tbuckley/cabot-search huggingface dataset:
A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350).
Authors: Sumit Kumar Subudhi, Ana Aparicio, Amado J. Zurita, Bernard Doger, William Kevin Kelly, Avivit Peer, Dana E. Rathkopf, Lawrence Ivan Karsh, Jeffrey J. Tryon, Nishi Kothari, Xin Zhao, Eugene Zhu, Deborah S. Ricci, Namphuong Tran, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

TPS5087 Background: Assessing multiple therapies in a single clinical trial can facilitate the rapid identification of new agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib (Nirap) is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. PARP inhibition may be especially lethal in tumor cells with genetic DNA damage response deficits (DRD). Based on promising preclinical and clinical data, this study is designed as a master protocol with nirap as a backbone therapy. Combination 1 assesses the safety and efficacy of nirap plus JNJ-63723283 (JNJ-283), an anti-PD-1 monoclonal antibody. Combination 2 assesses nirap plus abiraterone acetate and prednisone (AA-P). Methods: This multicenter, global, open-label study is currently open at 18 sites in 5 countries of the planned XX sites, and is enrolling patients with mCRPC who have progressed on ≥1 androgen-receptor targeted therapy for mCRPC. Enrollment at time of abstract submission was 25 for combination 1. When combined with AA-P, the RP2D has been determined to be nirap 200 mg. The recommended phase-2 dose (RP2D) of nirap plus JNJ-283 was determined in Part 1 based on the incidence of specified adverse events and PK data to be 480 mg every 4 weeks. For Part 2 of the study, patients are assigned to receive oral niraparib daily plus JNJ-283 infusions once every four weeks until disease progression, unacceptable toxicity, death, study termination. Part 2 is described in the table. Clinical trial information: NCT03431350. [Table: see text]
Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.
Authors: Xi Wang, Bo Zhang, Xuelian Chen, Hongnan Mo, Dawei Wu, Bo Lan, Qun Li, Binghe Xu, Jing Huang
Journal: Journal of Clinical Oncology (2019)

e15559 Background: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors, and reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy were not identified in ESCC. Methods: A total of 43 patients were retrospectively reviewed in the ESCC cohort of a phase I trial from our center. All patients received intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at a dose of 60 mg, 200 mg or 400 mg (4-week interval after first dose followed by a 2-week schedule) and repeated every two weeks until disease progression or intolerable toxicity. The associations between lactate dehydrogenase (LDH) as well as other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated. Results: With a median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free survival (PFS) and overall survival were 2.0 months (95% CI: 0-4.1 months) and 8.0 months (95% CI: 7.2-8.8 months), respectively. Notably, four patients achieved a PFS exceeding 12 months, including three patients with a long-lasting duration of response over 1 year. Patients with an elevated baseline lactate dehydrogenase had lower tumor response rates (8.3% vs. 32.3%, p = 0.02) as well as shorter PFS (median: 1.8 vs. 4.0 months; HR 0.39, p = 0.002) and overall survival (median: 4.2 vs. 10.4 months; HR 0.22, p &lt; 0.0001) compared with patients with normal levels. An increase of lactate dehydrogenase level during treatment was significantly associated with disease progression (p = 0.014). Multivariate Cox analysis identified LDH (HR = 0.18), C-reactive protein (HR = 0.27), number of involved organs (HR = 0.31), absolute monocyte count (HR = 0.33) and Eastern Cooperative Oncology Group performance status (HR = 0.36) as independent prognostic factors. Conclusions: Serum LDH, as is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients receiving anti-PD-1 treatment.
Effect of tivantinib on VEGF signaling pathways and apoptosis of gastric cancer cells with c-MET or VEGFA amplification.
Authors: Hyeong Su Kim, Dae Young Zang, Sung-Hwa Sohn, Bohyun Kim, Hee Jung Sul
Journal: Journal of Clinical Oncology (2019)

