bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of anti-CD19 chimeric antigen receptor (CAR) T cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19).
Authors: Galon Jerome , Rossi John , Turcan Sarah , Danan Corinne , Locke Frederick Lundry , Neelapu Sattva Swarup , Miklos David Bernard , Bartlett Nancy L. , Jacobson Caron Alyce , Braunschweig Ira , Oluwole Olalekan O. , Siddiqi Tanya , Lin Yi , Timmerman John , Reagan Patrick Michael , Lekakis Lazaros J. , Unabia Sherryonne , Go William Y. , Wiezorek Jeffrey S. , Bot Adrian
Published: September 2018

3025

Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.
Non-invasive clinical visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: A pilot study.
Authors: Markovic Svetomir , Galli Filippo , Suman Vera J. , Nevala Wendy Kay , Paulsen Andrew M , Hung Joseph C , Gansen Denise N , Erickson Lori A , Marchetti Paolo , Wiseman Gregory A. , Signore Alberto
Published: September 2018

3034

Background: Unique to modern immune therapy for cancer is that early in the course of treatment, patients frequently exhibit transient tumor enlargement (pseudo-progression, pPROG) due to tumor infiltration by lymphocytes (TIL). Currently, pPROG cannot be reliably distinguished from true tumor progression (PROG). There is a need for biomarker techniques to discriminate pPROG (effect of therapy) and PROG (therapy failure). Nuclear medicine offers radiopharmaceuticals capable of imaging immune cells; images can be fused to evaluate functional and anatomic characteristics of tumors, and potentially discriminate pPROG from PROG. Methods: In our study of metastatic melanoma patients, SPECT/CT imaging with 99mTc-interleukin-2 (99mTc-IL2) was performed to visualize TIL. Images were collected before/after 12 weeks of ipilimumab (IPI) or pembrolizomab (PEMBRO) therapy. The 99mTc-IL2 tracer was synthesized by conjugating succinimidyl-6-hydrazinopyridine-3-carboxylate (HYNIC-NHS) with commercial interleukin-2 (Aldesleukin). HYNIC-IL2 was incubated with tricine, 99mTcO4- (370-740 MBq) and SnCl2. After labelling 99mTc-IL2 was purified by reverse-phase chromatography and diluted in 5% glucose with 0.1% human albumin before injection. Five patients were enrolled in this study. Two patients failed to complete the 12 week 99mTc-IL2 scan due to discontinuation of IPI after: 1) grade 3 colitis and 2) patient refusal for adverse events attributed to IPI. No adverse events attributable to the tracer infusion were reported. Results: Metastatic lesions could be visualized by the tracer. Some lesions decreased in size, while others increased. A positive correlation was found between size and 99mTc-IL2 uptake, before and after therapy, suggesting the potential discrimination of tumor PROG (no 99mTc-IL2 uptake) from pPROG (high 99mTc-IL2 uptake). Immunohistochemical staining for TIL of 99mTc-IL2 positive and negative lesions are illustrated. Conclusions: The results demonstrate feasibility of 99mTc-IL2 imaging as a clinically useful tool capable of discriminating tumor PROG from pPROG. A clinical validation study is in progress. Clinical trial information: NCT01789827.
Tumor shrinkage and increased overall survival are associated with improved albumin, neutrophil lymphocyte ratio (NLR) and decreased durvalumab clearance in NSCLC and UC patients receiving durvalumab.
Authors: Powles Thomas , Jin Chaoyu , Zheng Yanan , Baverel Paul , Narwal Rajesh , Mukhopadhyay Pralay , Jin Xiaoping , Dennis Phillip A. , Gupta Ashok Kumar , Ben Yong , Ho Tony W. , Roskos Lorin
Published: September 2018

3035

Background: Progression of cancer is often associated with biomarkers of cancer inflammation, cachexia, and increased protein catabolism. Anti-PD1 and PD-L1 therapy have demonstrated durable responses across a number of tumor types. Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objective of this analysis was to prospectively assess potential correlations of longitudinal changes in ALB and NLR and durvalumab clearance (CL) rate to maximum decrease in tumor size and overall survival (OS) in patients (pts) with NSCLC and UC receiving durvalumab. Methods: Longitudinal target lesion size, serum chemistry, hematology and pharmacokinetic data were obtained from 3L+ NSCLC pts (n = 418) in study ATLANTIC and 2L+ UC pts (n = 182) in study 1108 during durvalumab treatment. Nonparametric correlations (Spearman’s rho) were evaluated between OS, maximum percent change in target lesion size, and the maximum percent change from baseline observed in ALB, NLR, and CL. Results: In NSCLC, maximum decrease in tumor size was correlated with increased ALB (r = 0.46, p < 0.0001), decreased NLR (r = 0.44, p < 0.0001), and decreased CL (r = 0.66, p < 0.0001). OS was similarly correlated with increased ALB (r = 0.47, p < 0.0001), decreased NLR (r = 0.41, p < 0.0001), and decreased CL (r = 0.76, p < 0.0001). In UC, decreased tumor size also correlated with increased ALB (r = 0.43, p < 0.0001), decreased NLR (r = 0.38, p < 0.0001), and decreased CL (r = 0.65, p < 0.0001). OS in UC also correlated with increased ALB (r = 0.50, p < 0.0001), decreased NLR (r = 0.33, p < 0.0001) and decreased CL (r = 0.82, p < 0.0001). Conclusions: In NSCLC and UC pts receiving durvalumab, tumor shrinkage and longer survival are associated with increased ALB, decreased NLR and decreased clearance of durvalumab. These findings support the hypothesis that durvalumab may be associated with a decrease in protein catabolism, inflammation and cachexia among pts who benefited from therapy. Additional biomarkers of cancer, inflammation and cachexia will be evaluated for relationships to clinical outcomes.
High-fidelity genome editing using NextGEN CRISPR (Clo51-dCas9) system for the production of allogeneic CAR-T cells.
Authors: Wang Xinxin , Li Xianghong , Barnett Burton , Martin Christopher , Hermanson David , Smith Jenessa , Rengarajan Srinivas , Tan Yening , Tong Min , Codde Rebecca , Ostertag Eric M. , Shedlock Devon J.
Published: September 2018

