bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced efficacy of anti-VEGFR2/taxane therapy after progression on immune checkpoint inhibition (ICI) in patients (pts) with metastatic gastroesophageal adenocarcinoma (mGEA).
Authors: Kankeu Fonkoua Lionel Aurelien , Chakrabarti Sakti , Sonbol Mohamad Bassam , Kasi Pashtoon Murtaza , Starr Jason Scott , Liu Alex John , Bois Melanie C. , Pitot Henry C. , Chandrasekharan Chandrikha , Ross Helen J. , Wu Tsung-Teh , Graham Rondell P. , Markovic Svetomir , Dong Haidong , Yoon Harry H. 
Published: May 2020

4541 Background: Anti-VEGFR2 therapy (ramucirumab/paclitaxel [RAM/TAX]) and ICI are approved as 2nd- and 3rd-line therapy (Tx), respectively, for pts with mGEA. We unexpectedly saw durable responses in 2 pts on RAM/TAX after progression on an ICI trial (KN-059; PMID 29674442). We performed a pilot to examine the clinical activity of ICI followed by RAM/TAX. Then we retrospectively compared the outcomes of pts who received this serial Tx to pts who received RAM/TAX without prior ICI. Methods: All pts with mGEA at Mayo Clinic who received RAM/TAX (2014-19) were included (N = 87). Outcomes were best objective response rate (ORR: complete [CR] or partial response) per RECIST1.1, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Chi square and multivariate (MV) logistic and Cox regression were used. Results: 15 consecutive pts with measurable mGEA received ICI immediately followed by RAM/TAX after irRECIST progression. Most pts (95%) did not respond to ICI. Yet on RAM/TAX, 100% (15/15) had tumor reduction (range -8% to -100%) with an ORR of 73% (11/15), including 3 CRs. In these pts (who received ICI followed by RAMTAX), PFS on RAMTAX was longer than on last chemotherapy before ICI (12.3 vs 3.0 m, P < .001). Outcomes on RAM/TAX in these pts were significantly better than in pts who received RAM/TAX alone (see Table). Associations were strengthened after adjusting for total lines of Tx, line of Tx of RAM/TAX, age, and ECOG PS. Exploratory analysis of paired tumor biopsies collected pre-ICI and on RAM/TAX in a small subset revealed that the frequency of intratumoral immunosuppressive FOXP3+ Tregs decreased on RAM/TAX, whereas the frequency of antitumor CD8+ T cells was preserved. Conclusions: RAM/TAX immediately preceded by ICI was associated with significantly higher OS, ORR, and DOR than RAM/TAX alone, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This novel sequence of therapy will be tested prospectively in a new randomized phase 2 trial (NCT04069273). [Table: see text]
Perioperative FLOT in elderly patients with resectable gastric cancer: Subgroup analysis from the observational RealFLOT study.
