bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Efficacy and safety of surufatinib in United States (US) patients (pts) with neuroendocrine tumors (NETs).
Authors: Dasari Arvind , Li Daneng , Sung Max W. , Tucci Christopher , Kauh John S. , Kania Marek K. , Paulson Andrew Scott
Published: May 2020

4610

Background: Surufatinib (S) is a targeted inhibitor of tyrosine kinases VEGFR1, 2, & 3, FGFR1, and CSF-1R. Safety and efficacy of S has previously been studied in China in early phase development, and in 2 randomized phase 3 placebo controlled trials (NCT02588170 & NCT02589821). These trials enrolled pts with NETs of extrapancreatic (epNET) and pancreatic (panNET) origin, respectively. Both trials are completed, stopping at their pre-planned interim analysis after meeting the primary endpoint of improved PFS. S demonstrated significant efficacy in pts with advanced epNETs, achieving a median Progression Free Survival [mPFS] of 9.2 v 3.8 months when compared to placebo. The mPFS achieved in pts with advanced panNETs is currently pending future disclosure at an upcoming scientific conference. Methods: A dose escalation (ESC)/expansion (EXP) study was conducted to evaluate and confirm the effects of S in US pts. Dose ESC was completed and the maximum tolerated dose and recommend phase 2 dose was determined to be 300mg QD; the same as previous trials. The primary objective of EXP was to evaluate anticancer activity in pts with select indications including panNETs and epNETs. Results: As of 21-Jan-20, 32 pts with heavily pre-treated progressive NETs (median prior lines of treatment [Tx]: 3; range 1-8) were enrolled. The 32 pts included 16 pts with panNET and 16 with epNET. All previously received everolimus and/or sunitinib. The median duration of Tx at the time of the data cut-off was 19 wks for all pts; 30.9 wks for panNET and 11 for epNET. 19 pts remain on active Tx (13 epNET and 6 panNET pts), 9 pts discontinued due to progression of disease, 2 withdrew consent and 2 discontinued due to adverse event (AE) (grade 3 tricuspid valve insufficiency, and grade 3 GI bleed). An objective response rate of 9.4% was observed. 3 panNET pts achieved a confirmed partial response (PR) and 1 had an unconfirmed PR per RECIST 1.1; no epNET pts achieved a PR. The safety profile of S remains consistent with previously completed trials. 27 pts (84.4%) had reported at least one adverse event (AE), and 16 pts (50%) reported ≥ grade 3 AE’s. The most common AE’s reported were: hypertension, fatigue, diarrhea, proteinuria and nausea. Pharmacokinetics (PK) analyses has shown similar exposure in panNET and epNET pts as was observed in ESC, and pts from the collective pool of pts. Conclusions: S has demonstrated promising antitumor activity in US pts with progressive NETs with a manageable safety profile. Additionally, PK and dose exposure data is consistent with trial results from large randomized phase 3 trials. Clinical trial information: NCT02549937 .
Phase II clinical trial of nab-paclitaxel plus gemcitabine in elderly patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma: BIBABRAX study.
Authors: Feliu Batlle Jaime , Jorge Fernandez Monica , Macarulla Teresa , Massuti Bartomeu , Albero Ana , Gonzalez Federico , Quintero Aldana Guillermo Alfonso , Mingorance J. Ignacio Delgado , Fernandez Montes Ana , Garcia Piernavieja Carmen , Valladares-Ayerbes Manuel , García Girón Carlos , Mondejar Rebeca , Vicente Pilar , Casado Esther , Gonzalez Cebrian Irene , Lopez-Vivanco Guillermo
Published: May 2020