3048

Background: Autologous chimeric antigen receptor (CAR) T therapies are highly efficient at targeting hematological malignancies, but the clinical applications have been limited by individualized manufacturing. Furthermore, there has been little success in treating solid tumors due to immunosuppressive microenvironments. Currently, genome editing technologies are being used to address both issues. However, the CRISPR/Cas9 system has significant safety concerns due to high incidence of off-target mutations and TALEN only works sufficiently in activated cells. A hybrid gene editing system, NextGEN (NG) Clo51-dCas9, can be targeted using gRNA, like CRISPR/Cas9, but exhibits little-to-no off-target cutting like TALEN, thereby overcoming limitations in the genome editing of resting T cells. Methods: We successfully developed a platform for production of allogeneic CAR-T cells with reduced receptivity to inhibitory signaling. Here, T cells were modified by piggyBac-mediated BCMA CAR gene delivery, along with NG reagents to knock out critical genes mediating rejection responses. Gene edited CAR-T cells were assessed by mixed lymphocyte reaction (MLR) and tumor killing. In addition, NG was used to knockout multiple checkpoint inhibitory receptors known to mediate key suppressive signals in T cells. Results: NG demonstrated high gene disruption efficiencies for all targets (84% for TCRα, 91% for TCRβ, 64% for β-2 microglobulin, and 40-60% for the surface inhibitory receptors PD-1, CTLA-4, Tim3, Lag-3, and TGFBRII). In contrast to CRISPR/Cas9, no off-target mutations were detected for multiple targets by deep-sequencing. In MLRs, disruption of TCR eliminated the GvHD response, while disruption of MHCI completely abrogated graft-rejection. Lastly, TCR/MHCI double knockout did not affect the ability to kill BCMA+ multiple myeloma cells in vitro. Conclusions: NG overcomes significant limitations of the CRISPR/Cas9 and TALEN systems with highly efficient genome editing in resting T cells. NG has great potential and flexibility for the manufacture of allogeneic CAR-T cells and for enhancing efficacy against solid tumors.
Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.
Authors: Yeku Oladapo O. , Purdon Terence , Spriggs David R. , Brentjens Renier J.
Published: September 2018

3050

Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies. The presence of an immunosuppressive cytokine and cellular microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, the presence of tumor associated macrophages (TAMs) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC) and NK cells, and has been shown to increase proliferation of T cells and enhance antigen presentation by macrophages. We hypothesized that CAR T cells genetically modified to constitutively secrete IL-12 would overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16ecto. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128-IL12 CAR T cells. We show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Mice treated with 4H1128-IL12 CAR T cells had decreased levels of F4/80+ CD11b+TAM’s. Genetic analysis of recovered TAM’s from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II and downregulation of Arg1. Recovered 4H1128-IL12 CAR T cells showed upregulation of FAS-L and recovered TAMs showed increased expression of FAS suggesting FAS/FAS-L engagement was responsible for decreased TAMs. Blocking the FAS/FAS-L pathway led to recovery of TAM populations in 4H1128-IL12 treated mice. Finally, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128-IL12 CAR T cells.
A randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab, a PD-L1 antibody, to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC).
Authors: Loibl Sibylle , Untch Michael , Burchardi Nicole , Huober Jens Bodo , Blohmer Jens Uwe , Grischke Eva-Maria , Furlanetto Jenny , Tesch Hans , Hanusch Claus , Rezai Mahdi , Jackisch Christian , Schmitt Wolfgang D , Von Minckwitz Gunter , Thomalla Jörg , Kummel Sherko , Rautenberg Beate , Fasching Peter A. , Rhiem Kerstin , Denkert Carsten , Schneeweiss Andreas
Published: September 2018

