tbuckley/cabot-search huggingface dataset:
Using single cell genomics to change the treatment of lung cancer.
Authors: Venessa T. Chin, Ghamdan Al Eryani, Rachael McCloy, Emily Stone, Adrian Havryk, Marshall Plit, Andrew Field, Neil Watkins, Alex Swarbrick, Joseph Powell
Journal: Journal of Clinical Oncology (2019)

e20563 Background: Lung cancer (LC) is common with a dismal prognosis. Although treatment with immunotherapy (IO) has improved survival outcomes, these therapies remain expensive. Even using biomarker selection, response rates still fall short of 50%. The majority of immune cell profiling done previously uses samples taken from early stage patients focusing on a single immune cell subtype. Here we use single cell RNA sequencing (scRNA-seq) and Cellular Indexing of Transcriptome and Epitopes by sequencing (CITE-seq) to characterise the innate and adaptive immune cell activation state and assess the response to exposure to IO in vitro from patients with advanced LC. Methods: Patients with locally advanced or metastatic LC having an Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) have biopsies collected for analysis. Cells are grown in culture +/- nivolumab for 48 hours. scRNA-seq and CITE-seq is conducted using established protocols. Transcriptomic and proteomic data on the innate and adaptive immune cell subsets assess markers of immune activation and/or suppression and the changes after nivolumab are quantified. Results are correlated with clinical outcomes. Results: In a locally advanced/metastatic population, EBUS-TBNA biopsies yield highly cellular samples with a heterogeneous population of immune cells able to be cultured +/- IO using novel, inclusive techniques. Transcriptomic clustering reveals distinct sub-populations within the T-cell, B-cell and innate immune cell compartments. Within these clusters, CITE-seq shows protein expression on individual cells can determine states of exhaustion, cytolytic ability, migratory potential and innate immune activation. Conclusions: Single cell genomics is feasible and informative in patients with advanced LC. This work will form the basis of a functional, real-time assay to assess individualised responses to IO therapy that has the potential to predict IO response.
Therapeutic efficacy comparison of six major EGFR-TKIs in non-small-cell lung cancer patients with an activating EGFR mutation: A network meta-analysis.
Authors: Fang Wu, Jingyi He, Sixuan Wu, Yan Huang, Yizheng Li, Lishu Zhao, Chunhong Hu
Journal: Journal of Clinical Oncology (2019)

e20671 Background: EGFR-TKIs are the standard in the first line treatment for patients with advanced NSCLC with EGFR activating mutations.This network meta-analysis was undertaken to compared all the EGFR-TKIs in terms of PFS, overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Methods: The PubMed and Embase databases were screened for relevant studies. We extracted data of ORR, DCR, PFS, and OS from enrolled studies and performed multiple treatment comparisons based on bayesian network meta-analysis. Due to the differences in design of each clinical study, two rounds of analysies were performed. We first compared the therapeutic efficacy of the first-generation TKIs (erlotinib and gefitinib), second-generation TKIs (afatinib or dacomitinib) and third-generation TKIs based on A7471028, ARCHER 1009, LUX-Lung 7, ARCHER 1050 and FLAURA studies. The following comparison between first-generation TKIs (gefitinib, erlotinib and icotinib) and second-generation TKIs was performed based on ICOGEN, A7471028, ARCHER 1009, WJOG 5108L, CTONG 0901, LUX-Lung 7 and ARCHER 1050 studies. Results: Eight trials with 2154 patients and 6 TKIs (gefitinib, erlotinib, icotinib, afatinib, dacomitinib and osimertinib) were included. The first round analysis indicated that Osimertinib ranked best among all the TKIs in terms of DCR, 1y-PFS and 1y-OS. Afatinib ranked first among these similar agents with ORR. The second round analysis showed that second-generation TKIs had potentially better efficacy compared with first-generation TKIs. Icotinib seemed to work best in first-generation TKIs and ranked first among first- and second-generation TKIs in terms of 1y-OS. Conclusions: The third-generation TKIs had better therapeutic efficacy compared with the first-generation TKIs and the second-generation TKIs. However, the second-generation TKIs had better efficacy compared with first-generation TKIs. [Table: see text]
A feasibility study of induction pemetrexed plus cisplatin followed by pleurectomy/decortication for malignant pleural mesothelioma (Japan Mesothelioma Interest Group 1101 Trial).
Authors: Seiki Hasegawa, Kohei Yokoi, Morihito Okada, Fumihiro Tanaka, Mototsugu Shimokawa, Takashi Daimon, Takashi Nakano
Journal: Journal of Clinical Oncology (2019)