4615

Background: FOLFIRINOX and nab-paclitaxel plus gemcitabine (nab-P+G) are the standard of care in the first-line treatment of mPC patients (pt) with good performance status. However, no standards of care exist for elderly ( > 70 years) pt as they are usually excluded in clinical trials. This study aimed to evaluate whether the clinical benefit of nab-P+G could be extended to elderly pt with mPC. Methods: This was an open-label, single-arm, multicenter, phase II trial, to assess the efficacy and safety of Nab-P+G in elderly pt (≥ 70 years) with ECOG PS 0–1 and untreated unresectable locally advanced or metastatic PC. Pt received four-week cycles of intravenous (i.v.) nab-paclitaxel 125 mg/m2, followed by i.v. gemcitabine 1,000 mg/m2, on days 1, 8 and 15, until disease progression. Efficacy was evaluated according RECIST v 1.1 criteria and safety according NCI-CTCAE v 4.0 criteria. Results: Eighty pt were enrolled in the study. Median age was 74.6 years (range 70-87.9), 57.5% were men, 71% had ECOG PS 1 and 86% metastatic disease. 16.3% of patients had a history of prior tumor surgical resection, 12.5% received chemotherapy and 3.8% radiotherapy. Primary tumor was located in head (32.5%), tail (25.0%) and body (22.5%). Nab-P and G was reduced in 49% and 41% of pt respectively. 15 pt definitely interrupt study treatment due to toxicity: neurotoxicity (7), asthenia (5), neutropenia (1), leukocytosis (1) and hepatotoxicity (1). Time until definite deterioration (reduction ≥10 points as compared to baseline in EORTC-QLQ C30) was 1.6 months and deterioration-free rate at 3 months was 54.3%. Overall response rate was 13.8%, clinical benefit rate 67.5%, median PFS 7.2 months and median OS 9.2 months. The most common treatment-related adverse events were asthenia (60.0%), diarrhea (40.0%), neutropenia (33.8%), hair loss (28.8%), thrombocytopenia (26.3%), and nausea (23.8%). Only asthenia and neutropenia presented a relatively high incidence of grade 3 and 4 toxicities (21.3%). At least 1 SAE was reported in 55% of pt. Conclusions: BIBABRAX study confirms the clinical benefit of nab-P+G in an elderly population with mPC, in terms of survival, clinical response and tolerance, therefore it could be considered a treatment option for elderly patients. However, it was unable to demonstrate the preplanned benefit on the quality of life. Further research is needed on treatment strategies that could reduce deterioration of the quality of life in these pt. Clinical trial information: NCT02391662 .
PANasta Trial: Cattell Warren versus Blumgart techniques of pancreatico-jejunostomy following pancreato-duodenectomy—A double-blinded multi-centered trial, trial results.
Authors: Halloran Christopher , Neoptolemos John P. , Platt Kellie , Jackson Richard , Reddy Srikanth , Oreilly Derek , Prachalias Andreas , Palmer Daniel H. , Menon Krishna , Davidson Brian , Gomez Dhanny , Ghaneh Paula
Published: May 2020

4619

Background: Pancreatic anastomosis failure following pancreatic head excision, for suspected pancreatic cancer, leads to longer recovery and failure to start or complete adjuvant chemotherapy. The aim of this study is to evaluate whether a Blumgart anastomosis (BA) reduces the post operative pancreatic fistula (POPF) rate compared to a more traditional Cattell-Warren anastomosis (CWA). Methods: Patients with suspected pancreatic cancer, undergoing elective pancreato-duodenectomy were randomized intra-operatively to either a BA or a CWA. Anastomoses were constructed according to prior agreed techniques and an operative manual describing key surgical steps. Quality control of these key steps and adherence to the arm of randomization was ensured by operative photographs. Surgical drain amylase was measured post-operatively to establish the primary end point of POPF. These were graded A (biochemical) or B and C (clinically relevant, CR-POPF). Secondary endpoints included: Entry in adjuvant therapy, hospital stay, mortality and survival. Overall survival was estimated using the method of Kaplan Meier and defined as the time from randomisation until death by any cause with alive patients censored at the end of study date. Results: Between May 5 2015 and August 7 2017, 238 patients were randomized, 2 patients withdrew, leaving 236 patients for analysis (112 BA, 124 CWA). Median age was 70 years, 63% were men. Median time from diagnosis to randomization (surgery) was 33 days for both arms. In the BA arm there were 28 POPF’s (15-A, 10-B and 3-C) and 32 in the CWA arm (18-A, 12-B and 2-C), p = 0.887. In total 27 patients (11.4%) developed a CR-POPF, BA 13 (5.5%), CWA 14 (5.9%), p = 0.857. 75% of eligible patients entered chemotherapy, with a median (IQR) time to the start treatment of 2.55 (2.27, 3.15) months for the BA group and 2.87 (2.56, 3.75) for the CWA group. Median hospital stay (IQR) in days was 13 (10-24) for BA and 14.5 (10-22) for CWA, p = 0.232. The overall surgical related mortally at 90 days was 1.7%. 44 study deaths were observed, 35 were due to disease progression (BA 19, CWA 16). A hazard ratio (95% CI) of 0.72 (0.4, 1.311) shows better, but not statistically significant survival for the CWA group. Conclusions: This is the largest surgical trial ever conducted comparing these techniques and there was no significant difference in the POPF rate between the BA and CWA anastomoses. In a UK population the clinically relevant POPF rate is 11% and 75% of eligible patients enter chemotherapy. Clinical trial information: ISRCTN52263879 .
A phase II trial of preoperative FOLFIRINOX followed by gemcitabine-based chemoradiotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC).
Authors: Wysota Michael , Jirgal Amanda , Acuna-Villaorduna Ana , Viswanathan Shankar , Kaubisch Andreas , Gadde Eswar , Kabarriti Rafi , Goel Sanjay , Chuy Jennifer W.
Published: May 2020

