bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase Ib/II clinical trial of a novel oxygen therapeutic in chemoradiation of glioblastoma.
Authors: Unger Evan C. , Lickliter Jason D. , Ruben Jeremy , Jennens Ross , Kichenadasse Ganessan , Gzell Cecelia , Mason Ralph , Carmody Raymond , Becker Jennifer , Zhou Heling , Sellenger Michael , Longacre Olivia , Graham Kaitlin , Stea Baldassarre
Published: September 2018

2561

Background: Tumor hypoxia limits the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). Additionally, patient biomarkers are strong predictors of responsiveness to TMZ. The purpose of this study is to evaluate the use of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. Methods: 11 adult GBM patients have been enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) an hour prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) with supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To confirm tumor re-oxygenation, patients underwent TOLD MRI before and after DDFPe administration. Archived tumor specimens were studied with GliomaSTRAT assay for methylated genes predictive of response. Patients were also studied with serial MRI scans per standard of care and followed for survival. Results: There were minimal acute adverse events related to DDFPe administration. One patient at each of dose levels 0.1 and 0.17 mL/kg developed symptomatic radiation necrosis, which was judged to be related to DDFPe. Enrollment has continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. TOLD MRI showed significant decrease in T1of tumor tissue consistent with tumor re-oxygenation (p=0.015) with no significant change in oxygenation of normal brain tissue. Historically, the average overall survival for GBM patients, for both TMZ responders and non-responders, is about 14.6 months. The progress chart for patient overall survival is listed below, 4 patients have died. All other patients are alive. Conclusions: DDFPe is a promising oxygen therapeutic for reversing tumor hypoxia. A Phase II study is being planned to assess its effectiveness. Clinical trial information: NCT02189109. [Table: see text]
A phase I study of the tolerability, safety, pharmacokinetics and preliminary antitumor effects of KBP-5209, a novel pan-HER inhibitor, in patients with advanced solid tumors.
Authors: Piha-Paul Sarina Anne , Sharma Sunil , Shih Chengkon , O'Neil Bert H. , Zhou Qinghong , Ding Yuli , Ou Na , Yu Tingting
Published: September 2018

2565

Background: KBP-5209 is a novel potent and irreversible inhibitor of tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that preclinically has demonstrated potent antitumor activities in esophageal and gastric cancers and NSCLC. Methods: This first-in-human study (NCT02442414) was conducted to determine tolerability, safety, pharmacokinetics and antitumor activity of KBP-5209 administered QD or BID in patients (pts) with advanced solid tumors. Dose escalation (DE) initially was based on a modified accelerated titration plan and then shifted to a standard 3+3 design. The starting dose was 20 mg QD. Eligible patients were adults with advanced, refractory solid tumors with ECOG PS < 1. A cycle was 28 days. DLTs were evaluated for during the first cycle. DE enriched for patients with tumors having molecular alterations in EGFR or HER2/3. Dose escalation continues so dose expansion has not initiated. Results: As of 26 Nov, 2016, 23 pts (15 females, 8 males) are a part of the evaluable population with a median age 57 (37-79) treated at doses of 20mg (1), 40mg (3), 60mg (7), 70mg (4), 80mg (6) QD and 20mg BID (2).Tumor types included breast (6), CRC (4), ovarian (3), H&N (2), sarcoma (2), and NSCLC, sinus, gastric, gallbladder, pancreas, CUP tumor (1 each). Tumor genetic profiles were available for 20 pts. DLTs were G3 diarrhea, nausea, and vomiting, which occurred in 1 pt at 80mg QD and G3 Diarrhea, occurring in 1pt at 80mg QD. The most common adverse events related to study drug were diarrhea (60.9%), nausea (47.8%), vomiting (43.5%), fatigue (21.7%), decreased appetite (17.4%) and lipase increased (17.4%). Serious adverse events (SAEs) related to study drug were reported in 4pts: diarrhea (1 pt, 70mg QD; 1pt, 80mg QD), nausea and vomiting (1pt, 70mg QD), and diarrhea, nausea and vomiting (1 pt, 80mg QD). Stable disease has been observed in 7pts up to 24 weeks, in which 2/28 pts (7%) achieved tumor shrinkage. Conclusions: Based on the present data, KBP-5209 has been well tolerated with a safety profile similar to other pan-HER inhibitors. For QD dosing, maximum tolerated dose has been identified as 70mg QD. The BID dose escalation continues. Clinical trial information: NCT02442414.
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]
DETERRED: PD-L1 blockade to evaluate the safety of lung cancer therapy using carboplatin, paclitaxel, and radiation combined with MPDL3280A (atezolizumab).
Authors: Lin Steven H. , Lin Yan , Price Justina , Parker Matthew , Gomez Daniel Richard , Welsh James William , Komaki Ritsuko , Kurie Jonathan M. , Simon George R. , Blumenschein George R. , Young Jenean A. , Phan See-Chun , Sandler Alan , Papadimitrakopoulou Vassiliki , Heymach John , Tsao Anne S.
Published: September 2018

