bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of supplemental estrogen on the outcomes of NSCLC patients in the SEER-Medicare database.
Authors: Heilbroner Samuel P. , Xanthopoulos Eric , Wang Tony J. C. , Cheng Simon
Published: September 2018

2590

Background: Women with lung cancer have better survival regardless of treatment type. Estrogen has been shown to have cancer-specific and non-cancer effects. However, there is conflicting data on the effect of estrogen hormone therapy on lung cancer incidence and mortality in women. We used the SEER-Medicare database to examine the association of estrogen use with overall and cancer cause specific survival in elderly women with non-small cell lung cancer (NSCLC). Methods: Patients in our cohort were women 65+ years old; were diagnosed with Stage I-IV NSCLC between 2007 and 2012; had Part A and B coverage one year before to one year after diagnosis without supplemental coverage from a HMO; had Part D coverage during the 6 months prior to diagnosis; were not in a nursing home at diagnosis. Using an intention to treat analysis, drug use was defined as having at least one Part D claim for estrogen within six months prior to diagnosis. Event free survival was assessed using a multivariate Cox proportional hazard model accounting for the patient (age, socioeconomic status, race, Charlson score) and tumor (stage, site, histology) characteristics. Results: There were 10,562 patients in our cohort. 688 used estrogen and 9,874 did not. The median age was 75 years with median overall survival of 1.0 year. There was a significant difference in age, socioeconomic status, race, Charlson score, stage, site, and tumor histology between the two groups (p < 0.05 for all). Estrogen use was associated with a significant improvement in overall and cause specific survival on univariate and multivariate regression (see table). Conclusions: Estrogen was associated with a significant improvement in survival. Limitations of this study are inherent to a retrospective claims-based database without knowledge of actual drug use or intent. [Table: see text]
Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204.
Authors: Perez Raymond P. , Riese Matthew John , Lewis Karl D. , Saleh Mansoor N. , Daud Adil , Berlin Jordan , Lee James J. , Mukhopadhyay Sutapa , Zhou Li , Serbest Gul , Hamid Omid
Published: September 2018

3003

Background: ECHO-204 is an ongoing, open-label, phase 1/2 (P1/2) study of epacadostat (E; potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (NSCLC, MEL, OVC, CRC, SCCHN, B-cell NHL [including DLBCL], GBM). Preliminary P1/2 safety and tolerability outcomes for the overall study population and P2 response for select tumor types (SCCHN, MEL, OVC, CRC) are reported. Methods: In P1 dose escalation, pts received E (25, 50, 100, 300 mg BID) + N (3 mg/kg Q2W); in P2 cohort expansion, pts received E (100 or 300 mg BID) + N (240 mg Q2W). Safety/tolerability was assessed in pts receiving ≥1 E + N dose. Response was assessed in RECIST v1.1 evaluable pts; for recently enrolled pt subgroups, only preliminary DCR (CR+PR+SD) is presented. Results: As of 29OCT2016,241 pts (P1, n = 36; P2, n = 205) were enrolled. No DLT was observed in P1. Most common TRAEs (≥15%) in pts treated with E 100 mg (n = 70) and E 300 mg (n = 135) were rash (33% and 22%, respectively), fatigue (26% and 31%), and nausea (24% and 19%). Rash was the most common grade ≥3 TRAE in E 100 mg and E 300 mg subgroups (10% and 12%). TRAEs led to discontinuation in 7% (E 100 mg) and 13% (E 300 mg) of pts. There were no TR-deaths. For the 23 recently enrolled, efficacy-evaluable SCCHN pts treated with E 300 mg, preliminary DCR was 70% (n = 16). Of 30 MEL pts, 8 were treated with E 100 mg and 22 were more recently enrolled and treated with E 300 mg. ORR (CR+PR) and DCR in MEL pts treated with E 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively. Preliminary DCR in MEL pts treated with E 300 mg was 64% (n = 14). Of 29 OVC pts, 18 were treated with E 100 mg and 11 with E 300 mg.ORR and DCR for OVC pts treated with E 100 mg were 11% (n = 2; 2 PR) and 28% (n = 5; 3 SD); for 11 OVC pts treated with E 300 mg, ORR and DCR were 18% (n = 2; 2 PR) and 36% (n = 4; 2 SD).For 25 CRC pts (all E 100 mg), ORR and DCR were 4% (n = 1; PR) and 24% (n = 6; 5 SD).Safety/efficacy evaluations are ongoing for all cohorts. Conclusions: E + N was generally well tolerated up to the maximum E 300-mg dose. P2 ORR/DCR outcomes are promising, particularly in SCCHN and MEL pts. Updated data will be presented at the meeting. Clinical trial information: NCT02327078.
Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells.
Authors: Santomasso Bianca , Park Jae Hong , Riviere Isabelle , Mead Elena , Halton Elizabeth , Diamonte Claudia , Purdon Terence , Senechal Brigitte , Li Daniel , Sadelain Michel , Brentjens Renier J.
Published: September 2018

