tbuckley/cabot-search huggingface dataset:
Trends in oncology trials termination due to toxicity over a period of 16 years.
Authors: Laura Vidal, Kelly Kevelin Curtis, Liat Vidal-Fisher, Gabor Kos, Keren Rachel Moss
Journal: Journal of Clinical Oncology (2018)

2535 Background: Pre-clinical studies may not fully determine the safety profile of an investigational agent resulting in the need to terminate studies due to safety concerns. Additionally, the development of effective new anti-cancer agents may undermine the risk-benefit ratio. We sought to determine the number of oncology studies indicated as terminated for safety reasons over the past 16 year period. Methods: Oncology and hematology trials listed as terminated due to safety or adverse event, between January 1 2002 and December 31 2017, and sponsored by biopharmaceutical industry were identified on the Citeline® Trialtrove database. Two periods were compared, prior to 2010 and from 2010. Results: 380 oncology trials were listed as terminated due to safety or adverse effects; 184 phase I and I/II, 147 phase II and II/III and 48 phase III and IV. 233 trials were terminated due to safety during 2002 – 2009 and 147 during 2010 - 2017. Considering the total number of trials terminated for all reasons, 10% of all terminations were due to safety reasons; 11% versus 9% in the early versus late 8 year period, respectively. For phases and period of time, 44% vs 57% phase I and I/II, 42% vs. 32% phase II, and 13% vs 10% phase III studies were terminated due to safety during 2002 – 2009 and 2010-2017 respectively. For trials performed in the elderly population, 33 trials (31 for > 65 years old and 2 for > 70 years old) were terminated for all reasons during the sixteen-year period: 21 trials terminated during 2002 – 2009 and 12 during 2010-2017. Of all 33 studies, 3 (9%) terminated due to safety (2 trials for > 70 years old). Despite small numbers, the percentage is similar to safety terminations in all trials - nonage specific. Conclusions: The percentage of trials terminated due to safety has decreased very slightly. When examined as a proportion of trials by phase, the overall trend toward improvement seems to be result for decrease in late phase study terminations, indicating toxicity profile is better characterized at earlier stages. Although few studies focus on elderly cancer patients, there appears to be no increased risk for discontinuation due to safety reasons in this population.
Neutrophil to lymphocyte ratio to predict outcome during ipilimumab treatment.
Authors: Michael Ryan Cassidy, Rachel Wolchok, Junting Zheng, Katherine Panageas, Jedd D. Wolchok, Daniel G. Coit, Michael Andrew Postow, Charlotte Eielson Ariyan
Journal: Journal of Clinical Oncology (2016)

e21008 Background: Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients. Methods: Using a prospectively maintained database, patients with unresectable Stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib) from 2006-2011 were identified. NLR was calculated before treatment and at 3-week intervals after treatment initiation. The median NLR was calculated for each timepoint and tested for association with overall survival (OS) and progression free survival (PFS) using landmark survival analyses and time-dependent Cox regressions. The association of relative change of NLR from baseline with OS/PFS was also determined. A multivariate model tested the association of NLR and OS/PFS with additional clinical factors. Results: There were 197 IPI patients and 36 BRAFi patients. The median NLR at each timepoint is shown (Table). In multivariable analysis adjusting for m stage, disease type, and gender, an NLR value above the median was associated with worse OS (HR 2.06-2.78, p < 0.001) and PFS (HR 1.83-2.54, p < 0.001) at every timepoint in the IPI cohort. In addition, a 30% increase in NLR above baseline was associated with a worse OS and PFS (HR 1.62 and 1.55, p < 0.05). In BRAFi patients, the median NLR did not significantly change with treatment and was not consistently associated with outcomes. Conclusions: A low NLR, whether measured prior to or during treatment with IPI, is associated with greater OS and PFS in patients with advanced melanoma. An increasing NLR was correlated with worse OS and PFS. The lack of NLR association with outcomes in BRAFi patients may be due to lower patient numbers or potential less relevance to outcomes with BRAFi compared to IPI. Median NLR Ipilimumab IPI 12-month OS (NLR ≤ versus > median) Median NLR BRAFi BRAFi 12-month OS (NLR ≤ versus > median) Baseline 4.4 61% vs 32%, p < 0.001 4.6 62% vs 29%, P = .09 Week 4 3.5 62% vs 29%, p < 0.001 4.4 41% vs 38%, p = 0.24 Week 7 3.4 63% vs 30%, p < 0.01 3.7 46% vs 25%, p = 0.2 Week 10 3.2 71% vs 21%, p < 0.01 4.7 68% vs 14%, p < 0.006
Safety and clinical activity of durvalumab in combination with tremelimumab in extensive disease small-cell lung cancer (ED-SCLC).
Authors: Daniel C. Cho, Amit Mahipal, Afshin Dowlati, Warren Allen Chow, Neil Howard Segal, Ki Y. Chung, Bryan J. Schneider, John J. Nemunaitis, Albiruni Ryan Abdul Razak, Frank Yung-Chin Tsai, Ani Sarkis Balmanoukian, Lyudmila Bazhenova, Feng Xiao, Natasha Angra, Shaad Essa Abdullah, Jason J. Luke
Journal: Journal of Clinical Oncology (2018)

