tbuckley/cabot-search huggingface dataset:
Impact of BRCA mutation status and time to platinum resistance on patients with advanced ovarian cancer.
Authors: Alexandra Tyulyandina, Maxim Filipenko, Alexey Rumyantsev, Ilya Pokataev, Valentina Nechushkina, Konstantin Morkhov, Anatoly Bulanov, Marina Stenina, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2019)

5561 Background: The influence of germline BRCA1/2 mutations (gBRCAmt) on ovarian cancer patients (pts) long-term survival remains controversial. Methods: 228 pts with serous and endometrial ovarian cancer stage Ic-IV were enrolled in the retrospective study. Next-generation sequencing testing of BRCA1/2 in blood was employed. Progression-free survival (PFS), overall survival (OS) and time to platinum resistance (TPR) were analyzed. TPR was defined as time from first line chemotherapy to registration of platinum resistance relapse. Results: The rate of pathogenic gBRCAmt was defined in 29.4% (67/228) pts. There was no any significant difference between BRCA1/2 mutation carries and non-carries in both PFS (18.3 and 16.7 months, p = 0.27, HR 0.79, 95%CI 0.52-1.20) and OS (71.9 and 79.1 months, p = 0.69, HR 0.88, 95%CI 0.46-1.68). However, TPR was significantly longer in pts with gBRCAmt than in germline BRCA wild type (gBRCAwt) pts (51.4 and 34.4 months, p = 0.05, HR 0.60, 95% CI 0.36-0.98). Pts with gBRCAmt had poor prognosis after registration of platinum resistance. gBRCAwt pts had longer survival than gBRCAmt after platinum-resistance relapse: 33.7 and 16.9 months respectively (p = 0.05; HR 1.85, 95%CI 1.02-4.08). Conclusions: Our finding provided possible explanation of equal survival of pts with or without BRCA1/2 mutations. Long-term sensitivity to platinum-based chemotherapy allowed pts with gBRCA1/2mt to control the disease for a long period of time. However the non-platinum regimens had less efficacy in pts with gBRCAmt than gBRCAwt after platinum resistance.
Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Toni K. Choueiri, Laurence Albiges, John B. A. G. Haanen, James M.G. Larkin, Motohide Uemura, Sumanta K. Pal, Gwenaelle Gravis, Matthew T Campbell, Konstantin Penkov, Jae-Lyun Lee, Keith A. Ching, Xinmeng Jasmine Mu, Xiao Wang, Weidong Zhang, Jing Wang, Aleksander Chudnovsky, Alessandra di Pietro, Paul B. Robbins, Robert J. Motzer
Journal: Journal of Clinical Oncology (2019)

101 Background: The phase 3 JAVELIN Renal 101 trial in previously untreated patients (pts) with aRCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate with A+Ax vs S (Motzer, ESMO 2018; LBA6_PR). Here, we report outcomes from biomarker analyses of baseline tumor samples. Methods: We correlated efficacy with the results of molecular analyses of tissue samples from all 886 pts enrolled in JAVELIN Renal 101. Nephrectomy or tumor samples were characterized by immunohistochemistry (CD8 and PD-L1), whole-exome sequencing (WES), and RNAseq. WES and RNAseq were used to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcomes. GES analyses included published and de novo signatures: effector T cell (T eff ), angiogenesis (angio),T cell-inflamed (T inf ), and a novel immune-related signature incorporating pathway indicators for T- and NK-cell activation and IFNγ signaling, among others. Results: PD-L1 expression (≥1% immune cells) was associated with the longest PFS in the A+Ax arm and the shortest in the S arm (HR, 0.63; 95% CI, 0.49, 0.81). Significant treatment arm–specific differences in PFS were observed relative to wildtype when mutations in genes such as CD1631L, PTEN, or DNMT1 were present. Tumor mutational burden did not distinguish pts with respect to PFS. High-angio GES was associated with significantly improved PFS in the S arm but did not differentiate PFS in the A+Ax arm. In the low-angio subset, A+Ax improved PFS vs S. Pts with high T eff and T inf in the A+Ax arm had longer PFS vs the S arm. In the A+Ax arm, PFS was enhanced in patients with immune GES–positive tumors vs those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p = 0.004), as well as in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p = 0.064). Updated efficacy, including overall survival, will be presented. Conclusions: These findings define molecular features that differentiate therapy-specific outcomes in first-line aRCC and may inform personalized therapy strategies for pts with aRCC. Funding: Pfizer and Merck KGaA. Clinical trial information: NCT02684006.
HD201: Analytical biocomparability and clinical trial progression of trastuzumab.
Authors: Jocelyn hii, Xavier Pivot, Lisa Soyeon Park, Michael Kim, Peggy Feyaerts, Kuo Wei Chan, Jeong-Hyeon Lee, Felicia Ang
Journal: Journal of Clinical Oncology (2019)

