tbuckley/cabot-search huggingface dataset:
Mechanisms of primary resistance to icotinib in Chinese non-small-cell lung cancer patients with EGFR uncommon mutations: A multicenter study.
Authors: Wen xian Wang, Chunwei Xu, You-cai Zhu, Quxia Zhang, Yu Chen, Yong Fang, Hong Wang, Wu Zhuang, Yun-jian Huang, Meiyu Fang, Yinbin Zhang, Liping Wang, Huibao Zhang, Ying Zhou, Yu Zheng, Xugang Hu, Weiping Jiang, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2019)

e20501 Background: Previous case series, retrospective studies and pooled survey studies have investigated the clinical efficacies of EGFR-TKIs in patients harboring EGFR uncommon mutations. However, part of patients with EGFR uncommon mutations do not exhibit objective responses to EGFR TKIs (primary resistance). The mechanism of primary resistance to icotinib in EGFR uncommon mutations NSCLC has not been clearly understood. Methods: We screened 3279 patients with NSCLC for EGFR uncommon mutations. Among them, 106 patients received icotinib treatment, and a total of 69 patients with stage IIIb-IV EGFR uncommon mutations NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted NGS to detect genes status of patients. Results: Among 69 patients treated with icotinib, 69.57% (48/69) developed acquired resistance, and 30.43% (21/69) had primary resistance. Using the specimens at the baseline, there were 6(28.57%) patients with EGFR extracellular domain mutation, 5(23.81%) patients with BCL2L11 loss (BIM deletion polymorphism), 3(14.29%) patients with MET amplification, 1(4.76%) patient with ERBB2 amplification, 1(4.76%) patient with MYC amplification, 1(4.76%) patient with PTEN mutation, 1(4.76%) patient with PIK3CA mutation, and 3 (14.29%) patients with unknown status. Conclusions: EGFR extracellular domain mutation, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN, PIK3CA mutations), MET amplification, ERBB2 amplification or MYC amplification might contribute to molecular mechanisms of primary resistance to icotinib in EGFR uncommon mutations NSCLC. The complexity and heterogeneity of EGFR uncommon mutations NSCLC that may confer primary resistance to icotinib using NGS platform.
PET-directed combined modality therapy for gastroesophageal junction cancer: First results of the prospective MEMORI trial.
Authors: Sylvie Lorenzen, Michael Quante, Isabel Rauscher, Julia Slotta-Huspenina, Karl Friedrich Becker, Wilko Weichert, Marcus Feith, Helmut Friess, Stephanie E Combs, Wolfgang Weber, Bernhard Haller, Martin K Angele, Markus Albertsmeier, Christiane Blankenstein, Stefan Kasper, Jens Peter Zimmermann, Hana Algül, Roland M. Schmid, Markus Schwaiger, Jens T Siveke
Journal: Journal of Clinical Oncology (2019)

4018 Background: We evaluated a PET-guided treatment stratification for improvement in obtaining negative surgical margins (R0) in resectable gastroesophageal junction (GEJ) adenocarcinoma. According to sequential 18 F-FDG PET, only 40–50% of patients (pts) respond to neoadjuvant chemotherapy (CTX). Early PET non-responders (P-NR) after induction CTX might benefit from changing to chemoradiation (CRT). Methods: 75 pts with resectable GEJ adenocarcinomas were enrolled in this interventional, prospective, non-randomized multicenter trial. Pts underwent baseline 18 F-FDG PET scan followed by 1 cycle of CTX (physicians’ choice, e.g. EOX, XP, mFOLFOX6). PET was repeated at day 14-21 and responders (P-R), defined as ≥ 35% decrease in SUVmax from baseline, continued with CTX. P-NR switched to CRT (41.4 Gy/23 fractions with weekly carboplatin/paclitaxel). Pts underwent surgery 4-6 weeks post-CTX/CRT. Primary objective was an improvement of R0 resection rates in P-NR above a proportion of 70% based on results from the MUNICON1/2 trials. Secondary endpoints include disease-free survival (DFS), overall survival (OS), measured from randomization to death from any cause, and translational endpoints. Results: Between 12/2014 and 07/ 2018 160 pts with resectable GEJ adenocarcinomas were prospectively screened with PET in three German university centers. Overall, 85 pts (53%) could not be included due to previously undetectable metastases (40/25%), no or too low FDG uptake of the primary tumor (21/13%), other reasons (24/15%). 75 eligible pts were enrolled in the study and 69 were evaluable. Based on PET criteria, 47 (68%) and 22 (32%) were P-R and P-NR, respectively. R0 resection rates were 94% (44/47) for P-R and 91% (20/22) for P-NR. Pathologic complete remission (pCR; &lt; 10% vital tumor cells), was 33% (15/46) in P-R and 55% (12/22) in P-NR. With a median follow-up time of 19 months (mo), estimated 18 mo DFS was 71%/61% for P-R/P-NR, respectively. Observed median 18 mo OS was 95% for P-R and 75% for P-NR. Conclusions: Alternative CRT for GEJ adenocarcinoma improved R0- and pCR rates among pts who were P-NR after induction CTX. PET response was prognostic for a prolonged OS and DFS. Clinical trial information: 2014-000860-16.
Immune checkpoint inhibitors (ICI): An analysis of FDA’s and EMA’s decision patterns and times for initial approvals and extensions of indication.
Authors: Christine Mayer-Nicolai, Elmar Schmitt, Markus Hartmann, Philippe Serrano
Journal: Journal of Clinical Oncology (2019)