8517 Background: Treatment options for ED-SCLC are limited, with standard first-line platinum and etoposide and second-line topotecan having limited clinical activity. Beyond these agents, no approved therapy prolongs survival. Dual checkpoint inhibition with the anti-PD-L1 durvalumab in combination with the anti-CTLA-4 tremelimumab has demonstrated a manageable safety profile and clinical activity in several solid tumor types. Here we present safety and clinical activity data for the combination in pretreated patients with ED-SCLC. Methods: In this phase 1 dose-exploration and expansion study, patients with ECOG PS 0–1 received durvalumab 20 mg/kg every 4 wks in combination with tremelimumab 1 mg/kg every 4 wks for 7 doses, then every 12 wks for 2 doses, followed by durvalumab 10 mg/kg every 2 wks for up to 12 mos, with retreatment permitted for progression after 12 mos of therapy. Antitumor activity was evaluated by investigator-assessed RECIST v1.1. Results: As of 20 Oct 2017, 30 patients (median age 63.5 y, 57% male, 70% ECOG PS 1) received treatment in the expansion phase. All patients had prior systemic therapy (median 2 prior therapies); 19 patients were platinum resistant/refractory. 20 patients (67%) reported ≥1 treatment-related AE (TRAE); the most common were fatigue (n = 7 [23%]) and pruritus (n = 7 [23%]). 7 patients (23%) had grade 3/4 TRAEs. No patients discontinued due to TRAEs and there were no treatment-related deaths. Confirmed ORR was 13.3% (2 CR, 2 PR; 95% CI 3.8–30.7), including 3 platinum resistant/refractory patients (1 CR with 2 prior therapies, 2 PR each with 1 prior treatment); median duration of response was 18.9 mos (95% CI 16.3–18.9). Disease control rate at 16 wks was 20.0% (95% CI 7.7–38.6). Median PFS was 1.8 mos (95% CI 1.0–1.9), median OS was 7.9 mos (95% CI 3.2–15.8), and 12-mo OS rate was 41.7% (95% CI 23.3–59.2). In addition, one patient with a brain metastasis was continuing in follow-up > 2 years after starting treatment. Conclusions: Durvalumab in combination with tremelimumab had a tolerable safety profile and promising activity in pretreated ED-SCLC. Responses were durable and seen in both platinum-sensitive and platinum resistant/refractory patients. Clinical trial information: NCT02261220.
P05.18 Comparison of N-acetylaspartate concentration decrease in hippocampal and white brain tissue after whole brain radiotherapy
Authors: P Pospisil, P Solar, M Bulik, P Burkon, P Slampa, J Sana, O Slaby, R Jancalek, T Kazda
Journal: Neuro-Oncology (2018)

