bluuebunny/crossref_metadata_2025 huggingface dataset:
FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma (JCOG1804E)—The short-term results of cohort A and B.
Authors: Yamamoto Shun , Kato Ken , Daiko Hiroyuki , Kojima Takashi , Hara Hiroki , Abe Tetsuya , Tsubosa Yasuhiro , Kawakubo Hirofumi , Fujita Takeo , Fukuda Takashi , Kadowaki Shigenori , Tsushima Takahiro , Hamamoto Yasuo , Nagashima Kengo , Aoki Kazunori , Mizoguchi Yukihiro , Kitano Shigehisa , Yachida Shinichi , Shiba Satoshi , Kitagawa Yuko
Published: January 2021

202

Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell cancer (ESCC) is CDDP + 5-FU (CF). Immune checkpoint inhibitors (ICI) such as nivolumab provide a survival benefit in ESCC, and have potential as NAC agents in lung, skin, and breast cancers, amongst others. However, whether ICI are efficacious in combination with cytotoxic agents, and whether ICI impact the safety of subsequent surgery after they are used as NAC for ESCC patients (pts) is currently unclear. Methods: FRONTiER is a multi-cohort phase I study designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. Histologically proven ESCC pts with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), 20–75 years old, PS ≤ 1, no prior therapies against any cancer were eligible. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 4 experimental cohorts, the NAC regimen of cohort A consisted of 2 courses of CDDP at 80 mg/m2, nivolumab at 360 mg/body on day 1 and 5-FU at 800 mg/m2 on days 1–5, q3wks. The regimen of cohort B consisted of one administration of nivolumab at 240 mg/body 2 weeks before chemotherapy, followed by the same treatments as cohort A. Results: Thirteen pts were enrolled to cohort A (n = 6) and B (n = 7). Characteristics were follows; median age: 62 (range: 34–75), PS 0/1: 9/4 pts, clinical stage I/II/III: 2/1/10 pts. One pt in cohort B was excluded from safety evaluation due to R2 resection, no DLTs were observed in 12 pts. The most frequent adverse events (≥ grade 3) were neutropenia in 6 pts during NAC, lung infection in 1, hyperglycemia in 1, pleural effusion in 1, infection (right neck) in 1, anemia in 1, abdominal pain in 1, and anatomic leakage in 1 during the postoperative period. Within 30 days post-operation, grade 2 adrenal insufficiency was observed in 1 pt of cohort B. No grade 4 adverse events or treatment-related deaths were seen. All pts received two courses of NAC + nivolumab and R0 resection was achieved in 12 pts (92.3%) without interruption of treatment. A pathological complete response was achieved in 2 pts (33.3%) in cohort A. Conclusions: Neoadjuvant CF + nivolumab with/without prior administration of nivolumab followed by surgery for locally advanced ESCC was well tolerated and showed promising efficacy. Clinical trial information: NCT03914443.
Final results of a phase III trial to evaluate bursectomy for patients with subserosal/serosal gastric cancer (JCOG1001).
Authors: Katai Hitoshi , Doki Yuichiro , Kurokawa Yukinori , Mizusawa Junki , Yoshikawa Takaki , Kimura Yutaka , Takiguchi Shuji , Nishida Yasunori , Sano Takeshi , Nakamura Kenichi , Sasako Mitsuru , Terashima Masanori ,   Stomach Cancer Study Group, Japan Clinical Oncology Group
Published: January 2021

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Background: We previously reported that the superiority of bursectomy was not demonstrated for subserosal(SS)/serosal(SE) gastric cancer by the second interim analysis performed with 54% of the expected events observed. We report the final 5-year follow-up data. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach, cT3(SS) or cT4a(SE). Patients were intraoperatively randomized to non-bursectomy arm or bursectomy arm. Primary endpoint was overall survival (OS), and secondary endpoint was relapse-free survival (RFS). A total of 1,200 patients were required to detect a hazard ratio of 0.77 with a one-sided alpha of 5% and 80% power. Results: A total of 1204 eligible patients with cT3 / cT4a gastric cancer were randomized (602 in non-bursectomy arm, 602 in bursectomy arm, respectively). Patients’ background and operative procedures were well balanced between the arms. The 5y-OS were 76.5% (95% CI, 72.8 to 79.7) in non-bursectomy arm and 74.9% (71.2 to 78.2) in bursectomy arm. Hazard ratio (HR) for bursectomy was 1.03 (0.83-1.27, one-sided p = 0.598). The 5y-RFS were 70.7% (66.9 to 74.2) in non-bursectomy arm and 66.8% (62.9 to 70.5) in bursectomy arm [HR: 1.131 (0.93-1.38)]. HR for death was almost similar in all sub-categories (0.73-1.29) except cN2 (13th edition of Japanese Classification of Gastric Carcinoma); HR classified by cN was 1.06 (95% CI: 0.75-1.49) for cN0 (n = 521), 1.25 (0.92-1.71) for cN1 (n = 525), and 0.59 (0.32-1.06) for cN2 (n = 158) (p = 0.048 for interaction). The most frequent site of recurrence was the peritoneum [74 (12.3%) in non-bursectomy arm, 73 (12.1%) in bursectomy arm], and bursectomy arm showed a trend of increasing liver metastasis (n = 45, 7.5%) as compared with non-bursectomy arm (n = 33, 5.5%). Six independent poor prognostic factors were identified by multivariable analysis for OS: age ≥ 66 (vs. ≤ 65) (HR, 1.30; 95% CI, 1.04-1.62), macroscopic type 3/5 (vs. type 0/1/2) (1.43; 1.15-1.79), total gastrectomy (vs. distal gastrectomy) (1.44; 1.03-2.02), pT3 (vs. pT1-2) (1.77; 1.17-2.676), pT4 (vs. pT1-2) (3.00; 1.99-4.53), pN1 (vs. pN0) (2.34; 1.52-3.59), pN2-3b (vs. pN0)(4.02; 2.82-5.74) and adjuvant chemotherapy (vs. without chemotherapy) (0.53; 0.42-0.67), but bursectomy was not significant (1.10 0.89-1.36). Conclusions: In the final analysis as well as in the interim analysis, bursectomy was not recommended as a standard treatment for cT3 or cT4 gastric cancer. Clinical trial information: UMIN000003688.
Nivolumab in advanced esophageal squamous cell carcinoma (ATTRACTION-1/ONO-4538-07): Minimum of five-year follow-up.
Authors: Kato Ken , Doki Yuichiro , Ura Takashi , Hamamoto Yasuo , Kojima Takashi , Tsushima Takahiro , Hironaka Shuichi , Hara Hiroki , Satoh Taroh , Iwasa Satoru , Muro Kei , Yasui Hirofumi , Minashi Keiko , Yamaguchi Kensei , Ohtsu Atsushi , Kitagawa Yuko
Published: January 2021