3019

Background: CD19-specific chimeric antigen receptor (CAR) modified T cells produce high and durable anti-tumor activity, but can be associated with treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity (NTX). NTX is poorly understood and it hasn't been clear where to focus further research. We report cerebrospinal fluid (CSF) data and neuroimaging characteristics of patients (pts) who developed severe NTX (sNTX) during our phase I clinical trial of CD19-specific 19-28z CAR T cells for adult pts with R/R B-ALL, which suggest new avenues for future research. Methods: 51 adult pts with R/R B-ALL were treated with 19-28z CAR T cells following conditioning chemotherapy at MSKCC. We analyzed the incidence and grade of NTX, CRS and correlative biomarkers in blood and CSF. Results: 21/51 treated pts developed sNTX (grade ≥3) complications such as encephalopathy, aphasia, depressed level of consciousness, myoclonus, and seizure. No pt developed grade 5 NTX and, in all but one case, neurologic symptoms fully resolved. We collected CSF by lumbar puncture and blood from 14 pts at the time of peak NTX. sNTX was correlated with pre-infusion disease burden (p = 0.013) and peak CAR T cell expansion in the blood (p = 0.0001), but we found no significant correlation between NTX grade and the CAR T cell concentration in the CSF during NTX. Instead CSF protein level was correlated with neurotoxicity grade (p = 0.0109). The cytokines IL6, IL8, IL10, IFNγ and GCSF were elevated in CSF over serum at the time of NTX and correlated with CSF protein levels (all p < 0.005). These were distinct from serum cytokines significantly associated with sNTX at d3 of T cell infusion: GMCSF, IFNγ, IL15, IL5, IL10, and IL2 (all p < 0.01). 4/21 patients developed a pattern of reversible MRI T2/FLAIR hyperintensity involving the bilateral thalami, dorsal pons, and medulla. Conclusions: NTX is predominantly reversible. MRI findings suggesting transient toxicity to deep grey structures and findings of a CSF-specific cytokine profile expand the hypotheses on the mechanism of NTX. Future studies will focus on determining the etiology of the CSF protein elevation and the distinct cytokine profile. Clinical trial information: NCT01044069.
Cytokine release syndrome (CRS) and neurotoxicity (NT) after CD19-specific chimeric antigen receptor- (CAR-) modified T cells.
Authors: Turtle Cameron John , Hay Kevin Anthony , Gust Juliane , Hanafi Laila-Aicha , Li Daniel , Liles W. Conrad , Wurfel Mark , Harju-Baker Susanna , Myerson David , Gonzalez-Cuyar Luis , Yeung Cecilia CS , Riddell Stanley R. , Maloney David G.
Published: September 2018

3020

Background: CD19 CAR-T cells have produced impressive responses in CD19+ ALL, NHL and CLL. Detailed understanding of the presentation and pathogenesis of CRS and NT will facilitate safe CAR-T cell use in multicenter trials. Methods: We treated 161 adults with B-ALL, NHL or CLL with anti-CD19 CAR-T cells, formulated in a 1:1 CD4/CD8 ratio and infused after lymphodepletion chemotherapy in a dose finding study (NCT 01865617) to identify a MTD in each disease. Results: 133 patients (pts) completed toxicity assessment. CRS developed in 71% (60% gr 1-2, 4% gr 3, 8% gr ≥4). Fever was the first sign of CRS and preceded organ toxicity, allowing safe outpatient administration of CAR-T cells. NT was observed in 40% (19% gr 1-2, 16% gr 3, 5% gr ≥4) and gr ≥3 NT presented a median of 4.5 days after CRS onset. The time from onset to peak of NT was 2 days. CRS and NT were reversible with the exception of 6 pts who died, 4 during the dose-finding phase of the study. In multivariable analyses, higher CAR-T cell dose and malignant B cells in marrow (BM) were associated with CRS; and CAR-T cell dose, malignant BM B cells, more intensive lymphodepletion, and prior neurologic comorbidities were associated with NT. Probability curves of response, CRS and NT in relation to blood CAR-T cell counts show that toxicity mitigation by CAR-T cell dose reduction may be feasible in B-ALL without impairing BM response; however, dose reduction may reduce nodal response in NHL and CLL. Analysis of clinical parameters revealed that pts who later developed severe CRS or NT could be identified early after CAR-T cell infusion by higher fever, greater vascular instability, and more severe hypoalbuminemia. Paired serum-CSF studies and autopsy data suggest blood-brain barrier disruption in severe NT. High serum IL-6, IL-15, MCP-1 and IL-10, and endothelial activation markers on day 1 after infusion correlated with subsequent toxicity, which identifies pts for early intervention to prevent severe toxicity. Conclusions: CAR-T cells can be safely administered in the outpatient setting. Clinical and laboratory biomarkers allow early identification of a small subset of pts who might develop serious toxicity, facilitating study of preventive strategies. Clinical trial information: NCT 01865617.
Maintenance immunotherapy in stage IV cancer patients who have a clinical benefit from chemotherapy.
Authors: Recchia Francesco , Candeloro Giampiero , Rea Silvio
Published: September 2018

3021

Background: Even if patients with stage IV cancer (AC) may have prolonged remissions with chemotherapy (CT), the majority of them, will eventually relapse. In vitro studies suggest that natural killer (NK) cells mediate lytic activity against cancer cell lines and that high expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis. We have shown that low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) increased NK cells and decreased VEGF, in patients with AC and a clinical benefit on CT (Clin Cancer Res 7: 1251, 2001). We hypothesized that IL-2 and RA, increasing NK and decreasing VEGF, could improve disease-free survival (DFS) and overall survival (OS) in a minimal residual disease setting. Primary endpoint was the evaluation of NK cells and VEGF; secondary endpoints were DFS, OS and toxicity. Methods: 500 patients with AC, and a clinical benefit from CT, were given subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg, 5 days/week, 3 weeks/month, until progression. NK cells, VEGF, response and toxicity were assessed every 4 months. Results: After a median follow-up of 112 months (range 63-200), a total of 4400 courses of CT and 2634 courses of immunotherapy were delivered. A statistically significant improvement of NK cells [from a mean of 309 ± 76/mm3 to a mean of 579 ± 74/mm3 (p < 0.001)] and a decrease of VEGF [from a mean of 520 ± 75 pg/mm3 to a mean of 150 ± 12 pg/mm3, (p < 0.001)], were observed. Eighteen-years DFS and OS were 29% and 32%, respectively. A significant improvement, with respect to NCI SEER data (*), was observed in the 5-year OS rate for the most common treated AC: Breast cancer 55% vs. 6% *; Lung cancer 22% vs. 4.3% *; Colorectal cancer 43.5% vs. 21%*. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: Our data show that immunotherapy with IL-2/RA, may determine, with an acceptable toxicity profile, a statistically significant improvement of NK cells, a decrease of VEGF, and better 5-year survival rates with respect to NCI SEER data, for all major stage IV cancers.
Response to first-line chemotherapy regimen to predict efficacy of nivolumab in lung cancer.
Authors: Kaderbhai Coureche Guillaume , Richard Corentin , Fumet Jean david , Aarnink Anne , Ortiz-Cuaran Sandra , Perol Maurice , Foucher Pascal , Coudert Bruno P. , Favier Laure , Lagrange Aurelie , Limagne Emeric , Hofman Paul , Saintigny Pierre , Ghiringhelli Francois
Published: September 2018

