bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemictabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
Authors: Duska Linda R. , Brown Jubilee , Jelovac Danijela , Moore Kathleen N. , McGuire William P. , Darus Christopher , Barroilhet Lisa Marie , Secord Angeles Alvarez
Published: September 2018

5532

Background: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib (paz) is a potent angiogenic small molecular inhibitor of the tyrosine kinases VEGRF-1, -2, -3, PDGFR, c-kit and has shown activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent, advanced ovarian cancer. Methods: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive ovarian cancer with up to 3 prior lines of chemotherapy, and measurable or evaluable disease. Patients were randomly assigned (1:1) to receive weekly gem 1000 mg/m2 with or without paz 800 mg QD and stratified according to platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. Intent-to-treat was defined as all eligible patients who receive any protocol treatment with analysis based on randomized arm. Results: As of 3/2017, we randomized 148 and treated 146 patients (target sample size 148 eligible patients who receive any protocol treatment). 75 (46 platinum resistant, 61%) were randomly assigned to receive gem/paz and 71 (41 platinum resistant, 58%) to receive gem only. 110 patients (75%) had received 2 or 3 prior lines. There were no unexpected toxicities or deaths. Adverse events were more common in the gem/paz group. The most common grade 3–4 AEs (gem/paz vs gem) were: neutropenia (25 [33%] vs 15 [21%]), fatigue (7 [10%] vs 1 [2%]), hypertension (11 [15%] vs 1 [1%]), elevated alanine aminotransferase (8 [11%] vs 0), thrombocytopenia (9 [12%] vs 12[3%]) and anemia (7 [9%] vs 2 [3%]). There were 2 GI perforations in the paz arm. Median time on therapy was 12 weeks (range 1-55 weeks). Of the 138 patients off study to date, 30 (22%) were for AE’s (23 on gem/paz arm). Conclusions: The gem/paz combination is tolerable in this population, with patients tolerating multiple cycles with manageable toxicity. Median follow-up and PFS data will be presented after 122 events (progression or death) have occurred per protocol (currently 117 events). Clinical trial information: NCT01610206.
Two prognostic populations of ovarian cancer patients defined by CA125 modeled kinetic parameter KELIM (AGO-OVAR 7 & 9; ICON 7 AGO/GINECO/ MRC CTU/GCIG trials).
Authors: You Benoit , Colomban Olivier , Freyer Gilles , Leary Alexandra , Ray-Coquard Isabelle Laure , Lortholary Alain , Hardy Bessard Anne Claire , Pfisterer Jacobus , Du Bois Andreas , Kurzeder Christian , Burges Alexander , Tod Michel
Published: September 2018

5554

Background: Longitudinal CA125 kinetics during treatment can be assessed by mathematical models. The modeled CA125 elimination parameter KELIM (with 3-4 timepoints) was an early prognostic factor in CALYPSO (Gynecol Oncol 2013). Validating the prognostic value of KELIM in phase 3 trial datasets with different 1st line treatments was warranted. Methods: Data from AGO-OVAR 9 (training set: carboplatin-paclitaxel (CP) +/- gemcitabine; n=1742); AGO-OVAR 7 (validation set: CP +/- topotecan; n=1308); and ICON 7 trials (validation set: CP +/- bevacizumab; n=1528) were analyzed. CA125 profiles were fit to nonlinear mixed effect equations, and KELIM estimated in all patients at 100 days. KELIM prognostic value was tested regarding PFS and OS against other prognostic factors (stage; pathology; grade; arms; GCIG CA125 criteria; Oza groups in ICON 7) using univariate/multivariate tests. Results: KELIM (≤ or > median 0.0598) had reproducible independent prognostic value for PFS (AGO 9: HR = 0.60 [0.53-0.69]; AGO 7: HR = 0.58 [0.40-0.83]; ICON-7: HR=0.65 [0.44-0.96]) and for OS (AGO 9: HR = 0.55 [0.47-0.64]; AGO 7: HR = 0.55 [0.35-0.86]; ICON-7: HR=0.49 [0.41-0.57]) by multivariate tests. Other significant factors for PFS & OS: stage IV in AGO7 & 9 (HR=6.0 to 8.3) and ICON 7 poor progn group (PFS HR=2.24 PFS; OS HR=2.22 [1.9-2.6]). KELIM prognostic value was independent on regimen arms (Table), maintained within ICON7 progn groups (best OS gain with bevac if poor progn & unfav KELIM), and better than GCIG CA125 (inconsistent progn value). Conclusions: The reproducible & independent early prognostic value of KELIM regarding PFS and OS is validated. Easily calculable online, it early discriminates 2 ovarian cancer populations for PFS & OS whatever treatments, and is a new reference prognostic factor. [Table: see text]
Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173.
Authors: Schmid Peter , Park Yeon Hee , Muñoz-Couselo Eva , Kim Sung-Bae , Sohn Joohyuk , Im Seock-Ah , Holgado Esther , Wang Yang , Dang Thao , Aktan Gursel , Cortés Javier
Published: September 2018

