bluuebunny/crossref_metadata_2025 huggingface dataset:
Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: An open-label, randomized, multicenter phase II/III trial.
Authors: Bi Feng , Qin Shukui , Gu Shanzhi , Bai Yuxian , Chen Zhendong , Wang Zishu , Ying Jieer , Lu Yinying , Meng Zhiqiang , Pan Hongming , Yang Ping , Zhang Helong , Chen Xi , Xu Aibing , Liu Xiufeng , Meng Qiu , Wu Liqing , Chen Feng
Published: May 2020

4506

Background: Sorafenib is still the standard first-line therapy for advanced hepatocellular carcinoma (HCC). Donafenib, a novel multikinase inhibitor, showed potential benefits in a previous phase Ib study in HCC. Methods: In this open-label, randomized phase II/III trial (ZGDH3), patients with unresectable or metastatic HCC, a Child-Pugh liver function score ≤ 7, and no prior systemic therapy were enrolled from 37 sites across China and randomized (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). Efficacy analysis was primarily based on the full analysis set (FAS). Results: Between March 2016 and April 2018, 668 patients were randomized (donafenib, 334; sorafenib, 334) and included in the intention-to-treat (ITT) set, of whom 659 were analysed by FAS (328 vs 331). Donafenib was associated with a significantly longer median OS than sorafenib in both FAS (12.1 months vs 10.3 months, hazard ratio 0.831, 95% confidence interval 0.699–0.988, p = 0.0363) and ITT (12.0 months vs 10.1 months, 0.839, 0.706–0.996, p = 0.0446). There were no significant differences in median progression-free survival (3.7 months vs 3.6 months, p = 0.2824), objective response rate (4.6% vs 2.7%, p = 0.2448), and disease control rate (30.8% vs 28.7%, p = 0.5532). Grade 3 or worse adverse events (AEs) occurred in 191 (57.4%) and 224 (67.5%) patients ( p = 0.0082), respectively, and AEs of special interest and those leading to treatment interruption occurred in 287 (86.2%) vs 309 (93.1%, p = 0.0049) and 101 (30.3%) vs 141 (42.5%, p = 0.0013). A numerically lower number of patients reported serious AEs (55 [16.5%] vs 67 [20.2%], p = 0.2307) with donafenib. Common AEs with donafenib included hand-foot skin reaction (50.5%), aspartate aminotransferase increased (40.5%), blood bilirubin increased (39.0%), platelet count decreased (37.8%), and diarrhea (36.6%). Conclusions: Donafenib significantly improves OS over sorafenib with favourable safety and tolerability. Donafenib is a promising superior first-line therapy for advanced HCC. Funding: Zelgen. Clinical trial information: NCT02645981 .
Laparoscopic sentinel node navigation surgery versus laparoscopic standard gastrectomy with lymph node dissection in early gastric cancer: Final three-year survival results of multicenter randomized controlled phase III trial (SENORITA trial).
Authors: Ryu Keun Won , Kim Young Woo , Min Jae Seok , An Ji Yeong , Yoon Hong Man , Eom Bang Wool , Hur Hoon , Lee Young Joon , Cho Gyu Seok , Park Youngkyu , Jung Mi Ran , Park Ji-Ho , Hyung Woo Jin , Jeong Sang-Ho , Han Mira , Nam Byung-Ho
Published: May 2020

4510

Background: The benefits and hazards of laparoscopic sentinel node navigation surgery (LSNNS), compared with laparoscopic standard gastrectomy (LSG) with lymph node dissection in early gastric cancer (EGC), are unknown. The SENORITA trial investigated the clinical impact of LSNNS in EGC in terms of short-term surgical outcomes, long-term survival and quality of life. Methods: This study is a prospective, multicenter, randomized controlled, non-inferiority trial. Patients with preoperatively diagnosed gastric adenocarcinoma with T1N0 of 3 cm or less in diameter, regardless of histology, except absolute indication for endoscopic resection were eligible. Patients were randomized to LSG or LSNNS using dual tracers. The primary endpoint is 3-year disease-free survival (3yDFS). Planned sample size per arm is 290 patients with the non-inferiority margin of 2.737 in hazard ratio (HR) assuming that LSG achieve 97% 3yDFS, 5% of type 1 error and 80% of power. Three-year recurrence-free survival (3yRFS), overall survival (3yOS) and disease specific death rate (3yDSDR) were evaluated as secondary endpoints. Results: From March 2013 to December 2016, 580 patients were randomized (LSG arm 292 vs. LSNNS arm 288). After 53 patients dropped out before surgery, operation was performed in 527 patients (269 vs. 258), representing the full analysis set. LSG was performed in 266 according to the protocol excluding 3 open conversion. After exclusion of 13 without LSNNS due to various reasons, LSNNS was performed in 245 patients according to the protocol. After median follow up of 47.5 months, 3yDFS were 95.5% and 91.8% (HR 1.901, CI 0.911 – 3.967), respectively. The 3yRFS was 98.9% and 95.2% (p=0.019), and 3yOS was 99.2% and 97.6% (p=0.166), and 3yDSDR was 99.5% and 99.1% (p=0.591), respectively. Conclusion: LSNNS in EGC did not show non-inferiority compared with LSG in terms of 3yDFS. However, 3yOS and 3yDSDR of LSNNS were comparable to LSG by the rescue surgery of recurrence. LSNNS might be an alternative surgical option instead of LSG in selected EGC patients. Clinical trial information: NCT01804998 .
FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel: Results from the phase II RAMIRIS Study of the AIO.
Authors: Lorenzen Sylvie , Thuss-Patience Peter C. , Pauligk Claudia , Goekkurt Eray , Ettrich Thomas Jens , Lordick Florian , Stahl Michael , Reichardt Peter , Soekler Martin , Pink Daniel , Probst Stephan , Hinke Axel , Goetze Thorsten Oliver , Al-Batran Salah-Eddin
Published: May 2020

