bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of neoadjuvant immunotherapy and targeted therapies on surgical resection in patients with solid tumors: A systematic review and meta-analysis.
Authors: Serrano Aybar Pablo Emilio , Parpia Sameer , Ruo Leyo , Tywonek Kasia , Lee Sandra , O'Neill Connor , Faisal Noor , Alfayyadh Ali , Gundayao Marylrose , Meyers Brandon M. 
Published: February 2020

511 Background: Neoadjuvant immunotherapy with anti-programmed cell death protein-1 (PD-1) or anti-programmed cell death ligand-1 (PD-L1) and tyrosine kinase inhibitor (TKI) therapy is currently being used to treat certain solid tumours prior to surgery. Neoadjuvant therapy may cause delays to resection potentially losing a window of opportunity. We explored the pooled proportion of patients with solid tumours receiving neoadjuvant therapy who completed planned surgical resection. Methods: Medline, CENTRAL and Embase databases were searched for single arm or randomized controlled trials studying neoadjuvant PD-1/PD-L1 immunotherapy or TKI therapy. Random-effects model was used to estimate the pooled proportion of patients undergoing planned resection, and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Results: From 368 relevant articles, eleven studies with a total of 382 patients receiving neoadjuvant PD-1 immunotherapy (n = 234) or neoadjuvant TKI therapy (n = 148) were analyzed. The types of tumours included hepatocellular carcinoma (1 study), renal cell carcinoma (8 studies), bladder carcinoma (1 study) or non-small cell lung cancer (1 study). The pooled proportion of patients who completed planned surgery after neoadjuvant therapy was 95% (95% CI 0.92 to 0.99). The overall partial response rate prior to surgery was 12% (95% CI 0.07 to 0.16) in the PD-1 therapy group and 46% (95% CI -0.12 to 1.03) in the TKI group. The pooled serious adverse events rate was 17% (95% CI 0.02 to 0.32) in the PD-1 therapy group and 29% (95% CI -0.10 to 0.68) in the TKI group. For all patients receiving neoadjuvant therapy, the pooled median overall survival was 23.41 months (95% CI 16.21 to 30.62) and median progression free survival was 7.46 months (95% CI 4.41 to 10.51). Conclusions: Neoadjuvant PD-1 or TKI therapy prior to surgery for solid tumours is safe, does not delay surgical resection and can result in a partial radiological response prior to surgery.
Major impact of personalized dosimetry using 90Y loaded glass microspheres SIRT in HCC: Final overall survival analysis of a multicenter randomized phase II study (DOSISPHERE-01).
Authors: Garin Etienne , Tzelikas Lambros , Guiu Boris , Chalaye Julia , Edeline Julien , De Baere Thierry , Tacher Vania , Robert Corentin , Assenat Eric , Terroir-Cassou-Mounat Marie , Regnault Hélène , Palard Xavier , Laffont Sophie , Campillo-Gimenez Boris , Rolland Yann 
Published: February 2020