Decreased hippocampal N-acetylaspartate (NAA, marker for viability and density of neurons) concentration after whole brain radiotherapy (WBRT) was described in our previous prospective study utilizing MR spectroscopy (MRS). It may be expected that mature neurons (so-called late-responding tissues in radiobiology) will be relatively radioresistant comparing to the radiosensitive population of hippocampal neuronal stem cells. The MRS spectra obtained from the white matter (WM) unaffected by metastases should therefore be relatively stable or without major variations over time. The aim of this secondary analysis of our previous study is to compare NAA decreases between hippocampus and white matter, which may contribute to elucidation of the mechanism of postradiation impairment of hippocampus leading to changes in cognitive functions after brain radiotherapy. Patients indicated for WBRT underwent MRS hippocampal examination. The areas of interest were temporal lobes, the voxel layer was modified to contain areas of both hippocampi and a portion of the WM of the occipital lobes. The control examination was performed 4 months after WBRT 10 x 3 Gy. The sum of absolute NAA concentrations in both hippocampi was compared with the sum of NAA absolute concentrations in the occipital lobes WM. In total, 14 patients had available MRS data from hippocampus and WM at both initial and control examinations. The mean decrease in NAA concentration in the hippocampus region was -12.8% (min -1.3%, max -23.9%) and in WM -9.5% (min +12.2%, max -28.7%; Wilcoxon Pair Test, p = 0.33). Study of postradiation changes in the brain, especially the hippocampus and other parts of brain involved in cognitive functioning, contributes to the clarification of the mechanism of alteration after WBRT as an iatrogenic side effect of this treatment in patients with brain metastases. The different response of hippocampus region and WM to irradiation would be in accordance with the hypothesis of a postWBRT alteration of hippocampal radiosensitive stem cells as one the major mechanism of this WBRT toxicity. However, our observed difference (-12.8% versus -9.5%) was not statistically significant, which may be due to the absence of normative standards describing these changes as well as due to a small power in statistical analyses. Further research on postradiotherapy changes in brain is needed to optimize the treatment of patients with brain tumors.
Analysis of the kinetics and effects of vemurafenib (V) + cobimetinib (C) on intratumoral and host immunity in patients (pts) with BRAFV600 mutant melanoma (BRAFmM): Implications for combination with immunotherapy.
Authors: Suthee Rapisuwon, Craig L. Slingluff, Jennifer Ann Wargo, Ryan J. Sullivan, Benjamin Izar, Ileana S Maudlin, Geoffrey Thomas Gibney, Waddah B. Al-Refaie, Bridget Haley, Michael B. Atkins
Journal: Journal of Clinical Oncology (2018)

9559 Background: Prior studies in pts with BRAFmM have shown increased density of tumor infiltrating lymphocytes (TIL) at 2 weeks (wks) with BRAF +/- MEK inhibition(i), but did not fully characterize kinetics or functional state of the TIL. To better assess the impact of BRAFi +/- MEKi on the tumor microenvironment, we conducted a study to evaluate serial tumor biopsies (Bx) and blood through the first 4 wks of V+/-C therapy (Tx). Methods: Subjects with Bx-accessible BRAFmM received either V alone or V+C Tx. Staging CT scans were performed at baseline, wks 6, 12 and q12 weeks until PD or study withdrawal. Tumor Bx and heparinized blood samples were obtained at baseline, day (d) 8, 15, and 29. Bx samples were formalin-fixed paraffin-embedded (FFPE), frozen in OCT, and processed for TIL. PBMC and plasma were isolated from blood. FFPE slides were analyzed by quantitative immunofluorescence (QIF), NanoString 770 Immune Panel and TCRseq (Adaptive). Frozen tumors were analyzed for single cell (sc)RNAseq. TIL and PBMC were analyzed by flow cytometry. Results: 5 pts (4M/1F) with BRAFmM were enrolled (3 received V and 2 V+C). All had initial tumor response (2 CR, 3 PR) and subsequent PD. No unusual or G4-5 toxicities were observed. In 4 of 5 tumors, CD8+ and CD4+ TIL increased by d8 or d15 by QIF and NanoString, waning thereafter. %CD4+ cells expressing CD45RO+ decreased over time suggesting a dominance of naïve T cells in new infiltrates. No specific change in %CD8+ TIL expression of CD45RO+ was seen. NanoString showed no significant change in FoxP3, arginase or TGFB1 expression and no change in IFNG, granzyme B or Caspase 3. Other analyses are in process. Conclusions: BRAFi +/- MEKi leads to tumor T cell infiltration by d8 that peaks at d15. CD4+ cells are increasingly antigen-inexperienced, while CD8 cells do not change. CD8 infiltrates are not accompanied by inflammatory or apoptotic response. Immune cell influx is not required for tumor response. The data suggest that T cell influx is not related to the generation of new anti-tumor immunity and that BRAF/MEKi Rx may, at best, augment an existing immune response rather than priming a new one. Clinical trial information: NCT01813214.
An open-label, phase 1b study of NEO-PV-01 with pembrolizumab plus chemotherapy in patients with advanced or metastatic nonsquamous non-small cell lung cancer.
Authors: Ramaswamy Govindan, Mark M. Awad, Lisa D Cleary, Melissa Ann Moles, Richard Gaynor, Matthew Jordan Goldstein, David R. Spigel
Journal: Journal of Clinical Oncology (2018)