Authors: Giommoni Elisa , De Vita Ferdinando , Pecora Irene , Iachetta Francesco , Strippoli Antonia , Satolli Maria Antonietta , Spallanzani Andrea , Puzzoni Marco , Nappo Floriana , Sisani Michele , Formica Vincenzo , Giovanardi Filippo , Pozzo Carmelo , Prisciandaro Michele , Di Donato Samantha , Pompella Luca , Salani Francesca , Tirino Giuseppe , Lavacchi Daniele , Antonuzzo Lorenzo ,   GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica)
Published: May 2020

4548 Background: The treatment strategy for patients with resectable gastric cancer changed in the last few years with perioperative treatments. FLOT regimen (fluorouracil, oxaliplatin, docetaxel) turned out to be feasible and effective, offering significant improvement in survival outcomes. However, the safety profile of triplet therapies for elderly patients deserves a special attention and, consequently, the best treatment strategy for these patients is still debated. Methods: Focusing on the elderly patient population (age ≥65 years), real-world data from patients with resectable gastric or gastro-oesophageal junction (GEJ) adenocarcinoma (T≥2 and/or N+) enrolled in the observational RealFLOT study were collected. Results: A total of 206 patients with resectable gastric or GEJ adenocarcinoma received perioperative FLOT at 15 Italian centers in routine clinical practice, between September 2016 and September 2019. The median age was 63 years (range 36-77) and 43% of patients enrolled (n = 89) were ≥65 years. Among elderly patients, 46 (52%) received FLOT for at least 4 full-dose cycles in the preoperative phase, 82 (92%) underwent surgery, and 56 (62%) started the postoperative phase. The primary end point of the study, pathological complete response (pCR) rate, was similar among patients aged ≥65 and < 65 (6.7% vs 7.7%, respectively). The distribution of pathological stages did not differ according to age (p = 0.473), and disease-free survival (DFS) is unrelated to the age of patients (log-rank 0.57; p = 0.89). The incidence of grade (G) 3-4 adverse events (AEs) was similar in the two age groups (Table) and the 30-day mortality rates after surgery did not differ according to age. Conclusions: FLOT regimen demonstrated to be feasible and safe in elderly patients since no differences were observed in terms of pCR, DFS and safety profile according to age. [Table: see text]
Hepatic arterial infusion of oxaliplatin plus raltitrexed in patients with unresectable hepatocellular carcinoma (HAIROX): A phase II, single-arm, prospective study.
Authors: Chen Shiguang 
Published: May 2020

4574 Background: Chemoembolisation and oral sorafenib are the recommended treatment for unresectable hepatocellular carcinoma (HCC); however, some patients respond poorly to these. Hepatic arterial infusion (HAI) chemotherapy may have potential benefit in these patients. We aimed to investigate the efficacy and safety of HAI of oxaliplatin plus raltitrexed in patients with unresectable HCC. Methods: In this phase II, single-arm clinical trial, we enrolled patients aged 18–70 years with unresectable HCC at the Fujian Cancer Hospital (China). We performed HAI with oxaliplatin (100 mg/m2 for 4 hours) and raltitrexed (3 mg/m2 for 1 hour). Treatment was repeated every 3 weeks and was discontinued either because of disease progression, unacceptable toxicity levels, or refusal of further treatment. We used Simon’s two-stage design. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. Results: Fifty-one patients were screened between January 5, 2018 and August 7, 2019. Of these, 39 patients (34 men and 5 women; median age, 53 years) were enrolled and included in the intention-to-treat population. Objective response was achieved in 18 (51.4%) of 35 patients in the per-protocol population and in 18 (46.2%) of 39 patients in the intention-to-treat population. Treatment-related grade 4 adverse events or deaths were not reported, and the observed grade 3 adverse events were elevated aspartate aminotransferase levels (5[12.8%]), elevated alanine aminotransferase levels (1 [2.6%]), leukopenia (1 [2.6%]), thrombocytopenia (1 [2.6%]), and abdominal infection (1 [2.6%]). Conclusions: HAI of oxaliplatin plus raltitrexed showed promising efficacy and acceptable toxicity levels in patients unresectable HCC, and further evaluation is warranted. Clinical trial information: ChiCTR-OOC-17014182 . [Table: see text]
Different organ-specific response to nivolumab to determine the survival outcome of patients with advanced hepatocellular carcinoma (aHCC).
