tbuckley/cabot-search huggingface dataset:
PDX validation of a 3D microtumor platform.
Authors: Ellen Sampson, Katya Nikolov, Paul T. Henderson, Christian Apfel, Chong-xian Pan, Maike Zimmermann, Ai-Hong Ma
Journal: Journal of Clinical Oncology (2019)

3029 Title: Patient-derived xenograft validation of a 3D microtumor platform Background: Patient-derived xenograft (PDX) mouse models are thought to most closely reflect the biology of a patient’s cancer. Unfortunately, growing sufficient tumor in a PDX model takes several months and more often than not, the tumor fails to grows at all. The SAGE Direct Platform, an in-vitro model, can create hundreds of live microtumors from virtually every patient’s viable biopsy and test a panel of clinically relevant drugs within no more than 1 week. Thus, concordance of results from a PDX model with results of the SAGE Direct Platform would support a rational for the platform to be potentially useful to predict tumor response in cancer patients. Methods: A bladder cancer from a 77 year old female was used to establish a PDX model. Mice were divided into three groups receiving either saline (control), cisplatin, or gemcitabine intraperitoneal on the days 1, 8, and 13, and tumor growth was observed. One tumor sample was used to create 3D microtumors and those were tested using the same drugs. Results: Tumor growth (exceeding 1,000 mm 3 ) was similar after cisplatin compared to control (4.8 vs. 3.7 weeks). After gemcitabine tumors initially shrank and only started growing a couple of weeks after the end of treatment so that 1,000 mm 3 was only reached after 10.2 weeks (p&lt;0.001 compared to cisplatin and control). In the SAGE Direct Platform the EC 50 of cisplatin was 97.3 µM and thus two orders of magnitudes higher than the EC50 of gemcitabine, which was 0.7 µM. Conclusions: Both the PDX model and the SAGE Direct Platform have shown this bladder cancer to be virtually resistant to cisplatin while very sensitive to gemcitabine. The next steps of these preliminary data could be to repeat this experimental design with other tumors and/or to start an observational cohort study in patients correlating the SAGE Direct Platform results to patient outcomes.
Mutation and treatment profiles of patients with concurrent EGFR and ALK actionable mutations (muts).
Authors: Jun Zhao, Caixia Liu, Hui Liu, Yong He, Liqiang Rao, Jiqing Hao, Xiang Liu, Zefeng Xie, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

3138 Background: Actionable muts in EGFR and ALK define two molecular subtypes sensitive to EGFR-TKIs and ALK-TKIs, respectively. Although generally mutually exclusive, they did co-exist in some cases. However, when and how do they co-exist are not well understood. Methods: Pts with concurrent actionable muts in ALK and EGFR were selected from our database. Their mutation profiles and treatment histories were analyzed. PFS was estimated using Kaplan-Meier method. Results: Among 341 ALK-positive ( ALK-pos) and 3804 EGFR-positive ( EGFR-pos) pts, 9 (2.6% of ALK-pos, 0.2% of EGFR-pos) had concurrent EGFR and ALK actionable muts, including 3 EX19Indel + EML4-ALK, 2 EX19Indel + STRN-ALK, 2 L858R + L1152R, 1 L858R + EML4-ALK, and 1 G719C + S768I + STRN-ALK. All 9 pts had lung cancer. One pt with EX19Indel + EML4-ALK was treatment naïve. The other 8 pts have taken ≥ 1 EGFR-TKIs. The mPFS of these pts on first-generation EGFR-TKIs was 22 mo (95% CI: 11 - NR). Except for 1 pt who progressed on Gefitinib and subsequently on Osimertinib had a T790M+C797G, the other 7 EGFR-TKI resistance pts had no common known resistance muts. 3 pts ordered NGS tests before taking EGFR-TKIs. None of them had ALK muts at that time. Later, 1 pt (19Indel) gained an STRN-ALK after 15 mo on Osimertinib, 1 pt (L858R) gained an EML4-ALK after 5 mo on Gefitinib, and 1 pt (L858R) gained an L1152R after 10 mo on Afatinib. Therefore, ALK muts were likely developed as resistance mechanisms during EGFR-TKIs therapies in these 3 pts. Unfortunately, with no information on ALK status before EGFR-TKI therapies, we can not tell if the ALK muts were also developed during and conferred resistance to EGFR-TKI therapies in the other 5 pts. Both STRN-ALK and ALK L1152R were recorded 4 times in our database, and they concurred with EGFR actionable muts in 3 and 2 of the 4 records, respectively. Conclusions: ALK and EGFR actionable muts concurred at a relatively low frequency in our pts. In some cases, ALK muts were developed during EGFR-TKI therapies. Developed either together or sequentially, some combinations of EGFR and ALK muts, such as L858R with L1152R and EX19Indel with ALK fusion, may form more easily or may be preferable than other combinations for the development or evoluation of tumors.
FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis.
Authors: Arlene O. Siefker-Radtke, Graeme Currie, Esteban Abella, Daniel A. Vaena, Arash Rezazadeh Kalebasty, Giuseppe Curigliano, Krzysztof Tupikowski, Zoran Gojko Andric, Iwona Lugowska, William Kevin Kelly
Journal: Journal of Clinical Oncology (2019)