3026

Background: Nivolumab is a monoclonal antibody, targeting PD-1 receptor and demonstrating durable clinical benefit in 20% of metastatic NSCLC patients in second and further treatment lines. The expression of one of the PD-1 ligand, PD-L1 assessed by IHC is associated with better outcome. However, robust predictive markers of efficacy are lacking. Methods: 115 pts with stage IV NSCLC (42 squamous, 73 adenocarcinoma) were included in this retrospective study in 4 different institutions. They received nivolumab (3 mg/kg IV Q2W) after at least one line of systemic platinum-based chemotherapy. Response to first line chemotherapy and to nivolumab (RECIST 1.1) was determined on CT scan by two physicians. Association between best response to first-line regimen and PFS, OS or response to nivolumab was determined using both Chi2 and Cox analysis. Results: 46 (40%), 44 (38%) and 25 (22%) patients experimented PR, SD and PD to first-line platinum-based chemotherapy. 25 (22%), 34 (29.5%), 56 (48.5%) experimented PR, SD and PD to nivolumab. 59.5% (53/89) of patients who experimented clinical benefit (SD+PR) to first-line also experimented clinical benefit to nivolumab while only 20% (5/25) of patients with PD as best response to chemotherapy experimented clinical benefit to nivolumab (Chi2 test p = 0.002). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Cox uni and multivariate models included age, histology and performance status underlined that patients with clinical benefit from chemotherapy had improved PFS with nivolumab (P = 0.002) (median PFS on nivolumab regimen of 4.9, 3.3 and 1.8 months for patients with PR, SD and PD to first-line, respectively). Similar results were obtained for OS (P = 0.03). Conclusions: Our data suggest that response to first-line chemotherapy may be a good surrogate marker of response, PFS and OS to post-platinum nivolumab in metastatic NSCLC.
Germ-line biomarkers disrupting microRNA regulatory pathways to predict toxicity and response to anti-PD-1 and anti-PD-L1 therapies.
Authors: Weidhaas Joanne B. , Telesca Donatello , Kalbasi Anusha , Salzman David , Ribas Antoni
Published: September 2018

3040

Background: Identifying responders to developing immune therapies is of high priority, yet identifying patients who will suffer from toxicity, which represents a unique spectrum of side effects, termed immune-related adverse events (irAEs), is critical. The complex host-specific response to immune therapies led us to hypothesize that germ-line mutations, present in both the tumor and in the host’s immune system, may be a source of biomarkers. As there is compelling evidence that recently discovered germ-line mutations disrupting microRNA (miRNA) networks act as biomarkers of treatment response and baseline immune status, we evaluated such mutations in patients treated with these therapies. Methods: Patients treated with anti-PD1 or anti-PDL1 therapy alone and clinically documented response and toxicity were tested with a panel of over 150 vetted germ-line miRNA based biomarkers. Of 85 patients evaluated for response, 75 had melanoma, and 10 had NSCLC. For analysis of toxicity, an additional 4 patients with other cancer types were included. Subjects were classified as responders (Complete, Partial) versus non-responders (Progressive, Stable), or as experiencing low irAEs (grade 0 and 1) versus high irAEs (grade 2 and above). We used Chi-squared analysis for base evaluation and then compared three classification techniques including classification trees, random forests and Bayesian probit regression with non-local priors. We estimated classification performance via leave-one-out cross validation. Results: By Chi-Squared analysis we found over a dozen biomarkers associated with response, and a dozen biomarkers associated with toxicity. These included germ-line mutations in 3’ untranslated regions as well as in miRNA promoter regions. We found that both classification trees and Bayesian probit compared reasonably well with random forests. We found a response signature with a specificity of 89% by Random Forests, and a toxicity signature with a specificity of 76% by Random Forests. Conclusions: We have shown that a new class of germ-line mutations disrupting miRNA regulatory networks can act as biomarkers of response and toxicity to anti-PD1 and anti-PDL1 therapy.
Feasible and efficient identification of neoantigens for personalized cancer immunotherapy in advanced refractory epithelial cancer patients.
Authors: Chen Fangjun , Zou Zhengyun , Du Juan , Wei Jia , Shao Jie , Su Shu , Ding Naiqing , Wang Qin , Zhou Shujuan , Sun Zhichen , Liu Baorui
Published: September 2018