207

Background:ATTRACTION-1/ONO-4538-07 (AT-1), an open-label, single-arm, multicenter phase 2 clinical trial conducted in Japan, evaluated the clinical activity and safety of nivolumab in patients with advanced esophageal squamous cell carcinoma (ESCC) refractory/intolerant to fluoropyrimidine-, platinum-, and taxane-based chemotherapy. We previously reported the 2-year follow-up findings of AT-1, in which nivolumab demonstrated antitumor activity with a manageable safety profile for these patients. Here we report the final findings from AT-1 at a minimum follow-up of 5 years. Methods:Patients aged ≥20 years with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 received 3 mg/kg nivolumab intravenously every 2 weeks in 6-week cycles until disease progression or unacceptable toxicity. The primary endpoint was centrally-assessed objective response rate (ORR), defined as the proportion of patients whose best overall response was either a complete or partial response. Secondary endpoints included overall survival (OS), investigator-assessed ORR, progression-free survival (PFS), change in tumor burden, time to response, time to disease progression, and duration of response. Results:Between February 25 and November 14, 2014, a total of 65 patients were enrolled. Sixty-four patients were evaluated for the efficacy, and all patients were evaluated for the safety. At the final database lock on August 6, 2020, 11 (17.2%, 95% confidence interval [CI] 9.9-28.2) of 64 patients had an objective response by central assessment. The median OS was 10.8 months (95% CI, 7.4-13.9), and the estimated 5-year OS rate was 6.3% (95% CI, 2.0-14.0). The median PFS was 1.5 months (95% CI, 1.4-2.8), and the estimated 5-year PFS rate was 6.8% (95% CI, 2.2-15.1). Treatment-related adverse events that occurred with a frequency of > 10% were diarrhea and rash. The presentation will include characteristics of long-term survivors as well as detailed efficacy and safety data of nivolumab. Conclusions:This final assessment represents the longest follow-up of patients with advanced ESCC treated with nivolumab. Nivolumab demonstrated continued long-term efficacy in these patients based on a minimum of 5-year long-term survival update of AT-1. Furthermore, no new safety signals with nivolumab were identified during long-term follow-up. These findings are consistent with those of nivolumab monotherapy for various types of cancer. Clinical trial information: No.142422.
Phase II study of sintilimab combined with FLOT regimen for neoadjuvant treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Li Ning , Li Zhi , Fu Qiang , Zhang Bin , Zhang Jian , Wan XiangBin , Lu Chaomin , Wang Jinbang , Deng Wenying , Wei Chen , Ma Yijie , Bie Liangyu , Wang Mengyu , Luo Suxia
Published: January 2021

216

Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer, increasing 5-year overall survival from 23% with surgery alone to 45% with FLOT, Although FLOT has been recognized as the first choice for neoadjuvant chemotherapy in gastric or GEJ adenocarcinoma, its efficacy needs to be improved. Sintilimab, a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in various cancers. We aimed to assess the activity and safety profile of the combination of FLOT and sintilimab for neoadjuvant treatment of gastric or GEJ adenocarcinoma. Methods: In this ongoing, single-arm, phase II study, we recruited patients from Henan Cancer Hospital in China with histopathologically diagnosed resectable gastric or GEJ adenocarcinoma who had clinical T3/N+ or higher stage. Patients were given 4 cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 80 mg/m2, leucovorin 200 mg/m2, fluorouracil 2600 mg/m2, 24-h infusion on day 1, q2w) in combination with 3 cycles of sintilimab (200mg, iv, d1, q3w), followed by D2 surgery and 4 postoperative cycles of FLOT. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and R0 resection rate and adverse events . Results: A total of 20 patients were enrolled in the study between Aug 10 2019 and Sep 15 2020. One patient refused surgery, one person's disease progressed. Two patients have not yet completed neoadjuvant treatment . 16 pts who experienced D2 resection, 10 (62.5%) achieved major pathologic response (MPR), including 3 (18.8%) with a pathologic complete response (pCR) in primary tumor. The R0 resection rate was up to 93.8%, The grade 3 or 4 treatment-related adverse events (TRAE) included lymphopenia(25%), anaemia (20%),fatigue (20%),leucopenia (15%), neutropenia (5%), diarrhea(5%), Alanine aminotransferase increased(5%),There was no surgical delays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of sintilimab and FOLT is a safe and efficacious treatment option for patients with gastric or GEJ adenocarcinoma, 18.8% pCR rate and 62.5%MPR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: NCT04341857.
Neoadjuvant PD-1 blockade in combination with chemotherapy for patients with resectable esophageal squamous cell carcinoma.
Authors: Cheng Chao , Yang Weixiong , Chen Wenfang , Yeung Sai-Ching Jim , Xing Xiangbin , Wang Xiaoyan , Bao Yong , Feng Shiting , Peng Fang , Liu Zhenguo , Zeng Bo
Published: January 2021