e14062 Background: In certain clinical settings ICI have demonstrated unprecedented patterns of efficacy, resulting since 2011 in regulatory approvals worldwide in a variety of cancer indications. As immuno-oncology (IO) drugs constitute today an intense area of oncology drug development, we sought to analyze and compare the regulatory approval decisions for ICI, issued until end of 2018 by the US FDA and the European Medicines Agency (EMA). Methods: We reviewed the biological license applications (BLA) of the 7 (EU: 6) ICI, for which marketing approval decisions for were granted so far. Together with parallel and extension of indication applications, 43 (FDA) respectively 23 (EMA) approval procedures were finalized between March 2011 and December 2018. We analyzed agency decision outcomes and timeline patterns; approval decisions issued for novel non-IO cancer drugs served as benchmarks. The primary variable for analysis was median approval time (MAT). Results: MAT for initial BLA applications for ICI in the USA were with 189 days [Interquartile range (IQR) 154-209] shorter than MAT for BLA and NDA approvals for non-IO drugs: for the 51 novel oncology drugs approved 2011-2018 by the FDA, MAT was 227 days [IQR 159-303]. With 181 days [IQR 155-184], FDA’s MAT for ICI line extensions did not differ from MAT for initial ICI approvals. For the EU, MAT for initial ICI marketing applications were with 373 days (IQR 326-413) also shorter than MAT for the 51 non-IO drugs approved 2011-18 (422 days [IQR 368-450]); for ICI line extensions, MAT was 254 days [IQR 187-293). Conclusions: For ICI as for novel non-IO cancer drugs, initial regulatory approvals are usually issued in the USA first. Regulatory approval times for initial approvals are shorter in the USA, compared to Europe, the same applies for ICI extensions of indication. FDA’s extensive granting of breakthrough therapy designations (BTD) helped to bring US MAT for initial ICI BLA down to 6 months – i.e. to the same time, FDA requires for its priority review of extensions of indication. For some ICI extensions of indication, the granting of BTD supported approval decisions within 3 months, supporting patients’ rapid access to novel therapies.
Association Between High Discharge Rates of Vulnerable Patients and Skilled Nursing Facility Copayments
Authors: Paula Chatterjee, Mingyu Qi, Norma B. Coe, R. Tamara Konetzka, Rachel M. Werner
Journal: JAMA Internal Medicine (2019)

This study uses data from the Centers for Medicare and Medicaid Services to investigate the association between Medicare copayment policies and discharge rates of vulnerable patients from skilled nursing facilities.
Hyperprogressive disease (HPD) in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI).
Authors: Salvatore Alfieri, Roberto Ferrara, Giuseppina Calareso, Stefano Cavalieri, Francesca Platini, Moela Mancinelli, Carlo Resteghini, Ester Orlandi, Nicola Alessandro Iacovelli, Letizia Ferella, Cesare Piazza, Giulia Apollonio, Donata Galbiati, Paolo Bossi, Cristiana Bergamini, Laura Deborah Locati, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2019)