556

Background: Pembro has shown efficacy and acceptable safety in pts with previously treated metastatic TNBC. The phase Ib KEYNOTE-173 study (NCT02622074) evaluated pembro + chemo as neoadjuvant therapy for locally advanced TNBC. We present cohorts A and B. Methods: Women aged ≥18 y with locally advanced, nonmetastatic TNBC; ECOG PS 0/1; and no prior chemo, targeted therapy, or immunotherapy within 12 mo were eligible. Dosing in A was single-dose pembro followed by 4 cycles of pembro Q3W + nab-paclitaxel (Np) weekly followed by 4 cycles of pembro + doxorubicin + cyclophosphamide Q3W. Dosing in B was the same as in A but with carboplatin Q3W added to pembro + Np. Concentrations were pembro 200 mg; doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2; Np 125 mg/m2 in A, 100 mg/m2 in B; and carboplatin AUC 6 (1 cycle = 21 d). DLTs were assessed at cycles 1-3 and 6-7. Dose levels were deemed toxic if ≥3 of the first 6 pts or ≥4 of 10 pts had DLTs. Surgery was 3-6 wk after treatment completion/discontinuation. Primary end points were safety and recommended phase 2 dose of pembro combined with chemo. Key efficacy end points were pathological CR (pCR) rate, defined as ypT0/Tis, ypN0, and ypT0 ypN0, and ORR (RECIST v1.1, investigator). pCR analyses included all pts. Results: By Jan 6, 2017, 10 pts were in each cohort. Median age was 53 y (range 32-71); most pts had invasive ductal histology (90%), primary tumor stage ≥T2 (90%), and nodal involvement (75%). DLTs (myelosuppression) occurred in 7 pts (3 in A, 4 in B) and were unrelated to pembro. Gr 3-4 treatment-related AEs (TRAEs) occurred in 8 pts in A and 10 pts in B; none were fatal. One pt in A and 2 pts in B discontinued for a TRAE (2 ALT elevations with pembro; 1 DVT with chemo). Overall ORR (CR+PR) before surgery was 80% (90% CI, 49-96) in A and 100% (90% CI, 74-100) in B. ypT0/Tis pCR rate was 70% (90% CI, 39-91) in A and 100% (90% CI, 74-100) in B; ypT0 ypN0 pCR rate was 50% (90% CI, 22-78) in A and 90% (90% CI, 61-100) in B; and yT0/Tis ypN0 pCR rate was 60% (90% CI, 30-85) in A and 90% (90% CI, 61-100) in B. Conclusions: Preliminary data suggest that pembro + chemo as neoadjuvant therapy for TNBC results in manageable toxicity and promising antitumor activity. Clinical trial information: NCT02622074.
Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.
Authors: Thaker Premal H. , Bradley William Hampton , Leath Charles A. , Gunderson Camille Catherine , Borys Nicholas , Anwer Khursheed , Musso Lauren , Alvarez Ronald David
Published: September 2018

5568

Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDB). Methods: Newly diagnosed advanced stage EOC patients being treated with NAC were eligible. The trial utilized a 3+3 design with GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: To date, 13 patients have been treated on-study with 12 patients receiving all 8 treatments of IP GEN-1 with no DLTs. The most common related toxicities were Gr 1 nausea, vomiting, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. One patient did not undergo IDB while on-study due to a cancer related pulmonary embolism and severe deconditioning. This patient has since improved and will have IDB. Conclusions: Adding GEN-1 to neoadjuvant T/C is safe and appears to be active in EOC patients. We are reporting the interim findings; final results with translational data to be presented. Clinical trial information: NCT02480374. [Table: see text]
Phase I study to evaluate the tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) of PM01183 (Lurbinectedin) in combination with olaparib in patients with advanced solid tumors.
Authors: Poveda Andres , Oaknin Ana , Romero Ignacio , Guerrero Angel , Fariñas-Madrid Lorena , Rodriguez-Freixinos Victor , Soto-Matos Arturo , Peris Carlos , Teruel Marisa , Lopez-Reig Raquel , Lopez-Guerrero Jose Antonio
Published: September 2018

5573

Background: PM01183 (Lurbinectedin) is a new anticancer drug that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment and is highly active in platinum resistant ovarian cancer. (Poveda A et al. ASCO 2014.abstr #5505). Olaparib (AZD2281, KU-0059436) is a polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerase (PARP) inhibitor of PARP-1,-2 and-3 with proven antitumoral activity in homologous recombination deficient tumors. The combination of PM01183 and Olaparib has shown synergistic activity in cell-lines, independent of BRCA mutation status. Methods: This phase I study evaluates the safety, PK and PD of PM1183 in combination with short course of Olaparib tablet formulation [days (d) 1-5] a cycle of 21 d, through a 3+3 dose escalation design (NCT02684318) Patients with advanced or metastatic solid tumors without established standard therapeutic alternatives were selected. Primary endpoints: safety (MTD, DLT and RP2D). Secondary endpoints: PK and PD (western blot analysis of RAD51 and p-gH2AX) profiles at 0h,4.5h, 6.5h and 24h at first cycle of treatment. Results: 20 patients were enrolled from Nov 2015 to Sep 2016 (15 ovarian, 5 endometrial) to 5 dose levels. 19/20 were evaluable for toxicity. Two dose limiting toxicities (DLTs) (both grade 4 neutropenia ≥ 4 days) occurred at the highest dose level (PM01183 2 mg/m2 iv d1 + Olaparib 250 mg [BID] oral on d 1-5. Grade 3 toxicities occurred in 30% of patients, including grade 3 neutropenia (6%) and grade 3 asthenia (10%). PK data are available from 19 patients. Median of PM01183 total clearance (11.0 L/h) is the same as when PM01183 is given as single agent. Clearance of Olaparib (7 L/h) is consistent with results reported elsewhere (5.1 – 8.6 L/h). PD: An overall increase of RAD51 and p-gH2AX was observed, being particularly evident in 56% of patients. Conclusions: The Recommended Dose for Phase II (RP2D) was PM01183 1,5 mg/m2 iv d1 + Olaparib 250 mg BID on d 1-5. This combination is feasible and without evidence of drug-drug interactions. A phase-II study at RP2D is ongoing. Clinical trial information: NCT02684318.
Racial disparities in ovarian cancer survival in New York state.
Authors: Temkin Sarah Madhu , Xu Zhaomin , Justiniano Carla Francesca , Becerra Adan Z , Aquina Christopher Thomas , Boscoe Francis P. , Schymura Maria J. , Fleming Fergal J. , Temple Larissa K. F. , Minasian Lori M. , Morrow Gary R.
Published: September 2018