4514

Background: Ramucirumab (Ram) as monotherapy or plus paclitaxel is a proven second-line option for advanced gastroesophageal adenocarcinoma (GEA). More and more patients (pts) are pretreated with docetaxel in the perioperative or first-line setting. These pts may benefit more from another, non-cross resistant chemotherapy backbone regimen. This trial evaluates the addition of Ram to FOLFIRI as second line treatment. Methods: This is a multicenter, randomized, investigator initiated, phase II trial. Pts with GEA who have progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomized 2:1 to either FOLFIRI plus Ram every two weeks (Arm A) or paclitaxel (days 1, 8, 15 of a 28-day cycle) plus Ram every two weeks (Arm B). Major endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and toxicity. Results: 111 pts (median age 61 years, 65% of pts had prior docetaxel therapy) were enrolled and 110 analyzed within intention to treat population (ITT, Arm A, 72; Arm B, 38). In the ITT, there was no significant difference in median OS (A, 6.8 vs. B, 7.6 months, HR 0.94, p = 0.77) and median PFS (A, 4.6 vs. B, 3.6 months, HR 0.72, p = 0.12). For pts with prior docetaxel use (71/110), median PFS was A, 4.3 vs. B, 2.0 months, HR 0.49, p = 0.008 and median OS was A, 7.5 vs. B, 6.4 months, HR 0.71, p = 0.25. In 101 pts with tumor assessment and included in the response analysis, ORR and DCR was 23% and 65% in Arm A and 11% and 60% in Arm B, respectively. 67 pts assessable for response were pre-treated with docetaxel. In these pts, ORR was 24% in Arm A and 9% in Arm B. Disease control rate (DCR) was 67% and 41% for Arm A and B respectively. Both therapies were similarly tolerable, final safety results will be shown. Conclusions: The RAMIRIS trial demonstrated feasibility of the combination of FOLFIRI and Ram. With a response rate of 24% and a median PFS of 4.3 months, docetaxel pre-treated pts seemed to derive pronounced benefit from FOLFIRI-Ram, providing a rationale for a phase III trial, which is currently ongoing. Clinical trial information: NCT03081143 .
ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma: Five year follow-up.
Authors: Neoptolemos John P. , Palmer Daniel H. , Ghaneh Paula , Valle Juan W. , Cunningham David , Wadsley Jonathan , Meyer Tim , Anthoney Alan , Glimelius Bengt , Falk Stephen , Segersvard Ralf , Middleton Gary William , Ross Paul J. , Wasan Harpreet Singh , McDonald Alec , Crosby Tom David Lewis , Psarelli Eftychia Eirini , Hammel Pascal , Hackert Thilo , Buchler Markus W. ,   European Study Group for Pancreatic Cancer (ESPAC)
Published: May 2020

4516

Background: The ESPAC-4 trial demonstrated that adjuvant GEM/CAP for pancreatic cancer significantly improved survival compared to GEM monotherapy. The aim of this study is to evaluate the long-term outcomes in the ESPAC-4 trial. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4-week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was five-year survival; secondary endpoints were toxicity and relapse free survival. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2-year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumor size was 30 mm, 61% were R1 resections, 80% were node positive and 40% were poorly differentiated. The data freeze was on 24 February 2020; median follow up was 60 months with 531 overall deaths, 280 in GEM, and 251 in GEM/CAP. Median (95% CI) survival (months) for patients treated with GEM/CAP was 27.7 23.3 – 31.2) and 26.0 (22.7 – 28.4) for GEM. Five-year (95% CI) survival rates were 20 (16 – 25) % for GEM and 28 (23 – 33) % for GEM/CAP. Stratified log-rank analysis revealed an HR=0.84 [95% CI, 0.70 – 0.99]; χ2 (1) = 3.87, P=0.049. 70 out of 366 GEM patients in the safety set reported 101 grade 3/4 serious adverse events, while 65 out of 359 GEM/CAP patients reported 97 grade 3/4 serious adverse events ( P=0.724). Conclusions: Adjuvant GEM/CAP for pancreatic cancer had a statistically significant improvement in survival compared to GEM monotherapy. Clinical trial information: 96397434 .
A prospective randomized controlled trial of selective transarterial chemoembolization using drug-eluting beads loaded with epirubicin versus selective conventional transarterial chemoembolization using epirubicin-lipiodol for hepatocellular carcinoma: The JIVROSG-1302 PRESIDENT study.
Authors: Ikeda Masafumi , Inaba Yoshitaka , Tanaka Toshihiro , Sugawara Shunsuke , Kodama Yoshihisa , Aramaki Takeshi , Anai Hiroshi , Morita Shinichi , Tsukahara Yoshinori , Seki Hiroshi , Sato Mikio , Kamimura Kenya , Azama Kimei , Tsurusaki Masakatsu , Sugihara Eiji , Miyazaki Masaya , Sone Miyuki , Arai Yasuaki
Published: May 2020