8518 Background: Although pleurectomy/decortication (P/D) has become a preferred surgical technique for malignant pleural mesothelioma (MPM), only a few prospective, multi-center clinical trials have been conducted. Here we present final results of a nationwide, prospective, multi-institutional study to evaluate the feasibility of induction chemotherapy followed by P/D. Methods: Eligibility criteria: a histologically confirmed diagnosis of MPM; clinical T1–3, N0–2, M0 disease; no prior treatment for the disease; age between 20 and 75 years; ECOG performance status of 0 or 1; and written informed consent. Treatment methods: Induction chemotherapy of pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 for 3 cycles, followed by P/D. Intraoperative conversion from P/D to extrapleural pneumonectomy (EPP) was permitted. Pulmonary function tests were performed at 3, 6, 12, 24, and 36 months after surgery. Primary endpoint was macroscopic complete resection (MCR) rate regardless of the surgical technique. Results: Of 24 patients enrolled, 20 patients were eligible: median age 66 (48–74); M/F: 17/3, Clinical stage I/II/III: 8/9/3; Histology epi/sar/bi: 19/1/0. Two discontinued protocol before surgery due to deteriorated FEV1 or adverse effect (AE) of chemotherapy, and the remaining 18 patients completed surgery with MCR: P/D in 15 patients and EPP in 3. The trial met the primary endpoint with MCR rate of 90% (18/20). There was no treatment-related 30- and 90-day mortality. There were two cases of chemotherapy-related grade 4 AEs, but no surgery-related grade 4 AE occurred. The overall survival rates at 1 and 2 years and median survival time (MST) after registration were 95.0% (95% CI, 69.5 to 99.3), 70.0% (45.1 to 85.3), and 41.4 months (19.7 to NA), respectively. The progression-free survival rates at 1 and 2 years and MST after registration were 84.7% (60.0 to 94.8), 42.4% (20.5 to 62.7), and 22.9 months (12.7 to 28.4), respectively. Recurrence occurred in 17 patients, and initial relapse sites were local in 17 (100%) and distal in 6 (35.3%). The best values of FVC and FEV1 during postoperative period were 78.0% and 82.5% of preoperative values, respectively. Conclusions: Induction chemotherapy plus P/D yielded a MST over 40 months with acceptable risks. Postoperative pulmonary function was approximately 80% of preoperative value. Clinical trial information: UMIN000009092.
Selected molecular markers as indicators of clinical profile, tumor characteristics and treatment outcome in squamous cell carcinoma of the larynx.
Authors: Elizabeth Mathew Iype, Lakshmi S, Rajan Balakrishnan
Journal: Journal of Clinical Oncology (2019)