220

Background: Programmed death-1 (PD-1) blockade may induce tumor regression in patients with advanced esophageal squamous cell carcinoma (ESCC), but little is known about the efficacy of PD-1 blockade in neoadjuvant therapy of resectable ESCC. Methods: Under an approved clinical trial protocol, a pilot study was conducted by enrolling patients with untreated, resectable (stage II or IIIA) ESCC. After written informed consent, each patient received two 21-day cycles of neoadjuvant treatment with camrelizumab (200mg), albumin-paclitaxel (260mg/m2) and carboplatin (area under the curve = 5) followed by surgical resection about 6 weeks after the first dose. The primary end points were safety and feasibility. We also reported the objective response rate (ORR), disease control rate (DCR) and tumor pathological response. Results: Between January 19, 2020, and July 21, 2020, we assessed 35 patients for screening, of whom 20 patients were enrolled. Neoadjuvant combination of camrelizumab, carboplatin and albumin-paclitaxel had an acceptable side-effect profile, and was not associated with delays in surgery. The ORR was 85%, and the DCR was 100%. Eighteen (90%) patients were taken into the surgery, and all of them successfully underwent R0 resection. Five (5/18 = 27.8%) patients had a pathological complete response (pCR), and eight (44.4%) patients had major pathological responses (MPR).The most common treatment-related grade 1–2 adverse events were leukopenia (12, 60%), neutropenia (11, 55%) and nausea (8, 40%). Two (10%) patients suffered grade 3 neutropenia. There was no grade 4 adverse events and treatment-related deaths. Conclusions: Neoadjuvant camrelizumab plus carboplatin and albumin-paclitaxel had manageable treatment-related toxic effects, did not delay surgery. This regimen induced pCR or MPR in 72.2% of resected tumor, demonstrating its antitumor efficacy in resectable ESCC. Clinical trial information: ChiCTR2000028900.
Camrelizumab in combination with preoperative chemotherapy for locally advanced esophageal squamous cell carcinoma: A single-arm, open-label, phase II study.
Authors: Wang Feng , Qi Yu , Meng Xiangrui , Fan Qingxia
Published: January 2021

222

Background:At present, esophageal cell carcinoma (ESCC) has a dismal prognosis with huge unmet clinical needs. With the potential benefit of combining PD-1 inhibitor with neoadjuvant chemotherapy (nCT), we conducted a phase II trial to assess the efficacy and safety of Camrelizumab (anti-PD-1 antibody) plus nCT for locally advanced ESCC. Methods:26 patients (pts) with histologically confirmed stage Ⅱ/Ⅲ/Ⅳa (cT2-4aN0-3M0) ESCC were enrolled from February 2020 to September 2020.The study was divided into two stages, stage1: we administered 1 cycle of Camrelizumab for induction therapy (200 mg q2 weeks); stage2: pts received 2 cycles of Camrelizumab (200 mg every 3 weeks) plus docetaxel and nedaplatin, followed by surgery within 4~6 weeks after neoadjuvant therapy completion. Primary endpoint was major pathologic response (MPR). Secondary endpoints included pathologic complete response (pCR), R0 resection rate, disease-free survival (DFS) and overall survival (OS). In total 40 pts will be enrolled. Results:At the cutoff date of Sep 22, 2020, 26 eligible pts were enrolled (65% males, median age 63), neoadjuvant treatment was completed in 17 pts and is ongoing in 7 pts. Thus far 12 out of 17 pts were resected, 5 pts are planned to undergo surgery, 1 pt had interval metastases preoperatively, 1 pt declined surgery. All patients underwent an R0 resection. Postoperative pathology showed that T stage decreased in 10 pts with 83% reduction rate. 5 pts (42%) reached major pathologic response, 3 pts (25%) reached pathologic complete response, the others maintained stable disease (33%). No grade 3 immunotherapy related AEs were observed, no surgery related mortality. The most common AEs (all grade, grade≥3) were anemia (31%, 3%), leukopenia (7%, 0%), neutrophil (3%,0%), hypoalbuminemia (21%, 0%), hematochezia (14%, 0%), fatigue (10%, 0%) and thyroid dysfunction (24%, 0% ). Date for median PFS and OS were not matured. Conclusions:Camrelizumab in combination with preoperative chemotherapy followed by surgery for locally advanced ESCC showed promising downstaging effect and MPR with good tolerance, and its efficacy and safety could be further studied in later trials. Clinical trial information: NCT03917966.
Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma.
Authors: Ku Geoffrey Yuyat , Wu Abraham Jing-Ching , Sihag Smita , Park Bernard J. , Jones David Randolph , Gu Ping , Maron Steven Brad , Sugarman Ryan , Chalasani Sree Bhavani , Shcherba Marina , Feder Lara , Cowie Kendall , Norris Jaclyn , Johnson Valerie , Tang Laura H. , Ilson David H. , Janjigian Yelena Y. , Molena Daniela
Published: January 2021