3062

Background: Adding an anti-PD-L1 checkpoint inhibitor durvalumab to standard chemotherapy (CT) may increase pathological complete response (pCR) in patients (pts) with TNBC. Methods: GeparNuevo randomizes pts to durvalumab (D) 1.5 g i.v. or placebo (pl) every 4 weeks (wks). D/pl monotherapy (0.75 g i.v.) is given for the first 2 wks (window phase), followed by a biopsy and D/pl plus nab-paclitaxel (nP) 125 mg/m² weekly for 12 wks, followed by D/pl plus epirubicin/cyclophosphamide (EC) q2 wks for 4 cycles. Randomization is stratified by stromal TILs (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). Pts with primary cT1b-cT4a-d disease, centrally confirmed TNBC, and sTILs status can be included. Primary objective compares pCR (ypT0 ypN0) rates. Secondary objectives are pCR rates in stratified subpopulations and according to other pCR definitions; response rates; breast conservation rate; toxicity; compliance and survival. Change in sTILs, Ki67 and other immune biomarkers before CT, after the window phase and after CT will be correlated with outcome. The first 10, 20 and 30 pts will be included in safety interim analyses (SIA). Sample size was planned assuming a pCR rate of 48% for pl (nP treated TNBC cohort in GeparSepto) and of 66% for D (as clinically meaningful benefit), requiring 158 pts to show superiority of D (2-sided α = 0.2, 80% power). Assuming a 10% drop-out rate 174 pts will be randomized. Results: Since 6/2016, 50 pts were recruited within 16 sites; data are presented as available until 01/2017. Median age is 49 years; 86% NST and G3 tumors; sTILs categories 40% low, 40% intermediate and 20% high. Blinded SIA was performed. No pt interrupted D/pl, one nP and one EC. Treatment delay was observed in 9 pts (20.0%) in D/pl, 18 (41.9%) in nP and 2 (13.3%) in EC; dose was reduced in 10 pts (23.3%) in nP and in 4 (26.7%) in EC. 10 pts (20%) had at least one grade 3-4 AE: 4 haematological and 6 non-haematological AEs. 4 SAEs and 5 immune related AEs were reported. 2 pts discontinued study treatment prematurely in the EC phase. Conclusions: The addition of D to standard nP-EC is feasible and does not result in an increased toxicity. Clinical trial information: NCT02685059.
Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids.
Authors: Ziemer Mirjana , Koukoulioti Eleni , Simon Jan-Christoph , Berg Thomas
Published: September 2018

3073

Background: The CTLA4-antibody ipilimumab, and PD-1-antibodies pembrolizumab as well as nivolumab have revolutionized antineoplastic therapies. Induction of autoimmune-like drug-induced liver injury (DILI) is within the spectrum of adverse reactions of these new drugs and has been observed in about 1-5 % of patients, developing predominantly within the first 6 to 12 weeks after start of treatment. Immediate application of systemic steroids and a permanent discontinuation of immune checkpoint-inhibition therapy are recommended for any alanine aminotransferase increase ≥ WHO grade 3. In severe autoimmune-like DILI the permanent discontinuation of the immune checkpoint inhibitor is recommended, as drug re-exposure might be associated with a significant risk of a fulminant DILI. Methods: We report six patients with severe grade 3 autoimmune-like DILI (according to Common Terminology Criteria for Adverse Events 4.3) treated with long-term application of budesonide, a liver-directed topical steroid. Results: Immune checkpoint inhibitors were stopped and methylprednisolone was applied initially with a dose of 1 mg/kg body weight and tapered thereafter. To reduce systemic steroids and to minimize the exposure time to systemic steroids, the topical steroid budesonide 3 mg three times per day was additionally given in combination with N-acetylcysteine and ursodeoxycholic acid. Under this multimodal approach transaminases normalized and the respective immune-checkpoint inhibitor could be re-started without re-manifestation of DILI under the continuous treatment with budesonide. Conclusions: Budesonide - a liver-directed topical steroid - might be an interesting approach to target liver related autoimmune adverse reactions induced by immune checkpoint inhibitors without compromising their anti-cancer effect. We were able to safely and effectively re-introduce and continue immune checkpoint inhibitors under the continuous application of the topical steroid without showing any further liver toxicity.
Somatic DNA mutations, MSI status, mutational load (ML): Association with overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) of CALGB/SWOG 80405 (Alliance).
Authors: Innocenti Federico , Ou Fang-Shu , Zemla Tyler , Niedzwiecki Donna , Qu Xueping , Tam Rachel , Mahajan Shilpi , Goldberg Richard M. , Mayer Robert J. , Bertagnolli Monica M. , Sanoff Hanna Kelly , Hochster Howard S. , Blanke Charles David , Venook Alan P. , Lenz Heinz-Josef , Kabbarah Omar
Published: September 2018

3504

Background: CALGB 80405 was a randomized phase III trial that found no difference in OS in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet). Primary tumor DNA from 361 pts, including KRAS mutant (mut) pts, has been profiled for somatic gene mutations/ML/MSI to discover molecular markers of OS. Methods: Mutations in 11 genes were determined by PCR, MSI by microsatellite analysis, and ML by next-generation sequencing (FoundationOne). Cox proportional hazard models are used, stratified by prior XRT and +/- adjuvant chemotherapy; adjusted by age, race, gender, synchronous vs. metachronous, liver metastases, sidedness, all RAS. Results: BRAF: Mut pts had shorter OS than wild-type (wt) pts (HR 1.92, 95% CI 1.34,2.75; p<0.001); HR 1.65 (1.09,2.50) after adjusting for sidedness (p 0.022). In mut pts longer OS is observed in Bev arm vs. Cet arm (p 0.041); in wt pts no arm difference is observed (p 0.291, table). MSI: OS does not differ between MSI-H and MSI-S pts (HR 0.78 [0.40, 1.52], p 0.450). In MSI-H pts longer OS is observed in Bev arm vs. Cet arm (p 0.002); in MSI-S pts no difference is observed (p 0.305, table). ML: Hypermutated MSI-H pts are excluded. In a subset of 205 pts, pts with ML>5 (N=93) have longer OS than pts with ML≤5 (N=112) (HR 0.65 [0.42,1.00], p 0.048). In Bev arm higher ML confers longer OS than lower ML (HR 0.85 [0.80,0.96], p 0.004); in Cet arm no difference is observed (HR 0.99 [0.90,1.09], p 0.862). Conclusions: BRAF is a strong negative prognostic factor in mCRC, even when sidedness is taken into account. ML is a novel marker for further evaluation. The effect of Bev and Cet in either BRAF mut or MSI-H pts should be tested in larger datasets. Updated results from more screened samples will be presented. [Table: see text]
Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).
Authors: Kopetz Scott , McDonough Shannon L , Lenz Heinz-Josef , Magliocco Anthony Martin , Atreya Chloe Evelyn , Diaz Luis A. , Allegra Carmen Joseph , Raghav Kanwal Pratap Singh , Morris Van Karlyle , Wang Stephen E. , Lieu Christopher Hanyoung , Guthrie Katherine A , Hochster Howard S.
Published: September 2018