e14719 Background: VEGFA is the key mediator of angiogenesis in cancer and previous studies reported that VEGFA expression was significantly up-regulated in gastric cancer tissues compared with matched normal tissues. We showed that increased levels of VEGFA are significantly associated with expression of hepatocyte growth factor receptor (MET) (r = 0.6255, P &lt; 0.0001). In addition, it is well known that c-MET is potentially a highly plausible target for cancer therapy in gastric cancer. In this study, cytotoxic activity of tivantinib were evaluated in gastric cancer cells with high c-MET expression or VEGFA amplification. Methods: In this study, Western blot and quantitative real-time PCR analysis were used to detect the expression of protein and genes after treatment of tivantinib. In addition, MTS, flow cytometry, and migration assay were used. Results: Tivantinib inhibited growths of a high c-MET-expressed or VEGFA-amplified cell lines. Furthermore, in migration and apoptosis analysis, tivantinib induced apoptosis of SNU620, MKN45 (carried VEGFB mutation), AGS, and MKN28 cells but not in KATO III (carried VEGFB and VEGFC mutation) cells. We also found that tivantinib inhibited the VEGF signaling pathway and MYC expression in VEGFA-amplified gastric cancer cell lines. Conclusions: The data indicate that tivantinib could be a potential therapeutic agent for the treatment of gastric cancer with high c-MET expression or VEGFA amplification.
United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.
Authors: Ahmad A. Tarhini, Sandra J. Lee, F. Stephen Hodi, Uma N. M. Rao, Gary Irvin Cohen, Omid Hamid, Laura Fulper Hutchins, Jeffrey Alan Sosman, Harriet M. Kluger, Vernon K. Sondak, Henry B. Koon, Donald P. Lawrence, Kari Lynn Kendra, David R. Minor, Carrie B. Lee, Mark R. Albertini, Lawrence E. Flaherty, Teresa M. Petrella, John M. Kirkwood
Journal: Journal of Clinical Oncology (2019)

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2 nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.
Paclitaxel/carboplatin with or without cetuximab for treatment of carcinoma with unknown primary (PACET-CUP): Results of a multi-center randomized phase II AIO trial.
Authors: Alwin Krämer, Alexander Stein, Gerdt Huebner, Michael Stahl, Stefan Kasper, Albrecht Kretzschmar, Claus-Henning Kohne, Viktor Grünwald, Ralf Hofheinz, Katharina Schütte, Harald Löffler, Carsten Bokemeyer, Gunnar Folprecht
Journal: Journal of Clinical Oncology (2019)

4120 Background: Paclitaxel/carboplatin is one of the standard regimens for empiric treatment of patients (pts) with carcinoma with unknown primary (CUP) when a specific therapy is not available. The EGFR antibody cetuximab demonstrated efficacy in several cancer types. Methods: Pts with newly diagnosed non-resectable, undifferentiated or adeno-CUP were randomized to 6 cycles paclitaxel 175 mg/m² and carboplatin AUC 5 every three weeks (arm A) or the same chemotherapy plus cetuximab (400 mg/m², then 250 mg/m² weekly; arm B) at 13 German centres. CUP pts belonging to favorable prognosis groups [i.e. women with isolated peritoneal carcinomatosis or axillary lymph node metastases, men with retroperitoneal lymph nodes, pts with specific tumor entities according to histology / immunohistochemistry] were excluded from the trial. The primary endpoint was progression-free survival (PFS), secondary endpoints were response rate (RR) and overall survival (OS). Results: Between 03/2010 and 03/2017, 72 pts were randomized to arm A and 78 pts to arm B. The median age was 61 years, 84 pts were male (40 and 44 pts in arm A and B). 58 pts had a performance status (PS) of 0 (24 and 34 pts), 89 pts a PS of 1 (47 and 42 pts in arm A and B), and one patient in arm A had a PS of 2. PFS and OS did not differ between arms. The median PFS was 3.7 [95%CI: 3.0 - 4.4] and 4.6 [95%CI: 2.9 - 6.2] months in arms A and B (HR 0.98 [95%CI: 0.70-1.37]), the median OS 8.1 [95%CI: 6.5 - 9.8] and 7.4 [95%CI: 5.1 - 9.6] months in arms A and B, respectively (HR 1.10 [95%CI: 0.77 - 1.56]). There was a statistically non-significant trend towards a higher RR with cetuximab: 11 pts had a partial response in arm A (15% [95%CI: 7.9 - 26%]), and 17 pts in arm B (22% [95%CI: 13%-33%], p = 0.30). Twenty-five pts in each arm had stable disease, and 36 pts in each arm had progressive disease or were not evaluable for response. Conclusions: This study represents one of the largest trials in pts with CUP and demonstrates that randomized trials are feasible in this disorder with high medical need. The outcome of CUP pts in the unfavorable prognosis group was not improved by adding cetuximab to empiric therapy paclitaxel/carboplatin. Clinical trial information: NCT00894569.
Association of microRNA-21 with efficacy of cetuximab in RAS wild-type patients in the FIRE-3 study (AIO KRK-0306) and microRNA-21’s influence on gene expression in the EGFR signaling pathway.
Authors: Lisa Miller-Phillips, Volker Heinemann, Arndt Stahler, Ludwig Fischer von Weikersthal, Florian Kaiser, Salah-Eddin Al-Batran, Daniel Neureiter, Christoph Kahl, Frank Kullmann, Markus H. Moehler, Werner Scheithauer, Celine Vazart, Karine Fontaine, Swantje Held, Dominik Paul Modest, Jens Neumann, Andreas Jung, Thomas Kirchner, Sebastian Stintzing
Journal: Journal of Clinical Oncology (2019)