226

Background: Based on the positive results of the CALGB 80803 study (J Clin Oncol 2017;35:1 [abstr]), we have added D to induction FOLFOX and pre-op CRT. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I-III GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received mFOLFOX6 ×2 prior to repeat PET/CT. PET responders (PETr) received 5-FU or capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 wks prior to and during CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg q4W ×6. Results: 36 Pts have been enrolled: 25 GEJ, 11 esophageal; 23 N+ and 32 T3/4. 26 of 36 Pts (72%) are PETr. 2 Pts developed metastatic disease after CRT and 9 Pts remain on preop treatment. 25 Pts have had surgery (Table). Pathologic complete response (pCR) was seen in 6 (24%); 5 Pts (20%) had ypT1N0 tumors with 99% response and 2 Pts (8%) had ypT0N1 with 99% response. 20 Pts (80%) had >90% response. 3 Pts had MSI tumors (2 PETr; 1 pCR, 1 T1aN0 99% response, 1 ypT2N0 90% response). Notable grade (gd) 3/4 adverse events (AEs) observed were neutropenia in 8 Pts (22%), diarrhea and vomiting in 2 Pts each (6%). Notable gd 1/2 AEs in ≥20%: anemia (31 Pts), thrombocytopenia (29 Pts), nausea (21 Pts), fatigue (25 Pts), increased AST (20 Pts), constipation and diarrhea (9 Pts), diarrhea (8 Pts). Immune-related AEs noted were gd 2 dermatitis (2 Pts), gd 3 hepatitis and gd 1 hypothyroidism in 1 Pt each. Median length of post-op stay was 8 days, with 12% anastomotic complication rate, including 1 Pt who died of hematemesis 16 days after discharge from 55-day hospitalization. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT is safe and feasible. pCR and near-pCR in ½ of operated Pts is encouraging and compares favorably to the pCR rate of 31% in CALGB 80803 Pts who received induction FOLFOX. The final pCR rate and correlatives for the fully accrued study will be presented. Clinical trial information: NCT02962063. [Table: see text]
KEYlargo: A phase II study of first-line pembrolizumab (P), capecitabine (C), and oxaliplatin (O) in HER2-negative gastroesophageal (GE) adenocarcinoma.
Authors: Uronis Hope Elizabeth , Rushing Christel , Blobe Gerard C. , Hsu Shiaowen David , Mettu Niharika B. , Wells James Leroy , Niedzwiecki Donna , Hartman Leighanne , Moyer Ashley , Hurwitz Herbert I. , Strickler John H.
Published: January 2021

228

Background: Gastric and esophageal adenocarcinomas are a leading cause of cancer death worldwide. Many of these patients (pts) present with locally advanced unresectable or metastatic disease and are treated with combination cytotoxic chemotherapy. Single agent P is FDA approved for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ) whose tumors have a combined positive score (CPS) ≥ 1 after disease progression on or after two lines of therapy including fluoropyrimidine and platinum and her2/neu-targeted therapy (if indicated). More effective therapy is needed earlier in the disease trajectory. We conducted a single-arm phase II trial to establish the safety and efficacy of first-line C and O + P. Methods: Pts with previously untreated metastatic GE adenocarcinoma regardless of PDL-1 status received intravenous (IV) P 200mg with IV O 130mg/m2 every three weeks and oral C 850mg/m2 twice daily for 14 days on/7 days off. After the 6 patient safety cohort, pts first completed a biomarker cycle that included fresh tumor biopsy before P and one week after P before chemotherapy started. Archived FFPE tumor samples were also obtained from all pts with available tissue. The primary endpoint was progression free survival (PFS); secondary endpoints included response rate (RR) and overall survival (OS). Results: 36 pts were enrolled and 34 pts were evaluable for efficacy (1 pt withdrew for personal reasons before end of cycle 1 and 1 pt had immune-related toxicity during cycle 1 and was taken off study before any efficacy assessment). 9 pts (26%) had an esophageal primary, 18 pts (53%) had a GEJ primary and 7 pts (21%) had a gastric primary. Median PFS was 7.6 months [95% CI: 5.8 to 12.2], RR was 72.7% [95% CI: 57% to 88%], and median OS was 15.8 months [95% CI: 11.6 to NE]. 27 patients (81.8%) had decrease in disease burden (ranging from -19% to -100%). After > 18 months of follow-up, 5 patients remained in durable complete response (CR). Immune-mediated treatment related adverse events (TRAEs) included thyroid disorders (n=5; 14%), colitis (n=4; 11%), adrenal insufficiency (n=2; 5%), and type 1 diabetes (n=1). Sixteen patients (44%) experienced grade 3 or 4 TRAEs. There were no grade 5 TRAEs. Conclusions: The combination of C and O + P had acceptable safety and significant clinical activity. These promising results indicate that C and O + P merits further study as a first line option for patients with unresectable locally advanced or metastatic GE adenocarcinoma. Updated survival and correlative data will be presented. Clinical trial information: NCT03342937.
Genomic characterization of a comprehensive collection of esophagogastric cancer patient-derived xenografts.
Authors: Moy Ryan H. , Mattar Marissa , Molena Daniela , Strong Vivian E. , Jones David Randolph , Coit Daniel G. , Tang Laura , Maron Steven Brad , Hechtman Jaclyn Frances , de Stanchina Elisa , Janjigian Yelena Y.
Published: January 2021