3505

Background: Metastatic colorectal cancer (mCRC) patients (pts) with BRAFV600 mutations have poor outcomes with standard of care chemotherapy and rarely respond to the BRAF inhibitor vemurafenib. In preclinical models, blockade of BRAFV600 by vemurafenib (V) causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab (C) with anti-tumor activity augmented by irinotecan (I). Methods: Pts with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Eligible pts had ECOG PS ≤1, and had received 1 or 2 prior regimens with no prior anti-EGFR agents. Randomization was stratified for prior irinotecan. Crossover from the control arm (IC) to the experimental arm (VIC) was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 pts were enrolled (99 eligible, 49 in the experimental arm) from 12/2014 to 4/2016, with median age 62 years, 59% female, and 39% with prior irinotecan therapy. PFS was improved with the addition of vemurafenib (HR 0.42, 95% confidence interval [CI] 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI 3.6 – 5.7) mos vs 2.0 (95% CI 1.8 – 2.1) months. Response rate was 16% vs 4% (P = 0.08), with disease control rate of 67% vs 22%. In pts with no prior irinotecan, median PFS was 5.7 (95% CI 3.0-6.1) months in the VIC arm vs 1.9 (95% CI 1.7 – 2.1) months in the IC arm. Grade 3/4 adverse events higher in the VIC arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. 23 pts (46%) in the IC arm crossed over at the time of progression, with median PFS from crossover of 6.0 months (95% CI 3.7 – 7.4). Overall survival (OS) data will be mature for ASCO 2017. Conclusions: These results demonstrate the clinical benefits of the VIC triplet (vemurafenib, cetuximab, and irinotecan) in pts with treatment-refractory BRAFV600 mutated mCRC, and support VIC as a potential new treatment option in this molecular subset. Clinical trial information: NCT02164916.
REsect: Blinded assessment of amenability to potentially curative treatment of previously unresectable colorectal cancer liver metastases (CRC LM) after chemotherapy ± RadioEmbolization (SIRT) in the randomized SIRFLOX trial.
Authors: Garlipp Benjamin , Gibbs Peter , Van Hazel Guy A. , Jeyarajah Rohan , Martin Robert C. G. , Bruns Christiane J. , Lang Hauke , Manas Derek M. , Ettorre Giuseppe Maria , Pardo Fernando , Donckier Vincent , Benckert Christoph , van Gulik Thomas M , Goere Diane , Schoen Michael , Pratschke Johann , Bechstein Wolf O. , Martínez de la Cuesta Antonio , Adeyemi Shola , Seidensticker Max
Published: September 2018

3532

Background: Secondary resection and radiofrequency ablation (RFA) of primarily unresectable LM from CRC can prolong survival and cure some patients (pts). Effective downsizing treatments are needed but their impact on secondary amenability to surgery/RFA is difficult to evaluate objectively. The added value of SIRT is not well established. Methods: Baseline (BL) and follow-up (FU) imaging at best response for CRC pts treated with FOLFOX chemotherapy±bevacizumab (bev) (CT) vs. CT+SIRT in the phase III SIRFLOX RCT were reviewed by 3−5 expert HPB surgeons (from a panel of 15) for resectability of LM. Reviewers were blinded to each other and to all clinical information incl. time of imaging (BL/FU). Resectability was defined as ≥60% of reviewers assessing a pt as resectable. For non-resectable cases, surgeons indicated whether a combination of surgery and RFA could completely remove all LM. Lesions deemed suitable for RFA by a surgeon needed to be confirmed by an interventional radiologist. Pts were defined as “clearable” if ≥60% of reviewers assessed them as amenable to complete removal of LM by surgery alone or surgery+RFA. Results: 472 pts were evaluable (CT, n = 228; CT+SIRT, n = 244). There was no significant difference in LM resectability at BL (CT, n = 25, 10.96%; CT+SIRT, n = 29, 11.89%; p = 0.77). At FU, significantly more pts in the SIRT arm had resectable LM (CT, n = 66, 28.95%; CT+SIRT, n = 93, 38.11%; p < 0.0001). Of 203 pts in the CT arm and 215 pts in the CT+SIRT arm deemed unresectable at BL, 46 (22.66%) and 67 (31.16%), respectively, were converted to resectability (p < 0.0001). Assessing “clearability” using surgery and RFA, again no difference was noted at BL (CT, n = 31, 13.60%; CT+SIRT, n = 42, 17.21%; p = 0.309). At FU, a trend in favor of CT+SIRT was seen (CT, n = 79, 34.65%; CT+SIRT, n = 102, 41.80%; p = 0.1296). Conclusions: The addition of SIRT to FOLFOX(±bev) based CT significantly increased the gain in resectability of primarily unresectable CRC LM compared with CT alone. For amenability to the combination of surgery+RFA, this effect was still seen, albeit attenuated. Subgroup analyses are ongoing. Clinical trial information: NCT00724503.
Hand-foot skin reaction (HFSR) and outcomes in the phase 3 CORRECT trial of regorafenib for metastatic colorectal cancer (mCRC).
Authors: Grothey Axel , Huang Liping , Wagner Andrea , Van Cutsem Eric
Published: September 2018