4511 Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. Reported response rates to immune checkpoint inhibitors (ICI) are approximately 20%. 20% of pts with mUC harbor FGFR3 mutations or fusions (M/F), which may result in lower sensitivity to ICI. V (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of both the wildtype and genetically activated receptor. This is a Phase 1b/2 study designed to evaluate V monotherapy window followed in combination of V with P(VP) (NCT03123055). Methods: This trial enrolled mUC pts with failure to ≥ 1 prior line of chemotherapy or recurrence ≤ 12 months of (neo)adjuvant chemotherapy, measurable disease and ECOG &lt;2. Treatment consisted of v at 25 mg/kg alone for 2 week monotherapy window followed by combination with P 200 mg q3w.during the V window paired tumor biopsy were obtained. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and activity [ORR]). Results: 35 pts have received treatment (Ph1b:8, WT:20, M/F+: 7). WT patients were unselected for PD-1 status, predominately male (55%) white (95%), all had received at least 1 line of prior chemo and 60% had Bellmunt scores of &gt; 1. The safety profile is consistent with previously reported data for P. TEAE occurring in &gt;20% of patients were nausea, anemia, diarrhea and fatigue. Six WT patients (30%) had responses (4 confirmed responses, 1 unconfirmed), and an additional patient with an iRECIST response. Responses occurred at a median of 3.5 months. At 4+ months of follow up, 13(65%) remain on treatment @ a median of 8 cycles (range: 1-13). At 5+ months the median PFS has not been reached. Conclusions: VP combination therapy is well tolerated with an encouraging ORR and prolonged PFS in the WT cohort; greater than one would anticipate from P alone based upon historical data. We will be reporting 9+ month preliminary PFS/OS and updated OOR/DOR data. Clinical trial information: NCT03123055.
Meta-analysis of toxicity data in thoracic and abdominal malignancies from: Clinical trials in tumor treating fields.
Authors: Ignace Vergote, Fernando Rivera, Miklos Pless, Giovanni L. Ceresoli
Journal: Journal of Clinical Oncology (2019)