3046

Background: Recent genomic and bioinformatic technological advances have made it possible to dissect the immune response to personalized neoantigens encoded by tumor-specific mutations.However, rapid and efficient identification of neoantigens is still fraught with difficulty, and a systematic evaluation of personalized neoantigens based immunotherapy in advanced refractory epithelial tumors is lacking. Methods: Tumor and ctDNA samples from 16 advanced epithelial cancer patients were underwent mutational profiling by cancer-associated genes panel. Neoantigens identification were performed by two strategies: As classic mode, somatic mutations were subjected to in silico analysis to predict potential high-affinity epitopes and mutated peptides were denovo synthesized; Hotspot mutations were matched to our customized driver mutation-derived neoantigens peptide library. Candidate neoepitopes were identified. Approximately 108 neoantigen loaded DC vaccine and 1010 bulk T cells composed of 109 neoantigen reactive CD8+T cells were generated for personlized immunotherapy. Results: Among the sequenced patients, 3 of 4 patients who utilized the classic mode and 6 of 12 patients who performed customized neoantigens library have successfully identified 1~2 neoantigens recognized by autologous T cells, respectively. Subsequently, a total number of 6 patients received immunotherapy targeting personalized neoantigen. To date, one patient with metastatic thymoma is achieving a complete and durable response beyond 9 months. In addition, immune related partial response was observed in another advanced pancreatic cancer patient. The remaining 4 patients achieved prolonged stabilization of disease with median PFS of 8.6 months. Conclusions: Our costomized neoantigens library can provide a novel approach for neoantigens screening in advanced epithelial cancer patients. Besides, targeted sequencing is sufficient for somatic variant and neoantigen identification. The combination of two strategies can accelerate the neoantigen-based translational immunotherapy research into the paradigm of precision medicine.
PD-1 blockade using pembrolizumab in adolescent and young adult patients with advanced bone and soft tissue sarcoma.
Authors: Scheinberg Tahlia , Lomax Anna , Tattersall Martin HN , Thomas David Morgan , McCowage Geoffrey Brian , Sullivan Michael James , Bhadri Vivek
Published: September 2018

3060

Background: Sarcomas represent 1015% of cancers in adolescent and young adult (AYA) patients, and survival for those with metastatic disease or after relapse is poor. Immunotherapy with checkpoint inhibition has improved outcomes in multiple tumour types, but there are limited data on the efficacy of immunotherapy in advanced sarcomas, particularly within the AYA population. Methods: We retrospectively reviewed AYA patients with advanced bone and soft tissue sarcoma who received self-funded pembrolizumab at Chris OBrien Lifehouse and Childrens Hospital Westmead. Initial response was evaluated after cycle three or four using RECIST v1.1 criteria. Results: Fourteen AYA patients with sarcoma received pembrolizumab 2mg/kg IV every 3 weeks from May 2015 to December 2016. Median age was 24 (14  35), male to female was 7:7, ECOG PS was 0  1 in 6 patients, 2 in 6 patients and 3  4 in 2 patients. Malignancy type included three patients with osteosarcoma (OS), five patients with Ewing sarcoma (ES), two patients with synovial sarcoma (SS), two patients with alveolar soft part sarcoma (ASPS), and one patient with each of embryonal rhabdomyosarcoma (RMS) and clear cell sarcoma (CCS). The median number of pembrolizumab doses was four (range 1  16), with one patient still receiving treatment at the time of last follow up. Treatment was generally very well tolerated with no G3-4 toxicity. One patient with ES had an excellent, sustained response; of the two patients with ASPS one had a radiological partial response with an excellent clinical response and one patient achieved stable disease. Three patients (two ES, one RMS) died of disease prior to first scheduled assessment and thus their response was not evaluable. The remaining 8 patients had progressive disease. Conclusions: Our data suggest further evaluation of the role of pembrolizumab in AYA patients with advanced sarcoma is warranted.
Racial disparities in the use of programmed death-1 checkpoint inhibitors.
Authors: O'Connor Jeremy , Seidl-Rathkopf Kathi , Torres Aracelis Z. , You Paul , Nussbaum Nathan C. , Fessele Kristen L. , Darius Katie , Adelson Kerin B. , Yin Emily , Presley Carolyn Jean , Chiang Anne C. , Ross Joseph S. , Abernethy Amy Pickar , Gross Cary Philip
Published: September 2018

3068

Background: There are concerns about racial disparities in access to trials of new cancer drugs, including the programmed death 1 checkpoint inhibitors (anti-PD1s). It is unknown whether these disparities extend to anti-PD1 treated patients in real-world practice. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes more than 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced non-small cell lung cancer (aNSCLC; n = 13,473), metastatic renal cell carcinoma (mRCC; n = 1,537), and advanced melanoma (n = 1,221). Within each cohort, we identified treatment type (anti-PD1 versus non-anti-PD1). Therapy lines containing study drugs were excluded. We used logistic regressions to model the use of anti-PD1s by race, adjusting for factors such as age, sex, stage at diagnosis and line of therapy. Results: Of 16,231 patients in our sample, 4,643 (28.6%) were treated with anti-PD1s. Racial distributions differed for anti-PD1 treated patients compared to non-anti-PD1 treated patients in the aNSCLC cohort (Table: p < 0.01), but not in the mRCC cohort (p = 0.84) or the advanced melanoma cohort (p = 0.96). In bivariate analyses of patients with aNSCLC, anti-PD1 treatment was associated with other race, male sex, stage II at diagnosis, squamous histology, smoking history and line of therapy (all p < 0.05). Adjusted models showed there were no significant differences in likelihood of receiving anti-PD1s when comparing black and white patients undergoing systemic therapy for aNSCLC (aOR for black vs. white: 0.86, 95% CI 0.72-1.02), mRCC (aOR 0.90, 95% CI 0.53-1.49), or melanoma (aOR 2.02, 95% CI 0.42-14.59). Conclusions: Among patients undergoing systemic therapy in a large national network of cancer clinics, we found no significant racial disparities in the use of anti-PD1s. [Table: see text]
Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC.
Authors: Diaz Luis A. , Marabelle Aurelien , Delord Jean-Pierre , Shapira-Frommer Ronnie , Geva Ravit , Peled Nir , Kim Tae Won , Andre Thierry , Van Cutsem Eric , Guimbaud Rosine , Jaeger Dirk , Elez Elena , Yoshino Takayuki , Joe Andrew K. , Lam Baohoang , Gause Christine K. , Pruitt Scott Knowles , Kang S. Peter , Le Dung T
Published: September 2018