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Background: Large-scale sequencing has identified multiple oncogenic drivers and molecularly defined subsets in esophagogastric cancer. However, besides therapies for HER2-positive and microsatellite instability-high disease, few genomic biomarker-driven treatments are currently approved. Patient-derived xenografts (PDXs) have emerged as promising preclinical models that capture the heterogeneity and biology of human tumors. Therefore, we established a comprehensive collection of esophagogastric cancer PDXs and performed next-generation sequencing (NGS) to genomically characterize these models. Methods: Starting in 2010, we developed an ongoing program for generating esophagogastric cancer PDXs from fresh tumor specimens that are acquired from surgical resections or biopsies and implanted into NOD scid gamma (NSG) mice either subcutaneously into flanks or orthotopically into the gastric wall. We reviewed clinical and pathologic characteristics of patients from whom established PDXs were derived, including stage, histology, HER2 status and treatment history. To identify oncogenic DNA alterations, NGS was performed on PDX material using MSK-IMPACT, a capture-based NGS platform. Results: From April 2010 to August 2018, we implanted 270 tumor samples, of which 112 were successfully engrafted (41.4%) including 57 gastric adenocarcinomas, 25 gastroesophageal junction adenocarcinomas, 23 esophageal adenocarcinomas, 4 squamous cell carcinomas and 3 small cell/high-grade neuroendocrine tumors. PDXs were generated from both primary tumors (n = 67, 59.8%) and metastases (n = 45, 40.2%), with many PDXs established from patients with metastatic disease who had progressed on standard therapy (n = 50, 44.6%). In addition, a large number of PDXs were derived from patients initially diagnosed with HER2-positive esophagogastric adenocarcinoma (n = 68, 60.7%). NGS of these PDXs demonstrated frequent alterations in TP53, receptor tyrosine kinases ( ERBB2, EGFR), cell-cycle mediators ( CDK12, CCNE1, CCND3) and histone methyltransferases ( KMT2C, KMT2D), consistent with clinical sequencing. Conclusions: Comprehensive molecular profiling demonstrates that esophagogastric cancer PDXs recapitulate the genomic heterogeneity and tumor biology of patients. This panel represents one of the largest described collections of esophagogastric cancer PDXs and serves as a powerful platform to investigate mechanisms driving tumor growth and metastasis, identify predictive biomarkers for treatment responsiveness and develop novel genomically-driven therapeutic strategies.
The incidence of Epstein-Barr Virus-associated gastric cancer in an Irish population.
Authors: Weadick Catherine , McLaughlin Ronan Andrew , Ramsey Megan , Al-Julandani Nabila , Power Derek Gerard , Bennett Michael William , Aird John , Duffy Austin G.
Published: January 2021

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Background: Gastric adenocarcinoma is the fourth most frequent cancer worldwide and the second leading cause of cancer deaths. According to The Cancer Genome Atlas (TCGA) 9% of gastric carcinomas are associated with Epstein-Barr Virus (EBV). EBV- associated gastric carcinoma (EBV-GC) has distinct clinicopathological features, with a marked lymphocytic infiltrate, a generally diffuse histological type and a better prognosis. The immune cell infiltration in EBV-GC suggests a role for immune checkpoint inhibition, which currently has modest activity in unselected gastric cancer. Methods: All cases of gastric or junctional adenocarcinoma diagnosed between Jan 2019 and March 2020 in Mater Misericordiae University Hospital (MMUH) and Jan 2017 and Jan 2019 in Cork University Hospital (CUH) were identified. Electronic medical records were retrospectively reviewed to collect demographic and clinicopathological data such as AJCC TNM stage, tumour subtype and grade, HER-2 status, MMR proficiency and EBV status as determined by EBV-encoded RNA in situ hybridization. Results: N = 103 cases of gastric or junctional adenocarcinoma were identified. 67 male, 36 female, median age 64.5 (range 34 – 95). 40/103 had undergone surgical resection. EBER-ISH was assessed in all patients. 8 of 103 (7.8%) patients showed EBV positivity. These cases were all male patients, median age 62 (range 51-73). The tumours were located as follows; 2 in the cardia, 5 in the body and 1 not documented. The specimens were graded as; 87.5% (7/8) tumours being poorly differentiated and 1/8 moderate to poorly differentiated. The tumour subtypes were specified as; 62.5% (5/8) diffuse, 12.5% (1/8) intestinal and 25% (2/8) mixed intestinal and diffuse. 5/8 patients were locally confined and underwent resection for N0 disease. 3/8 (37.5%) patients had metastatic disease. None of the 8 EBV-GC cases were identified as being HER-2 positive or MMR-deficient. Conclusions: EBV-GC accounted for 7.8% of all gastric cancers in two large tertiary referral centres in Ireland. 37.5% of these patients had metastatic disease. Given this frequency and a possible predictive role in selecting for immunotherapy we conclude that routine assessment of EBV status is feasible in advanced gastric cancer.
Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational, multicenter retrospective study.
Authors: Yoo Changhoon , Kim Jwa Hoon , Ryu Min-Hee , Park Sook Ryun , Lee Joycelyn Jie Xin , Tai Wai Meng David , Chan Stephen Lam , Ryoo Baek-Yeol
Published: January 2021