5579

Background: Disparities between black and white patients are well documented in gynecologic cancers but information on the contributions of social factors and medical comorbidities is sparse. We examined differences in outcomes amongst black and white women with ovarian cancer in New York State. Methods: Patients with incident ovarian cancer in the New York State Cancer Registry and the Statewide Planning and Research Cooperative System from 2006-2013 were included. Differences in social and demographic factors, comorbidities and tumor characteristics between black and white women were examined with bivariate analysis. Multivariable analyses were used to examine factors associated with specific treatments and survival. Results: Of 5969 patients, 87% were white and 13% black. Age, Hispanic ethnicity and median income were similar between groups. Black women were less likely to be married (27 vs 48%, p < 0.01); and less likely to be privately insured (20 vs 50%, p < 0.01). More black women had comorbidities by Charlson Comorbidity Index (CCI) (63 vs 51%, p < 0.01). Black women were more likely to have Stage IV disease and non-serous histology (p < 0.01). More black women were treated at academic medical centers (67 vs 50%, p < 0.01). Marital status, insurance, CCI, stage, histology and treatment site correlated to the type of treatment received (p < 0.01). Black women received different treatment and had higher odds of receiving no treatment 1.63 (1.24, 2.14); chemotherapy without surgery 1.26 (1.00, 1.59); lower odds of undergoing primary surgical management 0.71 (0.58, 0.86) or chemotherapy following surgery 0.79 (0.66, 0.96; and similar rates of neoadjuvant chemotherapy. The risk of 5 year mortality was 1.14 (1.02, 1.27) times higher for black women compared with whites. Marital status, CCI, stage and histology correlated with overall and disease specific survival among both black and white women (p < 0.01). Conclusions: Multiple factors, including race, are associated with receipt of treatment and survival in ovarian cancer. Treatment for ovarian cancer was significantly different amongst black women than white in New York State. Understanding modifiable influences on racial disparities is imperative to reducing race based differences in outcomes.
Clinical activity, safety and biomarker results from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer (rEC).
Authors: Fleming Gini F. , Emens Leisha A. , Eder Joseph Paul , Hamilton Erika Paige , Liu Joyce F. , Liu Bo , Molinero Luciana , Fasso Marcella , O'Hear Carol , Braiteh Fadi S.
Published: September 2018

5585

Background: The prognosis for patients (pts) with rEC remains poor, with a 5-y OS of 20%-26%. We report safety, clinical activity and biomarker data from a Phase Ia study of atezo (anti–PD-L1) monotherapy in rEC. Methods: Atezo 1200 mg or 15 mg/kg IV q3w was administered until toxicity or loss of clinical benefit. Pts were initially eligible based on PD-L1 status ( > 5% of tumor-infiltrating immune cells [IC; IC2/3], VENTANA SP142 IHC assay) and then enrolled regardless of PD-L1 status. Tumor-infiltrating lymphocytes (TILs) were assessed by H&E. The FoundationOne NGS panel was used for microsatellite instability (MSI) and tumor mutation load analyses. Confirmed ORR and PFS were assessed by RECIST v1.1. Results: As of March 31, 2016, 15 pts were evaluable for safety and efficacy (minimum follow-up, 11.2 mo). The median age was 61 y (range, 20-74 y), 53% were ECOG PS 1 and 93% had ≥ 2 prior systemic therapies; 10 (67%) pts had prior RT. Pts were MSI-H (1/15), MSS (7/15) or MSI unknown (7/15). EC subtypes were endometrioid (5/15), serous (5/15), ER+ leiomyosarcoma (1/15) or unknown (4/15). Five (33%) pts were IC2/3, and 10 (67%) pts were IC0/1. Seven (47%) pts had any related AE, mainly G1-2 (5 pts). No G4-5 related AEs occurred. Two pts had related SAEs (colitis; rash). ORR was 13% (2/15) by RECIST. Both pts achieved PR and were IC2/3. ORR for IC2/3 pts was 40% (2/5). One responder was MSS and heavily infiltrated with TILs (IC3, 70% TILs, 1.8 Mut/Mb, unknown subtype); the other responder was hypermutated, MSI-H and moderately infiltrated with TILs (IC2, 10% TILs, 237 Mut/Mb, endometrioid). DOR in the 2 responders was 7.3 and 8.1+ mo. mPFS was 1.7 mo (range, 0.6-11+ mo); mOS was 9.6 mo (range, 0.6-11.8+ mo). Of the remaining pts, 2 had SD, 9 had PD and 2 were non-evaluable. DCR (PR + SD) was 27%. A trend for higher PFS and OS was seen in IC2/3 vs IC0/1 pts. Conclusions: Atezo had a favorable safety profile in rEC, with durable clinical benefit in some pts. Clinical benefit appeared to increase with higher PD-L1 expression, suggesting a link between PD-L1 status and response. Hypermutation and/or high immune infiltration may be linked to response to PD-L1 blockade, and further evaluation is merited. Clinical trial information: NCT01375842.
Systematic analysis of parameters predicting pathological axillary status (ypN0 vs. ypN+) in patients converting from cN+ to ycN0 through primary systemic therapy (PST).
Authors: Liedtke Cornelia , Kolberg Hans-Christian , Kerschke Laura , Goerlich Dennis , Bauerfeind Ingo , Fehm Tanja N. , Fleige Barbara , Hauschild Maik , Helms Gisela , Lebeau Annette , Schmatloch Sabine , Schrenk Peter , Schwentner Lukas , Staebler Annette , Von Minckwitz Gunter , Loibl Sibylle , Untch Michael , Kuehn Thorsten
Published: September 2018