4518

Background: Transarterial chemoembolization (TACE) with selective catheterization into the segmental or subsegmental hepatic arteries supplying HCC is often performed to achieve the complete local control of HCC in the patients with a limited number of small sized nodules. To clarify which of TACE with drug-eluting beads loaded with epirubicin (DEB-TACE) or conventional TACE with epirubicin-lipiodol (cTACE) can achieve the complete response (CR) more frequently, we performed a randomized controlled trial of DEB-TACE vs. cTACE. Methods: Between March 2016 and May 2019, unresectable HCC patients with Child-Pugh class A or B who were scheduled to receive selective TACE were randomly assigned 1:1 to the DEB-TACE group and the cTACE group. The primary endpoint was the CR rate at 3 months, and the secondary endpoints were the CR rate at 1 month and rate of adverse events (AEs). The response and AEs were assessed according to the modified RECIST by an independent review committee and the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0., respectively. Results: A total of 200 patients (DEB-TACE, 99 patients; cTACE 101 patients) were enrolled from 22 Japanese institutions. The patient characteristics were well-balanced between the two groups. The median number of tumors was one in both groups and the median tumor size was 20.0 mm in the DEB-TACE group and 20.5 mm in the cTACE group. The table shows the CR rates and frequencies of AEs. The CR rates of cTACE at 3 and 1 months were significantly higher than those of DEB-TACE. The frequency of AEs (all grades), including pyrexia, malaise, increased serum total bilirubin (T-Bil) and increased serum alanine transaminase (ALT), was significantly higher in the cTACE group than in the DEB-TACE group. Conclusions: Selective cTACE appeared to have greater efficacy for local tumor control as compared to selective DEB-TACE, however, the frequencies of post-embolization syndromes were higher in the cTACE group than in the DEB-TACE group. Clinical trial information: UMIN000021250 . [Table: see text]
A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
Authors: Zhu Andrew X. , Finn Richard S. , Ikeda Masafumi , Sung Max W. , Baron Ari David , Kudo Masatoshi , Okusaka Takuji , Kobayashi Masahiro , Kumada Hiromitsu , Kaneko Shuichi , Pracht Marc , Mamontov Konstantin , Meyer Tim , Mody Kalgi , Kubota Tomoki , Dutcus Corina E. , SAITO KENICHI , Siegel Abby B. , Dubrovsky Leonid , Llovet Josep M
Published: May 2020

4519

Background: LEN is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT, approved for first line (1L) treatment of uHCC. PEMBRO, an anti-PD-1 monoclonal antibody, was granted accelerated approval for the treatment of patients (pts) with HCC after sorafenib therapy. We assessed the safety and efficacy of LEN + PEMBRO in uHCC. Methods: In this phase 1b trial (NCT03006926), pts received LEN 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW <60 kg) orally + PEMBRO 200 mg IV on Day 1 of a 21-day cycle. Primary endpoints were safety and tolerability for Part 1 and objective response rate (ORR) and duration of response (DOR) by mRECIST and RECIST v1.1 per independent imaging review (IIR) in the 1L setting for Part 2. Results: 104 pts (part 1, n=6; part 2, n=98) were enrolled. No DLTs were reported in Part 1; 100 pts were included in the 1L analysis of LEN + PEMBRO–4 pts (part 1) excluded due to prior sorafenib. At data cutoff (October 31, 2019) and median follow-up of 10.6 months, 37 pts continued treatment (LEN only, n=3; both drugs, n=34); median duration of treatment was 7.9 months (LEN, 7.6 months; PEMBRO, 7.4 months). Median OS was 22.0 months (95% CI 20.4–not estimable [NE]), median PFS was 8.6 months (95% CI 7.1–9.7), and ORR was 36% (95% CI 26.6–46.2) (RECIST v1.1 per IIR). Additional efficacy outcomes are shown in the table. Treatment-emergent adverse events (TEAEs) occurred in 99% of pts (grade ≥3, 85%; grade ≥4, 23%). The most common grade ≥3 TEAE was hypertension (18% of pts). Treatment-related AEs (TRAEs) occurred in 95% of pts (grade ≥3, 67%; grade ≥4, 4%). The most common grade ≥3 TRAE was hypertension (17% of pts). 36% of pts had serious TRAEs and 3 pts died from a TRAE (acute respiratory failure/acute respiratory distress syndrome, n=1; intestinal perforation, n=1; abnormal hepatic function, n=1). Conclusions: LEN + PEMBRO has promising antitumor activity with a tolerable safety profile. An ongoing phase 3 trial (NCT03713593) is assessing LEN + PEMBRO vs LEN alone as 1L therapy for uHCC. Clinical trial information: NCT03006926 . [Table: see text]
First-in-human phase I study of BVAC-B cell therapy in HER2-positive advanced gastric cancer.
Authors: Lee Jii Bum , Kwon Woo Sun , Kim Hyo Song , Jung Minkyu , Kim Sinyoung , Park Myunghwan , Kim Wuhyun , Choi Ki-Young , Oh Taegwon , Kang Chang-Yuil , Chung Hyun Cheol , Rha Sun Young
Published: May 2020