3064

Background: Immune checkpoint blockade in non-small cell lung cancer (NSCLC) may be enhanced when combined with radiation therapy. Atezolizumab (atezo) is a humanized and Fc receptor modified monoclonal antibody that blocks programmed death-ligand-1 (PD-L1) interacting with PD-1 or B7.1 sparing PD-L2, which may result in less pulmonary toxicity. We report the early safety data of combining atezo added sequentially after standard concomitant chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Methods: This is a phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N = 10) with CP after completing CRT, or II) concurrently (N = 30) with CRT followed by consolidation atezo with CP. We report on the early toxicity results from part I of the trial. Atezo was given at 1200 mg IV Q3 weeks with consolidation CP for 2 cycles after CRT followed by atezo monotherapy for up to one year. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Dose limiting toxicities were defined as any adverse events (AEs) ≥ grade 3 within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Results: From January to December 2016, 10 evaluable patients were enrolled. Seven patients have received consolidation atezo ranging from 1 to 14 doses, with 3 yet to receive atezo after completing CRT. Three patients reported potential immune-related AEs. One patient developed grade 3 arthralgia, and another developed grade 2 radiation-induced pneumonitis, which resolved with steroids. A third patient who experienced grade 3 dyspnea due to COPD exacerbation after 1 dose of atezo discontinued additional therapy. Of the 7 patients who have received atezo, 2 patients developed progression of disease after 6 and 8 doses of atezo. Conclusions: Atezo consolidation with 2 cycles of CP after CRT appears to be feasible and well tolerated with manageable toxicities. Additional data from part I will be reported. Conditions for proceeding after part I are met and part II of the study which adds atezo to CRT followed by atezo-CP consolidation is open for accrual. Clinical trial information: NCT02525757.
A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Jha Gautam Gopalji , Gupta Shilpa , Tagawa Scott T. , Koopmeiners Joseph S , Vivek Sithara , Dudek Arkadiusz Z. , Cooley Sarah A. , Blazar Bruce R. , Miller Jeffrey S.
Published: September 2018

3066

Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism exploited by tumors in order to prevent and defeat anti-tumor immunity. Sipuleucel-T has overcome this tumor mediated anergy only in part by its ex-vivo sensitization. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. We tested the hypothesis whether targeting the IDO pathway by indoximod will inhibit Treg and abrogate tumor-mediated immunosuppression permitting a robust and sustained immune response to sipuleucel-T. Methods: Patient (pts) with mCRPC received either indoximod or placebo orally for 10 weeks after completion of sipuleucel-T therapy. In the absence of radiographic or clinical progression, pts were continued on study drug for 3 more months. Immune monitoring was done similar to IMPACT study (NEJM 2010; 363:411-422) starting prior to sipuleucel-T therapy. The primary endpoint was augmentation of immune response to PA2024 measured at 14 weeks. Secondary endpoints include safety, clinical efficacy (PFS, OS) and HR-QOL Results: Of the 63 pts with CRPC screened, 46 eligible pts were randomized to indoximod (n = 22) or placebo (n = 24). Pts tolerated therapy with indoximod with no significant difference in adverse events between two arms. There was no difference in PSA progression nor difference in the primary endpoint of immune response to PA2024 for 35 pts who have completed study and have samples analyzed. Median OS has not yet been reached in the study. Median radiographic PFS was 10.3 months in the treatment arm vs 4.1 months in placebo arm (p = 0.011), 4.1 months being similar to PFS in the pivotal ‘IMPACT’ study. More Pts continued to complete maximum treatment on indoximod arm (40.9% vs 25%). Conclusions: Treatment with indoximod post sipuleucel-T therapy is well tolerated and led to a significant improvement in radiographic and clinical progression. Augmentation of immune response to PA2024 by ELISPOT or ELISA might not be right biomarker for augmented response assessment while studying inhibition of IDO pathway. Clinical trial information: NCT01560923.
Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.
Authors: Callahan Margaret K. , Odunsi Kunle , Sznol Mario , Nemunaitis John J. , Ott Patrick Alexander , Dillon Patrick Michael , Park Andrew J. , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph , Wolchok Jedd D.
Published: September 2018