3071

Background: Mismatch repair deficient cancers harbor high levels of microsatellite instability and somatic mutations. Treatment with anti-PD-1 antibodies has resulted in durable objective responses in MSI-H cancer. As part of the ongoing, global, multicenter phase 2 studies KEYNOTE(KN)164 and KN158, we assessed the efficacy of pembrolizumab in patients (pts) with MSI-H tumors. Methods: Both studies enrolled pts with MSI-H status determined locally by IHC or PCR. KN164 enrolled pts with MSI-H CRC and ≥2 prior therapies, whereas the multicohortKN158 study included pts with MSI-H non-CRC and ≥1 prior therapy. Eligible pts in both studies received pembrolizumab 200 mg Q3W until progression, unacceptable toxicity, or pt/investigator decision. Tumor response was assessed every 9 wk by independent review per RECIST v1.1. Primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety. Analyses were performed in pts from KN164 and KN158 who had ≥27 wk of follow-up as of Aug 3, 2016 and Oct 19, 2016, respectively. Results: KN164 enrolled 61 pts with MSI-H CRC (90% with ≥2 prior therapies) whereas KN158 included 21 pts with MSI-H non-CRC (42% with ≥2 prior therapies). In KN158 the most common tumor types were endometrial and small intestinal cancer (n = 4 each), cholangiocarcinoma (n = 3), and gastric and pancreatic cancer (n = 2 each). Median follow-up was 7.4 mo for MSI-H CRC and 4.5 mo for MSI-H non-CRC. ORR for MSI-H CRC was 26.2% (95% CI, 15.8%-39.1%), with 15 confirmed responses and 1 unconfirmed response, and ORR for MSI-H non-CRC was 42.9% (21.8%-66.0%), with 8 confirmed responses and 1 unconfirmed response. DCR was 50.8% (n = 31; 37.7%-63.9%) for MSI-H CRC and 66.7% (n = 14; 38.4%-83.7%) for MSI-H non-CRC. Median duration of response was not reached for either MSI-H CRC or non-CRC, and 100% of responses were ongoing. Survival and safety analyses are ongoing. Conclusions: Early results from KN164 and KN158 confirm the robust antitumor activity of pembrolizumab in heavily pretreated pts with MSI-H cancers. Clinical trial information: NCT02628067; NCT02460198.
Mutually exclusive expression of CD73 and PDL1 in tumors from patients (pt) with NSCLC, gastroesophageal (GE) and urothelial bladder carcinoma (UBC).
Authors: Martin Philip , Spitzmueller Andreas , Wu Song , Widmaier Moritz , KORN RENE , Althammer Sonja , Zha Jiping , Higgs Brandon W. , Cooper Zachary , Steele Keith
Published: September 2018

3079

Background: Tumors use multiple means of immune evasion, notably the programmed death-1 (PD1)/PDL1 pathway. Anti-PD1/PDL1 therapy induces anti-tumor activity and has improved pt outcomes. Activation of the immunosuppressive CD39/CD73/adenosine pathway might play a role in pts who do not benefit from anti-PD1/PDL1 therapies. We evaluated expression of CD73 and PDL1 and explored the association between CD73 and intraepithelial (IE) CD8+ cells (TILs) to begin to understand their potential interplay in cancer. Methods: Immunohistochemistry for PDL1, CD73 and CD8 was conducted on tumors of non-squamous NSCLC (NSq) (n=42), GE (n=50), and UBC (n=50). PDL1 and CD73 were scored by image analysis with Definiens software. IE CD8+ TILs were scored semi-quantitatively by a pathologist (0-2 = low; 3-4 = high). Using the top tertile of PDL1 and CD73 for high expression levels, a Fisher’s meta-analysis was calculated across the three indications. Results: Across all tumors, 25% (35/142) were PDL1 high (+), but CD73 low (-) and another 25% (35/142) were CD73+ but PDL1- (p=0.06, see table). This trend for mutually exclusive high expression of PDL1/CD73 was strongest in GE (p<0.01). In the PDL1+ group 76% (35/46) had high IE CD8+ TILs whereas in the CD73+ group only 35% (16/46) had high TILs (p<0.0001 using a proportions test). In the PDL1+/CD73- pt subset 77% (27/35) were CD8+ high vs only 23% (8/35) in the PDL1-/CD73+ subset. Conclusions: The identification of distinct pt subsets based on high PDL1 and/or CD73 expression suggests that tumors have multiple mechanisms of immune evasion. Increased IE CD8+ TILs were associated with PDL1 expression. The finding that PDL1-/ CD73+ tumors have lower IE CD8+ TILs compared to PDL1+/CD73- tumors suggests a role for CD73 in excluding IE TILs. Larger sample sets are needed to confirm these findings and to further explore any relationship with the tumor microenvironment. Our data suggests potential approaches to identify subsets of pts likely to benefit from immunotherapy targeting PDL1 and CD73. [Table: see text]
A phase I study of novel multi-HLA-binding peptides and a new combination of immune adjuvants against solid tumors.
Authors: Matsui Hiroto , Hazama Shoichi , Tamada Koji , Udaka Keiko , Koki Yasunari , Uematsu Toshinari , Arima Hideki , Furukawa Hiroyuki , Miyakawa Tomoya , Doi Shun , Kitahara Masahiro , Kanekiyo Shinsuke , Tokumitsu Yukio , Tokuhisa Yoshihiro , Sakamoto Kazuhiko , Suzuki Nobuaki , Takeda Shigeru , Yamamoto Shigeru , Yoshino Shigefumi , Nagano Hiroaki
Published: September 2018