560

Background: Optimization of axillary staging in patients converting from cN+ to ycN0 through PST is needed. The aim of this analysis was to develop a nomogram predicting the probability of ypN+ after PST based on clinical/pathological parameters. Methods: Patients converting from cN+ to ycN0 through PST from a prospective study (SENTINA arm C) were included. Univariate/multivariate analyses were carried out for 14 clinical/pathological parameters to predict ypN+ using logistic regression models. Odds ratios and 95% confidence intervals were reported. Model performance was assessed by leave-one-out cross-validation (LOOCV at .5 cut-offs) and ROC analyses. Calculations were performed using the SAS Software (Version 9.4). Results: 553 patients were assessed. Stepwise backward variable selection based on a multivariate analysis of all significant parameters resulted in a model (5M, Table, N = 369 evaluable) including ER (3.81; 2.25-6.44), multifocality (2.22; 1.26-3.92), LVI (9.16; 4.68-17.90), detection of SLN after PST (.50; .26-.95) and ycT (1.03; 1.01-1.06). In LOOCV, this model had an area under the curve of .81. Multivariate analysis of parameters available preoperatively showed an association between ypN0/ypN+, ER and ycT. Full subset selection resulted in a model (2M, N = 414) containing only ER (4.36; 2.80, 6.81) and ycT (1.04; 1.02, 1.07). Conclusions: A prediction model including parameters evaluable before/after definitive surgery resulted in a nomogram with acceptable accuracy. Limitation to parameters evaluable before surgery (i.e. ER, ycT) showed reduced accuracy that was comparable/superior to accuracy of using individual parameters. Since tumor biology was the strongest parameter in our models, we hypothesize that modern tumor biologic parameters such as gene expression profiling might optimize prediction of axillary status after PST improving patient counseling. [Table: see text]
Antitumor activity of trabectedin and lurbinectedin in germline BRCA2 carriers with metastatic breast cancer (MBC) as compared to BRCA1 carriers: Analysis of two phase II trials.
Authors: Balmana Gelpi Judith , Lubinski Jan Antoni , Arun Banu , Byrski Tomasz , Telli Melinda L. , Isakoff Steven J. , Fernandez Cristian , Lardelli Pilar , Kahatt Carmen Maria , Soto-Matos Arturo , Delaloge Suzette
Published: September 2018

574

Background: BRCA 1/2-associated breast cancer share homologous recombination deficiency, but also have independent and potentially actionable roles. Novel drugs with innovative mechanism of action, lacking cross-resistance with other used agents are needed for BRCA 1/2 MBC. Trabectedin (TR) and its analog, lurbinectedin (L), have shown to be active in BRCA 1/2 MBC. This study was sought to determine if there was a difference in activity of these agents between BRCA1 and 2 carriers. Methods: Safety and efficacy in MBC BRCA 1/2 were analyzed in 2 separate phase II trials of single agent TR and L. Results: 88 patients were evaluated: 34 with TR, 54 with L. Median age: 46 and 43, respectively. Median (range) prior chemotherapy lines: TR, 4 (1-10); L, 2 (0-5). Clinical responses were seen in the 2 trials (see table) and were higher in BRCA2 than in BRCA1 (33% vs 9% with TR and 61% vs 26% with L). Main adverse event was myelosuppression (grade 3-4 neutropenia / thrombocytopenia / febrile neutropenia: TR, 62.1%/24.3%/10.8% L, 66.7%/20.4%/20.4%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea/vomiting and high transaminases (grade 3/4 TR, 40.5%, L 18.5%). Conclusions: Remarkable activity of trabectedin and lurbinectedin as single agents was observed in BRCA 2 associated MBC. This finding warrants further investigation. One potential mechanistic rationale is the role of both lurbinectedin and BRCA 2 in transcription. Safety was acceptable and manageable in both studies. Clinical trial information: NCT01525589. [Table: see text]
Comparing outcomes of neoadjuvant endocrine therapy versus chemotherapy in ER-positive breast cancer: Results from a prospective institutional database.
Authors: LeVasseur Nathalie , Yip Walter , Li Huaqi , Willems Kaylie , Illmann Caroline , McDermott Miranda , Simmons Christine E.
Published: September 2018

581

Background: While neoadjuvant chemotherapy (NACT) has been established as the standard of care for medically fit patients, there has been renewed interest in utilizing neoadjuvant endocrine therapy (NET) for the treatment of women with estrogen-receptor (ER) positive, HER-2 negative breast cancer. Rates of pCR are known to be low in this population, but there is inconsistent data regarding downstaging and long-term outcomes in a non-trial setting with NET vs NACT. Methods: A prospective institutional databaseof breast cancer patients treated with neoadjuvant therapy at the British Columbia Cancer Agency from 2012-2016 was analyzed to identify all medically fit patients with ER positive, HER2 negative breast cancer. Patients were then divided into two groups: those who received NET or NACT. Baseline characteristics were compared between groups. A matched analysis (age, stage and grade) was then performed to compare rates of downstaging, pCR and scores from a validated neoadjuvant therapy outcomes calculator (CPS+EG). Results: A total of 154 patients met eligibility criteria for this study. One hundred and six patients (69%) received NACT and 48 (31%) received NET. Women offered NACT were significantly younger (51 vs 64y, p < 0.001) than those offered endocrine therapy and presented with a higher clinical stage (LR 27.93, p = 0.002). According to multiple linear regression for downstaging, clinical stage followed by NACT were the most important predictors of downstaging. When matched for age, stage and grade, downstaging was significantly higher with NACT (31/48, 65%) as compared to NET (12/48, 25%), p < 0.001. Of these, 12.5% achieved pCR with NACT as compared to 2.1% with NET, LR 4.243, p = 0.039. No significant differences in CPS+EG scores were identified when comparing NACT to NET. Conclusions: Significantly higher rates of downstaging were achieved with NACT as compared to NET when patients were matched for age, stage and grade. Rates of pCR remain low for ER-positive breast cancer patients. Although not validated with the use of NET, CPS+EG scores predicting long-term outcomes were not significantly different with NET compared to NACT.
Concurrent chemoradiotherapy with 3-weekly versus weekly cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: A phase 3 multicentre randomised controlled trial (ChiCTR-TRC-12001979).
Authors: Liang Hu , Xia Wei-Xiong , Lv Xing , Sun Rui , Zeng Qi , Li Si-Wei , Mo Hao-Yuan , Han Fei , Luo Dong-Hua , Ye Yan-Fang , Yang Jing , Ke Liang-Ru , Guo Ling , Chen Ming-Yuan , Cao Ka-Jia , Zhao Chong , Mai Hai-Qiang , Qian Chao-Nan , Guo Xiang , Yanqun Xiang
Published: September 2018

