bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial.
Authors: Hospers Geke , Bahadoer Renu R. , Dijkstra Esmee A. , van Etten Boudewijn , Marijnen Corrie , Putter Hein , Meershoek – Klein Kranenbarg Elma , Roodvoets Annet G. , Nagtegaal Iris D. , Beets-Tan Regina GH , Blomqvist Lennart K. , Fokstuen Tone , ten Tije Albert J. , Capdevila Jaume , Hendriks Mathijs P. , Edhemovic Ibrahim , Cervantes Andres , Nilsson Per J. , Glimelius Bengt , Van De Velde Cornelis J. H.
Published: May 2020

4006

Background: Local control in locally advanced rectal cancer (LARC) has improved. However, systemic relapses remain high even with postoperative chemotherapy, possibly due to low compliance. Short-course radiotherapy (SCRT) followed by delayed surgery with, in the waiting period, chemotherapy, may lead to better compliance, downstaging and fewer distant metastases. The main objective of the international multicenter phase III RAPIDO trial is to decrease Disease-related Treatment Failure (DrTF), defined as locoregional failure, distant metastasis, a new primary colon tumor or treatment-related death, by reducing the risk of systemic relapse without compromising local control. Methods: MRI-diagnosed LARC patients with either cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia or enlarged lateral lymph nodes considered to be metastatic were randomly assigned to SCRT (5x5 Gy) with subsequent six cycles of CAPOX or nine cycles of FOLFOX4 followed by total mesorectal excision (TME) (experimental arm) or, capecitabine-based chemoradiotherapy (25-28 x 2.0-1.8 Gy) followed by TME and optional, predefined by hospital policy, postoperative eight cycles of CAPOX or twelve cycles of FOLFOX4 (standard arm). Results: Between June 2011 and June 2016, 920 patients were randomized. Pathological complete response rates were 27.7% vs 13.8% (OR 2.40 [1.70 – 3.39]; p < 0.001) in the experimental and standard arms, respectively. At three years, cumulative probability of DrTF was 23.7% in the experimental arm and 30.4% in the standard arm (HR 0.76 [0.60 – 0.96]; p = 0.02). Probability at three years of distant metastasis and locoregional failure were, in the experimental and standard arms, 19.8% vs 26.6% (HR 0.69 [0.53 – 0.89]; p = 0.004) and 8.7% vs 6.0% (HR 1.45 [0.93 – 2.25]; p = 0.10), respectively. No differences in DrTF between hospitals with or without policy for postoperative chemotherapy were found (p = 0.37). Overall health ( p = 0.192), quality of life ( p = 0.125) and low anterior resection syndrome score ( p = 0.136) were comparable between the two treatment arms. Conclusions: A lower rate of DrTF, as a result of a lower rate of distant metastases, in high-risk LARC patients can be achieved with preoperative short-course radiotherapy, followed by chemotherapy and TME than by conventional chemoradiotherapy. In addition, the high pCR rate, achieved with the experimental treatment regimen can contribute to organ preservation. This treatment can be considered as a new standard of care. Clinical trial information: NCT01558921 .
Consensus molecular subtypes in colorectal cancer differ by geographic region.
Authors: Korphaisarn Krittiya , Lam Michael , Loree Jonathan M. , Ruiz Erika , Aguiar Samuel , Kopetz Scott
Published: May 2020

4061

Background: The consensus molecular subtypes (CMS) have emerged as a novel classification in colorectal cancer (CRC). However, these subtypes, were mostly derived from a US/European population, and have scant data in other ethnic groups. This study aimed to demonstrate molecular subtypes of CRC across geographic regions. Methods: Formalin fixed paraffin embedded (FFPE) tissue from untreated patients with stage II-III colon cancer from Brazil, Canada, Mexico, Thailand, and the US were evaluated. Gene expression profiling was performed at the University of Texas MD Anderson Cancer Center using NanoString’s nCounter technology and an optimized classifier for FFPE. Results: A total of 366 samples were included in this study, evenly distributed between the 5 international sites. While the US population matched previously reported distributions, the distribution of CMS subtypes varied substantially by region (P < 0.0001). While CMS1 was still associated with right-sided tumors (P < 0.001) and deficient mismatch repair (dMMR) (P < 0.001), the prevalence varied between 8% in Brazil to 30% in Mexico. CMS2 was found vary from 14% in Mexico to 47% in Brazil. The metabolic CMS3 subtype was present in only 3% in Thailand, but as high as 19% in Brazil. CMS4 was confirmed to be associated with higher stage (P = 0.047), and the prevalence was lowest in Brazil (14%) compared to 44% and 49% in US and Mexico, respectively. Expansion of study cohort is ongoing. Conclusions: CMS subtype prevalence differs substantially by geographic region in CRC. These variations suggest that transcriptomic-defined disease biology in international populations may be more heterogeneous than previously appreciated. Further studies in global populations are required to validate and extend these findings, which may have important impact for novel therapeutic development.
Somatic alterations of NF1 in colorectal cancer.
Authors: Arai Hiroyuki , Elliott Andrew , Xiu Joanne , Wang Jingyuan , Battaglin Francesca , Soni Shivani , Zhang Wu , Sohal Davendra , Goldberg Richard M. , Hall Michael J. , Scott Aaron James , Khushman Mohd , Hwang Jimmy J. , Lou Emil , Weinberg Benjamin A. , Marshall John , Lockhart Albert Craig , Shields Anthony Frank , Korn W. Michael , Lenz Heinz-Josef
Published: May 2020

