tbuckley/cabot-search huggingface dataset:
Prognostic value of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients with advanced solid tumors treated with PD-1 inhibitors.
Authors: Miguel Gonzalez Velez, Giselle Alexandra Suero-Abreu, Marshall McKenna, Camille Michelle Johnson, Martin Gutierrez
Journal: Journal of Clinical Oncology (2019)

e14132 Background: The use of PD-1 inhibitors (PD1) has been limited due to the lack of prognostic markers of response. Previous studies have suggested that indirect inflammatory markers such as neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) may correlate with response to treatment and improved survival. We sought to evaluate the impact NLR and PLR in a real world cohort of patients (pts) with advanced solid tumors treated with PD1. Methods: Records of all pts treated with PD1 between 2011-2017 at the John Theurer Cancer Center were reviewed. NLR and PLR were registered at baseline and longitudinally. We dichotomized as low (lNLR/lPLR), and high (hNLR ≥5/hPLR ≥160). Univariate logistic regression and Cox proportional hazards were used for progression free survival (PFS), and overall survival (OS). Landmark analyses were performed at cycles 2 (C2), and 5 (C5). Results: 178 pts received 1131 cycles of PD1. Median age was 65 (range 24-93); 43% were female. ECOG was ≥1 for 85%. 142 pts (80%), and 89 (50%) received ≥2C and ≥5C respectively. In univariate analyses, baseline hNLR and hPLR were independently associated with inferior OS (median 7.8 vs 18.3 months; HR 1.77, 95% CI 1.21-2.43; p = 0.004), ) and (median 6.4 vs 15.6 months; HR 1.42, 95% CI 1.09-2; p = 0.04) respectively. On landmark analyses, lNLR and lPLR were associated with longer PFS and OS at 2C, and 5C. Longitudinally, lNLR and lPLR correlated with response rate; NLR decreased by 0.08 (95% CI: -0.19 to -0.04; p = 0.03) and PLR by 17 (95% CI: -29 to -14; p = 0.07) per month in responders compared with non-responders. hNLR or hPLR did not correlate with increase in autoimmune toxicities. Conclusions: hNLR, hPLR are adversely prognostic markers in pts receiving PD1 inhibitors in a “real world cohort”. These markers correlate with a longitudinal response and may help predict response. Further prospective studies are needed to determine their utility in decision making during treatment.
Retrospective analysis of baseline clinical factors associated to CDDP-nephrotoxicity in locally advanced head and neck cancer (LAHNC) patients.
Authors: Francesca Platini, Francesco Barretta, Salvatore Alfieri, Stefano Cavalieri, Carlo Resteghini, Donata Galbiati, Laura Deborah Locati, Cristiana Bergamini, Roberta Granata, Giuseppina Calareso, Nicola Alessandro Iacovelli, Pasquale Quattrone, Fabiola Incandela, Paolo Bossi, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2019)

e17537 Background: CDDP is the standard of care for HNC. We performed a retrospective analysis related to baseline clinical characteristics and CDDP-nephrotoxicity in LAHNC patients (pts) treated in a curative setting with CDDP and concomitant RT (CRT) or with CDDP as part of induction chemotherapy. Methods: We collected data of LAHNC pts treated between 2008 and 2018 at the National Cancer Institute of Milan. CDDP was administered 100 mg/sm every 3 weeks or 50 mg/sm once a week during CRT, or 75 mg/sm during induction. Nephrotoxicity was assessed using creatinine increase (CreaIncr) recorded at day 6-20 post CDDP, graded according to CTCAE v4.0 and analyzed as a dichotomous variable (Grade&gt;0 vs Grade = 0). We used univariable logistic regression to investigate associations between CreaIncr and clinical variables. Continuous variables were modeled using 3-knots restricted cubic splines. Results: Overall, 204 pts were considered. Male: 74%; median age: 56 yrs [IQR 51-63]. CRT was performed in 179 pts (88%). Three-weekly schedule was performed in 75% of pts. The median CDDP dose was 250 mg [IQR 200-300]. One fourth had history of hypertension and 9% were on diuretics. At baseline, median [IQR] creatinine was 0.80 mg/dL [0.69-0.89], creatinine clearance 109 mL/min [98-129] and uricaemia 4.90 mg/dL [4.11-5.74]. In total, 44% pts suffered from CreaIncr (G1: 46 pts; G2: 39 pts; G3-G4: 5 pts) all of them occurred within the first 2 cycles. CreaIncr was observed in 92% of pts treated with CRT, 84% received 3-weekly CDDP. Baseline creatinine clearance, azotaemia and hypertension were not significantly associated with CreaIncr. Loop diuretics alone appeared a potential relevant factor [OR 4.72;95%CI 0.96-23.32;p = 0.057]. Concomitant drugs (ACE inhibitors, Sartans, Ca-blockers) [OR 1.48;95%CI 1.00-2.18;p = 0.050] and uricaemia [OR 1.95;95%CI 1.27-3.0;p = 0.006] were statistically significantly associated to CreaIncr. Conclusions: In our selected population we found that concomitant medications and uricaemia were significantly related to CreaIncr. A better understanding of clinical baseline factors may improve decision making in a setting where CDDP has a curative significance.
Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma.
Authors: Nirav Niranjan Shah, Fenlu Zhu, Dina Schneider, Carolyn Taylor, Winfried Krueger, Andrew Worden, Walter L. Longo, Mehdi Hamadani, Timothy Fenske, Bryon Johnson, Boro Dropulic, Rimas Orentas, Parameswaran Hari
Journal: Journal of Clinical Oncology (2019)