3551

Background: Cutaneous toxicity is a known adverse effect of multikinase inhibitors and has been associated with clinical outcomes (Granito 2016). In the phase 3 CORRECT trial (NCT01103323), the multikinase inhibitor regorafenib significantly improved overall survival (OS) vs placebo in patients with mCRC (hazard ratio [HR] 0.77, 95% CI 0.64, 0.94; 1-sided P = 0.0052). This retrospective analysis explored whether HFSR was associated with outcomes in CORRECT. Methods: Patients randomized to receive regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS and progression-free survival (PFS) (95% CI) were calculated using the Kaplan–Meier method. Patients who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of the 505 randomized patients, 500 received at least one dose of regorafenib. Among the treated patients, 47% (n = 235) had HFSR of any grade and 17% (n = 83) had HFSR grade 3. Of the patients who had HFSR, 69% (n = 162) had their first HFSR event (any grade) during the first treatment cycle. There was some imbalance in baseline characteristics between groups (Table). Survival was improved in patients who had HFSR at any time vs those who did not (Table). The OS benefit was also observed in patients who had the first HFSR event during Cycle 1 vs those who did not (median OS 7.2 vs 5.7 months; HR 0.66, 95% CI 0.51, 0.87). Conclusions: This post-hoc exploratory analysis suggests that patients who had HFSR had a greater treatment benefit from regorafenib. Since HFSR and survival are post-baseline assessments, results may be confounded by baseline factors or other unknown factors. Clinical trial information: NCT01103323. [Table: see text]
Response to pembrolizumab in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC).
Authors: Leal Alexis Diane , Paludo Jonas , Finnes Heidi D. , Grothey Axel
Published: September 2018

3558

Background: Anti-programmed death-1 (PD-1) antibodies have been shown to be effective in the treatment of dMMR CRC. We describe an updated analysis from a cohort of 19 patients (pts) with dMMR CRC treated with pembrolizumab. Methods: Pts were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through January 2017. All pts with dMMR CRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR = CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: Nineteen pts were included in this analysis; median age at diagnosis was 48.6 years (range 25-93); 53% were female. Most primary tumors were right sided (n = 12; 63%), 6 (32%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Twelve (63%) pts received ≥2 lines of therapy prior to pembrolizumab (range 1-4). Five pts received 2 mg/kg every 3 weeks, 11 received 200 mg/day every 3 weeks and 2 pts received 10 mg/kg (1 every 2 weeks, the other every 3 weeks). The most common alterations identified were loss of MLH1 (11/15) and PMS2 (12/15); 4 pts had germline mutations (mut) identified. KRAS mut was identified in 6/16 pts and 2 pts had BRAF mut. Three pts had MLH1 hypermethylation. Median number of cycles of pembrolizumab was 8 (range 1-35+), with 13 (68%) pts receiving ≥6 cycles. DCR at first assessment was 68%, with 5% CR, 47% PR and 16% SD. Median follow-up from diagnosis was 29 months (95% CI 18-42). Median OS was 103 months (95% CI 85-103); 12-month OS was 89%. Median OS from PD-1 therapy was 16.1 months (95% CI 16-NR); 12-month OS from PD-1 therapy was 79%. Median PFS was NR (95% CI 5-NR); 12-month PFS was 54%. At time of analysis, 9 pts remain on PD-1 therapy; 5 pts have died; 3 have received subsequent therapy. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated pts.
Prospective study of biomarkers in squamous cell carcinoma of the anal canal (SCCAC) and their influence on treatment outcomes: Final results.
Authors: Moniz Camila Motta Venchiarutti , Riechelmann Rachel Pimenta , Ribeiro Suilane Coelho , Rivelli Thomas Giollo , Bariani Giovanni Mendonca , Chen André , Franco Rejane , Nahas Caio , Pereira Allan Andresson Lima , Ortega Cintia , Sabbaga Jorge , Meireles Sibele , Coudry Renata A. , Hoff Paulo Marcelo
Published: September 2018