e14658 Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antimitotic treatment modality, which has been approved for the treatment of glioblastoma (GBM) by the FDA. Mild-moderate localized dermatitis was reported in 52% of newly diagnosed GBM patients treated in the EF-14 [NCT0091640] phase 3 trial (with only 2% having Grade 3 skin toxicity). The toxicity of TTFields has been investigated in a number of pilot studies for malignancies located outside of the brain, and here we present a meta-analysis of toxicities reported in them. Methods: A total of 192 patients from four pilot clinical studies in the following malignancies were included: Advanced lung cancer, advanced pancreatic cancer, pleural mesothelioma and recurrent ovarian cancer. All patients received chemotherapy in addition to TTFields. Adverse events (AEs) and their association with the treatment were evaluated using CTCAE Criteria. Toxicities were reported as incidence by body system and MedDRA term out of the number of patients who received any amount of TTFields treatment. Results: The median age of patients was 63 (range: 44-78), 73 (49-81), 67 (27-78) and 60 (45-77) for EF-15 [NCT00749346], PANOVA [NCT01971281], STELLAR [NCT02397928] and INNOVATE [NCT02244502], respectively. The incidence of several low grade gastrointestinal (GI) toxicities was ≥5%: constipation (16%), diarrhea (14%), nausea (27%), vomiting (13%). None of the GI toxicities was associated with TTFields. Low grade general disorders such as asthenia (12%) and fatigue (18%) were common but not associated with TTFields. The incidence of arrhythmias was ≤2%. 58% of the patients had dermatological AEs, but only 6% had grade 3 dermatitis. 9% of patients had low grade pruritus. Conclusions: No new safety signals associated with TTFields were identified in this meta-analysis. The incidence of TTFields-related skin toxicity was similar to that reported in glioblastoma patients. The application of TTFields to the torso is safe. Clinical trial information: [NCT00749346], [NCT01971281], [NCT02397928], [NCT02244502].
An open label, multicenter, phase 1b/2 study of rebastinib (DCC-2036) in combination with carboplatin to assess safety, tolerability, and pharmacokinetics in patients with advanced or metastatic solid tumors.
Authors: Anthony W. Tolcher, Pamela N. Munster, Lee S. Rosen, Curran Murphy, Christian Argueta, Keisuke Kuida, Rodrigo Ruiz-Soto, Filip Janku
Journal: Journal of Clinical Oncology (2019)

TPS2666 Background: Rebastinib is a potent, orally administered, kinase switch control inhibitor selectively targeting the tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells and has critical roles in angiogenesis. In addition, TIE2 is highly expressed in a subset of macrophages, TIE2-expressing macrophages (TEMs), which are known to have proangiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as carboplatin, increase the recruitment and activity of pro-tumoral TEMs, leading to chemotherapy resistance. Taken together, investigation of rebastinib in combination with a chemotherapy such as carboplatin, one of the most commonly used agents across different tumor types, is warranted in advanced solid tumors. Methods: This study is an open-label, Phase 1b/2, multicenter study in patients with advanced or metastatic solid tumors. The study has two parts: the first part is the 3+3 dose escalation phase designed to evaluate the safety, tolerability and pharmacokinetics of 50 mg and 100 mg rebastinib twice daily in combination with carboplatin of AUC 5 or 6 administered once every three weeks to determine the recommended phase 2 dose (RP2D). Patients who have exhausted all therapies and for whom carboplatin is considered appropriate treatment will be enrolled. The second part is the dose expansion phase with three cohorts: previously treated breast cancer, recurrent, platinum-sensitive ovarian cancer, and malignant mesothelioma to evaluate the safety, tolerability, and efficacy of the RP2D. A Simon’s two-stage design will be used in the second part and initially up to 18 patients will be enrolled into each cohort. If more than 4 responses are observed, then the cohort will be expanded up to 33 patients. This trial is expected to enroll up to 117 patients in total, with approximately 18 patients in the first part and up to 99 patients in the second part. The study is currently open only in the US. Clinical trial information: NCT03717415.
Experience with CXCL12 inhibitor NOX-A12 plus pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer.
Authors: Niels Halama, Ulrike Pruefer, Anna Frömming, Diana Beyer, Dirk Eulberg, Jarl Ulf B. Jungnelius, Aram Mangasarian
Journal: Journal of Clinical Oncology (2019)

e14143 Background: NOX-A12 is an inhibitor of the chemokine CXCL12 which prevents receptor engagement and blocks the formation of chemotactic CXCL12 concentration gradients. The OPERA study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination with pembrolizumab in metastatic microsatellite-stable (MSS) colorectal (CRC) and pancreatic (PaC) cancer where PD-1 inhibition alone has not shown clinical benefit. Methods: Patients received 300 mg NOX-A12 twice weekly during a 2-week monotherapy phase. Biopsies were taken from liver metastases before and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In a combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. Results: 11 of the patients had CRC and 9 PaC. All patients were heavily pretreated with 5 (CRC) and 3 median lines (PaC) of prior treatment. Best responses to last prior treatment was progressive disease for 95% of patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. At baseline, mean T cell density at the invasive margin was 327 cells/mm², clearly below the 600 cells/mm² that are predictive for a good prognosis. 2 weeks of NOX-A12 monotherapy induced Th1 cytokines (IFNγ, IL-2, IL-16) in approx. half of the patients. Although there were no objective responses, 25% of patients achieved stable disease; 7 patients showed prolonged time on treatment vs. the prior line of therapy. Updated figures for progression-free survival and overall survival for the whole patient cohort will be presented. Conclusions: In patients with MSS metastatic PaC and CRC cancer with impaired immune systems and a high tumor load that have failed multiple prior lines of therapy, NOX-A12 plus pembrolizumab shows induction of immune response, stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Clinical trial information: NCT03168139.
Quantitative assessment of tumor-infiltrating neutrophils to predict immunotherapy responses in metastatic melanoma.
Authors: Jesus Vera Aguilera, Thomas J. Flotte, Eunhee S. Yi, Trynda Kroneman, VeraJean Suman, Jonas Paludo, Robert R. McWilliams, Lisa A. Kottschade, Yiyi Yan, Matthew Stephen Block, Svetomir Markovic
Journal: Journal of Clinical Oncology (2019)