3593 Background: FIRE-3 compared first-line therapy with FOLFIRI plus cetuximab (cet) or bevacizumab (bev) in KRAS exon 2 wild-type (wt) patients with metastatic colorectal cancer. Recent analyses showed mircoRNA-21 (miR-21) expression level may be a predictive biomarker for anti-EGFR-therapy raising the question whether miR-21 influences gene expression in the EGFR signaling pathway. Methods: Reverse-transcription quantitative polymerase chain reaction assay identified quantitative miR-21 expression. Median expression was defined as a threshold value to discriminate FIRE-3 population into miR-21 low and high groups. Differential gene expression based on additional mRNA microarray data (Almac Inc, Xcel Array) was calculated by linear models adjusted for multiple testing followed by single sample gene set enrichment analysis (ssGSEA) to compare differentially enriched hallmarks of cancer gene sets. Overall response rate (ORR) was compared using Fisher´s exact test. Median progression-free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimation and log-rank test. Results: 333 RAS wt patients provided material for miR-21 expression analysis. In these patients, low miR-21 expression was associated with higher ORR (80.0% vs. 57.9%; p = 0.005) and longer OS (35.8 months (mo) vs. 25.9 mo; p = 0.005) when cet vs bev was added to FOLFIRI. High miR-21 expression was associated with comparable ORR (74.6% vs. 64.0%; p = 0.21) and OS (24.5 mo vs. 23.8 mo; p = 0.4). There was no significant difference in PFS in either group. By comparing miR-21 low and high groups using normalized mRNA microarray data, 538 genes were found to be significantly differentially expressed in RAS wt patients after adjustment for multiple testing. Including data from the two groups into ssGSEA yielded 23 hallmark of cancer gene sets that were significantly differentially enriched; among them, KRAS-signaling showed higher enrichment in the miR-21 high group (adjusted p = 2.09 E-13). Conclusions: MiR-21 expression level might be a predictive biomarker for anti-EGFR-therapy by modulating KRAS signaling in FIRE-3 patients.
Adjuvant carboplatin for clinical stage I testicular seminoma in New Zealand centers: Retrospective analysis of efficacy and long-term adverse effects.
Authors: Elias Aris Chandran, Aaron Farai Chindewere, Richard T. North, Michael B. Jameson
Journal: Journal of Clinical Oncology (2019)

e16041 Background: Adjuvant carboplatin reduces relapse risk in clinical stage I (CS1) testicular seminoma, though there is a paucity of long-term safety data. While some studies report that two cycles is more effective than one, there is no randomised trial evidence or consensus on the optimal number of cycles. European guidelines recommend a risk-based approach to consider adjuvant carboplatin in those with either rete testis involvement (RTI) or tumour size &gt; 4cm, and surveillance for other patients. We report long-term outcomes of 2 cycles of adjuvant carboplatin dosed at area under the curve (AUC) of 7 as standard management of CS1 seminoma since 2000. Methods: We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at the Waikato, Lakes and Bay of Plenty District Health Boards. We also collected information on mortality, causes of death and subsequent malignant neoplasms (SMN). Results: Of 160 patients, median age 39 (range 20-73) years, 154 received 2 cycles of carboplatin: 148 dosed at AUC7 and six at AUC6; another six patients had one cycle of carboplatin AUC7, curtailed due to toxicity in 3 patients. Two relapses occurred: one at 10 months (in hindsight stage 2a at diagnosis) and one at 22 months (died of pulmonary embolism 2 months after achieving complete response with BEP chemotherapy). Neither RTI (present in 21.3%) nor tumour size &gt; 4cm (in 43.1%) were predictive of relapse. No patients died of seminoma. At median follow up of 109 (range 17-209) months, relapse-free survival was 98.7%, overall survival was 97.5% and disease-specific survival was 100%. A SMN occurred in 11 patients (6.9%) at median 96 months and caused 4 deaths (melanoma, myeloma, small cell lung cancer and glioblastoma); 4 patients (2.6%) had a contralateral testicular germ cell tumour (at median 69 months). One patient had persistent grade 1 thrombocytopenia at 46 months. Conclusions: This data adds to the body of evidence that two cycles of carboplatin AUC7 is safe, effective adjuvant treatment for CS1 seminoma. It did not have significant long-term adverse effects in our population.
Characterization of the genetics of mucosal melanoma in patients treated with immunotherapy.
Authors: Elizabeth Iannotti Buchbinder, Jason L. Weirather, Michael P. Manos, Ryan C. Brennick, Patrick Alexander Ott, Rizwan Haq, Benjamin Izar, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2019)