4066

Background: NF1 encodes neurofibromin, which is a key GTPase-activating protein that downregulates RAS activation. Inactivating mutations in NF1 result in sustained activation of RAS signaling, a key driver for development of colorectal cancer (CRC), and have been suggested to be a potential mechanism of resistance to EGFR inhibition in RAS-wild type (WT) CRC. Little is known about molecular characteristics of NF1-mutated (MT) CRC. Methods: Tumor profiles from 8150 CRC patients (pts) with available NF1 mutation status were retrospectively reviewed. NextGen sequencing by a customized 592-gene panel was performed. Microsatellite instability (MSI) / mismatch repair (MMR) status, tumor mutational burden (TMB) and PD-L1 expression were tested. Molecular profiles between NF1-MT and NF1-WT pts were compared. Results: Out of 8150 pts, 176 (2.2%) had somatic NF1 mutations with pathogenic or presumed pathogenic function. A higher NF1-MT frequency was observed in MSI-H/dMMR vs MSS/pMMR (13.5% vs 1.4%, p < 0.0001), in right-sided vs left sided (2.9% vs 1.8%, p < 0.01), and in RAS-WT vs RAS-MT (3.0% vs 1.4%, p < 0.0001). In MSS/pMMR tumors, no association with sidedness was observed (right: 1.3% vs left: 1.2%, NS). The most prevalent co-mutations with NF-1 were APC (63.2%), ARID1A (57.5%), TP53 (51.5%), KMT2D (32.9%) and KRAS (32.4%) in all cases, and APC (76.2%), TP53 (69.5%), KRAS (38.8%), ARID1A (34.4%) and FBXW7 (21.5%) in MSS/pMMR cases. POLE mutation was observed in 18.4% of NF1-MT/MSS/pMMR pts. Compared to NF1-WT pts, NF1-MT pts had more frequent mutations in ARID1A (All: 57.5% vs 23.3%, p < 0.0001; MSS/pMMR: 34.4% vs 15.2%, p < 0.05), and less frequent mutations in KRAS (All: 32.4% vs 49.0%, p < 0.0001; MSS/pMMR: 38.8% vs 50.3%, p < 0.05). Also, NF1-MT pts had more frequent alterations in homologous recombination pathway compared to NF1-WT pts (All: 39.8% vs 7.5%, p < 0.0001; MSS/pMMR: 17.5% vs 4.4%, p < 0.0001). Mean TMB was significantly greater in NF1-MT than NF1-WT (All: 48.9/Mb vs 10.0/Mb, p < 0.0001; MSS/pMMR: 48.3/Mb vs 8.2/Mb, p < 0.0001). Also, PD-L1 positivity was higher in NF1-MT compared to NF1-WT (All: 12.9% vs 3.6%, p < 0.0001; MSS/pMMR: 7.1% vs 2.6%, p < 0.05). Conclusions: While more frequent than in RAS-MT pts, NF1-MT CRC was a small subset in RAS-WT pts. NF1-MT was associated with alterations in chromatin remodeling and DNA damage response pathways, as well as elevated TMB and PD-L1 expression, which may provide alternative therapeutic strategies beyond EGFR inhibition.
Prognostic differences of RAS mutations: Results from South Australian (SA) metastatic colorectal (mCRC) registry.
Authors: Price Timothy Jay , Piantadosi Cynthia , Townsend Amanda Rose , Padbury Rob , Roy Amitesh Chandra , Moore James , Maddern Guy , Roder David , Karapetis Christos Stelios
Published: May 2020

4067

Background: Effective targeting of RAS mutations has proven elusive until recently. AMG 510, a novel agent which targets KRAS G12C mutations (G12C MT), has shown promise in early phase clinical trials that included patients with mCRC. Prior reports have suggested that G12C MT may be predictive of poor outcome. Methods: We aimed to assess the prognostic implications of individual RAS in a population-based registry. The SAmCRCR collects data from all patients diagnosed with mCRC in South Australia prospectively. Individual RAS mutation data from patients entered into the SAmCRCR between February 2006 and December 2018 was reviewed. Survival was analysed for the more frequent mutations using Kaplan Meier method. Results: 1605 (33%) of the 4905 patients entered onto the registry had RAS mutation results available. Of these, 658 (41%) had RAS MT. The nature of the RAS MT was available in 563 (85.7% of those with RAT MT). Patient characteristics, frequency of individual RAS MT and median overall survival (OS) per RAS MT are noted in table. Low frequency MT made up an additional 16.3%. There were numerical differences in survival however there was no statistical difference in survival when comparing the various RAS MT, including the comparison of G12C to G12S (p = 0.38). Conclusions: Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ. [Table: see text]
Utility of circulating tumor DNA (ctDNA) versus tumor tissue genotyping for enrollment of patients with metastatic colorectal cancer (mCRC) to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis.
Authors: Nakamura Yoshiaki , Taniguchi Hiroya , Bando Hideaki , Esaki Taito , Komatsu Yoshito , Kato Ken , Takahashi Naoki , Kagawa Yoshinori , Kato Takeshi , Nishina Tomohiro , Satoh Taroh , Oki Eiji , Sunakawa Yu , Shiozawa Manabu , Yamamoto Yoshiyuki , Kawakami Hisato , Denda Tadamichi , Ohtsu Atsushi , Yoshino Takayuki
Published: May 2020