2510 Background: Anti-CD19 CAR-T cell therapy is a breakthrough treatment (tx) for patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Despite impressive outcomes, non-response and relapse with CD19 negative disease remain challenges. Through dual B-cell antigen targeting of CD20 and CD19, with a first-in-human bispecific lentiviral CAR-T cell (LV20.19CAR), we aim to improve response rates while limiting CD19 negative relapse. Methods: Pts were treated on a Phase 1 dose escalation + expansion trial (NCT03019055) to demonstrate safety of a 41BB/CD3z LV20.19CAR T cell for adults with R/R B-cell NHL. Safety was assessed by incidence of dose limiting toxicities (DLTs) within 28 days post-infusion. Starting dose was 2.5 x 10^5 cells/kg with a target dose of 2.5 x 10^6 cells/kg. All pts received fludarabine+cyclophosphamide for lymphodepletion. Results: 11 pts have completed tx to date. 9 pts in dose escalation and 2 pts in expansion phase. Median age was 54 years (46-67) and histology included DLBCL = 5 pts, MCL = 4 pts, and CLL = 2 pts. In dose escalation, 3 pts were treated at 2.5 x 10^5 cells/kg, 3 pts at 7.5 x 10^5 cells/kg, and 3 pts at 2.5 x 10^6 cells/kg with no DLTs. As a result, 2.5 x 10^6 cells/kg was selected for expansion. In terms of safety, 6 pts developed Grade 1-2 cytokine release syndrome (CRS) and 3 pts had Grade 1-2 neurotoxicity (NTX). No patient had grade 3-4 CRS or NTX and none required ICU level care. 4 pts required 1-2 doses of tocilizumab for CRS. The day 28 overall response rate (ORR) for all pts was 82% (6/11 = complete response (CR) and 3/11 = partial response). All CR pts remain in remission, the longest &gt; 1 year. All progressing pts underwent repeat biopsy, and all retained either CD19 or CD20 positivity. Additional pts are being enrolled in the expansion phase and updated data will be presented. Conclusions: Phase 1 results from the LV20.19 CAR T clinical trial demonstrate that infusion of 2.5 x 10^6 cells/kg is safe for further investigation with no DLTs among treated pts. Down-regulation of target antigens was not identified as a mechanism of resistance in progressing pts. With limited toxicity and encouraging ORR, dual targeted LV20.19CAR T cells merits further investigation. Clinical trial information: NCT03019055.
Stochastic cancer-immune coevolution: Implications for cancer incidence and immunotherapeutic efficacy.
Authors: Jason T George, Herbert Levine, Jeffrey J. Molldrem, Haven Garber
Journal: Journal of Clinical Oncology (2019)

