MT-5111 in NHPs used to model pharmacokinetics, planned MT-5111 dosing in humans is above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 has a short half-life that, while allowing for efficient tumor cell targeting, minimizes serum exposure to avoid systemic effects over time. Conclusions: A Phase 1, first in human, open-label dose escalation and expansion study of MT-5111 (NCT04029922) in subjects with HER2+ solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. MT-5111 represents a novel HER2 targeted therapy for patients with HER2+ cancers with potential to overcome mechanisms of tumor resistance to existing therapies.