3086

Background: Based on the exploratory analysis of our previous studies of peptide vaccine, we concluded that the combination of adjuvants hLAG-3Ig + Poly-ICLC is essential for controlling negative immune checkpoints and enhancing the induction of CTLs to overcome the traditional peptide studies. Another issue with peptide vaccines is human leukocyte antigen (HLA) restriction. Hence, we developed novel multi-HLA-binding peptides derived from the tumor antigens, HSP70 and GPC3, and confirmed the high expression in many types of cancer. Methods: For the identification of peptides, HSP70- and GPC3-derived peptides that have high binding affinity to each of HLA-A2402, 0201, and 0206 were selected as candidate peptides by a binding prediction system (NEC Corporation). We then identified priority candidate peptides by using a peptide-binding assay. Using peripheral mononuclear blood cells from cancer patients, CD8+ T lymphocytes were stimulated with the candidate peptides, and an enzyme-linked immunospot assay was performed. Finally, we identified HSP70- and GPC3-peptide. In this phase I study of a novel peptide cancer vaccine for metastatic solid cancer, primary objective was to evaluate its safety and toxicity. Secondary objective was to examine the immune and clinical response, and also to determine the recommendable dose. This study used a three-tiered dose-escalation strategy with 3 patients’ cohorts. In addition to the 3 scheduled cases, 3 more cases were added and 6 cases were enrolled at the recommended dose. Results: Twelve HLA-A*24:02-, 02:01-, and 02:06-matched patients (esophagus, 3; colon, 4; liver, 3; pancreas, 1; stomach, 1) were treated in this study. No severe adverse effects related to the treatment were encountered. Peptide-specific CTL induction with HSP70 and GPC3 was observed in 10 and 11 patients, respectively. We observed decreased tumor marker expression in 6 cases, and disease control was observed in f5 patients (4, 3, 8, 2, 2 months, respectively). Conclusions: The combination cancer vaccine therapy using multi-HLA-restricted peptides and hLAG-3Ig + Poly-ICLC was safe and effective for treating solid tumors; it therefore warrants further clinical studies. Clinical trial information: UMIN000020440.
Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial.
Authors: Stintzing Sebastian , Wirapati Pratyaksha , Lenz Heinz-Josef , Neureiter Daniel , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Kahl Christoph , Kullmann Frank , Moehler Markus H. , Scheithauer Werner , Held Swantje , Modest Dominik Paul , Jung Andreas , Kirchner Thomas , Tejpar Sabine , Heinemann Volker ,   FIRE-3 Investigators
Published: September 2018

3510

Background: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. CMS is grouping CRCs according to their gene-signature in 4 different types. Relevance of CMS for the treatment of mCRC remains unclear. Methods: Patients were grouped according to tumor CRC-CMSs. Using ALMAC’s Xcel tissue array, gene signatures of FIRE-3 tumor samples were analyzed. Survival was compared using Kaplan-Meier estimation and log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. Results: CMS classification could be determined in 385 specimens available from the ITT population (n = 592). In this KRAS exon 2 wt population (n = 385), frequencies were: CMS1 (10.4%), CMS2 (36.6%), CMS3 (11.7%), CMS4 (29.1%), non-consensus (12.2%). In RAS wt (n = 315), frequencies were: CMS1 (11.1%), CMS2 (38.1%), CMS3 (9.5%), CMS4 (29.5%), non-consensus (11.7%). Independent of the treatment, CMS was a strong prognosticator for ORR (p = 0.023), PFS (p < 0.001) and OS (p < 0.001). For data on CMS and treatment efficacy in the RAS wt population see the following table. Conclusions: CMS classification is prognostic for mCRC. The survival benefit in RAS wt previously observed for FOLFIRI cetuximab vs. FOLFIRI bevacizumab is not significantly different across CMS groups, although there are trends when comparing OS HR between categories with CMS4 showing the best HR. [Table: see text]
Comparison of long-term survival outcomes between laparoscopic and open surgery for mid or low rectal cancer treated with preoperative chemoradiotherapy: 7-year follow-up of COREAN trial.
Authors: Park Ji Won , Jeong Seung-Yong , Kang Sung-Bum , Joo Jungnam , Song Mi Kyung , Lim Seok-Byung , Choi Hyo Seong , Kim Duck-Woo , Chang Hee Jin , Kim Dae Yong , Jung Kyung Hae , Kim Tae-You , Kang Gyeong Hoon , Chie Eui Kyu , Kim Sun Young , Sohn Dae Kyung , Kim Jae-Sung , Lee Hye-Seung , Kim Jee Hyun , Oh Jae Hwan
Published: September 2018

3518

Background: Laparoscopic surgery for rectal cancer has been used widely. However, recent two randomized trials raised concerns about short-term oncologic safety of laparoscopic surgery for rectal cancer. The aim of this study was to evaluate the long-term oncologic safety of laparoscopic surgery for rectal cancer based on 7-year data from the Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial. Methods: COREAN trial was a non-inferiority, randomized controlled trial. Between April, 2006, and Aug, 2009, eligible participants with mid or low rectal cancer treated with preoperative chemoradiotherapy were randomly assigned (1:1) to laparoscopic (n = 170) or open surgery (n = 170). Seven-year outcomes included overall and disease-free survival, and local recurrence. Log-rank test and stratified Cox regression analysis were used for survival analysis. Analysis was by intention to treat. Results: The median follow-up times were 84 months (IQR: 61.5-97.0). No differences were found between laparoscopic and open surgery group in terms of overall and disease-free survival, and local recurrence (7-year overall survival: 83.2% [laparoscopic] vs 77.3% [open], p = 0.48; 7-year disease-free survival: 71.6% [laparoscopic] vs 64.3% [open], p = 0.20; 7-year local recurrence: 3.3% [laparoscopic] vs 7.9% [open], p = 0.08). Stratified Cox regression analysis adjusted for ypT, ypN and tumor regression grade showed no significant difference between groups in terms of overall and disease-free survival, and local recurrence. The hazard ratios for overall survival, disease-free survival and local recurrence (open vs laparoscopic surgery) were 0.96 (95% CI = 0.58-1.57), 1.03 (95% CI = 0.70-1.53), and 2.28 (95% CI = 0.82-7.16), respectively. Conclusions: The 7-year analysis confirm the long-term oncological safety of laparoscopic surgery for rectal cancer treated with preoperative chemoradiotherapy. The use of laparoscopic surgery does not compromise the long-term survival outcomes in rectal cancer. Clinical trial information: NCT00470951.
Colorectal cancer (CRC) patients surveyed by 18FDGPET-CT (PET-CT): An open-label multicenter randomized trial (NCT 00624260).
Authors: Sobhani Iradj , Baumgaertner Isabelle , Itti Emmanuel , Luciani Alain , Layese Richard , Natella Pierre Andre , Gornet Jean Marc , Andre Thierry , Goujon Gael , Aparicio Thomas , Taieb Julien , Bachet Jean-Baptiste , Ducreux Michel , Tournigand Christophe , Hemery Francois , Durand-Zaleski Isabelle , Bastuji Garin Sylvie
Published: September 2018