4071

Background: We recently reported that ctDNA genotyping had advantages compared with tumor tissue testing in terms of enrollment to matched clinical trials across a wide range of GI cancers (Nakamura Y, et al. ASCO-GI 2020). Here, we investigated the utility of ctDNA genotyping in mCRC in a SCRUM-Japan GI-SCREEN and GOZILA combined analysis. Methods: In GI-SCREEN, tumor tissue genotyping was performed using a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In GOZILA, NGS-based ctDNA genotyping was performed using Guardant360 since Feb 2018. All tests were conducted centrally in a CLIA-certified and CAP-accredited laboratory. Patients with actionable alterations were enrolled into matched company-sponsored or investigator-initiated interventional clinical trials. Results: As of Apr 2019, 2,791 mCRC patients (2,754 eligible for analysis) in GI-SCREEN and 470 (464 eligible for analysis) in GOZILA were enrolled. There were no significant differences in baseline patient characteristics between GI-SCREEN and GOZILA. Most of trials affiliated with GI-SCREEN (81%) or GOZILA (78%) targeted the RTK/RAS/RAF pathway. Compared with tumor testing, ctDNA genotyping significantly improved turnaround time (median, 12 vs. 34 days, P < 0.0001), sequencing success rate (96.1 vs. 92.3%, P = 0.002), and detection rate of actionable alterations (73.3 vs. 62.2%, P = 0.02). Among patients with actionable alterations, enrollment to matched clinical trials was achieved in 5.0% in GI-SCREEN and 12.1% in GOZILA ( P < 0.0001). Median time from enrollment in the respective screening study to enrollment in a matched clinical trial was 6.5 months in GI-SCREEN and 0.9 months in GOZILA, respectively ( P < 0.0001). Objective response rate and progression-free survival were similar in both groups (tissue vs. ctDNA; ORR: 18.8 vs. 17.1%, P = 1.00; median PFS: 2.2 vs. 2.2 months, HR=1.05 [95% CI, 0.71–1.55], P = 0.79). Conclusions: For patients with mCRC, ctDNA genotyping had advantages over tissue genotyping with shorter turnaround time and higher sequencing success and actionable alteration detection rate, which were associated with improved clinical trial enrollment without compromising the efficacy. Funding: SCRUM-Japan Funds. Clinical trial information: UMIN000029315 .
Circulating tumor DNA as a promising biomarker of relapse risk for stage II-III colorectal cancer.
Authors: Chen Gong , Wang Feng , Peng Jun-Jie , Cai San-Jun , Ding Ke-Feng , Xiao Qian , Wang Fu-Long , Wu Xiao-Jun , Pan Zhi-Zhong , Ding Pei-Rong , Kong Ling-Heng , Wan De-Sen , Fan Xiaojun , Liu Rui , Bao Hua , Zhang Junli , Pang Jiaohui , Wu Xue , Shao Yang , Xu Rui-hua
Published: May 2020

4079

Background: About 30-50% colorectal cancer patients undergoing a curative resection will experience disease recurrence ultimately. Early detection of recurrence is of great significance for improving the prognosis of colorectal cancer patients. Circulating tumor DNA (ctDNA) has been suggested to be a promising biomarker for postoperative surveillance and prognosis prediction in various cancers including colorectal cancer. However, its performance in predicting early recurrence of colorectal cancer as well as appropriate testing procedures still needs large-scale prospective studies to evaluate. Methods: A total of 246 patients with stage II-III colorectal cancer and underwent curative resection from three clinical centers of China were enrolled in this multicenter prospective cohort study. Tissue samples as well as serial plasma samples before surgery, 7 days and 6 months after surgery and 3 months interval afterwards until recurrence were collected, and subjected to deep targeted-panel sequencing containing 425 cancer-related genes. ctDNA baseline genomic alterations and dynamic changes were analyzed. Its performance in predicting early recurrence was evaluated and compared with other clinical routine investigations, including serum biomarkers CEA and CA199, and CT examination. Results: The ctDNA positive rates at baseline (before surgery) and 7 days after surgery were 72.9% and 18.1% respectively. Among 199 patients with complete survival data, 18 patients were recurrent during follow up period with a median disease-free survival of 280.5 days (114-461 days). At baseline, high clinical stage (p = 0.035), and PTEN mutation (p = 0.009) were significantly associated with increased recurrent risk; while APC mutation (p = 0.04) predicted a decreased recurrent risk. Detection of ctDNA 7 days after surgery [HR: 5.9 (1.94-17.97); p = 0.0004] or any time point before clinical recurrence [HR: 6.14 (2.3-16.38); p < 0.0001] was associated with a significantly higher recurrent risk, and the HR increased accordingly with ctDNA mutation level. In multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathological risk factors. CEA status was not significantly (p > 0.4) associated with disease-free survival. A risk scoring model comprising of clinical variables and ctDNA detection after surgery was constructed and can predict 18-month recurrence with an AUC of 0.77. Conclusions: ctDNA is a promising marker of risk stratification, and early relapse detection in resected stage II/III CRC patients. Clinical trial information: NCT03312374 .
Consensus molecular subtypes (CMS) as a marker for treatment and disease biology in metastatic colorectal cancer (CRC).
Authors: Lam Michael , Kanikarla Marie Preeti , Mehrvarz Sarshekeh Amir , Morris Van K. , Duose Dzifa Yawa , Zhang BaiLi , Chen Huiqin , Morris Jeffrey , Mehta Trupti R. , Katkhuda Riham , Kopetz Scott
Published: May 2020