e17522 Background: Laryngeal Squamous cell carcinoma is widely prevalent in India and is the fourth leading cancer in males. The possibility that specific tumour characteristics (demonstrable by immunohistochemistry) may aid the clinician in choosing optimal treatments for a specific tumour, holds great promise. Objectives of the present study were to study the expression of select molecular markers p53, Bcl-2 (Apoptotic markers), EGFR, Ki67, Cyclin D1 (Proliferation markers) and Cox-2 (Inflammatory marker) in LSCC so as to form a hypothesis that a particular group of markers will be useful in determining the prognosis of LSCC. Methods: We studied 72 cases of laryngeal squamous cell carcinoma in an attempt to determine relationship between their clinicopathological characteristics and treatment outcome with the six molecular markers. Samples from patients who underwent laryngectomy from Jan 2006 to Dec 2010 were taken and analyzed prospectively and followed up till Dec 2015 or till death. . Immunoreactivity in tissue sections was evaluated as negative when no positive cells were observed within the tumor, weak (1+) , moderate (2+) , and strong or intense (3+) . Data were analyzed using SPSS software package. Chi squared test or exact test were used to test the associations. Logistic regression analysis was used to estimate the odds ratios and 95% confidence intervals. The disease free survival time of each patient was calculated by taking the difference between the date of surgery and the recurrence date/ death date/ the last follow up date whichever is applicable. Results: Proliferation markers EGFR, Cyclin D1 and Ki 67, individually and collectively were predictive of extracapsular spread and perineural spread of tumour. Node negative patients having intense expression of Cyclin D1 or Ki 67 has bad prognosis.. The significant expression of Cox-2 was highly predictive of Node positivity. In older patients and in T4 stage the presence of P53 / Bcl-2 resulted in worse overall survival. Markers of aggressiveness were identified as p53, Bcl-2 Cox-2. Markers of invasiveness were EGFR, Cyclin D1 and Ki 67. Markers predicting survival were p53, BCl-2, Cyclin D1 and Ki 67. Conclusions: If Proliferation markers are detected preoperatively in biopsy specimens, has important implications in planning aggressive management Cyclin D1 or Ki 67 in Node negative patients indicate need for a neck dissection or irradiation. Cox-2 assessment will be useful in predicting the occult nodal metastasis for prophylactic treatment
Preoperative lymph node assessment in surgically resected pathologic T1 lung cancer patients: Real world clinical practice in China.
Authors: Xu Jinming, Xingpeng Han, Lunxu Liu, Xiangning Fu, Yin Li, Xiaofei Li, Lin Xu, Yang Liu, Heng Zhao, Deruo Liu, Yihe Wu, Jinlin Cao, Haiying Yang, Jian HU
Journal: Journal of Clinical Oncology (2019)

e20016 Background: Accurate lymph node assessment is crucial for clinical patient management and prognostic prediction. However, the procedures may not always be performed preoperatively due to time, cost or risk of procedure itself. Present study aimed to investigate the real world clinical practice of preoperative N staging in surgically resected pathologic T1 lung cancer patients in China. Methods: This is a multicenter retrospective study. Real world data on clinical and pathologic N staging was retrieved from electronic medical records in 10 thoracic surgery centers (LinkDoc Database). Kappa index was calculated to determine the agreement between clinical and pathologic N stage. Results: A total of 11360 patients who underwent surgical resection for pT1 lung cancer were identified during January 2014 to September 2017. Clinical N staging was available for 6057 (53.3%) patients. Of which, 959 (15.8%) patients were achieved by invasive procedures. Considering the 5795 patients with clinical and pathologic N staging data, the overall agreement was 89.0% with a kappa index of 0.4220 (95%CI: 0.3842-0.4598). This was 96.4% for N0, 22.1% for N1 and 39.8% for N2 when considering pathologic N stage as gold standard (Table). In general, upstaging (7.3%) was more common in our population. Conclusions: Over 50% of pathologic T1 patients had preoperative N staging in our clinical practice. Clinical N staging showed low accuracy for predicting lymph node status. The findings of our study highlight the increasing attention on clinical N staging and procedure optimization in China. [Table: see text]
KEYNOTE-427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non‒clear cell renal cell carcinoma (NCC-RCC).
Authors: Jae-Lyun Lee, Marek Ziobro, Rustem Gafanov, Vsevolod Borisovich Matveev, Cristina Suarez, Frede Donskov, Frederic Pouliot, Boris Yakovlevich Alekseev, Pawel J. Wiechno, Piotr Tomczak, Miguel Ángel Climent, Sang Joon Shin, Rachel Kloss Silverman, Rodolfo F. Perini, Charles Schloss, David F. McDermott, Michael B. Atkins
Journal: Journal of Clinical Oncology (2019)

