tbuckley/cabot-search huggingface dataset:
REACHAUT: First-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) in the real-world setting.
Authors: Christian F. Singer, Leopold Öhler, Daniel Egle, Richard Greil, Edgar Petru, Marija Balic, Maximilian Marhold, Georg Pfeiler, Christine Brunner, Werner Kwasny, Arik Armon Galid, Christoph Tinchon, Wolfgang Eisterer, Ferdinand Haslbauer, Michael Hubalek, Andreas Redl, Karin Hock, Mathias Hennebelle, Bernhard Mraz, Guenther G. Steger
Journal: Journal of Clinical Oncology (2019)

e12527 Background: RIB + aromatase inhibitor (AI) is approved as 1L treatment (tx) for HR+, HER2− MBC. Real-world data on efficacy and safety of RIB+AI are limited. REACHAUT, a prospective, noninterventional trial assessed the safety of RIB+AI in 1L setting in postmenopausal patients (pts) with HR+, HER2− MBC in a real-world setting. First interim analysis results about safety are presented. Methods: 75 postmenopausal pts with HR+, HER2− MBC, QTc &lt; 450 msec, and no prior ET for advanced disease were enrolled at 13 sites. 1L chemotherapy (CT) was allowed. Results: At data cutoff (25-Jan-2019), 61 pts were evaluable for safety (ongoing, n = 44; discontinued, n = 17). Median duration of follow-up was 29 d. Median age at baseline was 65 y ( &lt; 65 y, n = 28; ≥65 y, n = 33); ECOG performance status was 0 (n = 39) and 1 (n = 12). 42.6% had visceral (lung, liver) metastases (mets), while 34.4% had bone only mets. Most common prior tx included CT (29.5% in neoadjuvant/adjuvant/metastatic setting) and ET (41%). Pts received RIB in 1L (93.4%) and second-line (6.6%) setting. In 80.3% pts receiving RIB, the ET partner included letrozole (57.4%), exemestane (11.5%), anastrozole (9.8%). Median duration of RIB exposure was 100 d. Median time to first AE was 14 d. 83.6% pts experienced AEs with mild (63.9%) to moderate (50.8%) severity. Serious AEs were noted in 6.6% pts. Most common AEs were neutropenia (42.6%) and QTc prolongation (24.6%). 4.9% pts had hepatobiliary AEs. Due to AEs, dose adjustments (4.9%) and dose interruptions (19.8%) were needed. No deaths were reported; median PFS was not reached. Subgroup analysis by age ( &lt; 65 y vs ≥65 y) showed that the incidence of AEs was 55.9% vs 44.1%. Neutropenia was reported in 46.4% pts aged &lt; 65 y vs 39.3% pts aged ≥65 y; QT prolongation events were noted in 21.4% pts aged &lt; 65 y vs 27.2% pts aged ≥65 y. Dose adjustments and dose interruptions were needed in 14.3% and 46.4% pts aged &lt; 65 y vs 15.2% and 45.5% pts aged ≥65 y. Conclusions: Overall safety of RIB+AI in routine clinical practice in REACHAUT was consistent with that reported in the MONALEESA-2 study. In real-world setting, pt age ( &lt; 65 y vs ≥65 y) had minimal impact on AEs. Clinical trial information: NIS006622.
Impact of pericardial effusion for patients receiving immune checkpoint inhibitors.
Authors: Abir Khan, Henry Zhang, Christopher Chen, Jacob Morgan, Abdulrazzak Zarifa, Marwah Shahid, Juhee Song, Aung Naing, Juan Lopez-Mattei, Jean-Bernard Durand, Peter Y. Kim, Cezar Iliescu, Nicolas Palaskas
Journal: Journal of Clinical Oncology (2019)

e14121 Background: Various immune-related adverse events (IRAE) have been reported with the use of immune checkpoint inhibitors (ICI). Although a rare event, the increasing incidence of ICI related myocarditis and its reported high mortality raises concern. Cardiovascular IRAE such as pericardial effusions (PE) have been documented in case reports and case series but their clinical significance is unclear. Methods: Retrospective chart review was performed on 1075 patients receiving ICI between 2015 and 2017 with baseline echocardiograms without pericardial effusions and follow up echocardiograms at MD Anderson Cancer Center. We collected baseline characteristics, laboratory findings, echocardiograms, and dates of ICI initiation, PE development, last follow up and death. Overall survival (time from first ICI therapy to death or last follow up) was calculated. Univariate Fine-Gray regression analyses were conducted to identify variables associated with PE to account for death as a competing risk event. A p-value of less than 0.05 indicated statistical significance. Results: After initiation of ICI, 78 patients (7.3%) developed PE of which 45 patients died (58%) compared to 347 deaths (35%) out of the 997 patients without PE. The median follow-up time was 445 days. Univariate Fine-Gray analyses predicting PE demonstrated lower body surface area, lowest nadir in left ventricular ejection fraction (LVEF), higher troponin levels, lower platelet counts, absence of ectopy and hyperlipidemia, and lack of avelumab in therapy as well as a history of heart failure with preserved or reduced ejection fraction, hematologic cancer, and peripheral artery stents were significantly associated with higher incidence of PE. Conclusions: While the development of PE is an IRAE or progression of cancer itself cannot be determined, this study indicates patients receiving ICI who developed PE had higher mortality. Those with greater troponin levels and substantial decline in LVEF were shown to have a greater propensity of developing PE, suggesting the possibility of an underlying myopericarditis. If PE develops during ICI therapy, providers should consider an expedited workup and treatment of ICI related myocarditis.
A phase II study of S-1, oxaliplatin, and nab-paclitaxel, and itraconazole aimed at conversion surgery for advanced and recurrent gastric cancer.
Authors: Yoshihiko Nakamoto, Hiroshi Tsubamoto, Miyuki Sawazaki, Ayako Kakuno, Takashi Sonoda
Journal: Journal of Clinical Oncology (2019)

