tbuckley/cabot-search huggingface dataset:
ABT-165 plus FOLFIRI vs bevacizumab (bev) plus FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bev.
Authors: Zev A. Wainberg, Lan Wang, Huibin Yue, Monica Motwani, Sreeneeranj Kasichayanula, Martha Elizabeth Blaney, Louie Naumovski, John H. Strickler
Journal: Journal of Clinical Oncology (2018)

TPS3619 Background: The dual variable domain immunoglobulin ABT-165 targets human vascular endothelial growth factor (VEGF) and delta-like ligand 4 (DLL4). Combined VEGF and DLL4 blockade increased inhibition of subcutaneous xenograft growth of human colon cancer-derived cell lines vs blockade of either axis alone. In vivo, ABT-165 plus chemotherapy (CT) induced tumor regression with improved efficacy, vs anti-VEGF monoclonal antibody plus CT. In a phase 1 study, a tolerable recommended phase 2 dose was identified for ABT-165 plus FOLFIRI and showed promising efficacy. This phase 2 trial in progress assesses the efficacy/safety of ABT-165 plus FOLFIRI vs bev plus FOLFIRI in pts with second-line mCRC. Methods: This is an open-label, multicenter, phase 2 randomized (1:1) trial (NCT03368859) in pts (≥18 years; Eastern Cooperative performance status: 0–1) with histologically/cytologically confirmed mCRC who progressed after fluoropyrimidine/oxaliplatin and bev. ABT-165 (2.5 mg/kg) plus FOLFIRI (irinotecan: 180 mg/m2; leucovorin: 400 mg/m2; fluorouracil bolus: 400 mg/m2, infusion: 2400 mg/m2) or bev (5 mg/kg) plus FOLFIRI are given intravenously on day 1 of each 14-day cycle, until disease progression/intolerable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. Exploratory endpoints include biomarkers predictive for efficacy/safety, correlation of DLL4 levels with PFS, OS, and ORR, pharmacodynamic effects, and the efficacy/safety-exposure relationships in the ABT-165 arm. The hazard ratios of PFS and OS comparing the 2 groups are estimated using the Cox proportional hazard model. Kaplan-Meier methodology is used to estimate the PFS and OS curves, median PFS and OS, and their 90% confidence intervals. Safety is assessed by ABT-165 exposure, adverse events (AEs), serious AEs, all deaths, and changes in laboratory data and vital signs. Archival tissue is collected and evaluated for DLL4 expression and angiogenesis signature. Approximately 100 pts are planned to be enrolled, with recruitment initiated in January 2018. Clinical trial information: NCT03368859.
Identifying prognostic subgroups for outcomes in <i>BRAF</i><sup>V600</sup>-mutated metastatic melanoma patients (pts) treated with vemurafenib (V) ± cobimetinib (C): A pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.
Authors: James M. G. Larkin, Antoni Ribas, Keith Flaherty, Grant A. McArthur, Paolo Antonio Ascierto, Brigitte Dréno, Karl D. Lewis, Paul B. Chapman, Edward Francis Mckenna, Qian Zhu, Yong Mun, Axel Hauschild
Journal: Journal of Clinical Oncology (2016)