6006

Background: In intensity-modulated radiotherapy (IMRT) era, concurrent chemoradiotherapy (CCRT) with either every three week (ETW) or once a week (OAW) cisplatin is accepted practice for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, ETW and OAW were never prospectively compared in phase 3 clinical trials. This study is to assess the efficacy and toxicity profiles of CCRT with ETW versus OAW schedule of cisplatin. Methods: We conducted an open-label phase 3 multicentre randomised controlled trial in an endemic area. Patients with stage II-IVB NPC were randomly assigned to receive either cisplatin 100 mg/m² every 3 weeks for 2 cycles or cisplatin 40 mg/m² weekly up to 6 cycles concurrently with IMRT. IMRT in both groups was given as 2.19-2.34 Gy per fraction with five daily fractions per week for 6-7 weeks to a total dose of 68-70 Gy to the primary tumor and 62-68 Gy to the involved neck area. The primary endpoint was failure-free survival. Intention-to-treat population was adopted for efficacy analyses. Results: Of the 526 eligible patients, 267 were assigned to OAW arm, and 259 to ETW arm. Two arms were well-balanced in all prognostic factors. No difference was observed in overall tumor response between OAW and ETW (99.6% vs 98.9%, P = 0.624). After a median follow-up of 17.5 months (range 1.6-64.1), estimated 2 year failure-free survival rate was 92% (95% CI 87.7-96.3) in OAW and 88.3% (95% CI 83.2-93.4) in ETW (hazard ratio 1.056, 95% CI 0.58-1.92). The grade 3 or 4 toxicities were similar between two arms, but leucopenia and thrombocytopenia were significantly higher in OAW compared with ETW (24.8% vs 15.9%, P = 0.015 and 5.2% vs 1.1%, P = 0.01, respectively). Stomatitis (35.2% vs 32.6%, P = 0.576), leucopenia and nausea/vomiting (11.2% vs 12.5%, P = 0.684) were the most commonly observed grade 3 or 4 toxicities during both OAW and ETW arms. Conclusions: Weekly regimen of cisplatin as CCRT shows similar treatment efficacy but increased toxic effect of leucopenia and thrombocytopenia compared with 3-weekly schedule in LANPC. Longer follow-up is needed to fully assess prognosis and late toxicities. Clinical trial information: ChiCTR-TRC-12001979.
Phase III randomized trial comparing weekly versus three-weekly (W3W) cisplatin in patients receiving chemoradiation for locally advanced head and neck cancer.
Authors: Noronha Vanita , Joshi Amit , Patil Vijay Maruti , Agarwal Jaiprakash , Laskar Sarbani Ghosh , Budrukkar Ashwini Narsingrao , Murthy Vedang , Gupta Tejpal , D'Cruz Anil , Pai P. S. , Chaturvedi Pankaj , Chaukar Devendra , Pande Nikhil , Chandrasekharan Arun , Talreja Vikas , Vallathol Dilip , Manjrekar Aparna , Mathrudev Vijayalakshmi , Maske Kamesh , Prabhash Kumar
Published: September 2018

6007

Background: Chemoradiation (CRT) with cisplatin 100mg/m2 given 3-weekly is the standard of care in locally advanced head and neck squamous cell cancer (HNSCC). Substituting low dose weekly cisplatin has pharmacological rationale due to lower toxicity and enhanced radiosensitization but has never been compared to 3-weekly cisplatin. Methods: Phase III non-inferiority trial (CTRI/2012/10/003062) in patients with Stage III or IV (non-metastatic) HNSCC planned for radical CRT. Pts were stratified for T-category, N-category and intent of therapy (adjuvant versus definitive) and centrally randomized 1:1 to cisplatin 30mg/m2 weekly or 100mg/m2 3-weekly concurrently with radiotherapy. Primary endpoint was locoregional control (LRC); secondary endpoints included toxicity, compliance, response, progression-free survival and overall survival. The upper boundary of non-inferiority margin was set at 15%, assuming LRC of 60% with power 80% and alpha 0.05. Results: 300 pts were randomized,150 to each arm; median age 44 years (range: 25-67), males 89%; 71% were smokeless tobacco users. 61% were T4, 71% > N2. 93% pts received CRT as adjuvant therapy for high-risk disease; indication was perinodal extension in 84%, close/ positive margins 8%. Median total treatment time was 86 days (IQR: 79-95). Median RT dose was 60 Gy (IQR 60-60 Gy) using shrinking field technique. In the weekly arm, 133 pts (88.7%) received > 6 cycles; 14 (9%) required dose reduction, median cumulative cisplatin dose 210 mg/m2 (IQR 180-210). In the 3-weekly arm, 143 pts (95%) received > 2 cycles, median cumulative cisplatin dose 300 mg/m2 (IQR 200-300); 12 (8%) required dose reduction. At a median follow up of 20 months (range: 1-49), locoregional relapses (LRR) occurred in 42.2% pts in the weekly arm and 29.6% pts in the 3-weekly arm, leading to an absolute difference in LRR of 12.7% (95%CI:1.89-23.41), p=0.035 by Gray’s test, HR-1.58 (95%CI:1.02-2.46). Acute > grade 3 toxicity occurred in 85.3% pts in 3-weekly arm and 70.7% pts in weekly arm, p=0.002; 30.7% pts in the 3-weekly arm and 14% patients in the weekly arm required hospitalization for management of toxicity, p=0.001. Conclusions: 3-weekly cisplatin leads to 42% relative reduction in locoregional recurrence; it is superior to weekly cisplatin and should be the preferred regimen in CRT for HNSCC. Clinical trial information: CTRI/2012/10/003062.
Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC).
Authors: Uppaluri Ravindra , Zolkind Paul , Lin Tianxiang , Nussenbaum Brian , Jackson Ryan S , Rich Jason , Pipkorn Patrik , Paniello Randal , Thorstad Wade , Michel Loren , Mudianto Tenny , Oppelt Peter John , Wildes Tanya Marya , Dunn Gavin P , Piccirillo Jay F , Kallogjeri Dorina , Rodig Scott , Hagemann Ian S. , Chernock Rebecca , Adkins Douglas
Published: September 2018