3069

Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]
An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors.
Authors: Dredge Keith , Brennan Todd , Brown Michael Paul , Lickliter Jason D. , Bampton Darryn , Hammond Edward , Lin Liwen , Yang Yiping , Millward Michael
Published: September 2018

3083

Background: PG545 (pixatimod, pINN) is a novel immunomodulatory agent which stimulates dendritic cells (DC) via TLR9/IL-12 pathway to activate natural killer (NK) cells. It also inhibits tumour-associated macrophages in cancer models. We report on safety, PK, PD, and antitumor activity of PG545 monotherapy. Methods: In this dose escalation (3+3 design) study, eligible pts (ECOG≤1) with advanced solid malignancies who failed standard therapies received PG545 once weekly as a 1-hour i.v. infusion until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity based on RECIST (1.1) criteria, PK and PD (plasmacytoid DC & NKp46+NK cells from PBMC, and plasma cytokines/chemokines). Results: The study recruited 23 subjects across four cohorts (25, 50, 100 & 150 mg). Three dose limiting toxicities (DLTs) - hypertension (2), epistaxis (1) - occurred in the 150 mg cohort, which was identified as a non-tolerated dose level. No DLTs occurred in the 100 mg cohort, which was identified as the MTD. Six SAEs were reported to be possibly or likely related to PG545 treatment. No RECIST 1.1 objective responses were reported; best response was prolonged stable disease up to 24 weeks (mCRC), with disease control rate in evaluable subjects of 38% (6/16) at eight weeks. Exposure (AUC0-last) was proportional up to 100mg and mean half-life was 144 hours. At 50 and 100mg dose levels, two subjects in each cohort exhibited up to 4-fold increased numbers of NKp46+NK cells, IFN-α-producing pDCs, and increases (up to 25-fold) in plasma IFN-γ, TNF-α, IP-10 and MCP-1. Conclusions: PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies. These data, and the absence of toxicities associated with chemo- or immunotherapies, support the development of PG545 in combination clinical trials. Clinical trial information: NCT02042781.
Results of a first-in-human phase I study of INVAC-1, an optimized plasmid DNA encoding an inactive form of human telomerase reverse transcriptase (hTERT), in patients with advanced solid tumors.
Authors: Teixeira Luis , Medioni Jacques , Doucet Ludovic , Culine Stephane , Oudard Stephane , Adotevi Olivier , Dragon Durey Marie-Agnès , Kiladjian Jean-Jacques , Brizard Mara , Bourré Ludovic , Wain-Hobson Simon , DeFrance Rémy , Huet Thierry , Langlade-Demoyen Pierre
Published: September 2018