9536 Background: V therapy has shown improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), compared with dacarbazine (D) (BRIM-3), in pts with BRAFV600-mutated metastatic melanoma. C+V has shown clinical benefit (BRIM-7) and improved ORR, PFS, and OS compared with placebo + V (coBRIM). Clinical characteristics that predict improved outcomes with V±C are not defined. Pooled analysis of BRIM-2, BRIM-3, BRIM-7, and coBRIM was performed to identify pt subgroups prognostic for distinct outcomes on therapy. Methods: Eligible pts, defined in each study, were included regardless of treatment assignment. Recursive partitioning for censored response variable in a conditional inference framework was performed in the pooled dataset to model relationships between prespecified covariates and PFS. Prognostic subgroups identified by the model were applied to pooled treatment cohorts (D, V, and C+V). PFS was estimated using the Kaplan-Meier method. Results: In a pooled analysis of all pts (N = 1223), baseline lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS), and presence/absence of liver metastasis (LM) were significant prognostic factors for PFS, producing 5 subgroups with distinct outcomes in the pooled dataset. Outcomes in C+V cohorts (n = 305) are presented (Table). Trends were consistent in D and V cohorts. Conclusions: The model identified clinical characteristics (LM, ECOG PS) that refined identification of favorable subgroups. In C+V cohorts, all subgroups benefited vs V. Pts with normal LDH (±LM) had longer PFS than pts with elevated LDH (±LM, ECOG PS > 0). In favorable subgroups, PFS seemed durable with C+V (further follow-up required). PFS: C+V cohorts. Prognostic Subgroup n Events PFS, median (95% CI), months Normal LDH + no LM 126 33 14.9 (11.0-NE) Normal LDH + LM 38 12 16.6 (9.8-NE) Elevated LDH + ECOG PS 0 + no LM 55 23 10.1 (8.2-NE) Elevated LDH + ECOG PS 0 + LM 43 21 7.3 (5.8-NE) Elevated LDH + ECOG PS > 0 43 23 7.8 (5.4-NE) NE = not estimable.
SMART in the Management of Patients With Persistent Asthma
Authors: Yang Xia, Lexin Xia, Huahao Shen
Journal: JAMA (2018)

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Salvage high-dose chemotherapy in female patients with relapsed/refractory germ cell tumors: The EBMT experience.
Authors: Ugo De Giorgi, Sandrine Richard, Manuela Badoglio, Edward Kanfer, Jean Henri Bourrhis, Emmanuelle Nicolas-Virelizier, Bruno Lioure, Kim Vettenranta, Sonja Martin, Peter Dreger, Markus Kajo Schuler, Emanuela Scarpi, Giovanni Rosti, Frédéric Selle, Francesco Lanza, Marco Bregni
Journal: Journal of Clinical Oncology (2016)

5558 Background: A few small series have reported salvage high-dose chemotherapy (HDC) and hematopoietic progenitor cell transplantation (HSCT) in female patients with relapsed/refractory germ cell tumors (GCTs). We conducted a retrospective analysis of female GCTs treated with salvage HDC registered with the European Society for Blood and Marrow Transplantation (EBMT). Methods: Between 1986 and 2012, 60 registered female patients with GCT, median age 27 years (range 15-48), were treated with salvage HDC. Forty-three (72%) patients had primary ovarian GCT, 7 (12%) mediastinal, 5 (8%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two pts (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 (15%) patients received HDC as late-intensification of a previous regimen without evidence of metastasis. The conditioning HDC regimens consisted of a single cycle in 34 cases (57%), a multi-cycle regimen in 26 (43%), and comprised carboplatin in 49 of 60 cases (82%). HSCT consisted of peripheral blood progenitor cells in 37 cases (62%), autologous bone marrow in 22 (37%), and both in one (2%). Results: Nine cases who underwent late intensification HDC were not evaluable for response. Of the 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm-), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There weres 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1-219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm- following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3-219 months). Conclusions: Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.
Overall survival of PEGylated pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).
Authors: J. Randolph Hecht, Aung Naing, Gerald Steven Falchook, Manish R. Patel, Jeffrey R. Infante, Raid Aljumaily, Deborah J.L. Wong, Karen A. Autio, Zev A. Wainberg, Milind M. Javle, Johanna C. Bendell, Shubham Pant, Annie Hung, Peter Van Vlasselaer, Joseph Leveque, Martin Oft, Kyriakos P. Papadopoulos
Journal: Journal of Clinical Oncology (2018)