e14023 Background: Despite recent progress, robust treatment strategies that lead to durable remission are still lacking for many cancer types. This disease is difficult to treat owing in part to the complexity introduced by a heterogeneous population of cancer cells capable of evolving mechanisms of resistance to traditional therapy. Nonetheless, the discovery and continued optimization of T-cell immunotherapy has revolutionized the treatment of many cancers. This treatment strategy stands out from other approaches in its unique ability to co-evolve alongside an evading tumor. While promising, such therapies are also complex. For example, allogeneic stem cell transplantation leverages a donor-derived T-cell repertoire to treat patients with refractory hematologic malignancies and relies upon a delicate balance between desirable anti-tumor effects and potentially life-threatening graft-versus-host-disease. Currently, the decision to utilize this therapy and others like it is largely influenced by prior empirical evidence. Thus, there is great need for quantitative models of the cancer-immune interaction to generate testable predictions of treatment outcome, which could then be validated prior to T-cell immunotherapy administration. Methods: We develop a foundational mathematical model to investigate the properties of stochastic tumor-immune co-evolution using applied stochastic process theory and probabilistic analysis. We use this model to predict the effects of reduced immunity, T-cell diversity, and thymic turnover rates on cancer incidence, and compare model simulations to cancer evolutionary data. Results: We predict that changes in T-cell diversity, and to a lesser degree thymic turnover, increase the chance of tumor progression. When applied to experimental data, we demonstrate that the observations are consistent with co-evolution between an indolent cancer population and the adaptive immune system prior to clinical disease. Conclusions: Our results provide a fundamental framework for analyzing the interaction dynamics of an evolving threat like cancer and the adaptive immune system in order to better understand and predict immunotherapeutic efficacy.
QOL assessment integrated into the clinical care of cancer survivors to identify needs and direct care.
Authors: Christian S. Adonizio, Jamie Weeder, Erin Benner, Jesse Manikowski, Julie Hergenrather, Mark Wojtowicz, Julie I Woods
Journal: Journal of Clinical Oncology (2019)

6611 Background: Validated survey tools have been used to measure the quality of life (QOL) of patients treated for cancer, however, there are newer studies that have shown both an improvement in QOL, and improvement in overall survival using these tools. We integrated the Functional Assessment of Cancer Therapy – General Population (FACT-GP v.4) to direct the deployment of resources and interventions to improve the care of patients who have completed potentially curative therapy for cancer. Methods: This is an observational study of patients who received cancer therapy with curative intent in the last 18 months. The FACT-GP was administered by an RN via telephone. Patients contacted received and reviewed a Survivorship Care Plan (SCP) as defined by the American College of Surgeons Committee on Cancer. Patients who had a total score less than 60 on FACT-GP and/or had a score less than 12 on the Emotional Well-Being subscale (EWB) were considered high-risk and were referred to the Survivorship MDC for in-person evaluation. Results: From 10/1/2018 to 12/31/2018, 114 patients were referred to the cancer survivorship program. Of these, 64 (56%) patients had FACT-GP administered and were evaluated. 45 of these (70%) only completed the FACT-GP and received an SCP. 21 patients had a total score less than 60 and/or an EWB sub-score less than 12 and were identified as high-risk. 15 (72%) patients were seen in MDC, 4 (19%) patients were seen in conjunction with a scheduled appointment by the MDC team, 2 (9%) patients refused further evaluation. 66.7% of patients in the survivorship program were referred to Oncology Behavioral Health compared to 18.2% of all oncology patients. Survivorship patients in the cohort had a baseline utilization of the emergency department (ED) of 4.1% (10 of 241) from 1/1/2018 to 9/30/2018 and 0 (0 of 64) after the initiation of the intervention from 10/1/2018 to 12/31/2018. Conclusions: Integrating a validated QOL tool (FACT-GP) as a therapeutic intervention is feasible and may both identify needs and direct services for cancer survivors while possibly decreasing ED utilization. Clinical trial information: NCT03835052.
Preoperative platelet leukocyte ratio as an independent risk factor for postoperative outcomes in colorectal cancers.
Authors: Carrie E Ryan, Csaba Gajdos, Leili Pourafkari, Nader D. Nader
Journal: Journal of Clinical Oncology (2019)

3591 Background: Although preoperative platelet/leukocyte ratio (PLR) is a predictor of postoperative outcomes in various neoplasms, data is lacking for colorectal cancer (CRC). We hypothesized that elevated preoperative PLR would be an independent risk factor for postoperative complications and increased 30-day mortality in patients with surgically resected CRC. Methods: Patients undergoing resections for CRC were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2016 dataset. Logistic regression models for 30-day morbidity and mortality for PLR ≤28.4 and &gt;28.4 (calculated from ROC analyses) were completed. Univariate log-rank test, and multivariate Cox proportional hazards regression were used for time-to-event analyses and data are presented as odds/hazard ratio with confidence interval. Results: 98,398 patients were included in the study. Elevated PLR was an independent predictor of 30-day morbidity and mortality. Patients with high PLR were more likely to have a wound infection (1.022, 1.01-1.04), pneumonia (1.2, 1.17-1.23), require reintubation (1.23, 1.19-127), prolonged ventilation (1.31, 1.26-1.36), have renal insufficiency (1.17, 1.11-1.22), and have a postoperative myocardial infarction (1.23, 1.9-127). PLR value &gt; 28.4 was among independent predictors of mortality (1.67, 1.47–1.87), along with the ASA class, age, perioperative use of steroids, serum albumin and INR. (Table). Conclusions: Elevated PLR is a significant preoperative risk factor for 30-day morbidity and mortality. PLR may be considered as a potential risk assessment tool that predicts postoperative outcome following CRC resections. Multivariate analysis. [Table: see text]
An open label, multicenter phase II study combining imprime PGG (PGG) with pembrolizumab (<i>P</i>) in previously treated metastatic triple-negative breast cancer (mTNBC).
Authors: Steven O'Day, Virginia F. Borges, Bartosz Chmielowski, Ruta D. Rao, Maysa M. Abu-Khalaf, Alison Stopeck, Petros Nikolinakos, Melinda L. Telli, Bin Xie, Montaser F. Shaheen, Paulette Mattson, Michele Anne Gargano, Joanna Cox, Vassiliki Karantza, Michael Jon Chisamore, Bruno Osterwalder, Nandita Bose, Mark T. Uhlik, Jeremy Graff
Journal: Journal of Clinical Oncology (2019)

