bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC).
Authors: Tabernero Josep , Melero Ignacio , Ros Willeke , Argiles Guillem , Marabelle Aurelien , Rodriguez-Ruiz Maria E. , Albanell Joan , Calvo Emiliano , Moreno Victor , Cleary James M. , Eder Joseph Paul , Karanikas Vaios , Bouseida Said , Sandoval Federico , Sabanes Daniel , Sreckovic Sasha , Hurwitz Herbert , Paz-Ares Luis G. , Saro Suarez Jose M. , Segal Neil Howard 
Published: September 2018

3002 Background: CEA CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. In preclinical models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and upregulates PD-1/PD-L1. Methods: Intwo ongoing dose-escalation phase I studies, RO6958688 is given as monotherapy (S1) i.v. QW or in combination (QW) with atezolizumab 1200 mg Q3W (S2) in adult patients (pts) with advanced CEA+ solid tumors. In S1, 80 pts (mCRC: 68) were treated at dose levels from 0.05 mg to 600 mg; in S2, 38 pts (mCRC: 28) from 5 mg to 160 mg. In S1, a Bayesian logistic regression model with overdose control guided dose escalation. Data cutoff 25.01.17. Results: At doses ≥60mg (36 pts in S1; 10 in S2), CT scans revealed tumor inflammation within days of first dose, consistent with the mode of action of RO6958688. 2 (5%) pts in S1 (both microsatellite stable (MSS) and 2 (20%; 1 MSS) in S2 had a partial response (RECIST v1.1). Preliminary tumor size reduction ( > -10% and < -30% [stable disease]) was observed in 4 (11%) additional pts in S1 and 5 (50%) in S2. At week 4-6 FDG PET scan assessment, 10 (28%) pts with mCRC in S1 and 6 (60%) in S2 had a metabolic partial response (EORTC criteria). At all doses in S1, the most common related AEs were pyrexia (56.3%), infusion related reaction (IRR, 50%) and diarrhea (40%). The most common grade ≥ 3 (G3) related AEs were IRR (16.3%) and diarrhea (5%). 5 patients experienced DLTs: G3 dyspnea, G3 diarrhea, G3 hypoxia, G4 colitis and G5 respiratory failure (G4-5 at 600mg). DLT events were likely associated with tumor lesion inflammation. In S2, there was no evidence of new or additive toxicities, with 1 DLT at 160 mg (G3 transient increase of ALT in a patient with liver metastases). PK/PD data are reported separately. Conclusions: Evidence of antitumor activity was observed with RO6958688 monotherapy in ongoing dose escalation. Activity appeared to be enhanced with doses in combination with atezolizumab, with a manageable safety profile. Updated data will be presented. Clinical trial information: NCT02324257 and NCT02650713.
Preliminary results from a phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors.
Authors: Gulley James L. , Heery Christopher Ryan , Schlom Jeffrey , Madan Ravi Amrit , Cao Liang , Lamping Elizabeth , Marte Jennifer L. , Cordes Lisa M , Christensen Olaf , Helwig Christoph , Strauss Julius 
Published: September 2018

3006 Background: M7824 (MSB0011359C) is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the soluble extracellular domain of transforming growth factor-β (TGF-β) receptor II, which acts as a TGF-β trap. We report preliminary data from a phase 1 trial of M7824 in patients (pts) with advanced solid tumors. Methods: NCT02517398 is a phase 1, open-label, 3+3 dose-escalation study. Eligible pts receive M7824 at 1, 3, 10, or 20 mg/kg Q2W until confirmed progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is generally allowable. The primary objective is to determine the safety and maximum tolerated dose of M7824; secondary objectives include pharmacokinetics (PK), immunogenicity, and best overall response per RECIST v1.1. Results: 16 heavily pretreated pts with ECOG performance status 0-1 have received M7824. Our PK data show a dose-linear increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-L1 and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in 3 pts (skin infection secondary to grade 2 bullous pemphigoid [BP], lipase increased, and colitis with associated anemia); there were no grade 4-5 drug-related TEAEs. BP and colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were considered dose limiting in 1 pt. There was preliminary evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease (pancreatic; carcinoid). Conclusions: Preliminary data from this phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in pts with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. Clinical trial information: NCT02517398.
Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.
Authors: Curti Brendan D. , Richards Jon M. , Hallmeyer Sigrun , Faries Mark B. , Andtbacka Robert Hans Ingemar , Daniels Gregory A. , Grose Mark , Shafren Darren 
Published: September 2018