4089

Background: Consensus molecular subtypes (CMS) categorize colorectal cancer (CRC) into groups based on gene transcription and are prognostic in early-stage and first-line metastatic settings. Their impact on treatment history is unknown. We hypothesized that the best prognosis CMS2 would have higher utilization of liver-directed therapies and maintenance chemotherapy over the worst prognosis CMS4. Methods: Primary surgical resection specimens were annotated for CMS on a translational protocol in a 5FU-refractory metastatic CRC population. Specimens that had neoadjuvant chemotherapy or radiation were excluded. CMS1, CMS3 and indeterminate CMS were also excluded. Liver-directed therapies were defined as any surgery, direct injection of cytotoxics or microspheres, radiation or radiofrequency ablation. Multiple occurrences of liver-directed therapies or maintenance chemotherapy in the same patient were recorded once for statistical tests of association. Results: CMS1 (7.4%), CMS3 (8.2%) and indeterminate calls (4.1%) accounted for 20% of all samples tested. There were 43 (44%) CMS2 and 55 (56%) CMS4 patients eligible. Age, stage at diagnosis, mismatch repair and RAS mutational status were similar in both groups. Left-sided tumors were more common in CMS2 (79%) than CMS4 (42%), p = .001. The median overall survival (OS) from stage IV diagnosis was 40 [34 - 51] versus (vs) 28 [21 – 33] months (p < .0001) for CMS2 vs CMS4 respectively. Liver-directed therapy was greater in CMS2 (53%) vs CMS4 (31%), p = .024. The number further increased when multiple treatments in a single patient were taken into account. Microsphere injection, radiation and liver surgery combined with RFA were the most skewed towards CMS2 over CMS4. No difference in median OS was seen from first liver-directed therapy in CMS2 vs CMS4 (29 vs 27 months, p = .31). There was a trend towards greater maintenance chemotherapy in CMS2 (47%) vs CMS4 (29%), p = .076. Conclusions: Better prognosis with CMS2 is consistent with other studies. Significantly increased liver-directed therapy was observed in CMS2. Selection criteria for liver-directed therapy such as slowly progressing, oligometastatic and hepatic-confined disease may be enriching for CMS2 and gives insight into the natural history of this subtype.
Can FIT rule out colorectal cancer in symptomatic patients? Diagnostic test accuracy results from 9,822 patients in the NICE FIT study.
Authors: Georgiou Delisle Theo , D'Souza Nigel , Chen Michelle , Benton Sally , Abulafi Muti ,   NICE FIT Steering Group
Published: May 2020

4093

Background: The faecal immunochemical test (FIT) is a non-invasive quantitative test that measures occult blood in faeces (faecal haemoglobin, FHb). FIT is already used worldwide in colorectal cancer (CRC) screening programmes. Bowel symptoms have low specificity for CRC; to diagnose one patient with CRC, a large number of symptomatic patients require investigation. A negative FIT test, when blood is not detected, could be used to rule out CRC in symptomatic patients without invasive investigations such as colonoscopy. We report on the largest diagnostic accuracy study to date of FIT in symptomatic patients. Methods: Patients were eligible for recruitment if they experienced bowel symptoms meeting national high-risk criteria and were triaged to investigation with colonoscopy. Patients were excluded from analysis if they did not provide a valid FIT or did not undergo complete colonoscopy. Colonoscopy results were compared to FIT measurements of FHb, and the conduct of the tests was double-blinded. Quality assurance of endoscopy and clinical data was performed by senior clinicians. External statisticians analysed anonymised data. Results: 9822 patients from 50 sites across England participated in the study between October 2017 to March 2019. The most common colonoscopy finding was absence of any colorectal disease (31%). The prevalence of CRC at colonoscopy was 3.3%. The sensitivity of FIT at FHb thresholds of 2, 10 and 150 μg/g significantly decreased from 97.0% to 90.9% and 70.8% respectively (p < 0.01). FIT positivity rate at these thresholds increased from 7.6%, to 19% and 37.2% respectively (p < 0.01). The positive predictive value of FIT for CRC at FHb thresholds of 2, 10 and 150 μg/g was 8.7%, 16.1% and 31.1% respectively and the negative predictive value of FIT at these thresholds was 99.8%, 99.6% and 98.9% respectively. Conclusions: The results of this study support the use of FIT at the threshold of detectable blood (2μg/g) as an initial CRC rule-out test to triage patients with high risk CRC symptoms, reducing the number of unnecessary investigations. This is the first study to report that at the lowest threshold of detectable blood, FIT sensitivity is equivalent to the current gold standard investigation of colonoscopy. Clinical trial information: ISRCTN49676259 .
A population-based study of young-onset colorectal cancer patients: Effect of knowledge gaps among patients and providers on stage at diagnosis and quality of life.
Authors: Yarden Ronit , Newcomer Kim Lynn , Peterson Danielle ,   N2Young Advisory Board
Published: May 2020

4095

Background: Colorectal cancer (CRC) is one of the leading cause of cancer-related death in the US. Despite a decrease in overall incidence and mortality, there has been an alarming increase in CRC diagnosis among young adults (20-49 years old) and causes remain unknown. To explore the unique challenges and unmet needs of the young-adult patients many still establishing their life-long goals, the Colorectal Cancer Alliance launched a comprehensive survey for young-onset CRC patients and survivors via social media to track the self-reported pre-diagnosis awareness, path to diagnosis, and post-diagnosis quality of life experiences of this often overlooked group. Methods: A cross-sectional study, conducted in the form of an online survey, was launched via multiple channels of social media. The questionnaire was based on established instruments including PROMIS, EORTC-QOL-30, and EORTC-CR-29 and EORTC-SHC-22. Results: The survey was completed by 885 patients and survivors. The median age at diagnosis was 42 +/-7, significantly lower than the recommended screening age. Only 6% of respondents were diagnosed with Lynch syndrome although 29% reported some family history. Most respondents (63%) indicated they were not aware that CRC can affect people younger than 50, which may explain why the majority of patients waited more than 3 months and 23% waited over 12 months after noticing their symptoms to visit their doctor. The majority, 75%, of all patients visited 2+ doctors and 11% of those patients visited 10+ doctors before their doctor suspected colorectal cancer. A significant number of patients felt their doctors were dismissive of their symptoms. 77% of patients were diagnosed with advanced disease and were subjected to aggressive therapies that substantially affected their quality of life including neuropathy, anxiety, clinical depression, sexual morbidity, unemployment, and financial toxicity. Many young patients indicated that their doctors did not inform them about fertility preservation. Conclusions: Our survey indicates that medical professionals and young adults need to be aware of the increasing incidence of young-onset CRC, and the importance of timely screening when signs and symptoms are present, regardless of age.
Trastuzumab with trimodality treatment for esophageal adenocarcinoma with HER2 overexpression: NRG Oncology/RTOG 1010.
Authors: Safran Howard , Winter Kathryn A. , Wigle Dennis A. , DiPetrillo Thomas A. , Haddock Michael G. , Hong Theodore S. , Leichman Lawrence P. , Rajdev Lakshmi , Resnick Murray B. , Kachnic Lisa A. , Seaward Samantha A. , Mamon Harvey J. , Diaz Pardo Dayssy Alexandra , Anderson Carryn M. , Shen Xinglei , Sharma Anand K. , Katz Alan W. , Salo Jonathan C. , Leonard Kara Lynne , Crane Christopher H.
Published: May 2020