2550 Background: Checkpoint inhibitor (CPI) monotherapy shows limited clinical response in previously treated mTNBC patients (pts) (Table). Agents are needed that extend this benefit to more mTNBC pts. PGG is a novel, IV administered PAMP that, in pts with 20ug/ml anti-beta glucan antibody (ABA+), activates innate immune cells. Preclinically, PGG reprograms myeloid cells to repolarize the immunosuppressive tumor microenvironment &amp; enhance antigen presentation, driving T cell activation- the mechanistic basis to explore PGG + P in mTNBC patients. Methods: 44 mTNBC pts ( 1 line of chemotherapy [Tx] for metastatic disease, ABA) received PGG (4 mpk IV weekly) + P (200 mg IV q3w) until PD or intolerable toxicity. 1° endpoints were ORR by RECIST v1.1 &amp; safety. 2° endpoints included OS &amp; DCR. CT scans (q6 wks) were reviewed locally. Tumor biopsies (pre &amp; 6 wks on Tx) &amp; blood samples were assessed for PGG-mediated immune activation. Results: Table shows IMPRIME 1 clinical response data (Keynote086, PCD4989g shown for context). Confirmed response was also evident in pts with liver or visceral metastases, high LDH. 10 IMPRIME 1 pts were originally ER/PR+, received hormonal Tx and progressed to TNBC. Of these, 5 are confirmed PR, 4 SD (3 still on Tx), 1 PD. No unexpected safety signals were observed. Conclusions: These are the first clinical data to suggest that PGG provides added clinical benefit for pts with previously treated mTNBC and support further development of PGG + P for mTNBC. Clinical trial information: NCT02981303. [Table: see text]
Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.
Authors: Pasi A. Janne, Joel W. Neal, D. Ross Camidge, Alexander I. Spira, Zofia Piotrowska, Leora Horn, Daniel Botelho Costa, Anne S. Tsao, Jyoti D. Patel, Shirish M. Gadgeel, Lyudmila Bazhenova, Viola Weijia Zhu, Howard West, Sylvie Vincent, Jian Zhu, Shuanglian Li, Gregory J. Riely
Journal: Journal of Clinical Oncology (2019)

9007 Background: TAK-788 is an oral investigational EGFR/HER2 inhibitor under evaluation in NSCLC patients (pts) with EGFR exon 20 insertions. We report results of a phase 1/2 open-label, multicenter study (NCT02716116). Methods: Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results: As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (median 3.6 mo on treatment; median 3.8 treatment cycles); 24 pts remain on treatment. Antitumor activity in pts with EGFR exon 20 insertions is shown in Table. At data cutoff, 7/14 responses were confirmed with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Rate of treatment discontinuation due to AEs was 10.7% in pts treated at 160 mg. Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥3 TEAEs (≥5%) were diarrhea (26%) and hypokalemia, nausea, and stomatitis (7% each). Median dose intensity for pts treated with 160 mg qd was 93%. There is no clear trend that response to TAK-788 is enriched in particular EGFR exon 20 insertion variants. Conclusions: In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. Clinical trial information: NCT02716116. [Table: see text]
A novel drug to treat advanced melanoma.
Authors: Lingbin Meng, Xiaochun Xu, Ying Xin
Journal: Journal of Clinical Oncology (2019)