9556 Background: Mucosal melanomas can be effectively treated with checkpoint inhibitors, although the response rates are lower than those observed for melanomas arising in cutaneous sites. The mechanistic basis for the lower efficacy of immunotherapies in mucosal melanoma has been suggested to be related to their lower mutational burden. However, there has been limited characterization of the genetics in this melanoma subtype. Methods: Tumor genotyping was performed on all mucosal melanoma patients seen within the Dana Farber Cancer Institute from 2011 until the present by Oncopanel analysis. Results: We identified a total of 57 mucosal melanoma patients whose tumors had been genotyped. Of these 42 received immunotherapy and had response data available. Within the cohort of mucosal melanoma patients, 37.3% had durable clinical benefit (DCB) to their first line of IO therapy. These patients had an average mutational burden/megabase of 6.41 (95% CI 3.53-11.01) but tumor mutational burden did not correlate with response in this cohort. The pattern of mutations in mucosal melanomas was distinct from cutaneous melanomas, as the most frequent mutations were in SF3B1, ATRX, KIT and NF1 genes. Patients with KIT aberrations had a higher DCB rate compared patients with wildtype KIT (73 vs. 33%). In addition, there were several genetic differences observed based upon the site of origin of the mucosal melanoma. A higher rate of SF3B1 mutations was observed in patients with melanoma of anal/rectal origin while patients with vulvar/vaginal melanoma had higher rates of ATRX mutations, which frequently correlated with p53 ( TP53) mutations. Conclusions: This analysis is one of the first to look at genetic patterns in a large cohort of a relatively rare type of melanoma and correlate with response. Our findings confirm the low mutational burden observed in mucosal melanoma despite the high response rate observed in these patients. In addition, this study uncovered a higher rate of response to immunotherapy in mucosal melanoma patients with a KIT mutation.
Real-world application of liquid biopsy in gastrointestinal tumors: Experience from a comprehensive cancer center.
Authors: Enrique Sanz-Garcia, Laura Rodriguez, Rafael Alvarez-Gallego, Jesus Rodriguez-Pascual, Cesar Munoz, Lisardo Ugidos, Lucia Ceniceros, Valentina Boni, Maria José De Miguel, Cristina Almirall, Emiliano Calvo, Angel Ayuso-Sacido, Antonio Cubillo Gracián
Journal: Journal of Clinical Oncology (2019)

e14546 Background: Determination of circulating tumoral DNA (ctDNA) in plasma has recently emerged as an alternative to genomic testing in solid biopsy. Although different clínical trials have suggested that ctDNA alterations can tailor patient's treatment, its routinary utility in clinical practice is still controversial. Methods: A total of 74 consecutive plasma samples from 63 patients (pts) have been collected from October 2017 to December 2018 in our center and analyzed using two different next-generation sequencing (NGS) platforms: OncoTRACE (OT) and Guardant360 (G360). Main epidemiological, pathological and clinical data have been retrospectively extracted from medical records and correlation with ctDNA alterations have been performed using Chi-Square test. Application of liquid biopsy results has been decided after discussion in molecular tumor board and physician’s opinion. Results: OT and G360 were performed in 63 and 11 plasma samples respectively. Most part of the samples were from pancreatic (34; 45.9%) and colorrectal (CRC) (28; 25.7%) adenocarcinoma pts although biliary tract, gastric and oesophageal carcinoma pts were also included (4 each; 5.4%). Plasma samples were analyzed after progression to ≥two systemic therapies in 48.6%. At least one pathogenic alteration of ctDNA was detected in 44.6% of the samples. No correlation has been observed between presence of alteration in ctDNA and tumor origin, surgery of the primary, number and location of metastases and CEA and CA19.9. ctDNA alteration could be targetable with approved or experimental therapies in 14 pts (20.9%; 6 pts OT and 8 pts G360): 9 pts with CRC ( BRAF, EGFR, RAS, PI3KCA, PTEN), 2pts with pancreatic ( IDH1, BRCA1) and 1 pt with gastric, oesophageal and biliary tract carcinoma ( PTEN, EZH2, IDH1). However, these results have been applied in 4 pts (6% of all pts, 28.6% with targeteable ctDNA alterations): 3 pts were treatment-naïve and 1 pt had progressive disease to 2 systemic therapies. Most part of the patients with targetable alterations who did not receive treatment was due to clinical deterioration. Conclusions: Detection of alterations in ctDNA using NGS platforms is feasible in gastrointestinal tumor patients and can help physicians to decide treatment, especially in CRC. However, many patients could not be treated according to ctDNA as plasma samples were collected in late stages of the disease.