272

Background: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease progression on atezolizumab-bevacizumab is unclear. Methods: This multinational, multicenter, retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab in Korea, Hong Kong and Singapore between July 2016 and April 2019. Results: A total of 49 patients were included; the median age was 60 years (range, 3780) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib (n = 29), lenvatinib (n = 19), and cabozantinib (n = 1), were used as second-line therapy for all patients. The objective response rate (ORR) and disease control rate (DCR) were 6.1% and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI] 1.84.9) and 14.7 months (95% CI 8.121.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 months vs. 2.5 months; P= 0.004), although there was no significant difference in median OS (16.6 months vs. 11.2 months; P= 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7%) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome (HFS) (n = 26, 53.1%), fatigue (n = 14, 28.6%), hypertension (n = 14, 28.6%), and diarrhea (n = 12, 24.5%). Conclusions: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.
Risk factors, treatment patterns and survival of patients with incident hepatocellular carcinoma in France: A retrospective data analysis.
Authors: Mathurin Philippe , De Zelicourt Marie , Kelkouli Nadia , Blanc Jean-frederic
Published: January 2021

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Background: Despite the screening of patients at risk, hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage disease, with a very poor prognosis. Aim: To describe risk factors, treatment patterns and survival of patients with newly diagnosed HCC in France over the period 2015-2017 using SNDS, the national administrative healthcare database covering around 99% of the population. Methods: The database was searched for patients with a diagnosis of HCC (ICD-10: C220) from 1 January 2015–31 December 2017. Disease stage (Barcelona Clinic Liver Cancer B, C or D classification) was defined by the identification of treatment: transcatheter arterial chemoembolization (TACE) or radioembolization (TARE), HCC systemic therapy and/or best Supportive Care (BSC). Patients were followed up for a maximum of 2 years. Results: 21,071 patients were identified, mean age 69.2 years (SD: 11.1), 82.2% were male. Liver disease or diabetes was identified in 86.4% of patients. The most frequent risk factors were alcohol liver disease (42.7%), viral hepatitis and alcohol liver disease (7.2%), viral hepatitis alone (12.6%), NASH/NAFLD or diabetes (17.7%). At diagnosis, 6,571 (31.2%) received a curative HCC treatment. Within the total population, 8,616 patients (40.9%) were only managed by BSC, 6,571 (31.2%) received a treatment therapy, of which 3,184 (15.1%) had a TACE or TARE and 2 700 (12.8%) sorafenib. The 1-year survival rates by initial treatment were: curative (88.7%), TACE or TARE (70%), systemic therapy (32.2%) and only 17.8% with BSC. Conclusions: These results show the high burden of HCC, with more than two thirds of patients not receiving active treatment.
The implications of treatment delays in adjuvant therapy for cholangiocarcinoma patients.
Authors: Parsons Matthew , Lloyd Shane , Johnson Skyler B , Scaife Courtney L. , Garrido-Laguna Ignacio , Tao Randa
Published: January 2021

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Background: To understand the factors associated with timing of adjuvant therapy in the management of intrahepatic and extrahepatic cholangiocarcinoma and the impact of delays on overall survival (OS). Methods: Data from the NCDB for patients with pathologically proven non-metastatic adenocarcinoma of the bile ducts from 2004 to 2014 were pooled and screened. Patients were included only if they underwent surgery and adjuvant chemotherapy (CMT) and/or radiotherapy (RT). Patients who underwent neoadjuvant therapy or received CMT or RT with palliative intent were excluded. Pearson’s chi-squared test and multivariate logistic regression analyses were used to assess the distribution of demographic, clinical, and treatment factors. After propensity-score matching with inverse probability of treatment weighting, OS was compared between patients who had initiation of adjuvant therapy past various time points using Kaplan Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling. Results: In total, 7,422 patients in our analysis underwent adjuvant treatment. This represented 43% of the study cohort of 17,123 patients. Of the patients who underwent adjuvant treatment, 3,956 (53%) initiated adjuvant therapy by two months, 6,234 (84%) by 3 months and 6,987 (94%) by four months. High-grade disease, macroscopically positive margins, tumors larger than five centimeters, and unknown LVSI status, were associated with earlier initiation of adjuvant treatment at two months or earlier. Patients who received early adjuvant therapy were also more likely to be treated with a combination of CMT and RT. Factors associated with delay of adjuvant therapy beyond three months post-surgery included Charlson scores of one or greater and Hispanic race. After propensity score weighting, there was no survival difference between groups when comparing initiation of adjuvant therapy before or after two, three or four month time points Conclusions: We identified a number of patient characteristics related to the timing of initiating adjuvant therapy in patients with biliary cancers. There were no significant difference in OS associated with delaying adjuvant therapy beyond two, three or four month time-points. Our findings are relevant in the era of COVID-19 when minimizing patient exposure to health-care settings during a pandemic may need to be considered when deciding on the timing of adjuvant therapy. If a delay is necessary, our results suggest that there is no survival detriment to initiating adjuvant therapy beyond three or four months after surgery for biliary cancers.
Early tumor marker decrease to predict the efficacy of combination therapy with lenvatinib plus anti-PD-1 antibodies in unresectable hepatocellular carcinoma (uHCC).
Authors: Sun Hui-Chuan , Zhu Xiao-Dong , Huang Cheng , Shen Ying-Hao , Ge Ning-Ling , Zhu Jin-Jin , Xu Bin , Chen Yi , Li Mei-Ling , Zhou Jian , Fan Jia
Published: January 2021