e12505 Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2 positive breast cancer. HD201, developed and owned by Prestige Biopharma Pte Ltd is a biosimilar product to Herceptin (Trastuzumab). The development of HD201 from analytical biocomparability to clinical trial progression are demonstrated. Methods: Analytical biocomparability in terms of physicochemical (primary, higher order structure, glycan profiles, molecular and charge variants) and biological properties (inclusive of binding to Fcγ receptors and neonatal receptor) between HD201 and EU and US-Herceptin were compared. The first human study of HD201 (clinical phase I) was designed to assess the pharmacokinetic (PK) equivalence between HD201 and EU-Herceptin. In this randomised, blinded, single-dose comparative PK study, randomised healthy human subjects were subjected to a single 6 mg/kg IV dose of HD201 and EU-Herceptin following by PK and safety evaluations. Following this, a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) was designed to compare the efficacy, safety, and pharmacokinetics of HD201 to EU-Herceptin in 500 patients with HER2+ early breast cancer. Each group of patients (250 patients) were administered with either HD201 or EU-Herceptin once every 3 weeks up to 8 cycles in combination of a neoadjuvant chemotherapy comprising of docetazel followed by an anthracycline-containing regimen. Results: HD201 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. Clinical phase I study demonstrated that HD201 is safe and well tolerated with comparable PK profiles as EU-Herceptin after single dose administration to healthy male adults (Pivot et al., 2018). Analysis of sub study from clinical phase III has demonstrated comparable results with EU- Herceptin in terms of patient demographic, clinical response, safety and pharmacokinetic profile. Conclusions: HD201 is demonstrated to be equivalent in analytical biocomparability and in clinical response, safety and PK profile to Herceptin in human study. Additional data for Pharmacokinetic from Troika trial will be reported in Asco meeting. Clinical trial information: 2012-000805-56.
Case 4-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, W.B. Jerry Younger, Eugene J. Mark
Journal: New England Journal of Medicine (1987)

Presentation of Case First admission. A 48-year-old man was admitted to the hospital because of a pleural effusion.He was well until 16 months earlier, when a routine x-ray film of the chest (Fig. 1) showed a nodule in the right lung and right pleural thickening or effusion; the patient was asymptomatic. Four months later tomographic examination of the lungs revealed that the nodule had an irregular border. He entered another hospital, where a right thoracotomy disclosed a fibrotic lesion, which was removed. He was discharged feeling well, with small bilateral pleural effusions. Three months before admission pleuritic pain developed . . .
A first-in-human study of KY1044, a fully human anti-ICOS IgG1 antibody as monotherapy and in combination with atezolizumab in patients with selected advanced malignancies.
Authors: Sonia Quaratino, Richard Sainson, Anil Thotakura, Simon J Henderson, Kerstin Pryke, Anthea Newton, Nuala Brennan, Elisabeth Oelmann
Journal: Journal of Clinical Oncology (2019)