4569 Background: Efficacy of PD-1 inhibitors (or any therapy) in NCC-RCC has not been established. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced clear cell RCC (cohort A) and NCC-RCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed NCC-RCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Additional end points: duration of response (DOR), population description by sarcomatoid differentiation, histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26); 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At median follow-up of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CR, 33 [20.0%] PR). Median DOR was not reached. For responding pts, 81.5% had a response ≥6 mo. 12-mo PFS and OS rates were 22.8% and 72.0%, respectively. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified NCC-RCC; for responding pts, 82.1%, 50.0%, and 87.5% had a response ≥6 mo, respectively. Median DOR was not reached in any group. ORR (95% CI) was 44.7% (28.6-61.7) for pts with sarcomatoid differentiation (n = 38). ORR (95% CI) was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS &lt; 1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts. 6 pts died of AEs, 2 of TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in NCC-RCC, especially with papillary or unclassified histology. Safety profile of pembro was as expected. Updated data with additional follow-up will be presented. Clinical trial information: NCT02853344.
Efficacy and safety of apatinib as second-line or beyond therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: You Qin, Qian Ding, Xinhua Xu, Fengjun Cao, Siqing Ning, Haibo Zhou, Guiming Chen, Jing Huang, Gang Peng, Kunyu Yang
Journal: Journal of Clinical Oncology (2019)

e17517 Background: The aim of this study was to evaluate the efficacy and safety of apanitib in the treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who failed from one or more lines of therapy. Methods: Patients with recurrent and/or metastatic HNSCC after failure of at least one line of therapy were recruited in this open-label exploratory study. Subjects were initially given apatinib 250mg qd until disease progression or unacceptable toxicity. Dose reduction to 125 mg was allowed. Herein, we reported the preliminary results at the cut-of date of Jan 31, 2019. Results: Between Jul 2017 to Dec 2018, 17 patients were enrolled. The median age was 59 years; 94% were male; 88% had more than 2 lines of chemotherapy. The median PFS and OS were 5.71 and 7.86 months, respectively. Most treatment related adverse events (AEs) were in grade ½. The grade ¾ AEs were hypertension (1/17, 5.88%), fistula (2/17, 11.76%), mouth mucositis (2/17, 11.76%), proteinuria (2/17, 11.76%), and f bleeding (6/17, 35.29%). Conclusions: Apatinib showed promising efficiency with tolerable toxicity for recurrent and/or metastatic HNSCC patients who failed from one or more lines of therapy. Clinical trial information: ChiCTR1800015278.
DGM1 may serve as a novel genetic biomarker of response to enzastaurin in glioblastoma.
Authors: Nicholas A. Butowski, Ronald L. Shazer, Hong Sun, Isabel Han, Manoj A. Jivani, Wen Luo
Journal: Journal of Clinical Oncology (2019)

2023 Background: Despite countless clinical trials being conducted, little has changed over the last decade in the chemotherapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. We discovered a novel pharmacogenomic biomarker for enzastaurin (enz) in treating lymphoma (lymph). We evaluated if this biomarker can be used to predict enz response in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples from a ph 3 enz lymph trial and confirmed in an independent ph 2 enz lymph trial. The biomarker was then evaluated for its predictability in GBM using the archived DNA samples from a prior ph 1/2 enz GBM trial. Results: A novel biomarker, Denovo Genomic Marker 1 (DGM1), a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymph trials. Using DNA extracted from blood of pts from the single-arm ph 1/2 study of newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. In addition, we found pts in the GBM study receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of &lt; 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]; enz 500 mg/day was used in the lymph studies. Conclusions: These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymph and GBM. There is an ongoing biomarker-driven pivotal ph 3 study in lymph at 500 mg/day, and DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.
Association of relative neutrophilia with a distinct immunoinhibitory milieu in non-small cell lung cancer.
Authors: Kyle Gregory Mitchell, Lixia Diao, Hai T. Tran, Marcelo Vailati Negrao, Tatiana Karpinets, Jing Wang, Edwin Roger Parra Cuentas, Erin M Corsini, Alexandre Reuben, Lorenzo Federico, Chantale Bernatchez, Ara A. Vaporciyan, Stephen Swisher, Tina Cascone, Ignacio Ivan Wistuba, John Heymach, Jianjun Zhang, Don Lynn Gibbons, Cara L. Haymaker, Boris Sepesi
Journal: Journal of Clinical Oncology (2019)