3577

Background: While chemoradiation (CRT) is a curative treatment for SCCAC, many patients (pts) present primary resistance. As a rare tumor, the predictors of response in this setting remain unknown. Methods: Prospective cohort study aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status and mutations in tumoral DNA) associated with complete response (CR) following standard CRT for localized SCCAC. Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. CR at 6 months (m) measured by RECIST 1.1 was the primary endpoint. DNA mutations were analyzed by next-generation (NGS) TruSight Tumor26 panel. HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for response. Median age 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. At 6m 47 (62.7%) had CR, 18 (24%) partial response (PR) and 10 (13.3%) disease progression. HPV was evaluated in 67 and found in 47 (70.1%), the majority HPV16. PD-L1 was tested in 61, 10 (16.4%) had > 1% positive expression. Ki-67 was performed in 65, a median was 50% (1-90%) per patient. Clinical stage, HIV status, median KI-67, HPV and PD-L1 positivity, and treatment interruption were tested as predictive factors of CR in 6m by logistic regression. On multivariable analyses, ECII patients were 4.7 more likely to achieve CR than ECIII (OR 4.70 CI95%1.36-16.30; p = 0.015). HIV was borderline significant (OR 2.53 CI95% 0.9-7.1; p = 0.079). Analyzing the patients with PR and CR HIV+ was significantly associated with poor response. Patients HIV- were 5.7 more likely to achieve CR or PR (OR 5.72 CI95%2.5-13.0; p < 0.001). 25 patients had tumor samples proper for NGS, 17 had at least one pathogenic mutation. The most common mutated genes were PIK3CA and MET in 6. There was no differences in CR rates according to MET (50% vs 47.3%, p = 1) or PIK3CA (33.3% vs 47.3%, p = 0.6) mutation status. TP53 codon 72 polymorphism was present in 72% (n = 18) and was not associated with CR (44% VS 57%, p = 0.6). Conclusions: Our study suggests that HIV+ pts are less responsive to CRT.
Identification of a novel predictive genomic biomarker for response to combination bevacizumab in metastatic colorectal cancer (mCRC).
Authors: Byrne Annette T. , Smeets Dominiek , Miller Ian S. , Das Sudipto , Boeckx Bram , Depreeuw Jeroen , Gaiser Timo , Betge Johannes , Barat Ana , Murphy Verena , Moran Bruce , Fender Bozena , Klinger Rut , Ebert Matthias Philip , van Grieken Nicole C.T. , Ylstra Bauke , Gallagher William M. , Prehn Jochen , O'Connor Darran , Lambrechts Diether
Published: September 2018

3580

Background: Somatic copy number alterations (SCNA) are genomic alterations evident in cancers including mCRC. These alterations support biomarker discovery, allowing identification of variants that can be used to predict response to therapy. Herein, we studied the impact of SCNAs on mCRC patient response to bevacizumab (BVZ). Methods: SCNA data was assembled from mCRC tumors in the TCGA cohort (n = 676), from the CAIRO 2 study [n = 143] and from the ANGIOPREDICT cohort (n = 258) [Betge et al. Digestion 2016 94(3):129-137]. GISTIC v2.0 was used to identify the most frequent and overrepresented chromosomal aberrations. A region was considered deleted if the logR value was < 0.1 and amplified when the logR was > 0.1. A cutoff q-value of 0.25 was used to select significantly overrepresented SCNAs. To further explore the impact of new ANGIOPREDICT clusters and consensus molecular subtypes (CMS), [Guinney J et al Nat Med. 2015 21(11):1350-6], a panel of seven xenografts representing each CMS subtype was treated with FOLFOX (40mg/kg 5-FU, 13.4mg/kg folinic acid & 2.4mg/kg oxaliplatin) + B20 antibody (mouse avastin, 10mg/kg) for 4 weeks. Results: Unsupervised hierarchical clustering classified all 1077 tumors into 3 consensus SCNA subgroups termed ‘ANGIOPREDICT’ clusters 1-3. Concordance between CMS and ANGIOPREDICT clusters was evident: CMS1 - Cluster 1 78%, CMS3 - Cluster 1 50%. CMS2 - Cluster 2/3 92% and CMS4 - Cluster 2/3 84%. Tumors with intermediate or high copy number instability (ANGIOPREDICT cluster 2 & 3) showed improved progression free survival (PFS): 369d vs. 227d p = 1.36e-7) whereas tumors with low copy number alterations displayed a poor response to BVZ therapy (PFS: 147d vs 152d p = 0.906). Xenografts corresponding to CMS 2&4/ ANGIOPREDICT cluster 2-3 showed improved response to FOLFOX + B20 therapy and increased PFS (p < 0.001) vs. CMS1&3/ ANGIOPREDICT cluster 1. Conclusions: For the first time, in a large test and validation cohort including retrospectively collected and randomized controlled trial patient samples, we have identified a predictive genomic biomarker for BVZ therapy in mCRC. We have further demonstrated the utility of CMS subtyping to stratify patients to BVZ .
Right-sided colorectal cancer (RC): Response to first-line chemotherapy in FIRE-3 (AIO KRK-0306) with focus on early tumor shrinkage (ETS) and depth of response (DpR).
Authors: Holch Julian Walter , Stintzing Sebastian , Held Swantje , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Kahl Christoph , Kullmann Frank , Scheithauer Werner , Kirchner Thomas , von Einem Jobst C. , Modest Dominik Paul , Heinemann Volker
Published: September 2018