TPS2644 Background: The Inducible T-cell costimulator (ICOS/CD278) is related to the CD28 superfamily and is induced upon T cell activation. There is a hierarchical order of ICOS expression level, in which highly immunosuppressive TReg (CD4 + Foxp3 + ) present in the tumor microenvironment (TME) are at the top level of expression and CD8 T Eff cells are at the bottom level. In addition, ICOS expression on T Regs is higher in the TME than in the blood or spleen. Methods: KY1044, a fully human anti-ICOS IgG1 kappa monoclonal antibody, selectively binds to ICOS with high affinity (which is maintained at intratumoral acidic pH) and has a dual mechanism of action: it promotes the preferential depletion of intratumoral ICOS High T Regs resulting in an increase in the T Eff :T Reg ratio in the TME; and it stimulates ICOS Low T Eff cells. Preclinical data demonstrate that KY1044 monotherapy or in combination with anti-PD-L1 is associated with immune cell activation and anti-tumor response. In order to validate the dual mechanism of action in vivo, studies in mice and cynomolgus monkeys were conducted. Firstly, KY1044 injected i.v. at doses up to 100 mg/kg weekly were well tolerated in non-human primates. In addition, pharmacodynamic studies in mice and cynomolgus monkey confirm preferential depletion of ICOS High cells. KY1044-CT01 is an open-labelled first in human Phase I/II study assessing the safety, tolerability, PK, PD and anti-tumor activity of KY1044 administered every 3 weeks (Q3W) as an i.v. single agent infusion and in combination with atezolizumab (1200 mg, Q3W IV) in adult patients with advanced/metastatic malignancies. The primary endpoint of the Phase I dose escalations, designed as sequential but overlapping arms of KY1044 monotherapy and combination with atezolizumab, is safety and tolerability. Secondary endpoints are the characterization of pharmacokinetic, pharmacodynamic and efficacy profiles in all patients. In the Phase II part, the primary endpoint is overall response rate (ORR), and the measure of clinical efficacy will be confirmed as per RECIST 1.1. and immune-related (ir)RECIST. An intensive biomarker plan is integral to the study design to underpin the phenotypic and molecular changes in both peripheral blood and tumor. Clinical trial information: NCT03829501.
Multiple mutations in the EGFR gene in patients diagnosed with lung cancer.
Authors: Ekaterina P. Omelchuk, Oleg I. Kit, Natalia A. Petrusenko, Natalya N. Timoshkina, Dmitry Yu. Gvaldin, Elena Aleksandrovna Kalabanova, Sergey N. Kabanov, Yana V. Svetitskaya, Tatiana A. Snezhko, Irina S Mitashok, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e20542 Background: Lung cancer is the most common malignant tumor after breast cancer and is the main cause of cancer mortality. Mutations in the EGFR gene typical of lung cancer lead to constitutive activation of the epidermal growth factor receptor and malignant cell transformation. The purpose of this study was to identify associations between double and triple mutations in EGFR and clinical and pathological characteristics of patients in the South of Russia diagnosed with lung cancer. Methods: DNA was extracted from FFPE samples of 240 patients. Mutations in EGFR were detected using Cobas EGFR Mutation Test detection kit (Roche). Results: The mutant type of EGFR was identified in 24.6% of cases, and the most common activating mutations were ex19del (47.5%) and L858R (30.5%). Insertion in exon 20 was detected in 5.1% of mutation cases, G719X - in 3.4%. We also registered cases of identification of two or three mutations in one tumor: ex19del - L858R, ex19del - T790M, L858R - T790M with a frequency of 3.4% and G719X - ex20ins, ex19del - L858R - ex20ins with a frequency of 1.7%. Similar frequency is characteristic of the Caucasoid population of the USA. Multiple mutations in EGFR are associated with early manifestations of lung cancer and rapid progression of the disease. Two patients with two mutations EGFR T790M and L858R were of particular interest. According to the literature data, T790M is the most common somatic mutation that causes resistance to targeted therapy; however, rare cases could be associated with germinal variation of T790M. The primary T790M mutation is more common in patients with two or three mutations in EGFR. Conclusions: Mutations in the EGFR gene were detected in 24.6% of lung cancer cases in a patient population in the South of Russia. The frequency of two or three mutations in the EGFR gene was 0.33%. The timely detection of these mutations is particularly important for family cases when the risk group can be determined.
Changes in tumor mutational burden in serially biopsied non-small cell lung cancer.
Authors: James W. Smithy, David H. Hwang, Yvonne Y. Li, Liam Spurr, Andrew D. Cherniack, Lynette M. Sholl, Mark M. Awad
Journal: Journal of Clinical Oncology (2019)

e14286 Background: High tumor mutational burden (TMB) has been associated with response to checkpoint blockade in non-small cell lung cancer (NSCLC) and other malignancies. However, the degree to which TMB changes over time, across anatomical sites, and with intervening treatment remains unknown. To evaluate TMB changes across time points, we compared TMB in tissue specimens from patients with serially-biopsied NSCLC. Methods: Clinicopathologic characteristicsand changes in TMB were analyzed from patients with NSCLC and more than one biopsy that had undergone targeted next generation sequencing (NGS, OncoPanel) at the Dana-Farber Cancer Institute. Those representing distinct primary tumors by histology and/or discordant mutational profiles were excluded. Results: 134 NSCLC patients with more than one interpretable NGS result were identified; 23 were excluded due to separate primary tumors. Of the 111 remaining patients included in the analysis, the median time between samples was 14 months (range: 0 to 114 months). TMB correlated closely across all matched tumor pairs (Pearson’s r = 0.89), and greater variability in TMB was seen in biopsies taken from different anatomic sites (p = 0.04) compared to biopsies obtained from the same lesion. There was no significant change in median TMB with any intervening therapy, as TMB increased in some patients and decreased in others. Conclusions: In this observational study, TMB correlated closely across tumor pairs. However, these data suggest that sampling from different tumor sites may be associated with greater discrepancies in TMB. It is possible these differences could account for challenges in using TMB as a predictive biomarker for immunotherapy response. Further prospective investigation is needed to inform decisions regarding the need for repeat biopsy in patients starting immunotherapy with remote tissue samples.
Does weekly versus daily low-dose of concurrent cisplatin have any effect on compliance and clinical outcomes in cases of locally advanced head and neck cancers?
Authors: Ayush Garg, Piyush Kumar, Arvind Kumar Chauhan, Pavan Kumar
Journal: Journal of Clinical Oncology (2019)