TPS3134 Background: Cancer cells contain unique DNA mutations that result in altered amino acid sequences known as neoantigens. Evidence supports a central role for neoantigens as targets for tumor-directed immune responses. Tumor mutational burden as well as neoantigen load are associated with anti-tumor activity of checkpoint inhibitors. Chemotherapy plus anti-PD1 therapy in NSCLC has demonstrated improved efficacy over chemotherapy alone. This combination reduces early progression and may also modulate the tumor microenvironment. Neoantigen vaccines offer a rational combination partner for these therapies as a highly specific way to induce de novo T cell reactivity and to expand existing T cell responses against neoantigens. Here, we describe a clinical trial combining NEO-PV-01, a personal neoantigen vaccine designed specifically for the molecular profile of each individual’s tumor, with anti-PD1 and chemotherapy. Methods: NT-002 is a single-arm, phase 1B study evaluating the safety of administering NEO-PV-01 + adjuvant (Poly-ICLC) with pembrolizumab plus carboplatin and pemetrexed in patients with advanced non-small cell lung carcinoma who have received no prior systemic treatment. Patients undergo a baseline tumor biopsy and HLA typing. DNA and RNA sequencing is performed on tumor as well as peripheral blood. NEO-PV-01 is custom designed for each individual patient and contains up to 20 peptides 14-35 amino acids in length. The peptides are pooled into four groups and mixed with Poly-ICLC at the time of administration. On Day 1, patients will begin with 4 treatment cycles of pembrolizumab plus chemotherapy. Beginning on Cycle 5 (Week 12), patients will receive pembrolizumab monotherapy Q3W up to Week 103 without pemetrexed maintenance. Also beginning at Week 12, patients receive five priming immunizations with NEO-PV-01 over a three-week period followed by boosters at Weeks 19 and 23. The primary endpoint is safety. Secondary endpoints are ORR, CBR, PFS, and assessment of response conversion between Week 12 and Week 24. Exploratory endpoints include extensive immune monitoring with antigen-specific analyses of both peripheral blood and tumor. Clinical trial information: NCT03380871.
Determination of tumor mutational burden using FFPE material: Content and performance comparison of different gene panels.
Authors: Volker Endris, Ivo Buchhalter, Michael Allgäuer, Martina Kirchner, Jonas Leichsenring, Anna-Lena Volckmar, Fabian Stögbauer, Peter Horak, Simon Kreutzfeld, Hanno Glimm, Stefan Froehling, Olaf Neumann, Roland Penzel, Peter Schirmacher, Albrecht Stenzinger
Journal: Journal of Clinical Oncology (2018)

e15010 Background: Retrospective analyses of clinical studies have demonstrated that determination of tumor mutational burden (TMB) using whole-exome sequencing (WES) enables stratification of melanoma and lung cancer patients treated with checkpoint inhibitors into different outcome subgroups. While WES using FFPE material will not be feasible for high-throughput short TAT routine molecular diagnostics, next-generation sequencing in its current form using small gene panels will not be sufficient to determine TMB either. Here, we investigated the parameters and determinants that define the composition of gene panels that can be used TMB analysis in routine molecular diagnostics. Methods: In a first step we developed an in-silico pipeline to extrapolate cut-off values, sensitivity and specificities of gene panels that are already available or in development in the TCGA set of 9,000 tumors comprising more than 10 different tumor entities. In a second step, we analysed TMB of a total of 97 cases including 45 lung cancer samples and 20 colorectal cancer samples for which benchmark WES data or MSI status were available by using at least three different large gene panels, focusing on robustness, cut-off values, and gene content of the panels and their performance to identify classic driver mutations. Results: Our analyses provide deep insight into three critical parameters that determine the diagnostically applicable TMB gene panel: i) size and ii) composition of the gene panel and iii) bioinformatic pipeline used for filtering somatic vs. germline variants and low allelic variants including deamination artifacts. Our real-life data show that with large gene panels a clear separation of high mutational load cases (e.g. POLE mutated or MSI-high cases) vs. TMB low cases is well feasible. However, separating the grey zone bulk of tumors with intermediate TMB into responders and non-responders will be more challenging. Conclusions: While TMB is a promising predictive biomarker to identify patients who benefit from single or combinatorial checkpoint inhibitor therapy, standardization and definitions are required to successfully implement gene panel-based TMB analysis in molecular diagnostics.
Evolution of genomic instability in metastatic cancer.
Authors: Eric Yang Zhao, Erin D Pleasance, Martin R Jones, Yaoqing Shen, Caralyn R Reisle, Andrew J. Mungall, Richard Moore, Yongjun Zhao, Daniel John Renouf, Janessa J. Laskin, Marco A. Marra, Steven J. M. Jones
Journal: Journal of Clinical Oncology (2018)