Authors: Kim Han Sang , Hong Jung Yong , Cheon Jaekyung , Kim Ilhwan , Kim Chang Gon , Kang Beodeul , Kim Dae Jung , Kim Chan , Chon Hongjae , Choi Hye Jin , Lim Ho Yeong 
Published: May 2020

4584 Background: Previously, two phase III clinical trials of immune checkpoint inhibitors (ICI) failed to meet their primary endpoints, leading to doubts regarding the clinical activity of ICI monotherapy in patients with aHCC. Here, we comprehensively examined clinicopathological factors and estimated their association with survival outcomes in aHCC patients treated with nivolumab. Methods: A total of 261 eligible patients from 5 high-volume centers who were treated with nivolumab between June 9, 2012 and March 14, 2018 and had measurable diseases were reviewed. We reviewed more than 80 clinicopathological factors and categorized them into 6 areas: 1) demographics (n = 16); 2) baseline laboratory values (n = 19); 3) tumor burden (n = 12); 4) previous treatment (n = 12); 5) treatment response (n = 5); 6) toxicity profiles (n = 18). Their association with survival outcomes were evaluated, and organ-specific response evaluation, adapted from RECIST 1.1, was conducted. Results: Of the 261 patients, 218 (84%) had extrahepatic spread. The median follow-up time was 4.5 months. The median progression-free survival (PFS) and overall survival (OS) were 2.3 months (95% CI, 1.8-2.8) and 6.3 months (95% CI, 5.0-8.2). Objective response rate was 15%. Subgroup analyses revealed that compensated liver function (Child-Pugh score A5/6), surrogate markers for low tumor burden (low AFP, low PIVKA, and low LDH level), inflammatory markers (low C-reactive protein [CRP], low erythrocyte sedimentation rate [ESR], low neutrophil-to-lymphocyte ratio [NLR], high lymphocyte-to-monocyte ratio [LMR]), and low intrahepatic tumor burden were significantly associated with longer OS. A total of 456 individual lesions (liver, n = 249; lung, n = 124; lymph node, n = 35; others such as boner soft tissues, n = 48) were examined. Organ-specific response rates (hepatic tumor, 9%; lung, 25%; lymph node, 37%; others metastasis, 15%) were different, of which intrahepatic tumor was the least responsive organ to ICI treatment in aHCC. Conclusions: Underlying liver function, the tumor extent and burden, and the degree of plasma lymphocytes are crucial for determining tumor response to ICI in aHCC. Antitumor immune response to ICI differs in an organ-specific manner. The hepatic tumors of HCC may be less responsive to nivolumab than extrahepatic lesions.
A retrospective analysis of post second-line chemotherapy treatment outcomes for patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions.
Authors: Javle Milind M. , Sadeghi Saeed , El-Khoueiry Anthony B. , Goyal Lipika , Philip Philip Agop , Kelley Robin Kate , Borbath Ivan , Macarulla Teresa , Yong Wei-Peng , Tanasanvimon Suebpong , Pande Amit , Li Gary , Howland Michael , Berman Craig , Abou-Alfa Ghassan K. 
Published: May 2020

4591 Background: Cholangiocarcinoma (CCA) is the most common biliary tract malignancy with an estimated incidence of 8,000–10,000 patients/year in the US. Chemotherapy is the most common second-line treatment with reported outcomes in patients with CCA. Response rates of < 10% and median progression-free survival (PFS) times of ~3–4 months have been reported with second-line chemotherapy regimens, including FOLFOX in the ABC-06 trial. Fibroblast growth factor receptor 2 ( FGFR2) fusions occur in 13–17% of CCA and multiple targeted agents are in development for patients with FGFR2 fusions. To date, the outcome of patients with CCA and FGFR2 fusions receiving standard second-line chemotherapy is unknown. Methods: Patients with advanced CCA and FGFR2 fusions after prior treatment with gemcitabine-based chemotherapy were enrolled in a single-arm phase 2 study (NCT02150967) and received the FGFR1–3 selective TKI infigratinib (previously BGJ398) 125 mg orally qd on d1–21, cycles repeated q28 days until unacceptable toxicity, disease progression, investigator discretion, or withdrawal of consent. A retrospective analysis of a subset of patients who received infigratinib as third- or later-line treatment was performed. Investigator-assessed PFS and best overall response (BOR, per RECIST 1.1) following second-line chemotherapy (pre-infigratinib) and third-line or later-line infigratinib were calculated. Results: Of the 71 patients (44 women; median age 53 years) with FGFR2 fusions enrolled at the time of analysis (datacut 8 August 2018), 37 (52%) were included in this retrospective analysis. Median PFS with standard second-line chemotherapy was 4.63 months (95% CI 2.69–7.16) compared with 6.77 months (95% CI 3.94–7.79) for third- and later-line infigratinib. BOR for second-line chemotherapy was 5.4% (95% CI 0.7–18.2) compared with 21.6% for third- and later-line infigratinib (95% CI 9.8–38.2). Conclusions: Outcomes from second-line chemotherapy in patients with CCA and FGFR2 fusions were similar to those reported in the literature for all patients with CCA regardless of genomic status and remain dismal. Infigratinib administered as third- and later-line treatment resulted in a meaningful PFS and ORR benefit in patients with CCA and FGFR2 fusions. Clinical trial information: NCT02150967 .