6012

Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with > 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in > 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( > 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.
Correlation of constitutive PD-1 resistance in HNC with GM-CSF expression and presence of myeloid derived suppressor cells (MDSCs).
Authors: Seiwert Tanguy Y. , Bao Riyue , Tan Y-H Carol , Acharya Rajesh , Brisson Ryan J. , Kochanny Sara , Arshad Saba , Zuo Zhixiang , Saloura Vassiliki , Agrawal Nishant , Gooi Zhen , Blair Elizabeth A. , Lingen Mark W. , Vokes Everett E. , Gajewski Thomas , Savage Peter A , Khattri Arun
Published: September 2018

6049

Background: PD-1 checkpoint blockade is active in head and neck squamous cell carcinomas (HNC) with a response rate of ~18% and significant impact on survival. However, only a subset of patients benefits (Seiwert, Lancet Oncol). Biomarkers such as PD-L1 IHC and the Interferon-Gamma gene expression profile (INF-G GEP) identify inflamed tumors with a higher chance of response (~35-40%). However, it remains unclear why the majority of INF-G inflamed tumors still do not respond, or how to overcome constitutive resistance. Methods: 50 anti-PD-1 treated recurrent/metastatic HNC patients were included. Tumor RNA was analyzed using a 638-gene immune panel on the Nanostring nCounter. HPV status was assessed by HPV E6/E7 mRNA. T-cell inflamed phenotype was calculated using the 6-gene INF-G GEP (geometric mean) using both a low (6) and a high cutpoint. Differential gene expression was determined between inflamed-benefitting (IB) patients (defined as OS ≥ 250days), and inflamed-non-benefitting (INB) patients. Candidate biomarkers were evaluated in the entire cohort. Results: CD8 correlated highly with INF-G GEP (R = 0.80), suggesting T cell-driven inflammation. Comparing inflamed benefitting with inflamed non-benefitting tumors, the most differentially expressed gene was CSF-2, encoding GM-CSF, with 4-fold higher expression in inflamed non-benefitting (INB) tumors (with both cutpoints). In the overall anti-PD-1 treated cohort of 50 patients, CSF-2/GM-CSF correlated strongly with poor overall survival (P = 0.02), outperforming both HPV status, or PD-L1 expression in cox PH multivariate analysis. GM-CSF expression has been linked to myeloid derived suppressor cells (MDSC); MDSC marker CD34, as well as JAK2/IL10 were significantly elevated in inflamed non-benefitting (INB) tumors. There was no difference in M2 macrophage marker CD163 between the two groups. Conclusions: Constitutive resistance to PD-1 checkpoint blockade in inflamed HNC associates with expression of GM-CSF and Myeloid Derived Suppressor Cell (MDSC) markers. Strategies to deplete MDSCs, such as chemotherapy, should be considered in combination or sequentially with anti-PD-1.
Immunogenicity results using human papillomavirus (HPV) specific DNA vaccine, INO-3112 (HPV16/HPV18 plasmids + IL-12) in HPV+ head and neck squamous cell carcinoma (HNSCCa).
Authors: Aggarwal Charu , Cohen Roger B. , Morrow Matthew P , Kraynyak Kimberly , Bauml Joshua , Weinstein Gregory S. , Boyer Jean , Yan Jian , Mangrolia Drishty , Oyola Sandra , Duff Susan , Weiner David B. , Csiki Ildiko , Bagarazzi Mark L.
Published: September 2018