4119 Background: The therapeutic options for 2nd line therapy PDAC remain unsatisfying with 5-FU/LV plus oxaliplatin or nal-irinotecan resulting in a mOS of 5-6 mo. PDAC has been largely refractory to immune-oncology approaches and CD8+ T cells are rare in most PDAC. AM0010 stimulates survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune activation, durable stable disease and a 1yr survival of 22.5% was seen in salvage PDAC patients (pts) receiving AM0010 alone. AM0010 has synergistic anti-tumor activity with 5-FU/LV or oxaliplatin in preclinical models. Here we report on the safety, efficacy and overall survival of AM0010 + FOLFOX as 2nd and later line treatment in PDAC pts. Methods: PDAC pts progressing on a median of 2 prior therapies (range 1-5) were treated with AM0010 (5ug/kg SQ, qd) + FOLFOX (n = 21). The safety population (n = 25) included also 4 pts with prior oxaliplatin / 5-FU. Tumor responses were assessed with irRC. The survival population included all patients without prior platinum containing regimen. Biomarkers included the sequence analysis of blood derived T cells for T cell clonality. Results: AM0010 + FOLFOX, was generally well tolerated. G3/4 TrAEs included thrombocytopenia (56%), anemia (44%), neutropenia (36%) and fatigue (12%). Most cytopenias had a short duration and reaching retreatment criteria within 2-5 days after dose interruption. Dosing AM0010 for 5 days followed by a 2 days dose holiday has avoided G3/4 cytopenias. Grade1/2 but no higher grade neuropathy was observed in 16% of patients. Of 19 evaluable pts, 2 had an irCR, 1 had irPR with 100% reduction in tumor burden, ORR is 15.8%, DCR is 78.9%. With median follow-up of 23.4 months (range 18.9 - 28.9), mPFS was 2.6 mo, mOS was 10.2 mo and 1-year and 2-year survival was 43% and 28.8%, respectively. The expansion of previously non-detected T cell clones correlated with OS > 8 months. Conclusions: AM0010 in combination with FOLFOX is well tolerated in patients with metastatic PDAC, and has a reduced incidence of FOLFOX related neuropathy. Immune activation and overall survival are encouraging in this advanced PDAC population. This regimen is currently being studied in a phase 3 trial. Clinical trial information: NCT02009449.
A rational approach to dose optimisation of pembrolizumab using cost analysis and pharmacokinetic modelling and simulation.
Authors: Kayode Ogungbenro, Alkesh Patel, James Clark, Paul Lorigan
Journal: Journal of Clinical Oncology (2016)

9547 Background: Pembrolizumab is a PDL1 inhibitor licensed for the treatment of unresectable melanoma at a dose of 2mg/kg every three weeks. A population pharmacokinetic model based on two compartment first order elimination model has been used to describe the pharmacokinetics of pembrolizumab in advanced malignancies. Dose banding or the standardisation of doses into a defined set of ranges offers an alternative approach to precise dosing. The aim of this work is to evaluate using a simulated study and data from 43 patients treated at one UK centre the change in cost, drug exposure and target engagement between precise dosing (2mg/kg), banded and fixed dosing (150mg and 200mg) strategies. Methods: Data from 43 consecutive patients who received pembrolizumab with a median weight of 79.5kg (range 44-130kg). 5 cycles of treatment based on median time on treatment of Keynote-002 trial was assumed for cost evaluation. 1000 random individuals were evaluated in a simulated study for pharmacokinetic and pharmacodynamic assessment. The published population PK model were used to simulate change in exposure and probability of achieving reported trough level (10mg/L) required for maximum target engagement for different dosing strategies. Results: Based on 43 patients receiving 5 cycles of pembrolizumab, the costs of different strategies are illustrated in Table 1. The table also includes simulated area under the curve and mean probability of achieving a trough level of 10mg/L required for maximum target engagement before the second cycle of treatment for the different dosing strategies. Conclusions: Significant cost reduction can be achieved by banded and fixed dose strategies compared to precise dosing strategy while maintaining comparable level of exposure and target engagement. Pembrolizumab Drug Cost of 5 cycles* (£) (n=43) Relative Drug Cost Saving (%) (n=43) Simulated AUC Mean mg.day/L (SD) Mean prob of Target Engagement Precise (2mg/kg) 1,699,111 0 1359 (375) 0.51 Dose Band (10% variance) 1,518,825 (1,462,937 with vial sharing) 10.6 (13.9 with vial sharing) 1356 (359) 0.51 Fixed dose (150mg) 848,175 50 1384 (405) 0.53 Fixed dose (200mg) 1,130,900 33 1846 (540) 0.86 *United Kingdom cost
Dynamic angiogenic switch as predictor of response to chemotherapy+ bevacizumab in patients with metastatic colorectal cancer.
Authors: Antonio Cubillo, Rafael Alvarez-Gallego, Manuel Munoz, Gregory Russell Pond, Gema Sanchez, Maria Martin, Jesus Rodriguez-Pascual, Elena Garralda, Estela Vega, Rodrigo Toledo, Emilio De Vicente, Yolanda Quijano, Cesar Munoz, Lisardo Ugidos, Manuel Hidalgo, Sofia Perea
Journal: Journal of Clinical Oncology (2016)