3520

Background: Curative surgery is the best therapy of CRC and recurrences. We assessed whether adding semi-annual PET-CT to the usual surveillance would be cost-effective in high risk recurrent CRC patients. Methods: CRC patients (stage II tumor perforated, stages III and IV) in remission after curative surgery were randomly assigned (1:1) to trimester usual surveillance (control) or usual surveillance + semi-annual course PET-CT (intervention) for a 3-yr follow up period. Every 3 months, multidisciplinary committee decided about recurrence by yes/no/doubtful. If yes, curative surgery alone (when relevant), or chemotherapy alone (unresecable recurrence) were conducted; additional exams could be performed if doubtful. Primary composite endpoint (failure) comprised unresectable recurrence & death. The economic assessments according to standards (CHEERS) were performed and costs were compared between groups. Statistical tests for calculation of the relative risk (RR) were used and survival was analyzed using Kaplan-Meier method, Log-Rang test and Cox models. Results: Baseline characteristics of 239 patients (120/119) enrolled in 12 centers were balanced. The failure rate was 29.2% (31 unresectable recurrences & 4 deaths) and 23.5% (27 & 1) in Interventional vs Control, respectively with no significant difference (RR = 1.24, 95% CI: 0.81-1.90; P = .32). Similar results were observed in multivariate analysis (Cox models) adjusted for stage and tumor differentiation (HR = 1.33, 95% CI: 0.8-2.19, P = .27). Period until the unresectable recurrence was significantly shorter in Interventional (median = 7; IQR: 3-20 months) than in Control group (14.3; 7.3-27; P= 0.016). This was consistent with lower elevation (median; IQR) of tumour marker in interventional (3.8; 2.8-19) than in control group (10; 5.2-28.6) at the first recurrence time as compared to the baseline (p = 0.007). Overall (mean; SD) cost (euros)/patient was higher in the PET-Scan (9385; 11658) than in the control group (7027; 7656). Conclusions: Although recurrences were detected earlier in PET-CT group, the strategy was less effective, more expensive. This exam should not be advised routinely. Clinical trial information: NCT 00624260.
A large multicenter study evaluating prognosis and chemosensitivity of metastatic colorectal cancers with microsatellite instability.
Authors: Tougeron David , Sueur Benjamin , Sefrioui David , Gentilhomme Lucie , Lecomte Thierry , Aparicio Thomas , DES Guetz Gaetan , Artru Pascal , De La Fouchardiere Christelle , Moulin Valérie , Hautefeuille Vincent , Coriat Romain , Touchefeu Yann , Lecaille Cedric , Gael Goujon , Ferru Aurélie , Tourani Jean-Marc , Emambux Sheik , Taieb Julien , Zaanan Aziz
Published: September 2018

3536

Background: Deficient Mismatch Repair (dMMR) in colorectal cancers (CRC) represent 12% of all tumors. In non-metastatic CRC setting, dMMR are associated with good prognosis but also with resistance to adjuvant 5-FU chemotherapy. In metastatic CRC (mCRC) setting, dMMR is found in less than 5% and its influence on prognosis and treatment response is little known. Methods: This multicenter retrospective study included all consecutive patients with dMMR mCRC treated between 2005 and 2015 in 17 centers. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Prognostic variables were evaluated in univariate analysis using the Log rank test and in multivariate analysis using the Cox regression model. Results: A total of 198 patients with dMMR mCRC were included (median age 64.6 years). dMMR mCRC were mostly diagnosed with synchronous metastases (59%) and frequent peritoneal carcinosis (43%). Lynch syndrome was found in 34% of cases and 36% of tumors had a BRAFV600E mutation. Median OS was 20.6 months. A low risk Kohne's prognostic index (HR = 0.40 [0.22-0.72], p = 0.02) and absence of peritoneal carcinosis (HR = 0.51 [0.29-0.90], p = 0.02) were associated with better OS in multivariate analysis. Main first-line regimens were 5FU-based (n = 20), oxaliplatin-based (n = 75) or irinotecan-based (n = 46) chemotherapy. Median PFS on first-line treatment was 5.9 months. The objective response rate (ORR) was 0%, 19% and 36% for 5FU-based, oxaliplatin-based and irinotecan-based chemotherapies, respectively (p = 0.02). A trend for a longer PFS (3.3, 5.5 and 10.2 months, respectively, p = 0.06) and OS (17.7, 21.1 and 34.2 months, respectively, p = 0.05) was also observed for irinotecan-based chemotherapy. The addition of bevacizumab to chemotherapy was associated with a significant increase of ORR (p = 0.01) and PFS (p = 0.04) as compared to the addition of an anti-EGFR therapy. Conclusions: This study suggests that dMMR mCRC are associated with poor prognosis and chemoresistance, especially to 5FU-based chemotherapy. Efficacy of irinotecan and bevacizumab should be evaluated in a prospective trial in combination with immune checkpoint inhibitors.
Concordance of DNA mismatch repair deficient (dMMR)/microsatellite instability (MSI) assessment by local and central testing in patients with metastatic CRC (mCRC) receiving nivolumab (nivo) in CheckMate 142 study.
Authors: Kopetz Scott , Lonardi Sara , McDermott Raymond S. , Aglietta Massimo , Hendlisz Alain , Morse Michael , Leach Joseph W. , Neyns Bart , Chan Emily , Chen Franklin , Wong Ka Yeung Mark , Lee James J. , Garcia-Alfonso Pilar , Hill Andrew G , Lenz Heinz-Josef , Desai Jayesh , Moss Rebecca Anne , Cao Z. Alexander , Overman Michael J. , Andre Thierry
Published: September 2018