Clinical activity and safety of penpulimab (Anti-PD-1) with anlotinib as first-line therapy for advanced hepatocellular carcinoma (HCC).
Authors: Jiao Shun Chang , Bai Li , Dong Jiahong , Bai Chunmei , Hu Chunhong , Shen Liangfang , Qin Qun , Bai Yuxian , Fan Jia , Zang Aimin , Han Chun , Zhu Yanyun , Li Juan , Zhang Pengfei , Ye Sisi , Kang Xindan , Qiao Qian , Song Weifeng , Li Baiyong , Xia Yu 
Published: May 2020

4592 Background: Advanced HCC is a deadly disease with few systemic therapeutic options. VEGF blockade potentiates the effect of PD-1 inhibition by opposing the immunosuppressive effects of VEGF-A (increased DC maturation, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors). A sBLA has been submitted for an anti-PD-L1 + anti-VEGF combination as 1L treatment for advanced HCC. Penpulimab is a novel humanized anti-PD-1 IgG1 antibody with complete removal of Fc receptor mediated effect, and featuring slow antigen binding off-rate and high receptor occupancy. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Methods: In this open-label, multicenter phase Ib/II study, treatment-naive pts with advanced HCC received penpulimab 200mg Q3W in combination with anlotinib 8mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary objectives were to assess antitumor activity by ORR (RECIST v1.1). The secondary objectives were to assess antitumor activity by DCR, DoR, TTP, and to assess the safety and tolerability of the combination. Results: As of Jan 14, 2020, 31 pts (median age 56 years [23-74], male 81%, ECOG 0/1 [64%/36%], BCLC B/C [23%/77%], HBV/HCV [61%/7%]) received combined therapy (a median of 6 [1-15] doses). Treatment-related adverse events (TRAEs) occurred in 93.5% of pts (G3 in 9.7% [3/31], no G4, and leading to treatment discontinuation in 6.5% [2/31]). Most frequent TRAEs were increased AST (35.5%), increased ALT (29%), asthenia (22.6%), decreased platelet count (19.4%), increased blood bilirubin (19.4%), increased bilirubin conjugated (19.4%), and rash (16.1%). Of 25 evaluable pts (with the opportunity to be followed-up for ≥2 scans, 12 weeks), confirmed ORR was 24% (6/25) and DCR was 84% (21/25). Five responders remained in response with DoR ranging 1.4+ to 6.9+ months. Median TTP was not reached and 6m-TTP rate was 63% (95% CI: 38%, 81%). Conclusions: Penpulimab in combination with anlotinib had a manageable safety profile and encouraging antitumor activities in patients with advanced HCC. No unexpected AEs were identified beyond the established safety profile for each agent. Evaluation of penpulimab + anlotinib (10 mg QD) in a phase 3 study for 1L HCC is currently underway. Clinical trial information: NCT04172571 .
Complete responses (CR) in patients receiving atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in IMbrave150: A phase III clinical trial for unresectable hepatocellular carcinoma (HCC).