304

Background: Combination therapy with anti-angiogenic agents plus anti-PD-1 antibodies has shown high anti-tumor activity in uHCC. However, predicting the efficacy of this combination therapy remains a challenge. Methods: This study included consecutive patients with uHCC who received lenvatinib (8 mg/d regardless of body weight) and an anti-PD-1 antibody as first-line systemic therapy between Sep 2018 and July 2020, and had at least one imaging evaluation. Tumor response was assessed every 2 months (± 2 week) by the investigators using modified RECIST criteria. Patients were evaluated as having a radiological response (complete or partial response) or non-radiological response (stable disease or progressive disease) at the best overall response evaluation. Serum tumor markers for HCC, including alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), were evaluated at baseline and 2-3 weeks after therapy was initiated and their association with radiological response were assessed. Patients with baseline AFP or PIVKA-II between the upper limit of normal and the maximum measuring range of the kit were evaluable for AFP decrease or PIVKA-II decrease. Results: A total of 76 patients were eligible for this study. Baseline AFP ≥400 ng/mL or PIVKA-II ≥400 mAU/mL was not associated with radiological response (P = 0.167 and P = 0.916, respectively). At 2-3 weeks after the initiation of therapy, 51 patients were evaluable for AFP decrease; 78.4% experienced a > 20% AFP decrease and 51.0% experienced a > 50% AFP decrease. Patients with a > 50% AFP decrease had a higher rate of radiological response than those with AFP increase or a ≤50% AFP decrease (73.1% vs 32.0%, P = 0.003). In 57 patients evaluable for PIVKA-II decrease, 50.9% and 35.1% experienced a > 20% and > 50% PIVKA-II decrease, respectively. Patients with a > 50% PIVKA-II decrease had a higher rate of radiological response than those with PIVKA-II increase or a ≤50% PIVKA-II decrease (85.0% vs 29.7%, P < 0.001). Both AFP decrease > 50% and PIVKA-II decrease > 50% predicted radiological response, with an area under receiver operating characteristic curve of 0.706 (95% CI, 0.560-0.852, P = 0.012) and 0.752 (95% CI, 0.621-0.883, P = 0.001), respectively. Furthermore, patients with a > 20% AFP or PIVKA-II increase from baseline had a lower rate of radiological response (0% vs 57.4%, P = 0.043; and 21.7% vs 69.7%, P < 0.001, respectively). Conclusions: A tumor marker decrease was seen in most patients as early as 2-3 weeks after the initiation of the combination therapy. Early on-treatment AFP or PIVKA-II decrease may serve as a predictor for objective response for patients with uHCC receiving combination anti-angiogenic and immune therapy.
Low energy amplitude modulated radiofrequency electromagnetic fields to show antitumor effect in combination with standard treatment or as monotherapy in patients with advanced hepatocellular carcinoma.
Authors: Setogute Yone De Camargo , Costa Frederico , Sousa Micelange Carvalho , Lima Pablo Diego , Carvalho Luciana , Santos Elizabeth , Gumz Brenda Pires , Azevedo Fernanda , Sabbaga Jorge , De Castria Tiago Biachi , Fontes Jardim Denis Leonardo , Freitas Daniela , Horvat Natally , Franca Regis , Testagrossa Leonardo , Zanesco Tatiana , Iemma Antonio Francisco , Tuszynski Jack
Published: January 2021

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Background: Exposure to amplitude-modulated radiofrequency electromagnetic fields (EMF) in immortalized hepatocellular carcinoma (HCC) cell cultures and xenograft models demonstrated anti-tumor effect. Patients with advanced HCC exposed to systemic EMF showed objective response with potential survival benefit. Methods: An open-label, single center, prospective clinical protocol was performed in advanced HCC patients as an initial, second or third treatment modality. Systemic exposure to EMF modulated at patient-specific frequencies was applied as an add-on strategy (combination) to systemic conventional treatment or as a single therapeutic modality. A spoon-shaped antenna placed in the oral cavity delivered EMF over 90 minutes with monthly repetitions until death or consent of withdrawal. The primary objective was overall survival (OS) in comparison with historical control group of 45 advanced patients HCC from the same institution. Retrospective radiological review was conducted by two independent radiologists for objective response (OR) using RECIST1.1 criterion. Results: From March 2018 to April 2020, 55 advanced HCC patients were submitted to 373 EMF exposures. 87% were male, median age of 67, 84% were BLCL-C, 16% were Child-Pugh B, 29% had extra-hepatic metastasis, 55% had failed previous treatment and 71% had documented radiological progression. 31(56%) patients received EMF in combination with systemic therapy (25 sorafenib, 3 lenvatinib, 3 nivolumab). 24 patients received EMF as single treatment modality. The median OS for the entire patient cohort was 11.5 months. The median OS for combination treatment was 12.0 month and the median OS for single modality was 11.3 months. The median OS for the historical control was 5.3 month. The median OS from the entire cohort and the historical control were significant different (p = 0.0026) but the median OS from combination and single modality were not (p = 0.3434). Radiological images were available from 38(69%) patients. There were 6/38 (16%) documented objective responses (1 CR and 5 PR) and 30/38 (79%) patients experienced disease control. 4/21 (19%) OR were in patients using TKIs + EMF and 2/17 (12%) OR were in patients using EMF alone. Conclusions: EMF showed objective anti-tumor effect in combination with TKI or as single modality in advanced HCC patients. EMF showed improvement in overall survival in comparison with the historical control group supporting future development as a novel systemic treatment modality in advanced HCC patients. Clinical trial information: NCT 01686412.
Comparative landscape of actionable somatic alterations in advanced cholangiocarcinoma from circulating tumor and tissue-based DNA profiling.
Authors: Kasi Pashtoon Murtaza , Le Alexander D , Barrett Alex
Published: January 2021