4500

Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). The primary objective of RTOG 1010 was to determine if trastuzumab increases disease-free survival (DFS) when combined with trimodality treatment for patients with HER2 overexpressing esophageal adenocarcinoma. Methods: This open label, randomized phase III trial included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5cm of the stomach. All patients received chemotherapy (C) of paclitaxel, 50mg/m2 and carboplatin AUC = 2, weekly for 6 weeks, with radiation (XRT: 3D-CRT or IMRT, 50.4 Gy in 28 fractions) followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab 4mg/kg week 1 then 2mg/kg/weekly x 5 during CXRT then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery. HER2 status was determined by IHC and gene amplification by FISH. With a 2-sided alpha of 0.05, 162 DFS events provide 90% power to detect a signal for an increase in median DFS from 15 to 25 months. DFS and overall survival (OS) were estimated by the Kaplan-Meier method. and arms were compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 571 patients were entered for assessment of HER2 expression, 203 HER2+ patients randomized. The median follow-up for alive patients is 5.0 years. The estimated 2, 3, and 4-year DFS (95% CI) for the CXRT +trastuzumab arm were 41.8% (31.8%, 51.7%), 34.3% (24.7%, 43.9%), and 33.1% (23.6%, 42.7%), respectively, and for the CXRT arm were 40.0% (30.0%, 49.9%), 33.4% (23.8%, 43.0%), and 30.1% (20.7%, 39.4%), respectively; log-rank p = 0.85. The median DFS time is 19.6 months (13.5-26.2) for the CXRT +trastuzumab arm compared to 14.2 months (10.5-23.0) for the CXRT arm. The hazard ratio (95% CI) comparing the DFS of CXRT+trastuzumab arm to the CXRT arm was 0.97 (0.69, 1.36). The median OS time was 38.5 months (26.2-70.4) for the CXRT+trastuzumab arm compared to 38.9 months (29.0-64.5) for the CXRT arm, hazard ratio (95% CI): 1.01 (0.69, 1.47). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab including no increase in cardiac events. Conclusions: The addition of trastuzumab to trimodality treatment did not improve DFS for patients with HER2 overexpressing esophageal adenocarcinoma. Supported by NCI grants U10CA180868, UG1CA189867, U10CA180822 and Genentech. Clinical trial information: NCT01196390 .
Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2-positive resectable esophagogastric adenocarcinoma: Final results of the PETRARCA multicenter randomized phase II trial of the AIO.
Authors: Hofheinz Ralf Dieter , Haag Georg Martin , Ettrich Thomas Jens , Borchert Kersten , Kretzschmar Albrecht , Teschendorf Christian , Siegler Gabriele Margareta , Ebert Matthias Philip , Goekkurt Eray , Welslau Manfred , Mahlberg Rolf , Homann Nils , Pink Daniel , Bechstein Wolf Otto , Reichardt Peter , Gaiser Timo , Sookthai Disorn , Pauligk Claudia , Goetze Thorsten Oliver , Al-Batran Salah-Eddin
Published: May 2020

4502

Background: Perioperative FLOT is a standard of care for resectable, esophagogastric adenocarcinoma (EGA). This trial evaluates the addition of trastuzumab (tras) and pertuzumab (per) to FLOT for HER2-positive resectable patients (pts). Methods: PETRARCA is a prospective, multicenter, randomized, investigator initiated trial planned as a phase II/III investigation. We report the phase II part of this trial. Pts with HER2+ resectable EGA (≥ cT2 or cN+) were enrolled. Pts were randomized 1:1 to 4 pre- and post-operative cycles of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) (Arm A) or the same regimen with tras 8/6 mg/kg and per 840 mg q3w, followed by 9 cycles tras/per (arm B). Primary endpoint for the phase II part was the rate of pathological complete remission (pCR). Main secondary endpoints were DFS, OS and safety. Results: The trial closed prematurely and did not proceed to phase III. In total, 81 pts were randomized (A, 41; B, 40). Baseline characteristics were balanced (overall, male 79%; median age 60; cT3/T4 86%; cN+ 85%; GEJ 75%). 93% in arm A and 90% in arm B completed pre-OP treatment as planned. More pts had at least one dose modification in arm B (A, 44%; B, 70%). The pCR rate was significantly improved with tras/per (A, 12%; B, 35%; p = 0.02). Likewise, the rate of pathological lymph node negativity was higher with tras/per (A, 39%; B, 68%). R0-resection rate (A, 90%; B, 93%) and surgical morbidity (A: 43%; B, 44%) were comparable. Moreover, in-house mortality was equal in both arms (overall 2.5%). Median DFS was 26 months in arm A and not yet reached in arm B (HR 0.58, p = 0.14). After a median follow-up of 22 months median OS was not yet reached. DFS and OS rates [with 95% CI] at 24 months were 54% [38-71%] and 77% [63-90%] in arm A and 70% [55-85%] and 84% [72-96%] in arm B, respectively. In terms of toxicity more ≥ grade 3 adverse events were reported with tras/per (75% vs. 85%), especially diarrhea (5% vs. 41%) and leukopenia (13% vs 23%). Conclusions: The addition of tras/per to perioperative FLOT significantly improved pCR and nodal negativity rates in pts with Her2+ resectable esophagogastric adenocarcinoma at the price of higher rates of diarrhea and leukopenia. Clinical trial information: NCT02581462 .
Pembrolizumab versus paclitaxel for previously treated patients with PD-L1–positive advanced gastric or gastroesophageal junction cancer (GC): Update from the phase III KEYNOTE-061 trial.
Authors: Fuchs Charles S. , Özgüroğlu Mustafa , Bang Yung-Jue , Di Bartolomeo Maria , Mandalà Mario , Ryu Min-hee , Fornaro Lorenzo , Olesinski Tomasz , Caglevic Christian , Chung Hyun Cheol , Muro Kei , Van Cutsem Eric , Elme Anneli , Thuss-Patience Peter C. , Chau Ian , Ohtsu Atsushi , Bhagia Pooja , Wang Anran , Shih Chie-Schin , Shitara Kohei
Published: May 2020