6029 Background: HPD was described in 9% of cancer patients (pts) treated in phase I trials, in 13.8% of advanced non-small cell lung cancer and 29% of 34 HNSCC pts upon ICI. A better definition of the hallmarks and survival outcomes of HPD pts in a larger cohort of HNSCC is still lacking. Methods: We retrospectively analyzed all advanced HNSCC pts treated with ICI at our Institution between October 2014 and December 2018. Three scans, performed before ICI, at baseline and at first evaluation during ICI, were assessed according to RECIST 1.1. Tumor Growth Kinetics (TGK) pre- (TGKpre) and post-baseline (TGKpost) were measured as previously reported (Saâda-Bouzid E, Ann Oncol 2017). Pts were defined HPD if they had progression at first radiological evaluation and TGKpost/TGKpre ≥2. Correlation between HPD and clinical characteristics was performed by Fisher or t-student test. Median overall survival (mOS) and progression free survival (mPFS) were estimated using the Kaplan-Meier method and compared between HPD and non-HPD using the log-rank test. Results: Ninety pts were eligible: 18% were female, 4% had ECOG PS ≥ 2, 73% smoking history, 37% oropharyngeal cancer (61% HPV+), 65% locoregional disease (89% previously irradiated), 54% received combined immunotherapy, 75% in ≥ 2nd line. Two out of 90 pts had TGKpre = 0 and were not evaluable for TGK ratio. HPD was observed in 7.9% (7/88) of pts. HPD pts were significantly younger compared to non-HPD pts (median age 53 ± 3.7 vs 63.3 ± 0.9 years, p = 0.002) and had a significantly higher median neutrophil-lymphocyte ratio (NLR) (11.5 ± 3.5 vs 6.4 ± 0.4, p = 0.004). Overall, mOS and mPFS were 7.5 (95% CI: 4.2-10.8) and 2.2 months (95% CI: 0.9-3.4), respectively. At a median follow-up of 20.9 months (95% CI: 19-22.8), HPD pts had a significantly worse mPFS compared to non-HPD pts [1.8 (95% CI: 1.5-2.2) vs 3.5 (95% CI: 2.2-4.8) months; p = 0.001]. HPD correlated with a not significant trend in lower mOS compared to non-HPD group [3.7 (95% CI: 2.4-5.1) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.348]. Three (43%) out of 7 HPD pts early switched to chemotherapy after PD to ICI having a mOS of 8.1 months (range 3.7-25.3). Excluding these 3 pts, HPD correlated with a significantly worse mOS compared to non-HPD [2.6 (95% CI: 1.9-3.3) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.006]. Conclusions: HPD was identified in 7.9% of HNSCC and correlated with younger age and higher NLR. HPD pts who did not receive a subsequent treatment had poorer mPFS and mOS. The assessment of HPD in a control cohort of advanced HNSCC upon standard chemotherapy is ongoing.
Correlation of angiogenic and immunomodulatory proteins with clinical outcomes of durvalumab (anti-PDL1) in recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Xiang Guo, Brandon W. Higgs, Paul Baverel, Jean Fan, Nassim Morsli, Magdalena Wrona, Alejandro Javier Yovine, Shao-Chun Chang, Rosalin Arends, Lorin Roskos
Journal: Journal of Clinical Oncology (2019)

6048 Background: The potential for durvalumab, a PD-L1 blocking monoclonal antibody, to treat head and neck squamous cell carcinoma (HNSCC) is being evaluated in multiple clinical trials. We assessed circulating protein biomarkers in HNSCC patients prior to treatment to better understand pathways related to clinical outcomes and potentially relevant for targeting in combination with durvalumab. Methods: Sixty-six selected serum proteins were measured by multiplex immunoassay at baseline in HNSCC patients receiving durvalumab treatment: 106 patients with high PD-L1 (≥25% tumor cells; SP263 assay) in phase II HAWK trial and 52 patients with low/no PD-L1 in phase II CONDOR trial. Results: Multivariate Cox modeling demonstrated that higher baseline concentrations of angiogenic, pro-inflammatory, and myeloid-associated proteins (ANGPT2, CRP, IL6, S100A12) were associated with shorter overall survival (OS), while higher concentration of a bone formation marker and immunostimulatory hormone (BGLAP) correlated with longer OS in 158 durvalumab-treated HNSCC patients ( P&lt; 0.05). These 4 proteins also showed higher baseline levels in patients with progressive disease (PD) compared to stable disease (SD) and partial or complete responses (PR/CR), while BGLAP had lower levels in PD compared to SD or PR/CR (Mann-Whitney P&lt; 0.05). The 5 proteins remained significantly associated with OS in a multivariate model including PD-L1, ECOG, tumor size, and neutrophil count. Bone metastasis status had no impact on the association of BGLAP with OS, which has not been reported before in HNSCC. Interestingly, ANGPT2 level above median showed the highest hazard ratio (HR = 2.2, P &lt;0.001) among all evaluated variables. Furthermore, higher levels of VWF, an angiogenesis-related protein, correlated with shorter OS by univariate survival analysis ( P &lt; 0.001). Conclusions: Our results suggested an important role of angiogenesis in the resistance of HNSCC patients to durvalumab treatment, and ANGPT2 may have predictive utility for durvalumab combination with an anti-angiogenic agent. The predictive value of BGLAP remains to be evaluated in a randomized clinical study. Clinical trial information: NCT02207530; NCT02319044.
An EGFR extracellular domain mutation data in the East Asian non-small cell lung cancer populations and response to icotinib: A multicenter study.
Authors: Wen xian Wang, Chunwei Xu, Yu Chen, Xiuyu Cai, Yong Fang, Quxia Zhang, You-cai Zhu, Zongyang Yu, Gang Chen, Hong Wang, Wu Zhuang, Xiaohui Chen, Yun-jian Huang, Hong Shen, Song Zheng, Ji'an Zhou, Junhui Ye, Meiyu Fang, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2019)