3548

Background: MMR or MSI testing is recommended for mCRC pts and is often done locally by IHC or PCR testing, respectively (NCCN V1.2017) Nivo, a fully human anti-PD-1 mAb, demonstrated durable responses and a 12-mo OS rate of 73.8% in pts with mCRC locally assessed for dMMR/MSI-H status in the CheckMate 142 study (NCT02060188; Overman M, et al. 2017). Here we describe the results of local and central testing with respect to MMR/MSI status and clinical outcomes in the CheckMate 142 study. Methods: MMR/MSI status was assessed locally on archival tumor using IHC/PCR at screening and confirmed centrally by PCR (modified Bethesda panel) testing of tumor biopsy at enrollment. dMMR was defined by IHC as a loss of expression in ≥1 mismatch repair proteins. Stable microsatellite (MSS), low MSI (MSI-L), and high MSI (MSI-H), were defined as instability in 0, 1, or ≥2 markers, respectively. Pts with dMMR/MSI-H mCRC who progressed on or were intolerant of ≥1 prior line of therapy received nivo 3 mg/kg Q2W. Results: 74 pts were dMMR/MSI-H by local testing. Of these pts, 53 (72%) were centrally confirmed as MSI-H, 7 pts had insufficient tissue sample for PCR testing, and 14 pts had a central test that did not match local test results. Of the 14 pts, 3 pts with a clinical history of LS were identified locally as dMMR but centrally as MSS (Table). INV-reported ORR was 31.1% in 74 pts locally determined as dMMR/MSI-H, 35.8% in 53 pts locally and centrally confirmed as MSI-H, and 21.4% in 14 pts not centrally confirmed as MSI-H. Conclusions: The similar clinical activity between pts locally confirmed as MSI-H and pts who were centrally confirmed as MSI-H suggest local testing is appropriate for identifying the dMMR/MSI-H pts who may benefit from nivo monotherapy. Clinical trial information: NCT02060188. [Table: see text]
Prolonged (PI) vs short-term irinotecan (STI) administration: The Martha trial—A SICOG (Southern Italy Cooperative Oncology Group) randomized phase III study in the first-line setting of metastatic colorectal cancer (mCRC) patients (pts).
Authors: Formica Vincenzo , Ionta Maria Teresa , Giacomo Vessia , Maiorino Luigi , Casaretti Rossana , Natale Donato , Barberis Giuseppe , Filippelli Gianfranco , Greco Ettore , Blasi Livio , Mancarella Sergio , Russo Anna , Barbato Enrico , Di Lullo Liberato , Roselli Mario
Published: September 2018

3552

Background: FOLFIRI+bevacizuamab(B) is a standard first-line regimen for mCRC pts. It should be delivered until progression, though an early switch to a de-intensified maintenance regimen is often adopted because of toxicity. The MARTHA trial compared FOLOFIRI+B for 6 months(mo) followed by maintenance B monotherapy up to 12mo (PI arm) vs FOLOFIRI+B for 3mo followed by capecitabine+B for further 3mo followed by B monotherapy up to 12mo (STI arm). Methods: Chemotherapy-naïve pts with histologically confirmed mCRC and measurable disease were deemed eligible and randomized to PI or STI arm in a 1:1 ratio. Co-primary endopoints were progression free (PFS) and overall survival (OS). The Kaplan-Meier method was used for survival analysis. A novel analysis (the Death Pace Analysis, DPA) was performed to identify pts benefiting more from a specific treatment. A multivariable logistic regression analysis (MLRA) was used to identify clinicopathological predictors of DPA-defined patient subsets. Results: 199 pts (100 in PI arm, 99 in STI arm) were enrolled. A non-significant superior OS was observed for STI (HR 0.81, p 0.26), no PFS differences were seen. The DPA demonstrated a 6% of pts identifiable as STI-benefiting pts. According to MLRA including 15 common clinicopathological variables, baseline Hemoglobin (Hb) level was the only independent predictor of the DPA-defined STI-benefit status (OR 2.3, p 0.009, i.e. 2.3-fold increased risk of not being a STI-benefiting patient for 1-point increase in Hb). Indeed, among pts with low baseline Hb ( < 13 gr/dL, cutoff determined upon ROC analysis), n = 128, a statistically significant prolonged OS was observed for STI over PI arm (median OS: 21.8 vs 14.4 mo, respectively, HR 0.64, p 0.04).No survival difference was seen between arms in pts with high Hb. Conclusions: mCRC pts with low baseline Hb levels are better treated with a STI first-line strategy. Published preclinical data suggest that low Hb may increase the risk of developing early chemo-resistant and aggressive disease with the prolonged use of irinotecan. Clinical trial information: EudraCT 2008-004890-17.