12008 Background: Although metastasis underlies up to 90% of cancer-related mortality, genomic instability and mutation signatures are mostly studied in primary tumours. Mutation signatures are patterns of somatic mutation resulting from specific mutational processes (i.e. tobacco/UV exposure) and often evolve over time. Recent studies suggest that certain mutation signatures may predict chemotherapy response. Understanding mutational processes in metastatic cancers could uncover actionable targets and refine the understanding of progression and drug resistance. Methods: As part of the BC Cancer Agency Personalized Oncogenomics Project, mutation signatures were deciphered from 571 metastatic whole genomes from 12 cancer types totalling 13,249,678 somatic mutations. We created a novel Bayesian hiearchical model named SignIT (github.com/eyzhao/SignIT) to track temporal evolution of mutation signatures. Using real and simulated data, we showed that SignIT decomposes signatures and their temporal evolution more accurately than comparable methods. Previous chemotherapy treatments were catalogued for all patients by retrospective review. Results: We discovered 21 distinct mutation signatures, including 9 novel signatures (numbered M1-M9). Mutational processes associated with aging and cigarette smoke were early-arising. Signature 17 and M2 were consistently late-arising across cancer types and metastatic sites. Prior treatment with platinum-based chemotherapy was associated with depression of the homologous recombination deficiency signature 3 (p = 0.03). Platinum exposure was also associated with late elevation of signature 17. Conclusions: To date, this is the largest study of metastatic cancer whole genomes. Our findings revealed 9 novel mutation signatures, including potential markers of late disease and metastasis. We also observed temporal evolution of mutation signatures correlated with chemotherapy exposures. The association of decreasing signature 3 activity with platinum exposure suggests the restoration of homologous recombination as a resistance mechanism. These findings highlight the complexity of metastatic cancers, and the variety of factors which impact their mutagenesis.
Differences in chemotherapy-induced neuropathy (CIN) among younger and older cancer survivors.
Authors: Melisa L. Wong, Bruce A. Cooper, Judy Mastick, Melissa Mazor, Christine Miaskowski
Journal: Journal of Clinical Oncology (2018)

e22022 Background: Older age is associated with an increased risk of CIN, which can precipitate falls and functional decline. However, among cancer survivors with CIN, it is unknown if patient-reported and objective measures of CIN differ by age. Methods: In this cross-sectional study, cancer survivors with persistent CIN at least 3 months after completion of platinum and/or taxane chemotherapy completed questionnaires (CIN severity, interference with activities, sensory and motor symptoms) and underwent objective CIN testing (light touch, vibration, pain, cold sensation). Patient-reported and objective measures of CIN were compared among younger (age < 65) and older (age ≥65) survivors using parametric and nonparametric tests. Results: Of the 465 cancer survivors with CIN, mean age was 60.9 (SD 10.5) and 55% had breast cancer. CIN location did not differ by age (68% both hands and feet, 27% only feet, 5% only hands overall). Duration of CIN in the feet was longer among older survivors (4.9 vs 3.4 years, p < 0.001) but there was no difference in the hands. For patient-reported measures, older survivors reported less severe pain in the hands (0 none to 10 excruciating scale; 4.2 vs 4.9, p = 0.03) and feet (5.6 vs 6.3, p = 0.01) than younger survivors. In addition, older survivors reported lower interference with general activity, routine activities (dressing, toileting, typing), normal work, enjoyment of life, sleep, mood, relations with other people, and sexual activity than older survivors (all p < 0.05). There were no differences in sensory and motor symptom scores by age. In contrast, for objective measures, older survivors had worse light touch and cold sensation in the feet and worse vibration detection in the hands and feet (all p < 0.05). Conclusions: Despite having worse objective light touch, cold, and vibration sensation, older cancer survivors with CIN reported less severe pain and less interference with activities compared with younger survivors. This discordance highlights the importance of including both patient-reported and objective measures to assess CIN in cancer survivors to fully capture the symptom experience.