4638

Background: Preoperative (preop) therapy is widely accepted as the standard of care for patients (pt) with BR PDAC with limited evidence for a specific regimen. This study aimed to assess the efficacy of FOLFIRINOX (FOL) chemotherapy followed by gemcitabine-based chemo-radiotherapy (RT) as preop therapy in pt with BR-PDAC. Methods: This single arm Simon two stage phase II trial in pt with BR PDAC was conducted in two phases. The first phase included 4 cycles of FOL, and the second included weekly gemcitabine (1000 mg/m2) for 6 cycles with concomitant intensity-modulated RT (50.4 Gy in 28 fractions)(Gem/RT).The primary aim was to compare R0 resection rate (H0: ≤40% vs Ha≥60%) using one-sample one-sided Z test. Secondary outcomes, including overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier method. Results: Of 22 enrolled pt, 18 (81.8%) completed preoperative treatment. Median age at diagnosis was 63.4 years and 12 (54.5%) were female. There were 10 (45.5%) Hispanics, 4 (18.2%) non-Hispanic black, and 8 (36.4%) non-Hispanic white. Tumor location was predominantly head/neck (21, 95.5%), 15 (68.1%) had T2/3, and 9 (40.9%) had N2 (clinical) disease. Fourteen (64.6%) pt, had venous involvement, 5 (22.7%) had arterial, and 3 (13.6%), both. In the first phase, 20 (90.9%) completed 4 cycles of FOL, 6 (27.3%) required dose-reduction and dose was delayed in 12 (54.5%). Stable disease (SD) was achieved in 10 (52.6%), partial response (PR) in 8 (42.1%) and disease progression (PD) in 1 (5.3%) pt. Of 21 pt that entered the second phase, 18 (85.7%) completed 6 cycles of Gem/RT, 5 (26.3%) required dose-reduction and dose was delayed in 6 (31.6%). SD was achieved in 10 (55.6%), PR in 3 (16.7%) and PD in 5 (27.8%). All pt experienced at least one grade 1 adverse event (AE) and 12 (54.5%) at least one grade 3/4 AE, of which neutropenia was the most common-11 (50%). Of the 15 (68.1%) pt who underwent surgical resection, 12 (80%) achieved R0 margins and 5 (33.3%) required vascular reconstruction. The R0 rate among pt that received >1 cycle of FOLFIRINOX was 54.5%. Adjuvant chemotherapy was offered to 6/15 pt (40%). The PFS and OS will be reported. Conclusions: An R0 resection rate of 54.5% with this limited sample size is significant at the 10% level. Neoadjuvant FOLFIRINOX followed by concomitant Gem/RT was well-tolerated. The study will be amended to include adjuvant FOL in line with the PRODIGE intergroup adjuvant study results. Clinical trial information: NCT01897454 .
Comprehensive analysis of KRAS variants in patients (pts) with pancreatic cancer (PDAC): Clinical/molecular correlations and real-world outcomes across standard therapies.
Authors: Hendifar Andrew Eugene , Blais Edik Matthew , Ng Camille , Thach Dzung , Gong Jun , Sohal Davendra , Chung Vincent , Sahai Vaibhav , Fountzilas Christos , Mikhail Sameh , Gregory Gary , Brody Jonathan Robert , Lyons Emily , DeArbeloa Patricia , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J.
Published: May 2020