6073

Background: Oropharyngeal HNSCCa is frequently associated with HPV. We hypothesize that immunotherapy with INO-3112 will generate immune responses in patients (pts) with HPV+ HNSCCa. Methods: This Phase I/IIa trial included pts with p16+ locally advanced HNSCCa, ECOG PS 0-1. INO-3112 was delivered IM along with electroporation with the CELLECTRA device, Q3 weeks x 4 doses. Cohort 1 (C1) pts received INO-3112 pre and post-surgery; Cohort 2 (C2) pts received INO-3112 post cisplatin-based definitive chemoradiation. 1° and 2° endpoints were safety and immune responses. Pre- and post INO-3112 tissue samples (C1) were assessed for tumor infiltrating lymphocytes (TILs). Peripheral immune responses were assessed by ELISA for HPV16/18 specific antibody levels, and by IFNɤ ELISpot for antigen specific response, at each dose visit and q3 months (mos). Results: As of 08/2016, 22 pts were treated, completing accrual. C1: n = 6, C2: n = 16; 20 male, median age 57.5 years (32-76); base of tongue = 10, tonsil = 12; never smoker = 10. All pts are alive, median follow up is 15.9 mos (1-26). INO-3112 was well-tolerated with no related Grade 3-5 AEs. In 5 C1 pts post immunotherapy, increase in CD8+ infiltration into tumor was noted in 2 pts (1.6-3.6 fold) and decrease in FoxP3+ was noted in the other 3 (1.8-2.1 fold). This resulted in positive shift in CD8+/FoxP3+ ratio in neoplastic tissue in 4/5 pts. Peak mean/median antibody responses to HPV16 E7 and HPV18 E7 antigens for 19 evaluable pts were 1:1235/1:150 and 1:2853/1:450, respectively. As compared to baseline, 18 evaluable pts showed elevated HPV16/HPV18 specific T cell activity (by IFNɤ ELISpot), with peak mean/median responses of 179.99/68.33 SFU per 106 PBMC (HPV16) and 107.18/53.3 SFU per 106 PBMC (HPV18). Persistent cellular responses > 100 SFU/106PBMC were noted out to 12 mos. 3 pts have progressed; 1 pt received Nivolumab for progressive disease, and remains in CR. Conclusions: These data show that INO-3112 generates HPV-specific peripheral humoral and cellular immune responses that may persist out to 12 months and influences the composition of CD8+ and FoxP3+ immune infiltration into tumor tissue in HPV+ HNSCCa. Clinical trial information: NCT02163057.
Assessment of established patient reported outcomes (PROs) instruments measuring toxicities and quality of life (QOL) for patients (pts) with head and neck cancer (HNC) treated on ECOG 1308 and 2399 studies.
Authors: Cmelak Anthony , Flamand Yael , Li Shuli , Marur Shanthi , Murphy Barbara A. , Cella David , Forastiere Arlene A. , Burtness Barbara
Published: September 2018

6074

Background: HPV HNC pts are younger and have a higher cure rate than smoking-related pts, and therefore carry treatment toxicities longer. Dose deintensification and conformal RT may result in decreased toxicity. We report the impact of these techniques on patient outcomes in E2399 and E1308 as measured through PROs. Methods: Longitudinal data on acute and late toxicities were recorded prospectively at baseline, post-treatment, and at 6, 12, 24 and 30 months in HPV+ pts on E1308 and HIV+/- pts on E2399 using the following measures: E1308: FACT-HN, KATZ Index of Independence (ADL), Brief Fatigue Index (BFI), Instrumental Activities of Daily Living (IADL), and the Vanderbilt Head and Neck Symptom Survey Version 2 (VHNSS V2); on E2399: FACT-HN. We correlated acute and late toxicities with de-escalation of RT dose (69.3Gy to 54Gy) on E1308, and with IMRT (E1308) vs. conformal RT (E2399). Results: 38 pts on E1308 completed 12 mo VHNSS V2; 32 received low dose IMRT and 6 standard dose, and 56 E2399 pts completed 12 mo FACT-HN. Items from the VHNSS V2 showed that difficulty eating solids (40% vs. 89%, p = 0.011) and improved nutrition (10% vs 44%, p = 0.025) were statistically improved at 12 months by lowering IMRT dose from 69.3Gy to 54Gy. The FACT-HN showed an improvement in eating solids at 12 mo when comparing low dose IMRT vs. 3DRT (65% vs. 33% had no or minimal solid food problems, p = 0.057). No other statistically significant reductions in toxicity were noted on any of the other PRO instruments. Conclusions: Both FACT-HN and VHNSS V2 demonstrated an improvement in eating solids by reducing IMRT dose. FACT-HN demonstrated that IMRT is associated with an improvement in eating solids when compared to 3DRT. Analyses are exploratory and need to be validated using randomized data.Future studies should stress accurate and complete PRO data. The KATZ, BFI, and IADL were not sensitive to detecting differences in toxicities from IMRT dose reduction on E1308. The VHNSS V2 and FACT-HN instruments corroborated specific toxicities both by RT technique as well as IMRT dose, and will therefore be utilized in future ECOG-ACRIN HNC studies. Clinical trial information: NCT01084083.
Phase II study: Induction chemotherapy & transoral surgery as definitive tx for locally advanced oropharyngeal squamous cell carcinoma (OPSCC)—A novel approach.
Authors: Siegel Robert S. , Rafei Hind , Joshi Arjun , El-Shami Khaled , Taheri Reza , Guebre-Xabiher Hiwot , Sadeghi Nader
Published: September 2018