516 Background: 90Y loaded microsphere SIRT (radioembolization) is a treatment option in advanced HCC. However, no personalized dosimetric endpoints are currently used. The goal of this study was to compare the efficacy of 90Y loaded glass microsphere SIRT in HCC using a standard versus a personalized dosimetric approach. Methods: DOSISPHERE-01 was a multicenter, randomized phase 2 trial in unresectable HCC patients with at least one tumor ≥7cm. Treatment arm was randomly assigned (1:1) to standard dosimetry arm (SDA), with a goal to deliver 120±20Gy to the treated volume or to personalized dosimetry arm (PDA) with a goal to deliver at least 205Gy to the index lesion. The primary endpoint was the response rate (RR) of the index lesion according to EASL criteria. Secondary endpoints included dose response evaluation, safety and overall survival (OS). Results: Sixty HCC patients were randomized (PDA 31, SDA 29, intent to treat population-ITTP-), and 56 treated (28 in each arm). RR was significantly increased in the PDA versus the SDA, in the ITTP, respectively 64.5% versus 31% (p=0.0095) as in the safety population -SP- (treatment effectively received, personalized 35, standard 21), respectively 74.3% versus 14.3% (p<0.0001). Median OS was significantly increased in the PDA versus the SDA, in the ITTP, respectively 26.7m (CI 95%:11.7-NR) versus 10.6m (CI 95%:6-16.8), p=0.0096, HR=0.421 (95%CI:0.215-0.826), p=0.0119, as in the SP, respectively 26.7m (CI 95%:11.7- NR) versus 9.5m (CI 95%:4.8-14.9), p=0.0015, HR=0.342 (95%CI:0.171-0.683), p=0.0023. Median OS was 26.7m (CI 95%:13.5-NR) versus 6.0m (CI 95%:3.8-14.9) for the patients who received a tumor dose ≥205 Gy or <205 Gy respectively, p=0.0106, HR=0.336 (95%CI:0.154-0.735), p=0.0063. Treatment-related clinically relevant hepatic ≥grade 3 AEs were observed in 5.7% and 14.2% of the patients of the PDA and SDA arms, respectively, (p=ns). Conclusions: MAA SPECT/CT based personalized dosimetry is safe and dramatically increased RR and OS of HCC patients. These results question the interpretation of all phase 3 trials of SIRT designed without personalized dosimetry in HCC. Clinical trial information: 2015-A00894-45.
Analysis of OX40 agonist antibody (PF-04518600) in patients with hepatocellular carcinoma.
Authors: El-Khoueiry Anthony B. , Spano Jean-Philippe , ANGEVIN ERIC , Doi Toshihiko , Bullock Andrea J. , Harris William Proctor , Hamid Omid , Gougis Paul , Forgie Alison , Yang Wenjing , Liao Ken , Li Ruifeng , Taylor Carrie T. , Chou Jeffrey , Eskens Ferry 
Published: February 2020

523 Background: PF-04518600 (PF-8600) is a humanized agonist IgG2 monoclonal antibody to the tumor necrosis factor superfamily receptor OX40. PF-8600 was given to patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC) in dose expansion of a phase 1 study (NCT02315066). Safety and tolerability were primary endpoints and exploratory endpoints included biomarker analyses. Methods: Pts received either 30 mg (Arm 1) or 250 mg (Arm 2) of PF-8600 intravenously Q2W. Pts had pathologic diagnosis of advanced HCC, a Child-Pugh score of A or B7, and had ≤2 prior lines of therapy, or if treatment naïve, had declined standard of care. Radiological tumor assessments were conducted Q8W. Biopsy samples collected at baseline and wk 6 were analyzed by immunohistochemistry and RNA sequencing for pharmacodynamic (PD) analyses. Whole blood samples were collected longitudinally for DNA extraction for high-throughput sequencing of the T cell receptor β-chain. Results: Arm 1 enrolled 16 pts (mean age 65.6 yrs; range 54-81 yrs; prior PD-1/PD-L1: 5 pts) and Arm 2 enrolled 19 pts (mean age 61.7 yrs; range 26-79 yrs; prior PD-1/PD-L1: 3 pts). All grade treatment related adverse events (TRAEs) occurred in 69% of pts in Arm 1 and 58% of pts in Arm 2. The rate of ≥Grade 3 TRAEs was 31% and 16% in Arms 1 and 2, respectively. For both arms combined, the most common (≥10%) TRAEs were rashes and pruritus. In Arm 1, 8 pts (50%) and in Arm 2, 10 pts (53%) achieved stable disease (SD), with a mean duration of 18.4 (range: 14.0-30.3 wks) and 17.4 wks (range: 8.0-31.9 wks), respectively. PD effects were more evident in Arm 1 than Arm 2, including increased OX40 tumor expression and positive changes in gene signatures, reflecting an active anti-tumor immune response. Conclusions: PF-8600 was generally well tolerated and provided meaningful disease control. While safety and efficacy were not significantly different between the 2 doses, there were potential differences in the PD data. The safety and relative durability of SD in HCC pts may provide a rationale for exploration of combination therapy in this pt population. Clinical trial information: NCT02315066.
Nivolumab (NIVO) and drug eluting bead transarterial chemoembolization (deb-TACE): Preliminary results from a phase I study of patients (pts) with liver limited hepatocellular carcinoma (HCC).
Authors: Harding James J. , Yarmohammadi Hooman , Reiss Kim Anna , Chou Joanne F. , Capanu Marinela , Do Richard K. G. , Khalil Danny , El Dika Imane H. , Giardina Joseph Daniel , Merghoub Taha , Jarnagin William R. , Nadolski Gregory , Erinjeri Joseph Patrick , Soulen Michael C. , Tan Benjamin R. , Abou-Alfa Ghassan K. 
Published: February 2020