4534

Background: BVAC-B is an autologous B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HER2/neu gene and loaded with alpha-galactosyl ceramide, a natural killer T cell ligand. It may have activity against HER2/neu positive cancer. Preclinical data in mouse models have shown promising anti-tumor activity by eliciting broad spectrum of immune responses against HER2/neu positive tumor cells. We report here the results of phase 1 study of BVAC-B in HER2 positive advanced gastric cancer. Methods: Metastatic gastric cancer with IHC > 1+ of HER2/neu were eligible for enrollment. Two weeks before treatment, subjects were admitted to hospital for collection of PBMC and plasma by lymphapheresis. The PBMC were sent to Cellid for vaccine manufacturing which took a day. BVAC-B was given intravenously at 0, 4, 8, and 12 weeks. Subjects received low (2.5X 107 cells/dose), medium (5.0X 107 cells/dose) or high dose (1.0X 108 cells/dose). Endpoints included safety, tolerability and MTD for phase 2 trial. Exploratory outcomes included immune responses after BVAC-B administration. Results: As of January 29, 2020, 8 subjects were treated with BVAC-B at doses of 2.5X 107 cells/dose (n=1), 5.0X 107 cells/dose (n=1) and 1.0X 108 cells/dose (n=6). Median line of therapy at which BVAC-B was administered was 4 (range, 2-9). Mean duration treatment was 1.8 (range 1-4) cycles. The most common treatment related adverse events were fever (n=4, 50%). One subject enrolled in medium dose experienced cytokine release syndrome (G2) with high fever (39.3℃) and hypotension 8 hours after first administration, but was manageable with hydration and supportive management. Other adverse events included increase of AST and ALT (G1, n=1 and G2, n=2), and hypotension (G1, n=1). There were no adverse events which led to treatment discontinuation. Immunologic response analysis showed that BVAC-B induced activation of natural killer T cells, natural killer cells, HER2/neu specific T cells, and release of HER2/neu specific antibody upon vaccinations in few patients who were evaluated. Conclusions: BVAC B is feasible and has acceptable toxicity profile. We considered all dose evaluated in this study available for phase 2 study, given that the maximum tolerated dose is expected to exceed the maximum dose administered in this study. For clinically relevant effect, further studies are warranted, including earlier line of exposure to BVAC-B as well as combination treatments. Clinical trial information: NCT03425773 .
Impact of body measurements (BM) on overall survival (OS) and quality of life (QoL) in real-world patients (pts) with metastatic esophageal cancer.
Authors: Soriano Joelle , Hueniken Katrina , Bajwa Jaspreet K. , Dong George , Wang Wanning , Soberano Tyler , Taylor Kirsty , Brown M. Catherine , Chen Eric Xueyu , Knox Jennifer J. , Jang Raymond Woo-Jun , Wong Rebecca , Darling Gail Elizabeth , Xu Wei , Elimova Elena , Liu Geoffrey , Rozenberg Dmitry , McInnis Micheal , Fares Aline Fusco
Published: May 2020

4544

Background: Body fat and muscle influence prognosis in many cancer types. However, this association is unclear for real-world MEC pts, who are often in worse performance status than their previous baseline. In addition, the relationship of BM at presentation and QoL is unknown. We used real-world MEC pts to assess the importance of BM in OS and QoL. Methods: BM were done at baseline computed tomography in MEC pts, treated from 2006-2014 at the Princess Margaret Cancer Centre. Two radiologists (correlation 0.9-1.0) assessed L3 level using SliceOMatic to determine Skeletal Muscle Index (SMI - muscle area at L3 normalized by height), Visceral Adiposity Tissue (VAT), and Subcutaneous Adiposity Tissue (SAT). We used previously published cut-offs for sarcopenia based on sex and BMI, and the highest tertile as the cut-off for adiposity. We used prospectively collected QoL surveys including EuroQol 5D-5L (EQ5D) and the Functional Assessment of Cancer Therapy – Esophageal (FACT-E). Results: Of 200 pts, 164 (82%) were male, 180 (92%) were non-Asian; mean age was 62 y; ECOG: 0-1 = 142 (71%), 2 = 58 (29%); 69% had adenocarcinoma; 5% were underweight, 44% normal weight, 30% overweight, and 21% obese. 40 (20%) pts completed QoL measures. We found that 104 (52%) were sarcopenic at baseline, 66 (33%) had high VAT, and 67 (34%) had high SAT. A multivariable Cox model showed that sarcopenia and VAT were independent prognostic variables for three-year OS: sarcopenia increased the risk of death by 50% (adjusted hazard ratio, aHR 1.50, p 0.02), whereas every 100-cm2 increase in VAT improved OS by 24% (aHR 0.76, p 0.03). Finally, sarcopenic pts had significantly worse physical well-being (p 0.01) on FACT-E after adjusting for sex and age. Numerically, the EQ5D also showed lower scores in sarcopenic pts but this was not statistically significant (p 0.18). Conclusions: In MEC pts, sarcopenia and low visceral adiposity result in worse OS; sarcopenia is also significantly associated with poor QoL. Future work will need to focus on potential rehabilitation strategies such as nutritional support and exercise training to offset the poor prognosis associated with sarcopenia and reduced adiposity. [Table: see text]
Prognostic significance of nutritional markers in metastatic gastric and esophageal adenocarcinoma.
Authors: Ma Lucy Xiaolu , Taylor Kirsty , Espin-Garcia Osvaldo , Suzuki Chihiro , Anconina Reut , Allen Michael J , Honório Marta , Bach Yvonne , Allison Frances , Chen Eric Xueyu , Yeung Jonathan , Darling Gail Elizabeth , Wong Rebecca , Kalimuthu Sangeetha , Jang Raymond Woo-Jun , Veit-Haibach Patrick , Elimova Elena
Published: May 2020