e13000 Background: “Pan-negative” non-small cell lung cancer (NSCLC) patient specimens that lack mutations in known targetable genes. EGFR extracellular domain mutations (ECD) as novel oncogenic mutations are found in colorectal cancer, glioma, and neuroblastoma cases and has not yet reported in NSCLC. No enough evidence between icotinib treatment and ECD has been reported in NSCLC. Methods: Comprehensive mutational analyses were performed on 3279 NSCLC specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were firstly detected in EGFR, as well as the KRAS, BRAF, ALK, ROS1 and RET genes by next generation sequencing tumor DNA (ctDNA) and apply icotinib for treatment for EGFR ECD. Results: Of this entire cohort, sixteen (0.49%) patients (3279 cases) were identified with EGFR ECD, including p.L62R (2), p.R98Q (1), p.I213M (1), p.A237F (1), p.A289V (1), p.A289T (1), p.T302H (1), p.T354K (1), p.T363N (1), p.D368Y (1), p.T430S (1), p.A508V (1), p.N528D (1), p.K593Q (1) and G598V (1). During the treatment by icotinib, two cases (p.A289V, p.A289T) had partial response to icotinib for four and six months, which suggested that icotinib conferred sensitivity to A289X mutation. EGFR A289X mutations were sensitive to icotinib treatment in BaF3 cell lines and in xenograft models. These results paralleled those seen with the well-described EGFR oncogenic driver mutation, L858R, suggesting similar mechanistic underpinnings for the mutations. Conclusions: Here, a new EGFR driver mutation, A289X, was identified in the ECD of two NSCLC specimens. NGS may expand the EGFR mutations spectrum for icotinib treatment in NSCLC, however, it needs to be confirmed in more patients with NSCLC in East Asian and other populations.
Reporting of patient (pt) characteristics (c) and use of stratification factors (SF) in phase III trials for metastatic colorectal cancer (mCRC): Urgent need for standardization.
Authors: Robert Asa Horn, Daniel Tannenbaum, Van K. Morris, Benny Johnson, Michael J. Overman, Christine Megerdichian Parseghian, Scott Kopetz, Cathy Eng, Jane E. Rogers, Kanwal Pratap Singh Raghav, Arvind Dasari
Journal: Journal of Clinical Oncology (2019)

e15055 Background: An increasing number of pt and tumor c have predictive and prognostic implications in mCRC. However, there is no consensus on their reporting in trial results. Methods: Pt c and SF from 136 phase III trials of systemic therapies (Rx) in mCRC published between 1988 and 2018 (68,326 pts) were collected. Trials were also grouped per publication date (G1: 1988-97; G2: 98 – 2007; G3: 08-18). Patterns of reporting and trends across G were evaluated. Results: Pt c consistently reported were performance status, PS (98.5%), age (92.6%) and gender (90.4%); race (20.6%) &amp; weight/BMI/BSA were not (13.2%). Tumor c frequently reported were metastatic (met) spread (70.6%) while time intervals related to disease course (25%) and synchronous met vs not (19.1%) were omitted. Of note, primary site was largely reported as colon vs rectum (69%) and sidedness or anatomical location was discernable only in 10.3%. Prior Rx reporting focused on chemo (58.5%) with radiation and surgery and reported in 34% &amp; 28.7%. Reporting of prognostic factors was variable and limited: histology grade CEA, alk phos, LDH (range 10.3-15.4%). Only 11.8% of trials reported genomic factors - KRAS MT was included in all with BRAF MT in 4.4%. Of 140 trials used for SF analysis, 115 had ≥ 1 (range 1-7). Common SF were PS (60%), geography /institution (55.7%). Prior Rx (27%), met spread (24.3%) were sometimes used while primary site (7.8%), genomic factors (6.1%) rarely were. Trends across G are per Table. Conclusions: There is marked inconsistency in pt c &amp; SF reporting in mCRC trials. Consensus guidelines will aid in standardization of trial interpretation and future meta-analyses; and will need to be updated based on emerging data. [Table: see text]
Place of death and chemotherapy use at the end of life in colorectal cancer.
Authors: Katharina Schütte, Tobias Kroggel, Anke Rentsch, Ulrich S. Schuler, Conrad Heuchel, Gunnar Folprecht
Journal: Journal of Clinical Oncology (2019)