525 Background: Regional therapies in HCC impact the immune microenvironment and may augment the effects of immune checkpoint inhibitors. Methods: This is a multicenter phase 1 study of NIVO and deb-TACE in unresectable HCC pts (BCLC Stage B) and Child Pugh A cirrhosis (NCT03143270). The primary objective is to assess safety. Secondary objectives include response rate by RECIST v1.1, progression-free and overall survival by Kaplan-Meier methodology, and blood/tumor immune correlates. A 3 + 3 design sequentially evaluates 3 cohorts of differing schedules of NIVO relative to deb-TACE. Deb-TACE (75mg of doxorubicin) is administered on Day 0. NIVO is dosed at 240mg IV every 14 days for 1 year (Cohort 1: NIVO begins day +14 after deb-TACE; Cohort 2, interrupted NIVO dosing begins at Day -28 but is held on the Day 0 then restarted on Day +14; Cohort 3, continuous NIVO dosing begins on Day -28 without interruption). Results: As of July 2019, 9 pts have been treated [median 65 years (range: 54-76), male (89%), viral (44%;1 HBV, 3 HCV), non-viral (56%;2 EtOH, 1 NASH, 2 unknown), prior resection (44%), prior regional therapy (44%), 3 pts in each cohort]. No cases of treatment related liver failure, dose-limiting toxicity, or Grade 5 adverse events (AEs) were observed. Grade ≥3 AEs possibly related to nivolumab, deb-TACE, or both included: transaminase elevation (1 pt: day 1 post TACE resolved in 7 days without treatment; 2 pts: ≥30 days post TACE resolved with steroids between 20-41 days), post-embolization syndrome (1 pt: resolved in 5 days), asymptomatic lipase increase (1 pt: resolved in 14 days), post-procedural groin hematoma (1 pt: resolved in 2 days). All 9 pts were evaluable for efficacy: 2 (22%) confirmed PR and 7 (78%) SD. 4/9 pts remain on study with SD or better—2 pts continue > 18 months post embolization with durable PRs. 12 months OS rate was 71%. Ongoing correlates will be presented at a separate meeting. Conclusions: Nivolumab given at various times relative to deb-TACE appears safe and tolerable. Cohort 3 continues to accrue to provide a better estimate of safety and antitumor activity of the combination. Clinical trial information: NCT03143270.
Impact of baseline and concomitant corticosteroid therapy on the outcomes of hepatocellular carcinoma treated with immune checkpoint inhibitor therapy.
Authors: Pinato David James , Kaseb Ahmed Omar , Wang Yinghong , Saeed Anwaar , Szafron David , Jun Tomi , Naqash Abdul Rafeh , Lee ChiehJu , Khan Uqba , Nimkar Neil Satish , Paul Sonal , Bettinger Dominik , Hildebrand Hannah , Pressiani Tiziana , Abugabal Yehia I. , Personeni Nicola , Huang Yi-Hsiang , Rimassa Lorenza , Ang Celina , Marron Thomas Urban 
Published: February 2020

531 Background: The impact of corticosteroid treatment (CT) on the efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) is undefined. We evaluated whether CT administered at baseline (bCT) or concurrently to ICI (cCT) influences clinical outcomes of HCC patients treated with ICI. Methods: This retrospective, multi-center observational study was conducted across 9 tertiary academic referral centers collected 341 HCC patients who received ICI across 3 continents between January 1, 2016 and April 1, 2019. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of ICI commencement and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1) on 6-8 weekly periodic restaging. Results: Of 331 eligible patients, 254 (76%) had BCLC-C stage HCC and received mostly PD(L)-1 ICI monotherapy (n=250, 85%). Median OS was 12.1 months (95%CI 9.2-15.0 months) and median PFS was 8.1 months (95%CI 6.3-10 months). In total 81 patients (24%) received >10 mg prednisone equivalent daily either as bCT (n=15, 4%) or cCT (n=66, 20%). Indications for CT included procedure/prophylaxis (n=37, 45%), management of irAE (n=31, 37%), cancer-related symptoms (n=5, 2%) or comorbidities (n=8, 3%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in uni- and multi-variable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (2.4 vs. 11.3 months, p=0.01), OS (4.5 vs. 12.8 months, p=0.05) and reduced ORR (p=0.03) compared to cancer-unrelated indications. Conclusions: This is the first study to demonstrate that neither bCT nor cCT appear to influence response and OS following ICI in HCC. Worse survival and ORR in CT recipients for cancer-related indications appears driven by the poor prognosis associated with symptomatic HCC.
Immunotherapy versus biologics as second-line therapy in advanced hepatocellular carcinoma (HCC).
Authors: Al-Jumayli Mohammed , Hildebrand Hannah , Abbasi Saqib , Kasi Anup , Saeed Anwaar 
Published: February 2020