4557

Background: Malnutrition and sarcopenia (defined as low skeletal muscle mass) are recognized as poor prognostic factors in many cancers. Studies to date in gastroesophageal cancer have largely focused on patients (pts) undergoing curative intent surgery. This study aims to evaluate the prognostic utility of nutritional markers and sarcopenia in pts with de novo metastatic gastric and esophageal adenocarcinoma (GEA). Methods: Pts with de novo metastatic GEA seen at the Princess Margaret Cancer Centre from 2010-2016 with available pre-treatment abdominal computed tomography imaging were identified from an institutional database. Nutritional index (NRI) was calculated using weight and albumin, with moderate/severe malnutrition defined as NRI < 97.5. Skeletal muscle index (SMI) normalized by height was calculated at the L3 level using Slice-O-Matic software. Sarcopenia was defined as SMI < 34.4cm2/m2 in women and < 45.4cm2/m2 in men based on previously established consensus. Results: Of 175 consecutive pts, median age was 61, 69% were male, 79% had ECOG performance status 0-1, and 71% received chemotherapy. Median BMI was 24.2 (range 15.7-39.8), 70% of pts had > 5% weight loss in the preceding 3 months, and 29% had moderate/severe malnutrition. 68 pts (39%) were sarcopenic, of whom 46% were malnourished. Median overall survival (OS) was 9.3 months (95% CI 7.3-11.4) for all pts. OS was significantly worse in malnourished pts (5.5 vs 10.9 months, p = 0.000475) and displayed a non-significant trend in sarcopenic pts (7.8 vs 10.6 months, p = 0.186). On univariable Cox proportional hazards (PH) analysis, ECOG (p < 0.001), number of metastatic sites (p = 0.029) and NRI (p < 0.001) were significant prognostic factors, while BMI (p = 0.57) and sarcopenia (p = 0.19) were not. On multivariable Cox PH analysis, ECOG (p < 0.001) and NRI (p = 0.025) remained significant as poor prognostic factors for OS. Conclusions: This study demonstrates in a large cohort of de novo metastatic GEA pts that ECOG and NRI were significantly associated with poor OS. NRI was superior to BMI alone. Early identification of malnourished pts using NRI may allow for supportive interventions to optimize nutritional status. Further study is needed to determine whether these factors can be modified to improve prognosis in these pts.
Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): Plasma and tumor-based biomarker analysis.
Authors: Maron Steven Brad , Chatila Walid Khaled , Millang Brittanie M , Sabwa Shalom , Chou Joanne F. , Ling Lilan , Nagy Rebecca , Simmons Marc , Do Richard K. G. , Paroder Viktoriya , Gerdes Hans , Shah Pari M. , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn Frances , Merghoub Taha , Solit David B. , Schultz Nikolaus , Janjigian Yelena Yuriy
Published: May 2020

4559

Background: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity with median OS 27 months and 91% objective response rate in HER2-positive mEG cancer irrespective of PD-L1 status (NCT02954536; Janjigian ESMO 2019). Tumor biopsies and blood samples were collected in this phase II trial to identify molecular and immune predictors of response and resistance to PTC. Methods: Pre-treatment and post-progression biopsies were analyzed using WES and IHC (HER2, PD-L1). Peripheral blood was collected pre-treatment, every 9 weeks on-treatment and at progression for plasma ctDNA (Guardant 360, Guardant Health, Redwood, CA). Tumor-matched DNA alterations were identified by correlating ctDNA and solid tumor WES results. Landmark PFS analysis was used to compare ctDNA clearance status at 9 weeks post-treatment. Results: Baseline ctDNA was analysed from 31 of 37 patients of whom 84% (26/31) had tumor-matched ctDNA detected at baseline. Patients who cleared ctDNA at 9 weeks (n = 17/23) achieved a longer median PFS than those who did not - mPFS 12.3 months (95% CI 7.44-NA vs 3.9 months (95% CI 2.01-NA) (log-rank p = 0.02). On serial blood monitoring of 16 patients with eventual radiographic progression, ctDNA re-appearance preceded CT detection in 8 (50%) patients. WES was completed in 31 patients with pre-treatment, and 12 patients post-progression, including matched samples from 10 patients. Loss of HER2 over-expression/amplification was noted in 44% (7/16) of post-progression samples by IHC/FISH (2 IHC 0/1, 5 FISH-). In paired post-progression samples on WES, we observed loss of ERBB2 in 2 patients, and new amplifications of CCND1/3, FGF3/4/19, CDK6/12, KRAS, MYC, and MET, as well as mutations in KRAS, PIK3CD and PIK3RA. Plasma analysis at progression demonstrated copy number increases and/or new amplifications in MET, CKD6, PIK3CA, KRAS, FGFR2, EGFR and CCDN1 as well as KRAS, RB1, PTEN, NF1, NOTCH1, BRAF, and FGFR1 mutations. Conclusions: The majority of patients with previously untreated HER2 positive mEG have detectable plasma ctDNA at baseline. The re-appearance of ctDNA during therapy may serve as an early predictor of progression and help identify genetic drivers of acquired resistance. Loss of ERBB2 over-expression/amplification and activating MAPK alterations occur at PTC progression. Evaluation of tumor immune environment by multiplex IHC and additional ctDNA analysis is underway.
Prognostic role of mismatch repair deficiency (MMR-D) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy for metastatic and locally advanced unresectable gastric cancers (GCs).
Authors: Kim Eo Jin , Chae Heejung , Ryu Min-hee , Kang Yoon-Koo
Published: May 2020