e17569 Background: Concurrent Cisplatin with radiotherapy improves outcomes in locally advanced squamous cell carcinomas of the head neck.Cisplatin at 35mg/m 2 (weekly) raise compliance &amp; hospitalization. There are only few reports on efficacy and toxicity of low dose Cisplatin (6mg/m 2 ). Hence the purpose of this study was to evaluate the compliance and clinical outcomes between two concurrent cisplatin chemotherapy regimens &amp; to see long term effects. Methods: Total 50 patients were included in study from Nov 2015 to Mar 2017 with 25 in each group. Radiotherapy given 70Gy/35# in 7weeks &amp; Cisplatin at 35mg/m 2 weekly (Group I) and 6mg/m 2 daily (Group II). Assessment of toxicity was done by RTOG scoring criteria. WHO Response criterion was used to assess clinical response. Median follow up was 6 months. Results: Group I(80%) and Group II(84%)patients completed Radiotherapy. In Group I 48% patients received less than 6 cycles and Group II 40% received ≤25 cycles chemotherapy. Median OTT in Group I &amp; II in was 51 &amp; 52days. Neutropenia &amp; Mucositis statistically insignificant between both groups.There was no statistical difference in complete response between the two groups. In Group I 40% patients developed Progressive disease on follow up as compared to 12% in Group II(p-0.02). After 1.5 years of follow up, Group I vs Group II 4 patients had complete response, 6 had recurrence &amp; 11 vs 4 patients expired (p-0.03). At a median follow up of 6 months overall survival in Group I and II was 56% and 44%(p-0.39). While as median disease free survival in Group I &amp; II was 6.6 &amp; 11.9 months(p-0.14). Conclusions: Low dose daily Cisplatin offers ease of administration in the outpatient clinic, better tolerability and better quality of life.Group II patients were more compliant in terms of patients receiving chemotherapy or completing radiotherapy. At median follow up of 6 months there was no statistical difference in terms of overall and disease-free survival. The statistical difference was seen in terms of patients expired in Group I (44%) as compared to Group II (16%). Therefore, we need a larger number of patients for the use of low dose Cisplatin to be evaluated in future clinical trials.
Efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib in patients with advanced triple-negative breast cancer.
Authors: Jieqiong Liu, Zefei Jiang, Qian Li, Ying Li, Qiang Liu, Erwei Song
Journal: Journal of Clinical Oncology (2019)