533 Background: Sorafenib or lenvatinib are the current frontline options for advanced HCC. Multiple biologic agents including multi-Tyrosine Kinase Inhibitors (TKI) cabozantinib & regorafenib have been recently approved for the previously treated population. Immunotherapy (IO) agent Nivolumab have also been approved in the same setting. Due to lack of prospective head to head comparison, there is no standardized way for alternating those agents beyond frontline. Methods: We performed a retrospective review of KU cancer registry. Patients with advanced HCC were divided into 2 groups based on the 2nd line systemic regimen (IO vs non-IO). Kaplan–Meier and Cox proportional hazards models were utilized to evaluate progression free survival (PFS) and overall survival (OS). Results: Between 2016-2019, 98 patients were identified, 41 received IO, while 57 received biologics. All patients had sorafinib as 1st line therapy. Most patients have ECOG 0-1 and Child-Pugh class A or B. 55% had hepatitis C, 6% hepatitis B and 27 % have history of alcohol misuse. Almost 50% of patients have received prior liver directed therapy. Comparing IO vs non-IO groups, median PFS was 3.9 months vs 3 months and median OS was 10 months vs 10 months. There was no statistically significant difference in PFS & OS but there was a delay separation in the survival curve favoring IO. Similar outcome was seen in a sub-group analysis of the hepatitis C patients. Conclusions: This retrospective comparative review of current 2nd line regimens is one of the first & largest studies reported. In this study population, IO was not superior to multi-TKI as a 2nd line regimen. The late survival curve separation favoring IO might suggest a delay IO effect in a subgroup of patients. Future studies should define specific biomarkers that could predict response and allow treatment to be optimized depending on patient and tumor characteristics. Furthermore, combining IO plus multi-TKI might be a promising next step in development. A number of ongoing trials are testing this strategy including our CAMILLA trial of Cabozantinib plus Durvalumab, currently enrolling patients at the University of Kansas Cancer Center NCT03539822 .
Biomarker exploration for SHR-1210 plus GEMOX as first-line treatment in advanced biliary tract cancer.
Authors: Chen Xiaofeng , Wu Hao , Wu Xiaofeng , Shao Qianwen , Zhu Feipeng , Qian Xiaofeng , Zhao Fengjiao , Mao Weidong , Sun Jing , Wang Jian , Han Gaohua , Li Huajun , Zhu Dongqin , Zhu Liuqing , Li Changxian , Seesaha Poshita kumari , Shao Yang , Gu Yanhong , Li Xiangcheng , Shu Yongqian 
Published: February 2020