4566

Background: Although chemotherapy has been suggested to have the potential to cause a detrimental effect on treatment outcomes of localized GC with MMR-D, it remains unclear whether chemotherapy for metastatic/recurrent/unresectable GC with MMR-D would also adversely affect the survival outcomes. Anti PD-1 antibody (Ab) showed remarkable efficacy in patients with MMR-D and is being actively investigated in combination with cytotoxic chemotherapy. Hence, we aim to evaluate the impact of MMR status on treatment outcomes of advanced GC. Methods: We reviewed our database to identify all patients with HER2 negative, metastatic, recurrent, and locally advanced unresectable GC who received FP doublet chemotherapy from January 2015 to August 2018. For those who had an available tumor tissue, MMR protein expression was assessed by immunohistochemistry (IHC) and correlated with clinical characteristics and treatment outcomes. Results: Out of 895 patients identified from the database, 543 underwent IHC testing for MMR. The median age was 58 years (range, 24 – 86) with male comprising 64.0%. Most patients had initially metastatic disease (n = 382, 70.3%) followed by recurrent (n = 127, 23.3%) and locally advanced unresectable disease (n = 34, 6.3%). MMR-D was found in 4.4% (n = 24) and associated with age ≥ 65 years (50% vs. 29.9%; P = 0.04) and signet ring cell histology (0% vs. 17.7%, P = 0.01). According to our prognostic model (Koo DH et al, 2011), only 4.2% of patients with MMR-D were classified as Poor-risk group (vs. 16.8% of patients with MMR-P, p= 0.10). In the Good-risk group, patients with MMR-D (n = 10) had significantly shorter median progression-free survival (PFS, 6.0 vs. 9.0 months, P = 0.05) and overall survival (OS, 10.1 vs 20.9 months, P = 0.047) compared to those with MMR-P (n = 188), while there was no significant difference in survival outcomes depending on MMR status in the Moderate and Poor-risk groups. In multivariate analysis for OS, MMR status was a significant prognostic factor for OS in Good-risk group GC patients. Conclusions: GC patients with MMR-D had poorer median PFS and OS than those with MMR-P on standard cytotoxic chemotherapy in the Good-risk group. Thus, for Good-risk GC patients with MMR-D, anti PD-1 Ab alone might be considered rather than combining cytotoxic chemotherapy. Further investigation with next-generation sequencing is in process to determine underlying molecular mechanisms and will be presented in ASCO 2020.
PD-L1 positive esophagogastric (EG) cancer is associated with distinct bacteria.
Authors: Maron Steven Brad , Vanderbilt Chad , Sabwa Shalom , Bowman Anita , Chatila Walid Khaled , Tang Laura H. , Strong Vivian E. , Molena Daniela , Jones David Randolph , Coit Daniel G. , Schattner Mark , Nishimura Makoto , Ku Geoffrey Yuyat , Gerdes Hans , Kelsen David Paul , Ilson David H. , Schultz Nikolaus , Zehir Ahmet , Iacobuzio-Donahue Christine A , Janjigian Yelena Yuriy
Published: May 2020

4568

Background: Pembrolizumab is approved for chemotherapy-refractory PD-L1 CPS >1 mEG cancer. In clinical trials, pts with MSI-H, EBV+ and PD-L1 CPS >10 EG cancers derive the greatest benefit with immune checkpoint blockade (ICB). Pre-clinical data suggest that the gut microbiome modulates response to ICB; however, the EG cancer microbiome has not been characterized in EG cancer with respect to PD-L1 and MSI-H status. Therefore, we evaluated the EG tumor microbiome in the context of PD-L1 expression in order to define biologically unique EG tumor phenotypes for future therapeutic development. Methods: Clinical and pathologic characteristics, including age, stage at diagnosis, tumor PD-L1 CPS, HER2 IHC, EBV ISH, genomic analysis, treatment history and survival status were reviewed. CPS was stratified a priori using cutoffs of >1/>10/>20 due to biologic differences. MSK-IMPACT, a capture-based next-generation sequencing platform that detects mutations, copy-number alterations, and select fusions was used to detect non-human bacterial reads identified in the NCBI NT database. Bacterial species found in >2 pts were analyzed and stratified by highest PD-L1 CPS score for each individual patient (Vanderbilt, AMP 2018) and Bonferroni correction was used for odds ratio (OR) confidence intervals where each unique species was considered an independent hypothesis. Results: Molecular data from 311 pts was clinically annotated. PD-L1 results (Table) correlated with bacterial species identified on tumor sequencing. PD-L1 CPS >1 was associated with Selenomonas sputigena (OR: 8.2, 95% CI:1.2-53.6), and PD-L1 CPS >20 was associated with presence of Bifidobacterium dentium (OR: 7.4, 95% CI:1.1-48.5) and Prevotella denticola (OR: 4.2, 95% CI: 1.1-16.6) after multiple comparison correction for the 166 bacterial species identified in the cohort. No differences were seen between PD-L1 < 10 vs >10. Four patients were also found to have EBV+ tumors using this approach, including the 1/54 patients identified by EBER ISH. Conclusions: PD-L1 > 20 EG cancer represents a biologically unique subset, enriched for Bifidobacterium dentium and Prevotella denticola. Correlation between PD-L1 expression, microbial and immune environment, and survival on ICB is underway. [Table: see text]
Radiotherapy after esophageal cancer stenting (ROCS): A pragmatic randomized controlled trial evaluating the role of palliative radiotherapy in maintaining swallow.
Authors: Byrne Anthony Thomas , Adamson Douglas , Porter Catharine , Blazeby Jane M. , Griffiths Gareth Owen , Nelson Annmarie , Sewell Bernadette , Jones Mari , Millin Tony , Staffurth John , Crosby Thomas , Hurt Chris
Published: May 2020