1066 Background: PD-1/PD-L1 blockade monotherapy delivered positive outcomes in early-phase trials in advanced triple-negative breast cancer (TNBC). However, t he highest objective response rate (ORR) is 18.5%. IMPassion130 trial has demonstrated that only PD-L1 + TNBC had overall survival benefit from anti-PD-L1 antibody combined with chemotherapy. Preclinical studies found that antiangiogenic therapy could sensitize anti-PD-1 treatment via inducing PD-L1 expression and increasing CTLs infiltration in tumor microenvironment. Thus, we designed a phase II, open-label trial (NCT03394287) of SHR-1210 (anti-PD-1 antibody) in combination with apatinib (VEGFR2 inhibitor) in patients with advanced TNBC. Methods: 20-58 advanced TNBC patients whose systemic therapy lines in the metastatic setting was less than 3, will be randomly (1:1) enrolled from Sun Yat-sen Memorial Hospital to receive either SHR-1210 200mg Q2W plus apatinib 250mg, continuous dosing (d1-d14), or SHR-1210 200mg Q2W plus apatinib 250mg, intermittent dosing (d1-d7), until progression or unacceptable toxicities. Primary endpoint was ORR. Secondary end points included PFS, DCR, TTR, DoR, CBR, one year-OS and toxicity. Results: Until Jan 30, 2019, 34 patients were enrolled, 10 in the intermittent dosing arm, and 24 in the continuous dosing arm. 26 (76.5%) patients had prior systemic therapy in the metastatic setting. At the cutoff date (Jan 30, 2019), 28 patients were evaluable for ORR as per RECIST. The ORR was 47.4% (9 of 19) in the continuous dosing cohort, and no confirmed objective response was found in the intermittent dosing arm. The DCR was 68.4% in the continuous dosing arm, whereas it was 44.4% in the other arm. The median PFS was 2 months in the intermittent dosing cohort, while it was not reached in the continuous dosing cohort. The most common adverse events (AEs) was fatigue (65.0%), hand-foot syndrome (63.3%), and elevated aspartate aminotransferase and/or alanine aminotransferase (73.3%). There were no treatment-related deaths. Another 5 patients will be enrolled into the continuous dosing arm because of its favorable response. Conclusions: Anti-PD-1 antibody SHR-1210 combined with apatinib demonstrates favorable clinical activity and a manageable safety profile in patients with advanced TNBC. Clinical trial information: NCT03394287.
Distinguishing Stevens-Johnson syndrome/toxic epidermal necrolysis from clinical mimickers during inpatient dermatologic consultation—A retrospective chart review
Authors: Allison Weinkle, Cory Pettit, Aditi Jani, Jesse Keller, Yuanyuan Lu, Stephen Malachowski, John C. Trinidad, Benjamin H. Kaffenberger, Elizabeth N. Ergen, Lauren C. Hughey, David Smith, Lucia Seminario-Vidal
Journal: Journal of the American Academy of Dermatology (2019)
Neoadjuvant nivolumab in resectable non-small cell lung cancer: Extended follow-up and molecular markers of response.
Authors: Joshua E. Reuss, Kellie Nicole Smith, Valsamo Anagnostou, Jiajia Zhang, Marianna Zahurak, Justina Caushi, Hok Yee Chan, Haidan Guo, Matthew David Hellmann, Drew M. Pardoll, Julie R. Brahmer, Jamie E. Chaft, Patrick M. Forde
Journal: Journal of Clinical Oncology (2019)

8524 Background: Improved therapy is needed for patients (pts) with early-stage non-small cell lung cancer (NSCLC), as the majority relapse after curative resection. Our group reported the first trial of neoadjuvant PD-1 blockade in resectable NSCLC, finding therapy to be safe and feasible. Here we report extended clinical follow-up and long-term molecular response data from this trial. Methods: IV nivolumab 3 mg/kg was given every 2 weeks for 2 doses prior to surgery in 20 pts with resectable NSCLC at Johns Hopkins and MSKCC. Blood for correlative studies was taken prior to each dose of nivolumab, prior to surgery, 2-4 weeks post-surgery, and during long-term follow up. In a subgroup of pts, longitudinal molecular data was assessed in peripheral blood for circulating tumor DNA (ctDNA) and dynamics of tumor-infiltrating T-cell clonotypes. Results: At median follow up of 30 months (m), 15 of 20 pts are disease-free and alive. Two pts have died (one from relapsed disease). Median recurrence free survival (RFS) has not been reached. The 24m RFS rate is 69% (95% CI: 51-93). Thus far, presence of ctDNA at diagnosis and major pathologic response (MPR - ≤10% viable tumor in resected specimen) do not associate with RFS. One long-term immune-related adverse event has occurred (skin, G3). All pts who on pathologic review had ≥30% reduction in viable tumor in response to nivolumab demonstrated clearance of detectable ctDNA from blood prior to surgery. Pts with MPR experienced expansion of neoantigen-specific T-cells in peripheral blood. In one patient with ongoing disease free status, expansion of tumor-associated T-cells has persisted in peripheral blood beyond 15m from surgery. By contrast, in a patient who had detectable peri-operative ctDNA and 75% residual disease at surgery, minimal T-cell expansion was observed in peripheral blood, with a decreasing frequency of expanded T-cell clones over time that correlated with eventual cancer relapse. Conclusions: Long-term follow up reinforces the safety of neoadjuvant nivolumab in resectable NSCLC. Analysis of ctDNA and peripheral T-cell expansion in responders compared with non-responders suggests potential biomarkers for response and surveillance. While RFS data is encouraging, phase 3 trials are ongoing to evaluate efficacy of PD-(L)1 blockade in early-stage NSCLC. Clinical trial information: NCT02259621.