3586

Background: Recent evidence suggests that benefit from anti-EGFR treatment is restricted to RAS wild-type left-sided colorectal cancer (LC) (Holch JW et al. Eur J Cancer 2017). However, these results are preliminary. We therefore investigated patients with RC enrolled in the FIRE-3 trial, which evaluated the efficacy of first-line FOLFIRI plus either cetuximab (cet) or bevacizumab (bev) in RAS wildtype mCRC. New metrics of tumor dynamics were used to characterize the patients. Methods: The splenic flexure was used to differentiate LC from RC. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using Log-Rank test, hazard ratios (HR) and corresponding 95% confidence intervals. Central independent radiological data was used to calculate early tumor shrinkage ≥20% (ETS) and depth of response (DpR). Results: In total, 330 patients were assessable for central radiological evaluation. In patients with LC (n = 257), treatment with FOLFIRI + cet led to longer overall survival (OS) compared to FOLFIRI + bev (HR = 0.68, p = 0.016). In patients with RC (n = 68), OS was comparable between treatment arms (HR = 1.11, p = 0.715). In patients with RC and ETS < 20%, OS was inferior in patients treated with FOLFIRI + cet. In patients who reached ETS ≥20%, a comparable OS was evident between treatment arms (for further details of efficacy in patients with RC see table). Conclusions: Patients with RC do not represent a uniform population. ETS ≥20% defines a subgroup of patients where comparable treatment efficacy was observed with regard to OS, ORR and DpR by addition of cetuximab vs. bevacizumab to FOLFIRI. [Table: see text]
Early prediction of clinical outcomes in resected stage II and III colorectal cancer (CRC) through deep sequencing of circulating tumor DNA (ctDNA).
Authors: Diehn Maximilian , Alizadeh Ash A. , Adams Hans-Peter , Lee John J. , Klassen Susanne , Palma John F. , Hinzman Bernd , Lovejoy Alexander F. , Newman Aaron M. , Yao Lijing , Yaung Stephanie , Balasubramanyam Aarthi , Rohr Ulrich Peter , Rosenthal Andre , Kube Rainer , Steinmüller Thomas , Marusch Frank , Mantke Rene , Heise Michael , Pross Matthias
Published: September 2018

3591

Background: Adjuvant chemotherapy is offered to most pts with Stage III CRC, and to a subset with Stage II disease deemed at high-risk for recurrence. Nevertheless, risk stratification strategies remain suboptimal. Detection of minimal residual disease (MRD) through ctDNA analysis has been shown to identify pts at high recurrence risk in Stage II CRC, but not Stage III disease. Methods: The next-generation sequencing based AVENIO ctDNA Surveillance Kit (Research Use Only) was used to identify single nucleotide variants (SNVs) in tumor tissue within a cohort of 145 Stage II and III CRC pts following R0 surgical resection (n = 86 and 59 respectively; median follow-up = 32.1 mo). The same assay was used to monitor ctDNA with a single post-operative blood sample (mean surgery-to-phlebotomy time: 10 days). Regions from 197 genes recurrently mutated in CRC were interrogated, and pts were classified as ctDNA positive (+) or negative (-) in plasma based on the detection of SNVs previously identified in tumor tissue. Results: Variants were identified in 99% of tumors (n = 144) with a median of 4 SNVs/sample (range 1-24) and all post-operative plasma samples were successfully profiled. Pts with detectable ctDNA (n = 12) displayed a significantly shorter 2-year relapse-free survival (RFS; 17% vs 88%; HR 10.3; 95% CI 2.3-46.9; p < 0.00001), time to recurrence (TTR; HR 20.6; 95% CI 3.1-139.0; p < 0.00001) and overall survival (OS; HR 3.4; 95% CI 0.5-25.8; p = 0.041) than ctDNA- pts (n = 132). 11 (92%) of ctDNA+ pts developed recurrence compared to 9 (7%) of ctDNA- pts. Monitoring multiple variants doubled sensitivity of MRD detection compared to tracking a single driver mutation. TTR was shorter in ctDNA+ vs ctDNA- Stage II (HR 23.1, 95% CI 0.28-1900.4; p < 0.00001) and stage III pts (HR 17.9; 95% CI 2.7-117.3, p < 0.00001). TTR of Stage II and III ctDNA- pts was similar (p = 0.7). Conclusions: Our results indicate that ctDNA analysis can detect MRD within days after complete resection of CRC and accurately identifies pts at high risk of recurrence in both Stage II and III CRC. MRD detection via ctDNA sequencing may allow personalization of adjuvant treatment strategies.
Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC).
Authors: Cheng Ann-Lii , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Piscaglia Fabio , Baron Ari David , Park Joong-Won , Han Guohong , Jassem Jacek , Blanc Jean-Frédéric , Vogel Arndt , Komov Dmitry , Evans T.R. Jeffry , López-López Carlos , Dutcus Corina E , Ren Min , Kraljevic Silvija , Tamai Toshiyuki , Kudo Masatoshi
Published: September 2018

4001

Background: SOR is the only approved agent in uHCC and new options are needed. LEN, an inhibitor of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet derived growth factor receptor α, RET, and KIT, showed activity in uHCC in a phase II trial. We report a phase III trial of LEN vs SOR as first-line therapy for uHCC. Methods: In this randomized, open-label, noninferiority (NI) study, pts had uHCC, ≥ 1 measurable target lesion, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy. Pts were randomized 1:1 to LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) or SOR 400 mg twice daily. The primary endpoint was overall survival (OS). The OS hazard ratio (HR) and its 95% CI were estimated with a stratified Cox proportional hazard model. The predefined NI margin was 1.08. Secondary efficacy endpoints were progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR) by modified RECIST. Type I error rates for secondary efficacy endpoints were controlled with a fixed sequence procedure at 2-sided α = 0.05 after OS NI was claimed. Results: 954 Pts enrolled (LEN: 478; SOR: 476). Efficacy outcomes are shown in the table. A similar number of pts in both arms had treatment-emergent adverse events (TEAEs). Most common LEN TEAEs were hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%). Median (range) treatment duration was 5.7 mos (0−35.0) for LEN and 3.7 mos (0.1−38.7) for SOR. 13% Of LEN-treated and 9% of SOR-treated pts discontinued due to adverse events. 33% Of LEN-treated and 39% of SOR-treated pts received second-line therapy. Conclusions: LEN is noninferior in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR, as first line therapy for uHCC. TEAEs were consistent with the known LEN safety profile. Clinical trial information: NCT01761266. [Table: see text]
Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study.
Authors: Janjigian Yelena Yuriy , Ott Patrick Alexander , Calvo Emiliano , Kim Joseph W. , Ascierto Paolo Antonio , Sharma Padmanee , Peltola Katriina Johanna , Jaeger Dirk , Evans T.R. Jeffry , De Braud Filippo G. , Chau Ian , Tschaika Marina , Harbison Christopher T. , Cai Weiguo , Bendell Johanna C. , Le Dung T.
Published: September 2018