e23006 Background: Over the last decades, new drugs and multidisciplinary treatment increased the therapeutic options for palliative treatment of colorectal cancer (CRC). It is unclear, whether these options led to a more aggressive therapy at the end of life. Methods: For this retrospective cohort trial, we identified all stage IV CRC patients who received their complete therapy at an university hospital in Germany and investigated the use of palliative chemotherapy at the end of life (EOL) and the place of death (POD). Results: Between 01/2002 and 12/2012, 245 patients were treated with palliative chemotherapy for stage IV CRC and were evaluable for duration of palliative chemotherapy and place of death. 21% of the patients received chemotherapy within the last 30 days and 9% within 14 days before death. Overall survival of patients with chemotherapy use within the last 30 days of life was significantly shorter compared to patients without chemotherapy in the last month of life (12 vs. 20 months, p = 0.02), duration of palliative chemotherapy was non-significantly shorter (11 vs. 15 months, p = 0.29). Chemotherapy use was significantly more frequent used within 30 days before death from 2009-2012 (24%) compared to 2002-2005 (17%), p = 0.001. 58% of patients died in their residence (at home or in a nursing home), 27% on a general hospital ward (GHW)/ intensive care unit (ICU) and 15% on a palliative care unit (PCU) or hospice. Patients ≥70 years died significantly more often in their residence (70% vs. 53%; p = 0.013). From 2002-2005 to 2010-2012, less patients died in a GHW or ICU of acute care hospitals (39% vs. 16%; p = 0.007). Patients with a distance of ≤45 minutes to our institution more often died at home and in a PCU, Patients with a short therapy-free interval before death more often died in a hospital, (with chemotherapy in the last 30 days: 38%, with chemotherapy in the last 14 days: 45%). Conclusions: Although chemotherapy use at the EOL increased over the decade, more patients were able to die at home. Older patients and patients living in an urban centre more often died at home indicating that conditions for home care have improved independent of the duration of chemotherapy. However, patients with chemotherapy use at the EOL more often die in hospital.
What is the best therapy for grossly resected synovial sarcoma? Experience of the CWS Study Group.
Authors: Monika Scheer, Christian Vokuhl, Sabine Stegmaier, Marc W. Muenter, Thekla von Kalle, Paulina Serwa, Monika Sparber-Sauer, Bernarda Kazanowska, Felix Niggli, Ruth Lydia Ladenstein, Gustaf Ljungman, Kirsi Jahnukainen, Sebastian Bauer, Joerg Fuchs, Stefan S. Bielack, Ewa Koscielniak, Thomas Klingebiel
Journal: Journal of Clinical Oncology (2019)

10042 Background: Adjuvant therapy in patients with localized grossly resected synovial sarcoma (SS) still is a matter of debate. This analysis was performed to contribute to the clarification. Methods: SS patients of all ages with initially gross tumor resection registered in the prospective international CWS-trials 1981–2013 were evaluated. CWS-protocols currently recommend chemotherapy for all SS patients. Results: 185 patients with median age of 13.9 years (range 0.1–56.9) and median follow-up of 7.2 years (0.2-31.1) had 5-year event-free (EFS) and overall survival (OS) of 82.9%±5.7 (95%CI) and 92.5%±3.9, respectively. All but six patients received adjuvant chemotherapy. Best surgical treatment consisted of R0-resection in 107 and R1-resection in 70; no information in 7. 135 (73%) were irradiated. In the univariate analysis factors associated with EFS are tumor size and the application of chemotherapy; factors associated with OS are tumor site, size and invasiveness. In the multivariate analysis independent factors for adverse EFS are large tumor size and the application of chemotherapy, for OS tumor site and size. In the group of 58 patients with tumors &lt; 3cm one patient suffered metastatic recurrence (2%), in those 59 patients with tumors 3-5cm 3 suffered metastatic recurrence (5%). In 42 patients with tumors 5-10cm, 4 metastatic and 2 combined recurrences were reported (14%), and in those 13 patients with tumors &gt; 10cm 4 suffered metastatic and 1 combined relapse (38%). Conclusions: Patients with grossly resected SS treated according to the CWS recommendations have an excellent prognosis. A subgroup with very low metastatic potential probably does not need chemotherapy. Whether tumor size and surgery are sufficient criteria has still to be proven by long term results. Biological studies are needed.