536 Background: We conducted a trial to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as in untreated patients (pts) with biliary tract cancer (BTC) (NCT03486678). This study is to explore the predictive biomarkers for efficacy. Methods: Baseline lymphocyte count and lactate dehydrogenase (LDH) level were obtained from routine tests. Gene mutation and tumor mutation burden (TMB) from baseline tissue and blood samples were tested by the next generation sequencing (NGS) with a 425-gene panel. The expressions of PD-L1 and markers for lymphocyte, natural killer cells, and macrophages in baseline tumor tissue samples were analyzed by immunohistochemistry (IHC). Results: The median progression free survival (PFS) and overall survival (OS) in this trial was 6.2m and 12.1m, respectively. Firstly, pts with normal LDH level (≤271 U/L) had a tendency for longer PFS (6.2m vs 5.0m, p = 0.053) and significantly longer OS (p = 12.6m vs 6.8m, p < 0.001) than those with elevated LDH ( > 271 U/L). Low baseline lymphocyte count (≤ 1.1×109/L) was related to worse OS (12.6m vs 6.9m, p < 0.001) and PFS (6.2m vs 3.9m, p = 0.021). Secondly, baseline tissue and ctDNA gene mutations were detected in 33 and 30 pts, respectively. Tissue analysis showed that pts with STK11 (p = 0.0254), CTNNB1 (p < 0.001) and SMARCA4 (p = 0.0181) wild type showed significantly longer PFS than those with mutations. Pts with ARID1A gene wild type showed a tendency for longer PFS (p = 0.0634) and significantly longer OS (p = 0.0149). Gene mutations from baseline ctDNA revealed that pts with wild type SMARCA4, CTNNB1, STK11, and NF1 had longer PFS than those with mutations. Lastly, IHC meant that PD-L1 positivity may be related to longer PFS (TPS > 1%, p = 0.08; IPS > 1%, p = 0.05). Besides, pts with CD68+ HLA-DR+ macrophages > 0.01%, CD68+ HLA-DR- macrophages>2.5%, and CD56bright>1.7% and CD56dim > 0.05 also got PFS benefits (all p < 0.05). TMB (cutoff = 7 muts/mbp) was not associated with PFS. Conclusions: Despite limited sample size, biomarkers from routine blood test, gene mutation and immune microenvironment can be helpful to stratify pts who are sensitive to immunotherapy in advanced BTC. Clinical trial information: NCT03486678.
Treatment of hepatocellular carcinoma and liver metastases with hafnium oxide nanoparticles activated by SBRT: A phase I/II trial.
Authors: Jaksic Nicolas , Pracht Marc , Rolland Yann , De Baere Thierry , Durand-Labrunie Jerome , Nguyen France , Bronowicki Jean-Pierre , Vendrely Veronique , Sa Cunha Antonio , Croisé-Laurent Valérie , Rio Emmanuel , Le Sourd Samuel , Said Patricia , Freund Sebastian , Baskin-Bey Edwina , Gustin Pierre , Perret Christophe , Peiffert Didier , Deutsch Eric , Chajon Enrique 
Published: February 2020

537 Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056]. Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1). Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD. Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.
Expansion part of phase I study of E7090 in patients with cholangiocarcinoma harboring FGFR2 gene fusion and with gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression.
Authors: Morizane Chigusa , Ueno Makoto , Ioka Tatsuya , Tajika Masahiro , Ikeda Masafumi , Yamaguchi Kensei , Hara Hiroki , Yabusaki Hiroshi , Miyamoto Atsushi , Iwasa Satoru , Muto Manabu , Takashima Tsutomu , Minashi Keiko , Komatsu Yoshito , Nishina Tomohiro , Nakajima Takako Eguchi , Sahara Takatoshi , Funasaka Setsuo , Yashiro Masakazu , Furuse Junji 
Published: February 2020

538 Background: E7090 is a selective tyrosine kinase inhibitor against FGFR1-3. This first-in-human phase I study has been conducted in Japan and consists of 2 parts. Based on the toxic, pharmacokinetic, and pharmacodynamic profiles in Part 1, dose escalation study, the recommended dose was determined to be 140 mg QD for Part 2, an expansion study part restricted to patients with tumors harboring FGFR gene alterations. Here we provide the interim analysis results of Part 2. Methods: In Part 2, patients with cholangiocarcinoma harboring FGFR2 gene fusion (CCA cohort) and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression (GC cohort) were enrolled. Patients received oral dosing of E7090 until disease progression or unacceptable toxicity. Safety was assessed using CTCAE version 4.03. Tumor response was evaluated by site investigators using RECIST 1.1. Results: As of 31 March 2019, 16 patients including 6 patients in CCA cohort and 10 patients in GC cohort received E7090 in Part2. Median age was 63 years, 25% were female, ECOG PS of 0 and 1 were 50% respectively. 5 patients (83%) in CCA cohort and 1 patient (10%) in GC cohort achieved partial response as the best overall response. The disease control rates were 100% in CCA cohort and 30% in GC cohort, respectively. Median progression-free survivals were 8.3 months in CCA cohort and 2.8 months in GC cohort at the cut-off date. 2 patients with CCA remain on treatment. The most common treatment-related TEAEs occurring in 30% or more of patients in Part 2 were hyperphosphatemia (100%), palmar–plantar erythrodysesthesia syndrome (56%), paronychia (50%), dysgeusia (38%), stomatitis (31%), diarrhea (31%), increased AST (31%) and blood creatinine increased (31%). Grade≥3 treatment-related TEAEs were reported in 2 out of 16 patients (13%); they were increased AST, lipase increased and retinopathy. Conclusions: This study indicated that E7090 has a manageable safety profile in Part 2 and the promising clinical activity in CCA patients with FGFR2 gene fusion.