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.
PRKDC: A new candidate for checkpoint blockade immunotherapy?
Authors: Chen Ming Huang , Tan Kien Thiam , Cheng Jen Hao , Fang Wen-Liang , Yeh Yi Chen , Yeh Chun-Nan , Chang Yu Chan , Chen Shu-Jen , Hsiao Michael , Chao Yee 
Published: September 2018

3022 Background: Immunologic checkpoint blockade with antibodies that target CTLA-4 or PD-1/PD-L1 have demonstrated promise in a variety of malignancies. However, the treatment response rate of these immunologic checkpoint blockades remains low. Identifying predictive biomarkers to assist patient selection for immunotherapy have become a priority in both clinical and research settings. Methods: Mutations in patients who responded to immunotherapy were identified by Next-Generation Sequencing (NGS). Relationship between mutation of PRKDC, mutation load and known immune biomarkers were analyzed using datasets from The Cancer Genome Atlas (TCGA). Following up, the PRKDC protein expression was evaluated in 439 gastric cancer patients by immunohistochemical staining and their MSI statuses were evaluated by PCR. Results: We first identified PRKDC mutations in two responders to immune checkpoint therapy (1 HCC, 1 gastric cancer). From published literature, we further discovered that 66.7% (2/3) of lung cancer patients and 63.6% (7/11) of melanoma patients whose tumor harbored PRKDC mutation and responded to immunotherapy. Most of these mutations detected in responders were either truncating or located in functional domains. Further analysis showed that PRKDC mutation is significantly associated with high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer ( p= 0.008, p= 0.0108, p= 0.0166, p= 0.0183, p< 0.001 and p< 0.001, respectively). Interestingly, gastric cancer patients harboring PRKDC mutations or with MSI-H demonstrated significantly higher gene expression in PDL1, TIM3, LAG3, IFNG, CXCL9, CXCL10, GZMA and PRF1, compared to MSS patients ( p= 0.0016, p= 0.0142, p= 0.0017, p= 0.0034, p= 0.0118, p< 0.0001, p= 0.0001, p< 0.0102, respectively). Finally, we discovered low expression of PRKDC was a poor prognostic factor and significantly correlated with MSI-H in gastric cancers. Conclusions: PRKDC may be a potential biomarker that can identify responders to immune checkpoint inhibition.
Biologic and clinical relevance of an IFNG mRNA signature (IFNGS) and PD-L1 protein expression in tumor and immune cells in urothelial cancer (UC) patients (pts) treated with durvalumab (D).
Authors: Bais Carlos , Kuziora Michael , Morehouse Chris , Higgs Brandon W. , Raja Rajiv , Lee Young , de Los Reyes Melissa , Rebelatto Marlon , Steele Keith , Jin Xiaoping , Shi Li , Pilataxi Fernanda , Ben Yong , Antal Joyce , Gupta Ashok Kumar , Ranade Koustubh 
Published: September 2018