e21000 Background: Advanced melanoma is a type of malignant skin cancer without effective treatment. Ginsenoside-Rg3 (Rg3), a saponin component extracted from ginseng roots, has been revealed to have an anti-cancer effect. However, there is limited data about its involvement in advanced melanoma. In this study, we investigated the role of Rg3 in melanoma by evaluating its in-vivo efficacy to inhibit melanoma growth, lung metastasis and melanoma-induced angiogenesis. We also revealed the potential underlying mechanisms by examining ERK and Akt pathways. Methods: 6-week-old C57BL/6 mice were purchased and maintained in our animal center. A highly metastatic subline of murine B16 melanoma cells was kindly provided by Dr. Xiaochun Xu, M.D. Anderson Cancer Center. Five groups were designed for this experiment: control (PBS), 3 groups with different doses of Rg3(0.3mg/kg, 1.0mg/kg, and 3.0mg/kg), and 5-FU (20mg/kg). 7 mice per group were given subcutaneous injection of 2 x 10 6 melanoma cells on the right flank for xenograft assay. 5 x 10 5 melanoma cells wrer subcutaneously injected on the right hind footpad for metastasis assay.The formed tumor tissues and lungs were collected for tumor growth and metastasis analysis, immunohistochemical staining, and western blotting. Results: For tumor growth, all the 3 Rg3 groups had smaller size of tumor and reduced expression of PCNA, a marker for cancer cell proliferation. For lung metastasis, the 3 Rg3 groups showed a lower number of tumor colonies with a dose-dependent manner. For angiogenesis, the 3 Rg3 groups displayed suppression of tumor-induced neovascularization through inhibition of VEGF. Western results demonstrated both ERK and Akt pathways were down-regulated in the Rg3 groups. Interestingly, immunohistochemical staining showed a higher number of CD8 + T cell in Rg3 groups lungs, suggesting immune response may be activated to fight against melanoma. Conclusions: Rg3 can decrease melanoma growth and metastasis by down-regulating ERK and Akt pathways. It may also inhibit melanoma metastasis by mediating VEGF-activated angiogenesis. More importantly, Rg3 may activate immune system to fight against advanced melanoma. Our study is the first to indicate Rg3 may be a promising novel drug for advanced melanoma. Based on these results, we are performing a clinical trial to test its efficacy to treat advanced melanoma.
The association between <i>BRAF</i> mutation class and clinical features in <i>BRAF</i>-mutant Chinese non-small cell lung cancer patients.
Authors: Hong Zhu, Quan Lin, Yuping LI, Haoran Zhang, Huaxin Ding, Han Han-Zhang, Jing Lin, Jianxing Xiang
Journal: Journal of Clinical Oncology (2019)

e14681 Background: BRAF mutations, occurring in 2-4% NSCLC patients, can be classified into 3 classes based on signaling mechanism and kinase activity: V600-mutant RAS-independent kinase activating monomers (class I), RAS-independent kinase activating dimers (class II) and RAS-dependent kinase inactivating heterodimers (class III). The association between functional classes and clinical features of Chinese NSCLC patients remain elusive. Methods: Sequencing data of either plasma or tissue samples obtained from 8,405 Chinese (Stage I-IV NSCLC) patients were retrospectively analyzed to screen for BRAF mutations. Of the patients with BRAF mutations, 79% (188/238) were diagnosed with adenocarcinoma,7.6% with squamous cell carcinomas (SCC) and the remaining patients were either adenosquamous carcinoma or large cell carcinoma. Results: BRAF mutations were detected in 238 patients, revealing a prevalence of 2.8%. Among them, 32% (75/238), 21% (51/238) and 13% (31/238) had class I, II and III mutations, respectively. The remaining 35% (81/238) had other BRAF mutations. V600 (32%, 75/238) and G469 (13%, 32/238) were the 2 most predominant mutations. BRAF mutations, when considered collectively, including non-class I-III mutations, were more likely to occur in males ( p&lt; 0.01). However, class I mutations have a female predominance (p = 0.003); whereas, class II mutations showed a trend of male predominance (p = 0.09) and class III had no gender preference (p = 0.22). We also revealed no association between histology types and the class of BRAF mutations. Next, we investigated co-occurring classic lung cancer driver mutations in this cohort and revealed that patients with class II and III mutations were more likely to have concurrent KRAS mutations (p = 0.001). We also compared the overall survival (OS) of chemotherapy-treated patients and revealed comparable OS among the 3 groups. Conclusions: Our study revealed a 2.8% BRAF mutation rate in Chinese NSCLC patients. Our data also showed a male predominance when all BRAF mutations were considered collectively, and a female predominance for class I mutations. Furthermore, patients with BRAF V600E is less likely to have concurrent KRAS mutations.