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Background: Cholangiocarcinoma (CCA) is a target-rich disease. Despite this, treatment guidelines lack recommendations for broad molecular profiling in CCA to identify potentially actionable targets. Furthermore, comparative data assessing similarities and differences in actionable ctDNA and tissue based genomic biomarkers remain limited. As such, we sought to broadly characterize the genomic alterations that are linked to targeted therapies that may facilitate a more personalized approach to therapy. Methods: We retrospectively analyzed NGS data obtained from 137 advanced cholangiocarcinoma patients via Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations including single nucleotide variants, specific insertion/deletions, amplifications and gene fusions. Results: 110 patients were tested once and 27 patients had two or more tests available. Of the 174 genomic results, 113 were tissue-based NGS results, and 61 were liquid-based NGS results. The total number of unique alterations was found to be 296. Focusing on aberrations for which there are approved therapies in the same or other tumor types or inclusion in guidelines and/or active clinical trials, we found FGFR2 fusions (6.8%), IDH1/2 (8.4%), BRAF-V600E (2.5%), HER2 (3%), MET (0.7%), BRCA1/2/ATM (2%), PIK3CA (4.7%), and ERRFI1 (0.7%). This comprises ~30% (Table). Of note, within this bucket of actionable findings, if we focus on ctDNA liquid biopsy cohort, the proportion goes up to 33.1% vs. 23.2% for tissue based genomic testing. For example, comparison of liquid to tissue, FGFR2 fusion was noted in 11.3% vs. 3.4%, BRAF-V600E in 3% vs. 1% and HER2 0% vs. 3.8%, respectively. Also, no MSI-High patients but two (1.5%) had KRAS-G12C mutation. Notable differences in the prevalence of actionable somatic mutations in solid vs. liquid results were observed (Table). Conclusions: These data provide an updated benchmark for guiding the development of targeted therapies in molecularly profiled CCA and support the use of both solid and liquid biopsy molecular profiling to guide therapy selection in patients with advanced cholangiocarcinoma. Additionally, liquid biopsy molecular profiling can fill the void where tissue may not be readily available. [Table: see text]
Cost of treatment change among patients with neuroendocrine tumors (NET) treated originally with somatostatin analogs.
Authors: Tawfik Bernard , Ray David , Moynihan Meghan , Princic Nicole
Published: January 2021

365

Background: Understanding the economic implications of changes in treatment among patients with NET will be important as treatment sequencing continues to evolve. This study describes treatment characteristics and healthcare costs prior to and following treatment change from somatostatin analog (SSA) monotherapy to another therapy among a privately-insured NET patient population in the U.S. Methods: Patients with newly diagnosed NET and treated with SSA monotherapy were extracted from IBM MarketScan claims databases in 1/1/2014-3/31/2019. NET treatment change was captured ≥30 days after SSA start date (earliest new treatment = index date). Healthcare costs (reimbursed amount in 2019 dollars) were reported for 1, 3, and 6 months pre- and post-index intervals. Results: A total of 1,122 NET patients with SSA monotherapy were identified; 305 had further treatment changes (mean age: 58 years; female: 52%; metastatic disease at NET diagnosis: 49%). The majority of patients started on octreotide (81%) vs lanreotide (19%). Common treatment changes included alternate SSA (38%), targeted therapy (everolimus or sunitinib) (30%) or chemotherapy (23%). Fewer than 10% of patients were treated with PRRT 177Lu-dotatate or telotristat and 1% with a combination. Total healthcare cost increased from $12,376 to $25,647 (mean difference = $13,272 ±$24,189, p<0.001) for 1 month before/after treatment change, from $36,395 to $59,324 ($22,929 ±$41,764, p<0.001) for 3 months before/after, and from $66,786 to $109,224 ($42,438 ±$98,875, p<0.001) for 6 months before/after. Patients changing to targeted therapy had the largest 1 month interval cost increase ($19,677 ±$19,023, p<0.001) compared with patients changing to alternate SSA ($10,240 ±$14,112, p<0.001) and to chemotherapy ($4,057 ±$20,566, p=0.155). The differences were driven by increases in outpatient services and pharmacy prescriptions. Conclusions: The setting of rising costs after treatment change from SSA indicates treatment costs as the key driver, rather than NET disease severity. Future studies should investigate the clinical effectiveness of switching from SSA relative to the economic burden imposed by treatment change.