6078

Background: The standard of care for OPSCC includes chemoradiation (CRT) or surgery with adjuvant radiation (RT). However, RT is associated with significant life long morbidity. We assessed the efficacy of a two-drug induction regimen, followed by transoral robotic assisted surgery (TORS) & neck dissection for locally advanced OPSCC. Methods: This is an IRB approved single-arm phase II study for untreated stage III or IVA OPSCC patients (pts) with an ECOG < 2 and GFR > 50 cc. Induction chemotherapy consisted of cisplatin 75 mg/m2 and taxotere 75 mg/m2 every 21 days for 3 cycles. Tumor shrinkage was examined after each cycle. If the primary tumor was > 80% smaller, pts underwent TORS and neck dissection(s). At post-op visits, flexible laryngoscopy, blood work, and imaging with PET/CT and/or MRI were done. Short and long term toxicity, progression-free survival (PFS) and overall survival (OS), and quality of life (QOL) were evaluated. Results: Nineteenpts were treated and 14 are available for analysis. Thirteen were male, 12 were Caucasian, 2 were African-American, and 13 were HPV+. Median age at diagnosis was 57. Tumors involved the tonsil (11 pts) and base of tongue (3 pts). Three pts were stage III, and 11 were stage IVA. Tumor size was reduced on average by 58%, 84% and 92% after the 1st, 2nd and 3rd induction cycles respectively. Pathologic complete remission of primary disease occurred in 11 pts and in 7 pts with cervical lymph node disease. Four pts were given dose-reduced chemo and one pt was changed to carboplatin per protocol because of renal dysfunction. In addition, adverse events included three patients with grade I fatigue, neuropathy or nausea. Pre vs post tx QOL scores were not significantly different. At a mean follow-up (f/u) of 13 months (range 2.5 to 19.7), 13 pts are alive and well. Three pts recurred, and were treated with salvage CRT. One pt died of metastatic disease. Conclusions: Cisplatin + Taxotere is an effective induction tx for OPSCC, Induction tx followed by transoral & neck resections without RT is a promising tx model for OPSCC. It appears effective while avoiding adverse effects of RT. Longer f/u is required to assess its true efficacy. Clinical trial information: NCT02760667.
Cognitive technology addressing optimal cancer clinical trial matching and protocol feasibility in a community cancer practice.
Authors: Beck J. Thaddeus , Vinegra Michael , Dankwa-Mullan Irene , Torres Adam , Simmons Courtney C , Holtzen Helen , Urman Alexandra , Roper Nancy , Norden Andrew D , Rammage Melissa , Hancock Steven , Lim Kyungae , Rao Prasanna , Coverdill Sadie , Roberts Louisa , Williamson Paul , Howell Mickey , Chau Quincy , Culver Kenneth W. , Sweetman Robert William
Published: September 2018

6501

Background: IBM Watson for Clinical Trial Matching (CTM) is a cognitive computing solution that uses natural language processing (NLP) to help increase the efficiency and accuracy of the clinical trial matching process. This solution helps providers locate suitable protocols for their patients by reading the trial criteria and matching it to the structured and unstructured patient characteristics when integrated with the Electronic Medical Record (EMR). It is also designed to determine which sites have the most viable patient population and identify inclusion and exclusion criteria that limit enrollment. Methods: This project was a collaboration among Highlands Oncology Group (HOG), Novartis and IBM Watson Health to explore the use of CTM in a community oncology practice. HOG is in Northeast Arkansas and has 15 physicians and 310 staff members working across 3 sites. During the 16-week pilot period, data from 2,620 visits by lung and breast cancer patients were processed by the CTM system. Using NLP capabilities, CTM read the clinical trial protocols provided by Novartis, and evaluated the patient data against the protocols’ inclusion and exclusion criteria. Watson excluded ineligible patients, determined those that needed further screening, and assisted in that process. Feedback on the user experience was also obtained. Results: In an initial pre-screening test, the HOG clinical trial coordinator (CTC) took 1 hour and 50 minutes to process 90 patients against 3 breast cancer protocols. Conversely, when the CTM screening solution was used, it took 24 minutes. This represents a significant reduction in time of 86 minutes or 78%. Watson excluded 94% of the patients automatically, providing criteria level evidence regarding the reason for exclusion, thus reducing the screening workload dramatically. Conclusions: IBM Watson CTM can help expedite the screening of patient charts for clinical trial eligibility and therefore may also help determine the feasibility of protocols to optimize site selection and enable higher and more efficient trial accruals.
Changes in stage at diagnosis of screenable cancers after the Affordable Care Act.
Authors: Han Xuesong , Lin Chun Chieh , Jemal Ahmedin
Published: September 2018

6521

Background: Extensive evidence links inadequate insurance with later stage at cancer diagnosis, particularly for cancers that can be detected by screening. The Affordable Care Act (ACA) implemented in 2014 has substantially increased insurance coverage for Americans 18-64 years old. This study aims to examine any changes in stage at diagnosis after the ACA for the following cancers for which screening is recommended for individuals at risk: female breast cancer, colorectal cancer, cervical cancer, prostate cancer, and lung cancer. Methods: We used National Cancer Data Base, a nationally hospital-based cancer registry capturing 70% new cancer cases in the US each year, to identify nonelderly cancer patients with screening-appropriate age who were diagnosed during 2013-2014. The percentage of stage I disease was calculated for each cancer type before (2013 Q1-Q3) and after (2014 Q2-Q4) the ACA. 2013 Q4-2014 Q1 was excluded as a washout/phase-in period. Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated using log-binomial models controlling for age, race/ethnicity and sex if applicable. Results: 121,855 female breast cancer patients aged 40-64 years, 39,568 colorectal cancer patients aged 50-64 years, 11,265 cervical cancer patients aged 21-64 years, 59,626 prostate cancer patients aged 50-64 years, and 41,504 lung cancer patients aged 55-64 years were identified. After the implementation of the ACA, the percentage of stage I disease increased statistically significantly for female breast cancer (47.8% vs. 48.9%; PR = 1.02 [95%CI 1.01-1.03]), colorectal cancer (22.8% vs. 23.7%; PR = 1.04 [95%CI 1-1.08]), and lung cancer (16.6% vs. 17.7%; PR = 1.06 [95% CI 1.02-1.11]). A shift to stage I disease was also observed for cervical cancer (47.2% vs. 48.7%; PR = 1.02 [95% CI 0.98-1.06]) although not statistically significant. In contrast, the percentage of stage I decreased for prostate cancer (18.5% vs. 17.2%; PR = 0.93 [95%CI 0.9-0.96]) in 2014. Conclusions: The implementation of the ACA is associated with a shift to early stage at diagnosis for all screenable cancers except prostate cancer, which may reflect the recent US Preventive Services Task Force recommendations against routine prostate cancer screening.