3037 Background: PD-L1 can be induced by IFNG in tumor cells (TC) and immune cells (IC). TC PD-L1 expression prevalence in UC is low and the relevance of scoring TC (in addition to IC) is not fully understood. We recently reported a positive correlation between high levels of an IFNGS and outcome in a cohort of 30 UC pts treated with D. Here, we assessed the potential predictive value of the IFNGS in an additional 32 pts (total N = 62) and further explored the relationship between the IFNGS and TC and/or IC PD-L1 IHC expression patterns. Methods: Study CP1108 was a phase 1/2 trial evaluating D in pts with solid tumors; 191 UC pts received 10 mg/kg D with median follow up of 8.4 mo. 144 of these pts have available ORR and PD-L1 data and 62 pts have ORR, PD-L1 and IFNGS data. Pts with ≥25% TC or IC were scored as PD-L1 high (TC+ or IC+). Pts within the top tertile of IFNGS ( LAG3, PDL1, CXCL9, and IFNG mRNAs) tumor expression were scored positive. Cox proportional hazards models were used adjusting for age, gender, ECOG, smoking status, line of therapy, and liver metastasis at baseline. ORR was evaluated using RECIST v1.1. Results: IFNGS+ pts had increased ORR (45 vs 16%) and improved PFS (adj HR 0.3; p = 0.005) and OS (adj HR 0.18; p = 0.016) over IFNGS- pts. IFNGS expression was significantly higher in pts who were PD-L1 high (TC+/IC+) compared with TC-/IC- (low/negative) pts (mean IFNGS expression 3.5 vs 1.1; p = 0.0155) and also in TC+ or IC+ vs TC-/IC- (mean IFNGS 2.2 vs 1.1; p = 0.000127). TC-/IC+ and TC+/IC- groups had a mean IFNGS expression of 2 and 2.2 respectively. ORR in all 1108 UC pts with available IHC and ORR data (N = 144) was 29% for TC+/- pts, 36% in TC-/IC+ pts, and 7% in the TC-/IC- pts. Conclusions: IFNGS predicted improved outcomes in a cohort of 62 2L+ UC pts treated with D. TC-/IC- PD-L1 pts had lowest levels of IFNGS expression. Observations that TC+ (and IC+) pts contribute to IFNGS enrichment and that TC+/IC-, and TC-/IC+ pts have increased response vs TC-/IC-pts provides rationale for TC+ inclusion (in addition to IC+) in the SP263 PD-L1 scoring algorithm for UC. IFNGS is an additional potential predictive biomarker in UC pts that warrants further investigation.
Peritoneum metastasis (PM) as a prognostic factor in metastatic gastric cancer (MGC) treated with anti-PD-1/PD-L1 monotherapy.
Authors: Narita Yukiya , Sugiyama Keiji , Mitani Seiichiro , Honda Kazunori , Masuishi Toshiki , Taniguchi Hiroya , Kadowaki Shigenori , Ura Takashi , Ando Masashi , Tajika Masahiro , Muro Kei 
Published: September 2018

3051 Background: Anti-PD-1 monotherapy has proven effective for the patients (pts) with MGC. However, the identification of biomarkers for predicting clinical outcomes remain as critical needs. We aimed to identify baseline characteristics associated with time to treatment failure (TTF) or overall survival (OS) for anti-PD-1/PD-L1 monotherapy as second- or later-line therapy in MGC. Methods: Routine blood count parameters and clinical characteristics at baseline were retrospectively investigated in 31 pts with MGC in Aichi Cancer Center Hospital. Endpoints were TTF and OS following anti-PD-1/PD-L1 monotherapy. Kaplan-Meiyer and Cox regression analysis were applied for survival analyses. Results: Patient characteristics were as follows: median age (range), 68 (47–83); ECOG performance status (PS) 0/1, 21/10; PM +ve/-ve, 12/19; No. of metastatic sites 1–2/≥3, 18/13; No. of prior chemotherapy regimens 1–2/≥3, 11/20; and absolute eosinophil count (AEC) <150/≥150 /μl, 14/17. Objective response rate and disease control rate (RECIST ver. 1.1) were 26% vs. 0% (odds ratio [OR], 3.76; P = 0.12) and 79% vs. 50% (OR, 3.58; P = 0.12) in the PM -ve group (Cohort A) and the PM +ve group (Cohort B), respectively. On univariate analysis, the pts with poor PS, PM +ve, and high AEC were significantly poor TTF; and poor PS and PM +ve were significantly identified as prognostic factors of poor OS. On multivariate analysis, only PM +ve was independent negative impact not only for TTF but also for OS. Median TTF and OS were 5.4 vs. 1.3 months (M) (adjusted hazard ratio [HR], 4.29; 95%CI, 1.60–11.5; P < 0.01) and 28.2 vs. 7.5 M (adjusted HR, 3.68; 95%CI, 1.25–10.8; P = 0.02) in Cohort A and Cohort B. Six-months TTF probabilities of 42% vs. 0% ( P = 0.03) and one-year OS probabilities of 58% vs. 8% ( P< 0.01) were observed in Cohort A compared to in Cohort B. Conclusions: PM -ve in the pts treated with anti-PD-1/PD-L1 monotherapy was associated with better efficacy. In the pts with PM -ve, anti-PD-1/PD-L1 monotherapy could be adapted in first-line therapy. [Table: see text]
Durvalumab and tremelimumab in metastatic breast cancer (MBC): Immunotherapy and immunopharmacogenomic dynamics.
Authors: Santa-Maria Cesar Augusto , Kato Taigo , Park Jae-Hyun , Flaum Lisa E. , Jain Sarika , Tellez Claudia , Stein Regina Michelle , Shah Ami N. , Gross Leeaht , Uthe Regina , Gradishar William John , Cristofanilli Massimo , Nakamura Yusuke , Giles Francis J. 
Published: September 2018