4503

Background: KEYNOTE-061 ( NCT02370498) is a global phase 3 study of pembrolizumab vs paclitaxel as second-line therapy for GC. At the time of primary analysis (data cutoff: Oct 26, 2017), in patients with PD-L1–positive status (combined positive score [CPS] ≥1), pembrolizumab did not significantly prolong overall survival (OS) vs paclitaxel (9.1 months vs 8.3 months) but did elicit a longer duration of response (DOR) and a favorable safety profile vs paclitaxel. We present results of KEYNOTE-061 in patients with CPS ≥1, ≥5, and ≥10 after 2 additional years of follow-up (cutoff: Oct 7, 2019). Methods: Adult patients with GC that progressed after platinum + fluoropyrimidine chemotherapy were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for up to 35 cycles (~2 y) or standard-dose paclitaxel. OS and progression-free survival (PFS) in the CPS ≥1 population were the primary end points. Comparisons were made using stratified log-rank tests. Results: At the time of this analysis, 366/395 patients with CPS ≥1 had died (92.6%). Pembrolizumab prolonged OS vs paclitaxel in PD-L1–positive patients (Table). No significant differences appeared between groups in PFS (Table). Objective response rate (ORR) was higher for pembrolizumab in the CPS ≥10 group, and DOR was longer with pembrolizumab using all CPS cutoffs (Table). There were fewer drug-related adverse events (AEs) with pembrolizumab than paclitaxel in the overall population (53% vs 84%). Conclusions: This long-term analysis found that second-line pembrolizumab prolonged OS among patients with PD-L1–positive GC and led to fewer drug-related AEs vs paclitaxel. Clinical trial information: NCT02370498 . [Table: see text]
Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: Kelley Robin Kate , Sangro Bruno , Harris William Proctor , Ikeda Masafumi , Okusaka Takuji , Kang Yoon-Koo , Qin Shukui , Tai Wai Meng David , Lim Ho Yeong , Yau Thomas , Yong Wei-Peng , Cheng Ann-Lii , Gasbarrini Antonio , De Braud Filippo G. , Bruix Jordi , Borad Mitesh J. , He Philip , Negro Alejandra , Kudo Masatoshi , Abou-Alfa Ghassan K.
Published: May 2020

4508

Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]
Sintilimab in patients with advanced esophageal squamous cell carcinoma refractory to previous chemotherapy: A randomized, open-label phase II trial (ORIENT-2).
Authors: Xu Jianming , Li Yi , Fan Qingxia , Shu Yongqian , Wu Zhijun , Cui Tongjian , Gu Kangsheng , Tao Min , Wang Xiuwen , Cui Chengxu , Xu Nong , Xiao Juxiang , Gao Quanli , Liu Yunpeng , Zhang Tao , Zhou Hui , Wang Yan , Xu Linxinyu , Ma Zhuo , Wang Yanqi
Published: May 2020

4511

Background: Patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line chemotherapy have limited treatment options. The study aims to evaluate the efficacy and safety of sintilimab, a PD-1 inhibitor, versus chemotherapy in these pts, and explore predictive value of PD-L1 and neutrophil-to-lymphocyte ratio (NLR) on efficacy of sintilimab. Methods: The open-label, multi-center phase 2 trial (NCT03116152) enrolled advanced ESCC pts refractory to first-line chemotherapy, and randomly assigned (1:1) them to receive sintilimab (200mg, Q3W) or chemotherapy (paclitaxel, 175mg/m2, Q3W; or irinotecan, 180mg/m2, Q2W), intravenously. The primary endpoint was overall survival (OS). Explorative endpoint were effects of PD-L1 and NLR on efficacy of sintilimab. Results: From May 16, 2017 to Aug 30, 2018, 190 pts were randomly assigned to sintilimab or chemotherapy (n = 95 per group). With the median follow-up of 7.2 months for sintilimab group and 6.2 months for chemotherapy group, the median OS in sintilimab was significantly higher than chemotherapy (7.2m vs. 6.2m, hazard ratio [HR] 0.70, P = 0.034). The objective response rate (ORR) was greater in sintilimab than chemotherapy with 12.6% vs. 6.3%, and the median duration of response was longer (8.3m vs. 6.2m). Incidences of treatment-related adverse events (TRAEs) of any grade (54.3% vs. 90.8%) and of grade 3-5 (20.2% vs. 39.1%) were both numerically less in sintilimab than in chemotherapy. The ORR in sintilimab versus chemotherapy in pts with tumor PD-L1 tumor proportion score (TPS) ≥1% and with TPS ≥10% were 20.2% vs. 0%, and 35.7% vs. 0%, respectively. In sintilimab group, pts with low NLR ( < 3) had a significant longer median OS (HR 0.54, P = 0.019) than with high NLR. Conclusions: Sintilimab was superior to chemotherapy with a significantly prolonged survival benefit and a favorable safety profile in pts with advanced ESCC refractory to first-line chemotherapy. High tumor PD-L1 expression (TPS ≥1% or ≥10%) might indicate more response benefit to sintilimab for these pts, and low NLR might be a positive predictive factor for sintilimab. Clinical trial information: NCT03116152 .
Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC).
Authors: Oh Do-Youn , Lee Kyung-Hun , Lee Dae-Won , Kim Tae Yong , Bang Ju-Hee , Nam Ah-Rong , Lee Young , Zhang Qu , Rebelatto Marlon , Li Weimin , Kim Jin Won
Published: May 2020