4014

Background: In the phase 3 ONO-12 study, 3rd- or later-line nivolumab (N) monotherapy prolonged OS vs placebo in Asian pts with adv G/GEJ cancer (median OS, 5.3 vs 4.1 mo; HR, 0.63; P < 0.0001; ASCO-GI 2017, Kang YK et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). The phase 1/2 CheckMate 032 study showed favorable clinical activity of N ± ipilimumab (I) in Western pts with adv CTx-R G/E/GEJ cancer (NCT01928394). We report updated long-term follow-up data of G/E/GEJ pts in CheckMate 032. Methods: Pts received N 3 mg/kg Q2W (N3), N 1 mg/kg + I 3 mg/kg Q3W (N1+I3), or N 3 mg/kg + I 1 mg/kg Q3W (N3+I1). Primary endpoint was ORR. Secondary endpoints included DOR, OS, PFS, and safety. Efficacy in pts by PD-L1 status was assessed. Results: 160 heavily pretreated pts (79% had ≥ 2 prior Tx) were enrolled (N3, n = 59; N1+I3, n = 49; N3+I1, n = 52); 24% had PD-L1+ (≥ 1%) tumors. ORR was 12% in N3, 24% in N1+I3, and 8% in N3+I1. In pts with PD-L1 ≥ 1%, ORR was 19% (3/16) in N3, 40% (4/10) in N1+I3, and 23% (3/13) in N3+I1; in pts with PD-L1 < 1%, ORR was 12% (3/26), 22% (7/32), and 0% (0/30), respectively. Median DOR was 7.1 mo in N3, 7.9 mo in N1+I3, and NA in N3+I1. OS in all pts and in pts with PD-L1 ≥ 1% is in the Table. Grade 3–4 treatment-related AEs reported in ≥ 10% of pts in any treatment arm were diarrhea (N3, 2%; N1+I3, 14%; N3+I1, 2%), ALT increased (N3, 3%; N1+I3, 14%; N3+I1, 4%), and AST increased (N3, 5%; N1+I3, 10%; N3+I1, 2%). Conclusions: N ± I led to durable responses and long-term OS in heavily pretreated Western pts with adv G/E/GEJ cancer, which is consistent with the clinical activity observed in Asian pts in the ONO-12 study. Safety was consistent with prior reports. These data support ongoing investigation of N ± I in pts with adv G/E/GEJ cancer. Clinical trial information: NCT01928394. [Table: see text]
A randomized phase III trial on the role of esophagectomy in complete responders to preoperative chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC).
Authors: Park Sook Ryun , Yoon Dok Hyun , Kim Jong Hoon , Kim Yong-hee , Kim Hyeong Ryul , Lee Hyun Joo , Jung Hwoon-Yong , Lee Gin-Hyug , Song Ho June , Kim Do Hoon , Choi Kee Don , Lee Jeong Hoon , Ryu Jin-Sook , Cho Kyung-Ja , Kim Sung-Bae
Published: September 2018

4020

Background: To investigate the role of esophagectomy in pts who achieved clinical complete response (cCR) with CRT for locally advanced ESCC. Methods: Pts with resectable cT3-T4a anyN M0 or anyT N+ M0 thoracic ESCC, 20-75 yrs, and ECOG PS ≤2 received 2 cycles of induction XP (capecitabine 1000 mg/m2 bid D1-14 + cisplatin 60 mg/m2 D1 q3w) followed by CRT (50.4 Gy/28 fx, X 800 mg/m2 bid x 5 d/w and P 30 mg/m2 weekly). Pts with cCR were randomized to surgery (S) or observation (O). The primary endpoint was disease-free survival (DFS). Results: From Nov 2012 to March 2016, 86 pts (17.7% of the target number) were enrolled. The slow accrual caused early closure of the study. 81 pts completed CRT, and 38 pts (44.2%) achieved cCR among whom 37 pts were randomized to S (n=19) or O (n=18). The compliance rates differed between the allocated arms (68.4% in the S arm vs 100% in the O arm; P=0.020). In both Intent-to-treat (ITT) and as-treated analysis, there were no significant differences in DFS, PFS, TTP, and OS in both arms although the S arm tended to have better DFS, PFS and TTP than the O arm (Table 1). In the as-treated analysis, the relapse rate was 23.1% (3/13) in the S arm and 45.8% (11/24) in the O arm ( P=0.288). All 10 locoregional only relapse in the O arm were considered resectable, of whom 8 pts underwent surgery (n=7) or endoscopic dissection (n=1). In the as-treated analysis, the S arm had a higher R0 resection rate (92.3% vs 42.9%; P=0.031) and lower pTNM stages ( P=0.0005) than the O arm. Conclusions: Watchful waiting might be a valuable option in pts with thoracic ESCC who have cCR to CRT. Further large-scale studies are necessary to confirm our results and to optimize treatment decision in the individual pt. Clinical trial information: NCT01740375. [Table: see text]