3087

Background: INVAC-1 is an optimized plasmid encoding an inactive form of human telomerase reverse transcriptase (hTERT). hTERT is a prototype of shared tumor antigen expressed in more than 85% of human tumors. Telomerase activation is associated with maintenance of telomere length and accounts for the unlimited proliferative capacity of cancer cells. In preclinical models, INVAC-1 triggered Th1-polarized hTERT-specific CD8+ and CD4+T-cell immune responses and anti-tumor effects. Here, we report clinical and pharmacodynamics results of the first clinical study with INVAC-1 as a single agent in solid tumors. Methods: A 3+3 design phase 1 First in Human study evaluating INVAC-1 given monthly for 3 cycles using electroporation-based intra-dermal (ID) injection was conducted. Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included immune response and anti-tumor activity. Results: 20 patients (pts) with refractory/progressive solid tumors were enrolled in two centers. 3 escalating doses were studied: 100 µg (3 pts), 400 µg (3 pts) and 800 µg (14 pts). At 3-month data cut-off, no dose limiting toxicities or treatment related SAEs have been reported; no MTD was defined. The most common treatment-related adverse events were grade 1 or 2: asthenia and local reaction at injection site. 12 pts experienced stable disease and clinical benefit. For 10 pts, the treatment was extended beyond the per-protocol 3-month duration, up to nine months for 2 pts. IFN-g polarized anti-hTERT immune responses were detected in 55% of pts, in response to INVAC-1 treatment. Conclusions: Results from this study indicate that INVAC-1 ID was safe, well tolerated and strongly immunogenic at the doses and schedule tested. Early anti-tumor activity has been observed. The RP2D of INVAC-1 is therefore a monthly ID injection of 800 µg. These results encourage a future evaluation of INVAC-1 is solid tumors, as well as in hematologic malignancies, either as monotherapy or in combination with various immunotherapeutic drugs. Clinical trial information: NCT02301754.
Total neoadjuvant chemotherapy to facilitate delivery and tolerance of systemic chemotherapy and response in locally advanced rectal cancer.
Authors: Cercek Andrea , Roxburgh Campbell SD , Strombom Paul , Smith Jesse Joshua , Temple Larissa K. F. , Nash Garrett Michael , Guillem Jose G. , Paty Philip , Yaeger Rona , Stadler Zsofia Kinga , Segal Neil Howard , Reidy Diane Lauren , Shia Jinru , Vakiani Efsevia , Wu Abraham Jing-Ching , Crane Christopher H , Gollub Marc Jeffrey , Garcia-Aguilar Julio , Saltz Leonard , Weiser Martin R.
Published: September 2018

3519

Background: The most common therapy for locally advanced (T3/4 or N+) rectal cancer (LARC) consists of preoperative chemoradiotherapy (chemoRT) followed by surgery and adjuvant chemotherapy. Recently, use of total neoadjuvant therapy (TNT) with preoperative chemotherapy in addition to chemoRT prior to resection has been accepted as an alternative. Methods: Of 811 consecutive patients (pts) who presented with LARC at our cancer center in 2009-2015, 320 received chemoRT with planned adjuvant chemotherapy, and 308 received TNT (induction FOLFOX/CAPOX chemotherapy followed by chemoRT). Treatment and outcome data for those two cohorts were compared. Results: Pts in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort (p < 0·005 and p < 0·001, respectively). The complete response (CR) rate, which includes pathological CR (pCR) and clinical CR (cCR) at 6 months post-treatment, was 21% in the chemoRT with planned adjuvant chemotherapy cohort and 36% in the TNT cohort. The median follow-up was 40 months in the chemoRT with planned adjuvant chemotherapy cohort and 23 months in the TNT cohort. Fewer distant recurrences were seen in patients who had T downstaging (p < 0·001), N downstaging (p < 0·005), a cCR (p = 0·005), or a pCR (p < 0·005). There was no statistically significant difference in distant-recurrence-free survival between the two cohorts. Conclusions: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer treatment, which categorizes TNT as a viable treatment strategy that facilitates superior compliance and delivery of systemic therapy. Given its high CR rate, TNT may be beneficial as part of a nonoperative treatment strategy aimed at organ preservation.
Circulating tumor DNA (ctDNA) utilizing a high-sensitivity panel to detect minimal residual disease post liver hepatectomy and predict disease recurrence.
Authors: Overman Michael J. , Vauthey Jean-Nicolas , Aloia Thomas A. , Conrad Claudius , Chun Yun Shin , Pereira Allan Andresson Lima , Jiang Zhiqin , Crosby Shadarra , Wei Steven , Raghav Kanwal Pratap Singh , Morris Van Karlyle , Tan Michelle , Maslan Annie , Talasaz AmirAli , Mortimer Stefanie , Kopetz Scott
Published: September 2018