e21039 Background: Tumor-infiltrating neutrophils (TINs) and their myeloid precursors play an important role in cancer biology. While activated neutrophils have been shown to kill tumor cells, there is growing evidence that neutrophils may also support tumor progression by impairing T cell-dependent anti-tumor immunity. We hypothesized that low TINs would be associated with better responses to immunotherapy (IO). Methods: Pretreatment biopsies from 15 metastatic melanoma (MM) pts treated with anti-CTL4 and anti-PD-1 therapy from 2012-17 were collected and stained with myeloperoxidase (MPO). Slides were scanned at 40x magnification on the Aperio ScanScope AT Turbo brightfield instrument (Leica Biosystems) at a resolution of 0.25 microns per pixel. To indicate the region of analysis, the digital pen tool was used to trace a minimum 85% of tumor. Ten fixed-sized boxes were placed on the hottest staining region in a second annotation layer on the image. The boxes equaled 1mm 2 in total area. If the tumor tracing had an area of 1mm 2 , or less, boxes were not placed on the image. The selected tissue was analyzed using an Aperio imaging quatification algorithm . The number of 3+ cells were considered positive for neutrophils and used in subsequent calculations. Quality control review was performed on a subset of cases by Anatomic Pathologists. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors (RECIST). Overall survival (OS) was calculated using the Kaplan Meier method. Results: The median number of treatment lines before the biopsy was 1 (range 0-2). The treatment immediately following the biopsy consisted of ipilimumab (n = 10, 66.6%), pembrolizumab (n = 4, 26.6%), ipilimumab/nivolumab (n = 1, 6.6%). The median number of neutrophils in the biopsy hotspot was 92/mm2 (range 6-219) for the entire cohort. For patients achieving PR and CR after 4 cycles of therapy, the median neutrophils were 36/mm2 (IQ 14-78) while the median was 106/mm2 (IQ 60-138) for patients who had progressive disease,( p = 0.04). There was no correlation between the numbers of neutrophils in the biopsy with the absolute neutrophil count in the peripheral blood (R value: 0.012). Conclusions: Decreased TINs are significantly associated with better responses to IO in MM pts. Measurements of TINs may help to select patients who are likely to benefit from anti-CTL4 and anti-PD-1 therapy. Additionally, exploration of whether combining therapies that decrease neutrophils intratumorally should be explored.
Dissecting lung development and fibrosis at single-cell resolution
Authors: Donna L. Farber, Peter A. Sims
Journal: Genome Medicine (2019)

Single-cell transcriptome profiling has enabled high-resolution analysis of cellular populations in tissues during development, health, and disease. Recent studies make innovative use of single-cell RNA sequencing (scRNAseq) to investigate mechanisms that allow immune cells to interact with tissue components in the lung during development and fibrotic lung disease.
ROCKET: A randomized, multicenter phase 2 study of RRx-001 + irinotecan versus regorafenib in 3<sup>rd</sup>/4<sup>th</sup> line colorectal cancer.
Authors: Tony R. Reid, George A. Fisher
Journal: Journal of Clinical Oncology (2019)