e15126 Background: There is a need to develop biomarkers to predict the outcome of patients with metastatic colorectal cancer (CRC) treated with chemotherapy (Ch) plus Bevacizumab (B). It has been reported that during exposure to B there is a switch in the plasma levels of angiogenesis growth factors and related cytokines called angiogenic switch (AS). It is not known if variations in AS among patients is related to the response to treatment with angiogenesis inhibitors. This study aimed to determine the influence of AS in the PFS of patients with metastatic colorectal cancer treated with Ch + B. Methods: Patients with untreated metastatic colorectal cancer with ECOG 0-1 performance status 0-1 were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for six cycles either followed by maintenance treatment with bevacizumab plus capecitabine until progression. Angiogenic related cytokines (HGF, PIGF, MCP-3, MM-9, Eotaxin, bFGF and IL-18) were prospectively analyzed at baseline and every eight weeks). AS + was defined by A) doubling of PIGF compared to baseline or B) PIGF elevation with a simultaneous elevation of any two of bFGF, HGF, MCP-3, IL-18 or MMP-9 compared to baseline Results: Of 71 patients, 41 (57.8%) progressed with a median PFS of 10,1 (95% CI: 8.3 to 13,7) months. Forty-five (63.4%) patients developed an AS including 28 patients were AS + observed at first evaluation. Thirty five, six, and four patients were deemed AS + based on both criteria, criteria A or B respectively.. Median PFS for the 45 patients with AS was 11,4 (95% CI:8,6 to 15,8) months versus 8.3 (95% CI: 5.6 to 16.4) months in the 26 AS - patients (p = 0.04). The overall disease control rate (PR + CR + stable disease in AS + patients was 96% versus 58 % in AS – patients (p < 0.001). Conclusions: Development of AS is associated with better PFS and disease control in patients with metastatic CRC treated with bevacizumab in combination with chemotherapy. These data support continuing studying dynamic changes in circulating angiogenic factors and cytokines as markers of angiogenesis inhibitors effectiveness. Clinical trial information: NCT02075086.
Patient-reported outcomes and quality of life in ALTA: The randomized phase 2 study of brigatinib (BRG) in advanced ALK+ non–small cell lung cancer (NSCLC).
Authors: Corey J. Langer, Hui Huang, Joice Huang, David Kerstein, William Reichmann, Rebecca M Speck, William R Lenderking
Journal: Journal of Clinical Oncology (2017)