3522

Background: Preliminary data suggests that ctDNA can serve as a marker of minimal residual disease following colorectal cancer (CRC) tumor resection. Applicability of current ctDNA testing is limited by the requirement of sequencing known individual tumor mutations. We explored the applicability of a multi-gene panel ctDNA detection technology in CRC. Methods: Plasma was prospectively collected from CRC patients (pts) undergoing hepatic resections with curative intent between 1/2013 to 9/2016. In a blinded manner 5ml of preoperative (preop) and immediate post-operative (postop) plasma were tested using a novel 30kb ctDNA digital sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes based on the landscape of genomic alterations in ctDNA from over 10,000 advanced cancer pts with a high theoretical sensitivity (96%) for CRC. Median unique molecule coverage for this study is 9000 for cfDNA inputs ranging from 10 – 150 ng (media input preop = 27 ng, median input postop = 49 ng) with 120,000X sequencing depth on an IIlumina HiSeq2500. Results: A total of 54 pts underwent liver metastectomies with curative intent with a median follow-up of 33 months. Preop blood was a median of 49 days from last systemic chemotherapy and 3 days prior to surgery; postop blood was a median of 17 days after resection. Tumor mutations from standard of care hotspot multigene panel testing (at MDACC) were identified in 46 of 54 pts (85%). Preop ctDNA mutation detection rate was 80% (43/54) and 44% (24/54) in postop setting, with postop median allele frequency of 0.16% (range 0.01% to 20%). In pts with a minimum of 1 year follow up, sensitivity of postop ctDNA for residual disease was 58% (95%CI; 41%-74%), and specificity was 100% (66%-100%). In 43 patients who underwent successful resection of all visible disease, postop detection of ctDNA significantly correlated with RFS (P = 0.002, HR 3.1; 95% CI 1.7-9.1) with 2-year RFS of 0% vs. 47%. Recurrence was detected in ctDNA a median of 5.1 months prior to radiographic recurrence. Conclusions: The detection of postop ctDNA using an NGS panel-based approach is feasible and is associated with a very high rate of disease recurrence.
Variability in genomic alterations between right- and left-sided microsatellite stable (MSS) metastatic colorectal cancer and impact on survival.
Authors: Yaeger Rona , Chatila Walid , Lipsyc Marla , Sanchez-Vega Francisco , Hechtman Jaclyn Frances , Cercek Andrea , Stadler Zsofia Kinga , Middha Sumit , Kundra Ritika , Syed Aijazuddin , Zehir Ahmet , Varghese Anna M. , Segal Neil Howard , Vakiani Efsevia , Ladanyi Marc , Berger Michael F. , Kemeny Nancy E. , Shia Jinru , Saltz Leonard , Schultz Nikolaus
Published: September 2018

3534

Background: Metastatic colorectal cancers (mCRCs) with a right-sided primary site are associated with shorter survival and insensitivity to EGFR inhibitors compared to those originating in the left side of the colon or rectum. Methods: We performed targeted gene sequencing of 928 consecutive MSS mCRCs. Primary tumor site was divided into right-sided for cecum to distal transverse colon (n = 242), left-sided for splenic flexure to rectum (n = 673), or unknown colonic location (n = 13). Histologic subtypes were conventional (adenocarcinoma not otherwise specified), conventional with mucinous features ( < 50% mucinous), mucinous, signet ring, and poorly differentiated. To evaluate receptor tyrosine kinase (RTK) signaling, we analyzed ligand mRNA expression in TCGA. Results: Overall survival from time of metastasis was shorter for right-sided than left-sided primary site (survival at 5 years: 45% v 67%, p < 0.001). Right-sided tumors had more mutations (5.60 v 4.62 per MB, p < 0.001) but fewer copy-number changes (0.18 v 0.22 fraction genome altered, p = 0.001) compared to left-sided tumors. Alterations of KRAS, BRAF, PIK3CA, PTEN, AKT1, RNF43, and SMAD4 were significantly enriched in right-sided tumors, and of APC and TP53 in left-sided tumors. In a multivariate model, APC (HR = 0.7, p = 0.03), BRAF (HR = 3.7, p < 0.001), and KRAS (HR = 1.7, p < 0.01) alterations predicted for survival, but primary site did not (HR = 0.74, p = 0.07). Amphiregulin, epiregulin, neuregulin, and HGF expression was significantly higher in left-sided tumors. We found a higher proportion of conventional histology (83% v 63%) and moderate differentiation (82% v 69%) for left versus right-sided cases. Conclusions: We find that within MSS mCRC there are significantly more oncogenic mutations in right-sided tumors, and the difference in survival between right- and left-sided mCRC is primarily driven by differences in mutations. Left-sided tumors more commonly exhibit a “simpler” conventional histology that is lower grade and may rely on native RTK signaling, such as EGFR, for growth, providing a potential mechanism for the differential sensitivity to EGFR inhibitors seen by primary tumor site.