4569

Background: Most patients with oesophageal cancer (OC) present with incurable disease; 80% of new cases, and deaths, occur in low and middle income nations. Median survival for advanced disease is 3-5 months, a majority requiring intervention for dysphagia. Insertion of self expanding metal stents is the commonest way of palliating, but dysphagia may recur within three months owing to tumour progression. Evidence reviews have called for trials of combination treatment for OC dysphagia. The ROCS study (funding - UK NIHR programme) examined effectiveness of palliative radiotherapy, following stent, in maintaining swallow. It also examined impact on quality of life, bleeding events, and survival. Methods: A multicentre RCT with follow up monthly for a year. Patients referred for stent insertion as primary management of dysphagia related to incurable OC were recruited in secondary care, with all planned follow up at home. Patients were randomised 1:1 to stent insertion alone or stent insertion plus palliative radiotherapy at a dose of 20Gy in five fractions or 30Gy in ten fractions. Primary outcome was difference in proportions of participants with recurrent dysphagia at 12 weeks, defined as deterioration of 11 points or more in the dysphagia scale of the EORTC QLQ-OG25 questionnaire. Secondary outcomes included quality of life, bleeding risk, survival. Results: 220 patients were randomised Dec 2013-Aug 2018 at 23 UK sites. Addition of radiotherapy did not reduce the proportion of primary events at 12 weeks: 49% in control arm vs 45% in the intervention, adjusted OR 0.82 (95%CI 0.40-1.68; p = 0.587) and it was less cost effective. Sensitivity analyses did not alter the results. Dysphagia deterioration-free survival was similar in both arms: adjusted HR 0.92 (95%CI 0.68-1.26; p = 0.618). Median survival was 19.7 weeks in control arm and 18.9 weeks in the intervention. Those in the radiotherapy arm had significantly fewer bleeding events (18.6% compared to 10.3%), giving a number needed to treat of 12. Conclusions: Palliative external beam radiotherapy is widely accessible to patients with advanced cancer. ROCS is the largest trial assessing its role in combination with stenting for OC dysphagia, and is the first to prospectively assess impact on bleeding risk. It demonstrates no reduction in risk of dysphagia recurrence at 12 weeks, nor impact on survival. Reductions in bleeding events should be considered in the context of patient described trade offs of fatigue and burdens of attending hospital. Clinical trial information: NCT01915693 .
IDH1 mutation detection in plasma circulating tumor DNA (ctDNA) and association with clinical response in patients with advanced intrahepatic cholangiocarcinoma (IHC) from the phase III ClarIDHy study.
Authors: Aguado Elia , Abou-Alfa Ghassan K. , Zhu Andrew X. , Macarulla Teresa , Fan Bin , Nejad Parham , Choe Sung , Jiang Liewen , Gliser Camelia , Pandya Shuchi Sumant , Wu Bin
Published: May 2020

4576

Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) are detected in ~13% of IHCs. Ivosidenib (IVO) is a first-in-class, oral inhibitor of the mutant IDH1 (mIDH1) protein. In ClarIDHy, a global, phase 3, double-blind study in previously treated patients with advanced m IDH1 IHC (N = 186), IVO demonstrated an improvement in progression-free survival (PFS) vs placebo (hazard ratio 0.37, p < 0.001) (Abou-Alfa et al., Ann Oncol 2019; NCT02989857). Feasibility of m IDH1 detection in plasma ctDNA from patients with IHC was demonstrated and was highly concordant with mutation status in tumor tissue (Aguado-Fraile et al., Cancer Res 2019). This analysis was extended to the larger patient cohort from ClarIDHy, and longitudinal m IDH1 detection from ctDNA was assessed and correlated with clinical response. Methods: Baseline plasma and tumor tissue samples were obtained before randomization; longitudinal plasma samples were collected on day 1 of each treatment cycle. m IDH1 status in tissue was prospectively and centrally confirmed using Oncomine Focus Assay. A BEAMing digital PCR test was used for quantification of m IDH1 in plasma. IDH1 mutation clearance ( IDH1-MC) was achieved when plasma m IDH1 variant allele frequency was below the assay’s sensitivity (0.02% for R132C/L/S/G; 0.04% for R132H). Results: m IDH1 detection in plasma ctDNA and tissue was concordant in 92% (193/210) of samples screened. As of 31 Jan 2019, median PFS was 2.7 months for IVO vs 1.4 months for placebo. Longitudinal analysis with biomarker data available as of Jan 2020 demonstrated IDH1-MC in plasma from 10 IVO-treated patients with PFS ≥2.7 months (n = 36) vs 0 patients with PFS < 2.7 months (n = 40). No IDH1-MC was observed in patients treated with placebo, irrespective of response (n = 49). Conclusions: These results reinforce the feasibility of IDH1-R132 detection in plasma from patients with IHC, with a 92% concordance with detection in tumor tissue, supporting m IDH1 detection in liquid biopsy as a viable patient selection strategy where tissue exhaustion can limit conventional methods. Plasma IDH1-MC was also observed in a subset of IVO-treated patients who achieved disease control. Clinical trial information: NCT02989857 .
Primary tumor (p-bx) versus metastatic tumor (m-bx) tissue versus liquid biopsy (lb) in intrahepatic cholangiocarcinoma (IHCC): A comparative comprehensive genomic profiling (CGP) study.
Authors: Ross Jeffrey S. , Sokol Ethan , Pavlick Dean , Vergilio Jo-Anne , Killian Jonathan Keith , Lin Douglas I. , Williams Erik Abraham , Danziger Natalie , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Edgerly Claire I. , Huang Richard , Madison Russell , Schrock Alexa Betzig , Alexander Brian Michael , Venstrom Jeffrey , Reddy Venkataprasanth P. , McGregor Kimberly , Elvin Julia Andrea
Published: May 2020

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Background: Genomic alterations (GA) characteristic of IHCC are well known. We queried whether GA from Pbx would differ from Mbx and Lbx in IHCC. Methods: Hybrid-capture based CGP was performed on 1,268 tissue samples of advanced stage IHCC using Pbx in 1,048 cases and Mbx from 220 cases and 364 Lbx cases (solid tissue: 318-327 genes, Lbx: 72 genes). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC. Results: Mbx sites included: lymph nodes (63), soft tissues (47), peritoneum (34), lung/pleura (27), omentum (15), bone (10), abdomen (7), GYN tract (5), liver (4), brain (2), Upper GI (2), colon (2), bladder (1), and adrenal (1). The GA/sample and biomarkers of immuno-oncology (IO) drug response were similarThe KRAS mutation frequency including G12C alterations was doubled in Mbx compared to Pbx and Lbx (p < 0.001). Frequencies of untargetable GA were similar overall. IDH1 (p < 0.001) and FGFR2 GA known to be enriched in IHCC were less frequent in Mbx than Pbx. Both IDH1 and FGFR2 were identified in Lbx. GA in STK11 (p < 0.001) and SMAD4 (p = 0.0016) were more frequently identified in Mbx. Conclusions: GA found in Pbx vs Mbx and Lbx in IHCC are significantly different; the Mbx cohort features greater KRAS and lower IDH1 and FGFR2 GA. Lbx detected more IDH1 GA than Mbx. This suggests that the Mbx group may contain non-IHCC cases whose metastatic lesions were actually derived from other primary sites and incorrectly assigned the diagnosis of IHCC. [Table: see text]
Adjuvant lenvatinib in combination with TACE for hepatocellular carcinoma patients with high risk of postoperative relapse (LANCE): Interim results from a muticenter prospective cohort study.
Authors: Chen Jin-hong , Lu Lu , Wen Tian-Fu , Huang Zhi-Yong , Zhang Ti , Zeng Yong-Yi , Li Xiang-Cheng , Xiang Bang-De , Lu Cai-de , Xu Xiao , Qin Lun-xiu
Published: May 2020