Authors: Finn Richard S. , Qin Shukui , Ikeda Masafumi , Galle Peter R. , Ducreux Michel , Kim Tae-You , Kudo Masatoshi , Lim Ho Yeong , Breder Valeriy Vladimirovich , Merle Philippe , Kaseb Ahmed Omar , Li Daneng , Feng Yin-Hsun , Verret Wendy , Xu Derek-Zhen , Hernandez Sairy , Ding Beiying , Zhu Andrew X. , Cheng Ann-Lii 
Published: May 2020

4596 Background: In the Phase III IMbrave150 trial, statistically significant and clinically meaningful improvements in OS and PFS were seen with atezo + bev vs sor in pts with unresectable HCC who had not received prior systemic therapy (Cheng, ESMO Asia, 2019). Historically, CR rates have been low in HCC clinical trials. Here we report the baseline characteristics for IMbrave150 pts with a CR. Methods: IMbrave150 enrolled systemic treatment-naive pts with unresectable HCC. Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg BID until unacceptable toxicity or loss of clinical benefit per investigator. Co-primary endpoints were OS and PFS by independent review facility (IRF)–assessed RECIST 1.1. The key secondary endpoints IRF ORR per RECIST 1.1 and IRF ORR per HCC mRECIST were also part of the study statistical testing hierarchy. Results: The ITT population included 336 pts randomized to atezo + bev and 165 pts randomized to sor. With a median follow-up of 8.6 mo (data cutoff, Aug 29, 2019), OS HR was 0.58 (95% CI: 0.42, 0.79; P = 0.0006) and PFS HR was 0.59 (95% CI: 0.47, 0.76; P < 0.0001) with atezo + bev vs sor. ORR was 27% vs 12% ( P < 0.0001) per IRF RECIST 1.1 and 33% vs 13% ( P < 0.0001) per IRF HCC mRECIST with atezo + bev vs sor, respectively. For responders (per IRF RECIST 1.1), median time to response was 2.8 mo (range, 1.2-11.3) with atezo + bev and 3.3 mo (range, 1.2-7.2) with sor. CR per IRF-assessed RECIST 1.1 was achieved by 18 pts in the atezo + bev arm and 0 pts in the sor arm. The baseline characteristics for atezo + bev CR pts are shown in the table. Additional characteristics will be shown. Conclusions: IMbrave150 demonstrated statistically significant and clinically meaningful improvement in both OS and PFS with atezo + bev vs sor in pts with unresectable HCC who have not received prior systemic therapy. Pts achieved CRs regardless of poor prognostic factors or etiology. Atezo + bev may be a practice-changing treatment for pts with unresectable HCC. Clinical trial information: NCT03434379 . [Table: see text]
Results from TreeTopp: A randomized phase II study of the efficacy and safety of varlitinib plus capecitabine versus placebo in second-line (2L) advanced or metastatic biliary tract cancer (BTC).
Authors: Javle Milind M. , Oh Do-Youn , Ikeda Masafumi , Yong Wei-Peng , McIntyre Nicola , Lindmark Bertil , McHale Mark 
Published: May 2020

4597 Background: Patients with advanced or metastatic BTC who progress on first-line (1L) gemcitabine-based doublet chemotherapy have few 2L treatment options. Varlitinib is a reversible small molecule pan human epidermal growth factor receptor (HER) inhibitor with low nanomolar potency against HER1 (EGFR), HER2 and HER4 with promising early results in advanced BTC. Methods: TreeTopp (NCT03093870) was a global, multicenter, double blind phase 2 study in which patients with advanced BTC who progressed after 1L therapy that included ≥6 doses of gemcitabine, with radiographically measurable disease based on RECIST v1.1, ECOG PS 0 or 1 and albumin ≥3 g/dL were randomized (1:1) to varlitinib (300 mg BID) plus capecitabine (1000 mg/m2 BID 14 days on/ 7 off)(V+C) or placebo plus capecitabine (P+C). The dual primary endpoints were Objective Response Rate (ORR) and Progression Free Survival (PFS) defined as the time from randomization to radiological progression assessed by Independent Central Review. Secondary end points included Overall Survival (OS). Results: Overall, 127 patients were randomized (V+C, n = 64; P+C, n = 63) from May−Dec 2018 