4641

Background: Approximately 90% of PDAC tumors are driven by activating KRAS mutations. The biological and clinical impact of common KRAS variants (e.g. G12D, G12V, G12R) and less common variants (e.g. G12C, Q61H, Q61R) remains largely unknown despite the emergence of variant-specific treatment strategies. Methods: We retrospectively analyzed real-world outcomes from 1475 PDAC pts who underwent molecular profiling via the Know Your Tumor program. Overall survival (OS) and progression-free survival (PFS) were analyzed by choice of 1st line standard therapies. Outcomes in pts with specific KRAS mutations were compared against the KRAS G12D cohort using Cox regression. Based on our prior data, tumor profiles with actionable molecular findings (DDR mutations or other drivers) were evaluated separately. Results: The prognostic/predictive value of specific KRAS variants revealed differences in real-world outcomes (Table). OS was greater in pts with KRAS G12V and G12R variants, as was PFS on 5FU-Based Therapy (e.g. FOLFIRINOX) but not for Gemcitabine/nab-Paclitaxel. Opposing trends were noted for KRAS Q61. Pts with KRAS wild type tumors as well as both actionable subgroups also had an improved OS. Conclusions: In this large national dataset, we demonstrate that KRAS mutation status and specific variants appear to be prognostic as well as predictive in pancreatic cancer. [Table: see text]
Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC).
Authors: Harbeck Nadia , Im Seock-Ah , Barrios Carlos H. , Bonnefoi Herve R. , Gralow Julie , Toi Masakazu , Ellis Paul , Gianni Luca , Swain Sandra M. , Im Young-Hyuck , De Laurentiis Michelino , Nowecki Zbigniew , Shah Jigna , Boulet Thomas , Liu Haiying , Macharia Harrison , Trask Peter , Song Chunyan , Winer Eric P. , Krop Ian E.
Published: May 2020

500

Background: The standard of care for HER2-positive EBC is chemotherapy plus one year of HER2-directed therapy. However, recurrence—particularly in high-risk populations—remains a problem, as does systemic chemotherapy-associated toxicity. In KAITLIN, we aimed to improve efficacy and reduce toxicity by replacing taxanes and trastuzumab with T-DM1. Methods: KAITLIN (NCT01966471) is a phase 3, randomized, open-label study that enrolled 1846 patients with adequately excised, centrally confirmed HER2-positive EBC either node-positive (LN+); or node-negative, HR-negative, and tumor size > 2.0 cm. Within 9 weeks of surgery, patients were randomized 1:1 to 3-4 cycles of anthracycline-based chemotherapy followed by 18 cycles of T-DM1 3.6 mg/kg + pertuzumab 420 mg q3w (loading dose [LD] 840 mg) (AC-KP) or taxane (3-4 cycles) + concurrent trastuzumab 6 mg/kg (LD 8 mg/kg) + pertuzumab 420 mg q3w (LD 840 mg) (AC-THP). Patients were stratified by world region, nodal status, HR status, and anthracycline type. Adjuvant radiotherapy and/or endocrine therapy was administered after 4 cycles of HER2-targeted therapy when indicated. The co-primary endpoints were invasive disease-free survival (IDFS) in the LN+ and in the ITT populations applying a hierarchical testing procedure. Secondary endpoints included overall survival (OS), patient-reported outcomes (PROs), and safety. Results: KAITLIN did not meet its co-primary endpoints. In LN+ patients (n = 1658), there was no significant difference between arms in IDFS event risk (stratified hazard ratio = 0.97; 95%CI 0.71–1.32). Three-year IDFS was 94.1% with AC-THP and 92.7% with AC-KP. Results were similar in the ITT population (stratified hazard ratio = 0.98; 95%CI 0.72–1.32; 3-year IDFS: 94.2% vs 93.1%). OS data are immature with an event rate of ~4%–5% in each arm. During the study overall, there was a similar incidence of grade ≥3 AEs (55.4% vs 51.8%) and SAEs (23.3% vs 21.4%) with AC-THP and AC-KP, respectively. More patients receiving AC-KP than AC-THP discontinued T-DM1 or trastuzumab, respectively, because of AEs (26.8% vs 4.0%). PRO data will be presented. Conclusions: Replacing adjuvant taxane and trastuzumab with T-DM1 did not result in significantly improved efficacy or overall safety. Nonetheless, in this high-risk population, a favorable IDFS outcome was achieved in both study arms. HP + chemotherapy remains the standard of care for patients with high-risk HER2-positive EBC. Clinical trial information: NCT01966471 .
Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Lee Chung-Han , Shah Amishi Yogesh , Hsieh James J , Rao Arpit , Pinto Alvaro , Bilen Mehmet Asim , Cohn Allen Lee , Di Simone Christopher , Shaffer David R. , Girones Sarrio Regina , Gunnestad Ribe Sara , Wu Jane , Schmidt Emmett V. , Perini Rodolfo F. , Kubiak Peter , Smith Alan D. , Motzer Robert J.
Published: May 2020