4580

Background: Surgical resection was the main treatment for hepatocellular carcinoma (HCC) in China. Multiple clinical studies had demonstrated that the overall survival (OS) of the surgical resection group was significantly better than the transcatheter arterial chemoembolization (TACE) or radiotherapy group even for HCC patients with BCLC stage B or C. There was no standard adjuvant therapy for HCC patients to decrease the post-operative tumor relapse. For HCC patients with high recurrence risk, TACE significantly reduced tumor recurrence, prolonged the disease free survival (DFS) and OS, and was recommended as the adjuvant therapy. However, its effect is not very satisfactory. The purpose of this study was to assess the efficacy and safety of lenvatinib in combination with TACE versus TACE alone as adjuvant therapy in HCC patients with high recurrence risk after resection. Methods: This is a muti-center prospective cohort study. The criteria of HCC patients with high postoperative recurrence risk included: accompanied with gross vascular or bile duct invasion (tumor thrombi in portal vein, hepatic vein or bile duct); or tumor rupture or invasion of adjacent organs; or grade 2 of microvascular invasion (MVI) (M2) along with the tumor number more than 3 or the maximum diameter of tumor larger than 8cm or tumor showed invasive growth with unclear boundaries and imcomplete capsules. The patients were divided into two groups, the lenvatinb (8mg qd for weights < 60kg and 12mg qd for weights≥60kg) in combination with TACE (Len+TACE) group and the TACE group. Results: A total of 90 patients were enrolled into the study, while 45 patients in the Len+TACE group and 45 in TACE group. The media age was 52 years (range from 23 to 73 years). Most patients were males (82.2%) and 66 patients had HBV background (73.3%). There were no significant differences between the two groups in the baseline clinicopathological characteristics including gender, age, HBV background, liver cirrhosis, liver function, tumor characteristic and AFP level. The media DFS was 12.0 months (95% CI 8.0-NA) in the Len+ TACE group, which was longer than that of TACE group (8.0 months, 95% CI 6.0-12.0, P = 0.0359; HR 0.5, 95% CI 0.3-1.0). The most common grade 3 or 4 adverse events were hypertension (11.1%) and diarrhea (7.7%) in the Len+TACE group. Conclusions: Lenvatinib in combination with TACE was effective and safe as adjuvant therapy, which can prolong the DFS of HCC patients with high recurrence risk after resection. Clinical trial information: NCT03838796 .
Adjuvant concurrent chemoradiotherapy in extrahepatic cholangiocarcinoma.
Authors: Shaib Walid Labib , Zakka Katerina Mary , Tian Feng , Chen Zhengjia , Patel Pretesh R. , Lin Jolinta Y , Wu Christina , Akce Mehmet , Alese Olatunji B. , El-Rayes Bassel F.
Published: May 2020

4583

Background: Resected cholangiocarcinomas are rare and have high relapse rates. Adjuvant chemotherapy is the standard of care (BiLCAP Trial). Adjuvant radiation therapy benefit is not well defined. This study aims to evaluate survival outcomes of the effect of adjuvant chemoradiotherapy compared to chemotherapy in extrahepatic cholangiocarcinoma (EHC) using the National Cancer Database (NCDB). Methods: Patients with resected EHC between 2004 and 2013 were identified from the NCDB using ICD-O-3 histology and topography codes: 8140, 8160, 8161, 8162 and C24.0. Patients with neoadjuvant therapy were excluded from this analysis. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received. Results: A total of 236 EHC patients were identified. Males comprised 60.6% and 88.1% were Caucasian. Median age was 64 (range, 31-84) years. The majority were distal (72.0%, N = 157) followed by perihilar (20.6%, N = 45), hilar (6.4%, N = 14) and cystic (0.9%, N = 2). Distribution across stages I-III was 28.8% (N = 68), 56.8% (N = 134), and 14.4% (N = 34), consecutively. Adjuvant chemotherapy was given in 37.7% (N = 89) and adjuvant chemoradiotherapy in 62.3% (N = 147). The median dose of radiation was 50.4 Gy. Adjuvant chemoradiotherapy was mostly given in regional node positive disease (p = 0.016) and negative surgical margin (p = 0.002) compared to regional node negative disease and positive surgical margin, respectively. The use of adjuvant chemoradiotherapy was associated with improved OS compared to chemotherapy alone in univariate (HR 0.64; 95% CI 0.44-0.93; p = 0.019) and multivariable analysis (HR 0.65; 95% CI 0.44-0.96; p = 0.030). Median survival and 1 year-OS for patients that received chemoradiotherapy was 33.8 months (95% CI 28, NA) and 87.7% (80.9%, 92.1%) compared to chemotherapy alone which was 23.8 months (95% CI 18.9, 35.4) and 75.5% (64.9%, 83.3%). Conclusions: Adjuvant chemoradiotherapy was associated with improved survival in patients with resected EHC compared to chemotherapy alone. This conclusion warrants further prospective studies to confirm these results.