9066 Background: The ALTA trial (NCT02094573), an open-label, phase 2, randomized, multicenter, international study, evaluated the efficacy and safety of BRG (arm A: 90 mg qd and arm B: 180 mg qd with 7-day lead-in at 90 mg) in patients (pts) with advanced anaplastic lymphoma kinase–positive (ALK+) NSCLC whose disease had progressed on prior therapy with crizotinib (CRZ). The objective of this analysis was to describe pt-reported outcomes (PROs) in the ALTA study. Methods: PROs were collected using the EORTC QLQ-C30 at baseline and on the first day of each cycle. Multivariable mixed effects models were constructed to estimate adjusted mean changes from baseline in QLQ-C30 scores. Cumulative distribution function (CDF) plots of EORTC QLQ-C30 change scores from baseline to Cycle 5 were generated to evaluate a clinically meaningful threshold of individual pt change, which was determined through anchor- and distribution-based methods. Results: Among 222 randomized pts, 208 (94%) completed the questionnaire at baseline and at least 1 on-treatment PRO follow-up. In multivariable analyses, there were no statistically significant differences in Global Health Status (GHS)/QOL between arms over time when adjusted for baseline score, ECOG status, and presence of liver or bone metastases. At Cycle 5, CDF plots indicated that 80% of all pts experienced an increase or no change in GHS/QOL scores; 50% of all pts experienced a clinically meaningful improvement. At Cycle 5, 80% of all pts reported a reduction or no change in pain score, and 90% of all pts reported a reduction or no change in dyspnea score. Approximately 30% of pts had clinically meaningful reductions in these symptoms. Less than 15% and &lt; 5% of all pts reported clinically meaningful worsening of nausea/vomiting and diarrhea scores, respectively, at Cycle 5. Conclusions: Treatment with BRG for CRZ-refractory ALK+ NSCLC resulted in improved GHS/QOL scores and reduction in pain and dyspnea scores, while rates for nausea/vomiting and diarrhea were minimally worse. These pt-level benefits support BRG as a promising treatment option. Clinical trial information: NCT02094573.
Prognostic factors associated with benefit to post-operative chemotherapy: A National Cancer Data Base analysis.
Authors: Jessica Lyn Geiger, Neil McIver Woody, Chandana A. Reddy, Shlomo A. Koyfman, Nikhil Purushottam Joshi, Joanna Bodmann, Bridgett Ann Harr, Denise I. Ives, Jodi Ferrini, Brian Burkey, Joseph Scharpf, Eric Lamarre, Brandon Prendes, Robert Lorenz, David J. Adelstein
Journal: Journal of Clinical Oncology (2017)

6072 Background: Addition of chemotherapy to adjuvant radiation (RT) confers an OS benefit and is recommended in HNSCC patients with nodal extracapsular extension (ECE) and positive surgical margins based on pooled data. The purpose of this study is to retrospectively evaluate a larger patient data set in an attempt to confirm this observation and to assess current patterns of practice. Methods: The National Cancer Data Base (NCDB) was queried to identify patients with HNSCC who were treated with primary definitive surgery followed by adjuvant RT between 2004 and 2012. For patients treated with surgery and post-operative RT with or without chemotherapy, the effect of the systemic therapy on OS was explored using multivariable Cox proportional hazards modeling and stratified by patient and disease factors. Results: 6,351 patients were identified meeting study criteria; 3157 patients (49.7%) received adjuvant RT alone, and 3194 patients (50.3%) received adjuvant chemoradiotherapy (CRT). An increase in chemotherapy usage was observed over time (6% of patients in 2004; 16% in 2012). No difference was seen in OS by use of CRT (median OS 8.3 years in patients without CRT vs. 9.4 years in patients with CRT, p = 0.0893). On multivariate analysis OS was improved in younger patients, patients with less co-morbidity, oropharynx, lower T and lower N. OS was also improved in patients given chemotherapy if either ECE or positive surgical margins were present (HR 1.166, p = 0.0438) but not in those with negative surgical margins and no ECE (HR 1.037, p = 0.5888). Nonetheless, chemotherapy was given to 38% of post-operative patients without these risk factors and not given to 35% of patients with risk factors. Conclusions: This NCDB analysis confirms an OS benefit with addition of chemotherapy to post-operative RT in HNSCC patients with ECE or positive surgical margins but not in patients without these risk factors, consistent with current guidelines. National practice patterns, however, do not mirror these recommendations. These results are subject to limitations of retrospective analysis of a large database and further studies are needed to better elucidate high risk factors benefiting from intensifying adjuvant therapy.