4520

Background: In aBTC, GemCis is the standard of care as 1st-line treatment. Immunotherapies have shown early promising efficacy in some BTC patients (pts). We assessed D (anti-PD-L1) ± T (anti-CTLA-4) and GemCis in 1L BTC pts, including an extensive biomarker analysis (NCT03046862). Methods: Pts were first enrolled in the biomarker cohort (BMC) to receive 1 cycle of Gem 1000 mg/m2 + Cis 25 mg/m2 on D1 & D8, followed by GemCis + D 1120 mg and T 75 mg, Q3W until disease progression (PD). Subsequent pts were allocated to GemCis + D (3 combo cohort [3C]) or GemCis + D+T (4 combo cohort [4C]) until PD. In all cohorts, tumor biopsies were obtained pre-treatment, after 1 cycle, and at PD. Blood samples for ctDNA were obtained every cycle. Results: 121 pts were enrolled. Median follow-up durations were 28.5 months (m; 95% CI, 26.5-30.5), 11.3 m (95% CI, 9.1-13.5), and 11.9m (95% CI, 8.4-15.4) in the BMC, 3C, and 4C arms, respectively. Efficacy data are shown (Table). The most common adverse events (AEs, any grade) were neutropenia (54.5%), nausea (59.5%), and pruritus (55.44%). The most common grade 3/4 AEs were neutropenia (50.4%), anemia (35.5%), and thrombocytopenia (16.5%). In the BMC cohort, frequent mutations were found in DNA damage repair, cell cycle regulation, and genome instability genes (eg, ATM, BRCA2, POLE, MSH2, CDKN2A). Distinct somatic variants were detected in responders vs non-responders. Baseline tissue TMB did not correlate with PFS or OS. Reductions in ctDNA variant allele frequency (VAF) were more prominent among responders during early D+T cycles. ctDNA VAF on C3, D1 was significantly correlated with ORR ( P< 0.015). Pretreatment PD-L1 expression was not associated with efficacy, but PD-L1 expression after 1st GemCis cycle trended with improved PFS. Conclusions: These are the first clinical data of D±T plus chemotherapy in chemo-naïve aBTC pts. The addition of immunotherapy to chemotherapy was tolerable and showed very promising efficacy. Biomarker analyses show early signs of markers associated with response. The combination of GemCis + D is being investigated in the Phase 3 TOPAZ-1 trial (NCT03875235). Clinical trial information: NCT03046862 . [Table: see text]
Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomized controlled trials.
Authors: Ronellenfitsch Ulrich , Jensen Katrin , Seide Svenja , Kieser Meinhard , Schwarzbach Matthias , Slanger Tracy E , Burmeister Bryan , Kelsen David Paul , Niedzwiecki Donna , Piessen Guillaume , Schumacher Christoph , Urba Susan , Van De Velde Cornelis J. H. , Ychou Marc , Hofheinz Ralf Dieter , Lorenzen Sylvie
Published: May 2020

4533

Background: Disease-free survival (DFS) is an appealing surrogate endpoint for overall survival (OS) in trials on neoadjuvant or adjuvant cancer therapy, because it is available faster and with less follow-up effort. The aim of this study was to assess if DFS can be a valid surrogate endpoint for OS when comparing neoadjuvant treatment followed by surgery to surgery alone for gastroesophageal adenocarcinoma. Methods: Individual patient data (IPD) from eight randomized controlled trials (n = 1,126 patients) which compared neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma were used for the analysis. Correlation between OS-time and DFS-time was calculated. Kaplan-Meier survival curves and corresponding hazard ratios (HRs) for treatment effects were separately determined for each trial. Subsequently, HRs were pooled in a meta-analysis using a random-effects model. An error-in-variables linear regression model was used to compare observed and predicted values. The minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS was estimated by calculating the surrogate threshold effect. Results: OS-time correlated strongly with DFS-time. HRs for OS and DFS were highly similar for all single trials. The meta-analysis yielded almost identical overall HRs for treatment effects on OS and DFS. The determination coefficient for the association between HRs for OS and DFS was 0.912 (95% confidence interval 0.75-1.0), indicating a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect was calculated at 0.79, indicating that a future trial yielding a hazard ratio for the treatment effect on DFS < 0.79 could be expected with a 95% probability to yield a hazard ratio for the treatment effect on OS < 1. Conclusions: DFS and OS strongly correlate both after neoadjuvant therapy followed by surgery and after surgery alone for gastroesophageal adenocarcinoma. Likewise, the treatment effects on the two endpoints are very similar. Consequently, DFS can be regarded an appropriate surrogate endpoint for OS in trials on neoadjuvant therapy for gastroesophageal adenocarcinoma.
Camrelizumab combined with FOLFOX as neoadjuvant therapy for resectable locally advanced gastric and gastroesophageal junction adenocarcinoma.
Authors: Liu Ying , Han Guangsen , Li Hongle , Zhao Yuzhou , Zhuang Jing , Wang Gangcheng , Li Baodong , Wang Jinbang , Li Zhimeng , Xia Qingxin , Ma Jie , Zhang Chengjuan , Yu Juan , Li Ke , Xu Shuning , Qiao Lei , Kuang Gaizhen , Li Danyang
Published: May 2020