e14047 Background: Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with poor prognosis in non-small cell lung cancer (NSCLC); the biological underpinnings of this observation have not been fully elucidated. We examined the relationships between peripheral neutrophil counts (PMN), NLR, circulating cytokines and angiogenic factors (CAF), and tumor microenvironment (TME) features in NSCLC. Methods: 150 patients with resectable NSCLC were enrolled in an immunoprofiling project. A panel of 43 CAFs was used to analyze preoperative plasma samples. Chemotherapy-naïve patients with CAF and a complete blood count ≤30 days preoperatively were included (n = 66; Table). For a subset, transcriptional signatures (MCP-counter, n = 50) and flow cytometry (n = 19) were used to identify TME phenotypes. Results: Increased PMNs were associated with increased pro-inflammatory CAF such as IL-1b (r = 0.392) and IL-6 (r = 0.339), as well as Th17/Tc17 associated CAF IL-17A (r = 0.320) and TNF-a (r = 0.368). Elevated NLR was inversely correlated with the lymphocyte activation marker soluble CD27 (r = -0.320, p = 0.009). This negative association was mirrored in the TME, as tumor neutrophil signatures were inversely correlated with a local IFN-g gene signature (r = -0.626, p &lt; 0.001). Interestingly, a Th17/Tc17 peripheral signature (elevated IL-17A) was associated with an enrichment of CD8 + TIM3 + cells (r = 0.623, p = 0.042) in the tumor. While this requires confirmation in a larger cohort, this correlation provides a potential rationale for targeting TIM3 in this population. Upon analysis of clinical characteristics, peripheral PMNs and NLR were higher among patients with squamous histology (PMN p = 0.009; NLR p = 0.034) and positively correlated with tumor size (PMN r = 0.344, p = 0.004; NLR r = 0.363, p = 0.003). Conclusions: A relative neutrophilia in NSCLC patients is associated with an inflammatory milieu suggestive of a Th17/Tc17 presence and decreased lymphocyte activation that is reflected within the TME. Further investigation is needed to define the role of NLR as a predictive biomarker and to identify whether neutrophils or Th17/Tc17 T cells could serve as a therapeutic target to improve immunotherapy response in NSCLC.[Table: see text]
Immunomodulation by HDAC inhibition: Results from a phase Ib study with vorinostat and pembrolizumab in metastatic urothelial, renal, and prostate carcinoma patients.
Authors: Roberto Pili, David I. Quinn, Costantine Albany, Nabil Adra, Theodore F. Logan, Andrew Greenspan, Justin Budka, Nur Damayanti, Mark A Green, James W. Fletcher, Mark Tann, Sara I Edwards, Heather Burney, Hao Liu, Noah M. Hahn
Journal: Journal of Clinical Oncology (2019)

2572 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that HDAC inhibitors have synergistic antitumor effects in combination with PD-1 inhibition in tumor models by inhibiting the function of Tregs and MDSCs. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial, renal and prostate carcinoma. Methods: The primary objective was to evaluate the safety and tolerability of this combination strategy. The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and one week OFF) and a fixed, standard dose of pembrolizumab (200 mg IV every 21 days). Patients were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve urothelial and renal cancer pts = 15), Cohort B (previously treated, anti-PD1/PD-L1 resistant urothelial and renal cancer pts = 14), and Cohort C (prostate cancer pts = 14). Results: Dose levels 1 (4 enrolled, 3 evaluable) and 2 (4 enrolled, 3 evaluable) were completed without DLTs and 200 mg was the Phase II recommended dose for vorinostat. The most common resolved grade 3/4 toxicities were acute kidney injury (n = 1), anemia (n = 1), diarrhea (n = 1), and hypothyroidism (n = 1) in the dose expansion cohorts. We have enrolled 43 pts (37 evaluable) in the dose expansion cohorts. For Cohort A, B, and C the median PFS were 2.8 months, 5.2 months, and 3.5 months. Two PR were observed including the dose escalation phase. Two PCA pts have achieved undetectable PSA. We have performed several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells, PDL-1 staining and PSMA PET scans in a subset of pts. Conclusions: The results from this phase Ib suggest that the combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint resistant UC/RCC pts and immune checkpoint naïve PCA pts. Clinical trial information: NCT02619253.