5008

Background: LEN, a multikinase VEGFR inhibitor, plus everolimus is approved for advanced RCC after prior VEGF-targeted therapy. PEMBRO, an anti-PD-1 antibody, plus axitinib is approved as first-line therapy of advanced RCC. We report phase 2 results of the RCC cohort of a phase 1b/2 trial (Study 111/KEYNOTE-146) of LEN + PEMBRO in patients (pts) who progressed after ICI therapy. Methods: We performed a multicenter, open-label study of pts with mccRCC, who previously had disease progression by RECIST (confirmed ≥ 4 weeks later) during or following ICI therapy. Pts had measurable disease by immune-related RECIST, and ≥ 1 prior therapy. Pts received LEN 20 mg orally once daily plus PEMBRO 200 mg IV every 3 weeks until disease progression or toxicity. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks. The primary endpoint was objective response rate (ORR) at Week 24 by irRECIST. Results: 104 pts were enrolled. At data cutoff (January 12, 2020), 71 (69%) pts were still on study treatment. Most pts had ≥2 prior anticancer regimens (58%). 91 of 104 pts were evaluable for response at Week 12 (13 pts NE at Week 12); 46 of 91 pts achieved a confirmed partial response for an ORR of 51% (Table). Median progression-free survival (PFS) was 11.7 months and median duration of response (DOR) was 9.9 months. The most common treatment-related adverse events (TRAEs) were fatigue (49%), diarrhea (44%), proteinuria (37%), hypertension (31%), nausea (31%), dysphonia (29%), stomatitis (29%), and arthralgia (27%). There was 1 grade 5 TRAE (upper gastrointestinal hemorrhage). 43% of pts required dose reduction and 12% of pts discontinued treatment due to TRAEs. Response and safety data will be updated to include all pts evaluable at an April 9, 2020 cut-off. Conclusions: LEN + PEMBRO demonstrated promising antitumor activity in pts with mccRCC with disease progression following ICI therapy. No new safety signals were detected. Efficacy outcomes by investigator review per irRECIST. Clinical trial information: NCT02501096 . [Table: see text]
Thromboembolism (TE) in patients (pts) with bladder cancer treated with checkpoint inhibitors (CPIs).
Authors: Sheng Iris Yeong- Fung , Gupta Shilpa , Reddy Chandana A. , Angelini Dana E , Funchain Pauline , Sussman Tamara A. , Sleiman Joseph , Gilligan Timothy D. , Ornstein Moshe Chaim , Khorana Alok A.
Published: May 2020