and demographics/baseline characteristics were generally well balanced, although the V+C arm had a lower proportion of females vs. P+C (31% vs. 48%). The odds ratio for ORR was numerically higher with V+C vs. P+C was 2.278 (9.4% vs. 4.8%, p = 0.42), the HR for PFS for V+C vs. P+C was 0.90 (median PFS, 2.8 vs. 2.8 months; p = 0.63), and the HR for OS for P+C vs. V+C was 1.11 (median OS, 7.8 vs. 7.5 months; p = 0.66). Although not powered to evaluate sub-group interactions, in sub-group analysis, V+C showed PFS benefit versus P+C in two sub-groups; gallbladder cancer (GBC, HR = 0.55, 95% CI: 0.25, 1.22; median PFS, 2.9 vs. 1.6 months) and females (HR = 0.59, 95% CI: 0.28, 1.23; median PFS, 4.1 vs. 2.8 months). There was no PFS benefit for V+C vs. P+C among males and non-GBC. Toxicities were generally balanced between arms apart from a slightly higher incidence of hyperbilirubinemia, diarrhea and fatigue in the V+C vs. P+C arm. Grade 3/4 toxicities were reported in 66% and 59% of patients in the V+C and P+C arms, respectively. Conclusions: V+C is well tolerated but did not improve ORR, PFS or OS vs. P+C in 2L advanced BTC. Exploratory analyses suggested that patients with GBC and female patients achieved comparatively higher median PFS with V+C vs. P+C. Clinical trial information: NCT03093870 .
Phase Ib dose escalation and cohort expansion study of the novel myeloid differentiating agent MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Sarker Debashis , Sodergren Mikael , Plummer Elizabeth Ruth , Basu Bristi , Meyer Tim , Huang Kai-Wen , Evans T.R. Jeffry , Spalding Duncan , Ma Yuk Ting , Palmer Daniel H. , Chee Cheng Ean , Pinato David James , Reebye Vikash , McVeigh Daniel , Raulf Nina , Vasara Jenni , Andrikakou Pinelopi , Habib Robert , Blakey David , Habib Nagy A. 
Published: May 2020

4601 Background: MTL-CEBPA is the first small activating RNA to enter clinical trials and upregulates C/EBPα, a master regulator of myeloid cell differentiation. We previously reported a favourable safety profile of MTL-CEBPA as a single agent in HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, 3 out of 5 patients (pts) treated with sorafenib off study had a complete response (CR) of 7-18 months duration; 2 pts of which demonstrated resolution of lung metastases for > 1 year. Here we provide new data on pts prospectively treated with MTL-CEBPA + sorafenib. Methods: Primary objective was to assess safety and tolerability of MTL-CEBPA 90-130mg/m2 QW or BIW in combination with sorafenib 400mg BD administered to HCC patients either concomitantly or sequentially, in cohorts either tyrosine kinase inhibitor (TKI) naive or resistant. Secondary objectives included preliminary assessment of activity by response rate (RECIST v1.1) and immune landscape analysis. Results: As at the cut off date of 1 Feb 2020, 12 pts have been treated with MTL-CEBPA co-administered with sorafenib and 14 pts with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3-4) in these groups include facial flushing (4/0), raised AST (4/2) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). Of 14 evaluable pts in the TKI naive cohorts, 2 pts had CR, 3 pts had partial response and 7 had stable disease. 9/10 pts in the TKI resistant cohorts evaluable for efficacy had stable disease. Flow cytometry demonstrated statistically significant decreases in frequency of immature CD66+CD10− neutrophils and myeloid derived suppressor cells. IHC demonstrated significant reduction in M2 macrophages in tumour biopsies. Conclusions: MTL-CEBPA + sorafenib is well tolerated with an acceptable safety profile. This study has confirmed signals of objective response to the combination treatment in TKI naïve HCC patients with viral aetiology, warranting expanded development in these patients. Updated efficacy and safety data will be presented. Clinical trial information: NCT02716012. [Table: see text]