4536

Background: Neoadjuvant chemotherapy has been demonstrated to improve the pathological complete response(pCR) and 5-year survival rate of patients with locally advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). Immunotherapy has become a new promising treatment for advanced GC/GEJC. Therefore, we intended to evaluate the safety and efficacy of Camrelizumab (anti-PD-1 antibody) combined with FOLFOX as the neoadjuvant therapy for patients with locally advanced GC/GEJC. Methods: Eligiblepatients were locally advanced GC/GEJC with clinical stage≥T2 and/or positive lymphoglandula confirmed by endoscopic ultrasonography (EUS) and imaging. They received 4 cycles neoadjuvant therapy which including Camrelizumab(200mg ivgtt D1), FOLFOX(Oxaliplatin 85mg/m2 ivgtt D1, 5-Fu 400mg/m2 iv D1, LV 200mg/m2 ivgtt D1, 5-Fu 2.4mg/m2 CIV 46 hours) every 14 days. Imaging evaluation was performed in 2-4 weeks after neoadjuvant therapy. Patients without progression disease (PD) received D2 radical gastrectomy. The primary endpoint was pCR, the secondary endpoints were R0 resection rate and safety. Results: From July 24 2019 to January 31 2020, 16 patients were eligible. The median age was 57 years (29-72 years). A total of 11(69%) males and 5(31%) females, ECOG PS 0 (n=9, 56%), ECOG PS 1 (n=7, 44%). All the patients completed 4 cycles treatment and none of them was confirmed PD by image. One of the patients refused gastrectomy and withdraw from the study. The other 15 patients underwent operation. Unfortunately, intraperitoneal metastases were confirmed in 2 patients during operation. 13 patients received D2 radical gastrectomy and all of them experienced R0 resection. Among the 13 evaluable patients, 1 patient (8%) was observed pCR, 3 patients (23%) experienced TRG1, 10 patients (77%) achieved stage reduction. Notably, 8 patients (62%) had lymphonodus pCR. The grade 3-4 treatment-related AEs were neutropenia (n=3, 19%), leukopenia (n=2, 13%) and anorexia (n=1, 6%). No serious AEs resulted in termination of treatment. Either severe immune-related AEs or treatment-related death was not observed. Conclusions: Camrelizumab combined with FOLFOX as neoadjuvant regimen in patients with locally advanced GC/GEJC showed promising pCR with good tolerance. Clinical trial information: NCT03939962 . [Table: see text]
Enhanced efficacy of anti-VEGFR2/taxane therapy after progression on immune checkpoint inhibition (ICI) in patients (pts) with metastatic gastroesophageal adenocarcinoma (mGEA).
Authors: Kankeu Fonkoua Lionel Aurelien , Chakrabarti Sakti , Sonbol Mohamad Bassam , Kasi Pashtoon Murtaza , Starr Jason Scott , Liu Alex John , Bois Melanie C. , Pitot Henry C. , Chandrasekharan Chandrikha , Ross Helen J. , Wu Tsung-Teh , Graham Rondell P. , Markovic Svetomir , Dong Haidong , Yoon Harry H.
Published: May 2020

4541

Background: Anti-VEGFR2 therapy (ramucirumab/paclitaxel [RAM/TAX]) and ICI are approved as 2nd- and 3rd-line therapy (Tx), respectively, for pts with mGEA. We unexpectedly saw durable responses in 2 pts on RAM/TAX after progression on an ICI trial (KN-059; PMID 29674442). We performed a pilot to examine the clinical activity of ICI followed by RAM/TAX. Then we retrospectively compared the outcomes of pts who received this serial Tx to pts who received RAM/TAX without prior ICI. Methods: All pts with mGEA at Mayo Clinic who received RAM/TAX (2014-19) were included (N = 87). Outcomes were best objective response rate (ORR: complete [CR] or partial response) per RECIST1.1, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Chi square and multivariate (MV) logistic and Cox regression were used. Results: 15 consecutive pts with measurable mGEA received ICI immediately followed by RAM/TAX after irRECIST progression. Most pts (95%) did not respond to ICI. Yet on RAM/TAX, 100% (15/15) had tumor reduction (range -8% to -100%) with an ORR of 73% (11/15), including 3 CRs. In these pts (who received ICI followed by RAMTAX), PFS on RAMTAX was longer than on last chemotherapy before ICI (12.3 vs 3.0 m, P < .001). Outcomes on RAM/TAX in these pts were significantly better than in pts who received RAM/TAX alone (see Table). Associations were strengthened after adjusting for total lines of Tx, line of Tx of RAM/TAX, age, and ECOG PS. Exploratory analysis of paired tumor biopsies collected pre-ICI and on RAM/TAX in a small subset revealed that the frequency of intratumoral immunosuppressive FOXP3+ Tregs decreased on RAM/TAX, whereas the frequency of antitumor CD8+ T cells was preserved. Conclusions: RAM/TAX immediately preceded by ICI was associated with significantly higher OS, ORR, and DOR than RAM/TAX alone, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This novel sequence of therapy will be tested prospectively in a new randomized phase 2 trial (NCT04069273). [Table: see text]