3052 Background: PD-1/PD-L1 inhibitors produce modest responses in MBC; adding CTLA-4 inhibitors can augment anti-tumor activity in other cancers. Immunopharmacogenomics characterize immune-cancer cell interactions and may predict response. Methods: A single arm study was designed to determine the efficacy of durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor), and immunopharmacogenomics in pts with metastatic ER+ or TNBC. The primary clinical endpoint was to assess ORR using a Simon 2-stage design (28 pts needed for type 1 error rate of 4%, 80% power). 18 pts were enrolled in the first stage; ≥4 responses were needed to proceed with the second stage. Pts were treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks to complete 1 year of therapy (option to renew for an additional year); biopsies at baseline and 2 months were collected. T-cell receptor (TCR) sequencing using mRNA isolates was conducted at baseline and 2 months, whole exome sequencing and immune-gene expression profiling were conducted at baseline. Results: From 01-09/2016, 18 evaluable pts were accrued (11 ER+; 7 TNBC). Responses are shown in the table below; the ORR did not meet criteria to proceed to the second stage. Notably, one pt with TNBC with PD had pseudoprogression, thus 5/7 (71%) pts with TNBC had clinical benefit. Median PFS was 3.8 months (95%CI 2.2-11.2) for the entire cohort (TNBC not reached), and median OS has not been reached. No grade 4 AEs were observed; grade 3 immune-related AEs included hepatitis (n = 3), nephritis (n = 1), and myocarditis (n = 1). Proportions of abundant TCR-β clonotypes (≥ 0.5% frequency) were increased in 2-month samples compared to baseline in TNBC compared to ER+, p = 0.004, and associated with responses. Remaining correlative analysis is ongoing and will be presented at ASCO. Conclusions: Response rates to PDL-1 and CTLA-4 inhibition were low in unselected MBC, however, high rates of clinical benefit were observed in TNBC. Immunopharmacogenomic may help identify phenotypes most likely to respond. Future studies in TNBC are warranted to confirm findings. Clinical trial information: NCT02536794. [Table: see text]
Phase 2 study of pembrolizumab in combination with azacitidine in subjects with metastatic colorectal cancer.
Authors: Lee James J. , Sun Weijing , Bahary Nathan , Ohr James , Rhee John C. , Stoller Ronald G. , Marks Stanley M. , Lembersky Barry C. , Beasley H. Scott , Drummond Summer , Streeter Natalie , Shuai Yongli , Lin Yan , Herman James , Zarour Hassane M. , Chu Edward 
Published: September 2018