5042

Background: Most pts with bladder cancer will be treated with immunotherapy. There is concern for increased TE risk with CPIs in this already high risk population. We present the first analysis of the incidence and outcomes of venous (VTE) and arterial (ATE) thromboembolism in pts with bladder cancer treated with CPIs. Methods: Consecutive pts with bladder cancer treated with CPIs at the Cleveland Clinic from 1/2015 to 12/2019 were identified and TE events noted. Overall survival (OS) was estimated using Kaplan-Meier method and the impact of VTE on OS was evaluated using Cox proportional hazards regression. Results: Of 274 pts, 72% were men (median age 73.3 years, 89% white), 82% had pure UC, 92% had lower tract disease, and 67% had a Bajorin score ≥1 (median KPS 90, 61% visceral metastases), 59% had prior systemic therapy (median 1, range 0-4) and 36% had prior TE (14% ATE, 19% VTE, 0.4% both). At CPI initiation, 24% were on antiplatelet therapy, and 15% on therapeutic anticoagulation. CPI (median doses 5, range 8.5-59) included: 40% atezolizumab, 3% nivolumab, 57% pembrolizumab. VTE occurred in 14% (n = 37), including 8% DVT, 4% PE, 2% both. DVT locations were 56% lower limb, 26% upper limb, 15% visceral vein, 4% visceral+upper limb. 2% (n = 5) had ATE (1% CVA, 0.4% visceral, 0.4% left subclavian). 92% of VTE and all ATE occurred within 6 months of CPI initiation. The incidence of TE was 10.9% (95%CI 6.6%—15.1%) at 6 months and 19.8% (95%CI 13.3%-26.4%) at 12 months. 82% of VTE (mean 6 days) and all ATE (mean 5 days) resulted in hospitalization. Multivariate analysis showed TE (HR 2.296, 95%CI 1.451-3.632, p = 0.0004), Bajorin score 1 (HR 1.490, 95%CI 1.036-2.142, p = 0.0315), and Bajorin score 2 (HR 3.50, 95%CI 2.14-5.74, p < 0.0001) were independently associated with worse OS. Conclusions: CPIs in bladder cancer pts are associated with a high TE risk, especially within six months of initiation. TE is associated with worsened survival. Further investigation into the risk factors for CPI-associated TE is needed to identify if benefits exist from thromboprophylaxis.
Prognostic role of early interim [18F] fluoro-deoxy-glucose positron emission tomography in patients with advanced seminoma undergoing standard treatment.
Authors: Raggi Daniele , Bandini Marco , Giannatempo Patrizia , Farè Elena , Marandino Laura , Colecchia Maurizio , Padovano Barbara , Serafini Gianluca , Alessi Alessandra , Necchi Andrea
Published: May 2020

5055

Background: In patients (pts) with advanced seminoma, efforts are underway to tailor a risk-adapted treatment strategy to the individual pt. Our main objective was to prospectively determine the prognostic value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT2) after two cycles of bleomycin, etoposide and cisplatin (BEP) or EP chemotherapy under standardized treatment and PET evaluation criteria. Methods: Pts with advanced-stage seminoma were treated with BEP or EP according to guidelines. PET/CT examinations were performed at baseline, after two cycles in all pts and after chemotherapy at physician’s choice. PET/CT response was qualitatively evaluated by two independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to the guidelines (at baseline, after treatment, during follow-up). The primary endpoint was the relapse-free survival (RFS). Results: From 01/2009 to 01/2017, 75 consecutive pts were enrolled, of whom 70 were evaluable. The clinical stage was IIA-B and IIC-III in 40% and 60% of the pts, respectively. Eight pts (11.4%) received consolidation radiotherapy. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these pts presented with stage IIC-III. The median follow-up was 79 months. Five-year RFS of PET/CT2-positive pts was 75% (95%CI: 60-95%) compared with 97.8% (95%CI: 93.7-100%) of PET/CT2-negative pts (p = .002). This significant improvement in RFS was maintained when analyzing only pts with clinical stage IIC-III (p = 0.04) and by excluding those who received consolidation RT (p = 0.02). An increasing linear association was found between the maximum diameter of retroperitoneal lymph nodes and the rate of PET/CT2+. In univariable Cox regression analyses, PET/CT2+ (HR: 12.9, 95%CI: 1.5-106.9, p = 0.02) and elevated HCG levels (HR: 6.3, 95%CI: 1.2-32.3, p = 0.03) were significantly associated with RFS, whereas IGCCCG risk group was not (p = 0.1). PET/CT2 result was also associated with the tumor shrinkage post-BEP (p = 0.009), whereas complete response at CT did not predict the RFS (p = 0.3). Conclusions: No residual FDG-uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, may outperform the utility of standard prognostic risk groups and may be more accurate to predict the RFS compared to standard response criteria. Benchmark RFS estimates for the design of the next clinical trials of chemotherapy de-escalation are offered.