3526 Background: The purpose of this study was to assess the efficacy of combination therapy with RRx-001, an aerospace-derived macrophage repolarizing agent with epigenetic and vascular normalization properties, plus irinotecan vs. regorafenib plus irinotecan in 3 rd /4 th line metastatic colorectal cancer that previously received treatment with irinotecan. Methods: Between June 2014 and August 2015, 34 patients were enrolled. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly until progression followed by intravenous infusion of irinotecan at 180 mg/m 2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m 2 on day 1 in a 21-day cycle. Results: The survival follow up for RRx-001 + irinotecan range was approximately 14.5 months (mean 6.0 months, median 5.0 months, standard deviation 4.5 months). The survival follow up for regorafenib range was approximately 10.8 months (mean 4.5 months, median 4.0 months, standard deviation 3.9 months). The median survival time was 8.6 months for RRx-001 + irinotecan and 4.7 months for regorafenib. The median progression free survival was 7.5 months for RRx-001 + irinotecan vs. 1.7 months for regorafenib. In addition, the toxicity profile of RRx-001 + irinotecan was dramatically improved compared with regorafenib. The regorafenib arm was terminated for futility at interim analysis, after which any enrolled patients only received RRx-001 co-infused with an aliquot of autologous blood to evaluate the safety of that method of administration. Conclusions: The results of this trial demonstrate improved efficacy and efficacy of RRx-001 + irinotecan compared with regorafenib in patients with metastatic colorectal cancer. Clinical trial information: NCT02096354.
The prognosis of patients with recurrent or persistent ovarian clear cell carcinoma: Results from a randomized phase III study (JGOG3017/GCIG).
Authors: Eiji Kondo, Tsutomu Tabata, Nao Suzuki, Daisuke Aoki, Osamu Tokuyama, Kiyoko Kato, Tetsutaro Hamano, Yoshio Kotera, Keiichi Fujiwara, Eizo Kimura, Fumitoshi Terauchi, Toshiyuki Sumi, Aikou Okamoto, Nobuo Yaegashi, Takayuki Enomoto, Toru Sugiyama
Journal: Journal of Clinical Oncology (2019)

5515 Background: There are currently no concise data on prognosis in patients with recurrent or persistent clear cell carcinoma (CCC). The JGOG3017/GCIG was a randomized phase III trial to compare paclitaxel plus carboplatin (TC) to CPT-11 plus cisplatin (CPT-P) for stage I to IV CCC patients who have been diagnosed by central pathological review (CPR). A total of 619 patients were eligible for efficacy analyses. The aim of this study was to investigate prognosis of these patients with recurrent or persistent CCC. Methods: We estimated median and restricted mean survival time (RMST) of post-progression survival (PPS) of patients with recurrent or persistent CCC by platinum sensitivity, treatment arm, crossover chemotherapy, primary stage, residual tumor, performance status and ethnicity. PPS rates at 6, 12, 18 and 24-month were also calculated. Results: Among the 619 patients, the recurrence rate of stages was as follows: 6.3% (6/96) in stage IA/IB, 14.6% (46/315) in stage IC, and 54.8% (114/208) in stage II- Ⅳ. The recurrence rate of surgical situations was as follows: 19.4% (106/544) in complete surgery, 75% (27/36) in optimal, and 84.6% (33/39) in suboptimal. Overall, 166 of 619 patients had recurrent disease. The median PPS were 14.0 months (95% confidence interval [CI], 12.6 – 17.9) for all patients, 13.5 months (95% CI, 11.4 – 19.6) in the TC group (n=77) and 14.4 months (95% CI, 11.0 - 18.8) in the CPT-T group (n=89), with no significant difference between the two groups (hazard ratio, 1.02; 95% CI, 0.71 - 1.47, log-rank P = 0.898). The RMST of PPS for all patients was 14.6 months (95% CI, 13.3 - 15.8). Median PPS for patients with platinum-resistant (44.6%, n=74) and platinum-sensitive (53.0%, n=88) disease were 10.9 months (95% CI, 8.9 - 13.3) and 18.8 months (95% CI, 15.0 - 28.7) (HR, 1.88; 95% CI, 1.30-2.72, p&lt;0.001), respectively. Conclusions: The median PPS of patients with platinum-resistant recurrence was significantly shorter than that of patients with platinum-sensitive recurrence. Data on PPS in patients with recurrent CCC that will be the basis of a future clinical trial in such patients were obtained.