3054 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has relatively poor tumoral infiltration of CD8+ T cells and is resistant to pembrolizumab (Pembro) when compared to MSI-H mCRC. DNA hypomethylating agent induces epigenetic expression of multiple genes including cancer-testis antigens in CRC, which are recognized by cytotoxic CD8+ T cells in vitro and in vivo. This trial tested whether concurrent treatment with azacitidine (Aza) could enhance the anti-tumor activity of Pembro. Methods: This is a phase 2 trial to evaluate anti-tumor activity and safety of Pembro plus Aza in patients (pts) with previously treated mCRC without any further standard chemotherapy option. Pts received Pembro 200 mg IV on day 1 of each cycle Q3W and Aza 100 mg daily SQ injection on days 1-5 of each cycle Q3W. Primary endpoint was response rate (ORR) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Tumor tissues were collected for correlative studies. Results: Thirty-one pts were enrolled [median age, 61 years (range, 30-79); 17 M/14 F; ECOG PS 0/1 (58%/42%); 30 pts with MSS mCRC]. Pts received at least 2 lines of prior systemic chemotherapy for mCRC (median, 3; range, 1-5). Thirty pts received at least one dose of study therapy (median, 3 cycles; range, 1-8). Ten pts could not complete the first 3 cycles due to rapid symptomatic tumor progression. One pt with MSS mCRC achieved PR and 3 pts had SD as best response. The ORR was 3% (1/30; 95% CI, 0.1-17%). Seven pts with PD at the end of cycle 3 continued on study therapy, and 2 pts had stabilization of tumor progression. Median PFS was 2.1 months (95% CI, 1.8-2.8), and median OS was 6.2 months (95% CI, 3.5-8.7). While treatment-related adverse events (TRAEs) were reported in 63% of pts, most of the TRAEs were Gr 1/2 (96%). Frequent TRAEs possibly related to Aza were anemia (n = 5), constipation (n = 5), and leukopenia (n = 4); and possibly related to both Aza and Pembro were nausea (n = 5) and fatigue (n = 5). Gr 3 TRAEs included anemia (n = 1), ALT elevation (n = 1), and alkaline phosphatase elevation (n = 1). Conclusions: Pembro plus Aza is feasible with a tolerable safety profile but appears to have minimal anti-tumor effect for MSS mCRC. Clinical trial information: NCT02260440.
Predictive and prognostic value of systemic inflammatory response biomarkers in patients receiving nivolumab for metastatic non-small cell lung cancer (NSCLC).
Authors: Gervais Claire , Boudou-Rouquette Pascaline , Jouinot Anne , Huillard Olivier , Alexandre Jerome , Arrondeau Jennifer , Giraud Frédérique , Chapron Jeanne , Alifano Marco , Revel Marie-Pierre , Dusser Daniel , Damotte Diane , Mansuet-Lupo Audrey , Goldwasser Francois 
Published: September 2018

3055 Background: Nivolumab is the first checkpoint immunotherapeutic agent approved for NSCLC. By enabling host immune-mediated cytotoxic activity against tumor cells, nivolumab induces a tumor response in 15% of patients (pts). However, host-related parameters to predict nivolumab activity are still missing. We evaluated the predictive and prognostic value of the presence of a systemic inflammatory response. Methods: From July 2015 to December 2016, we measured at nivolumab initiation the Glasgow Prognostic Score (GPS), a cumulative prognostic score based on C-reactive protein and albumin, the neutrophil-lymphocyte ratio (NLR), the Nutrition Risk Index (NRI) and the Prognostic Nutritional Index (PNI). Univariate and multivariate analyses tested the association between initial patient characteristics and clinical outcome. Results: The characteristics of the 57 consecutive pts analyzed are: median age of 66 years (range 41-78), 65% non-squamous cell lung cancer, 61.4% males and 52.6% Performance Status (PS) 0-1. GPS was 0 in 27 (47.4%), 1 in 21 (36.8%) and 2 in 9 (15.8%) pts. In multivariate analysis, parameters associated with disease progression (per RECIST 1.1) were GPS (1-2 vs 0; HR 1.45 [1.11-1.90], p= 0.009) and number of metastatic sites (>2 vs ≤ 2; HR: 0.75 [0.57-0.98], p = 0.04). Overall survival was significantly worse for pts with PS 2-3 vs PS 0-1 (p=0.01) and for pts with GPS 2 vs GPS 0-1 (p=0.01). The GPS was an independent predictive marker of progression and was superior to other inflammation-based prognostic scores in our cohort (Table). Conclusions: The Glasgow Prognostic Score (GPS) allows identifying patients with disease progression and long survivors among metastatic NSCLC patients treated with nivolumab. [Table: see text]