4026 Background: Preclinical and clinical studies demonstrated that itraconazole, a common anti-fungal agent, has anticancer activity. The purpose of this study was to evaluate the efficacy of the chemotherapy with itraconazole on unresectable, metastatic, and recurrent gastric cancer. Methods: All patients were referred to our clinic with a clinical diagnosis of unresectable gastric cancer. The regimen consisted of 160 mg/m2 nab-paclitaxel IV on day 1, 100 mg/m2 oxaliplatin IV on day 1, 60 mg/m2 S-1 orally on days 1-7, and 400mg itraconazole orally on days -1 to 3, repeated every 3 weeks. Conversion surgery was allowed. The primary endpoint was overall survival (OS). Results: Between 2015 and 2018. 23 patients were enrolled. Their median age was 68 years (range 40-80 years); stomach/gastroesophageal junction: 21/2; Stage IIIA/IIIB/IV: 2/1/20. Among 10 patients who had liver metastases, 2 had simultaneous lung metastases. Nine patients had peritoneal dissemination. Five patients with stage IV had recurrent disease after primary surgery followed by adjuvant S-1. The other 18 patients had no history of surgery or chemotherapy. Response rate was 70% (CR/PR: 2/14). Among 12 patients (67%) who had conversion surgery, R0 resection was conducted in 8 and no residual tumor was observed in 2. Among enrolled 23 patients, median OS was 22 months (95%CI: &gt; 12 months) and 1-year OS rate was 81.8% (95%CI: 46.7%―95.5%). Grade 3/4 neutropenia in 5 (22%), no grade 3/4 thorombocytopenia, grade 2 peripheral sensory neuropathy in 6 (26%). Conclusions: The addition of itraconazole to chemotherapy showed promising efficacy with high conversion surgery rate and with acceptable toxicities. Clinical trial information: UMIN000021340.
Blood-based TMB detection and dynamic monitor in local advanced non-small cell lung cancer (NSCLC) patients.
Authors: Xi Yang, Zhengfei Zhu
Journal: Journal of Clinical Oncology (2019)

e20039 Background: TMB detection has been recommended by NCCN guidelines as an effective biomarker for immunotherapy of advanced non-small cell lung cancer(NSCLC). Blood based TMB(b-TMB) detection is considered to be able to predict the efficacy of immunotherapy in patients with advanced NSCLC. Concurrent chemoradiotherapy is the standard treatment for locally advanced NSCLC(LA-NSCLC) and subsequent consolidated immunotherapy has become the standard treatment. Therefore, the b-TMB status and dynamic changes in patients with LA-NSCLC are particularly important. Methods: We enrolled 7 patients with LA-NSCLC, each receiving 60Gy chest radiotherapy and docetaxel plus cisplatin weekly regimen chemotherapy. We tested the TMB by next-generation sequencing with 520 genes panal in tissues and blood of each patient at baseline. In addition, b-TMB was measured dynamically in 6 patients at different time points during chemoradiotherapy, each two patients were tested for over four times within one week of treatment, two weeks later and four weeks later. Results: As shown in the table, the baseline b-TMB matched the tissue TMB. Except for one ALK fusion patient, the positive rate of b-TMB was 100% and the Spearman correlation value was 0.899(p = 0.015). B-TMB fluctuated but did not change much within first two weeks of concurrent chemoradiotherapy. After the fourth week of chemoradiotherapy, b-TMB significantly decreased in all patient. Conclusions: In patients with LA-NSCLC, b-TMB is a reliable biomarker, which is likely to change in the later stage of concurrent chemoradiotherapy. Its dynamic monitor will help to distinguish which patients may benefit from consolidated immunotherapy after concurrent chemoradiotherapy. [Table: see text]
Answering real-world questions using real-world data: Understanding dynamic treatment decisions and outcomes in metastatic colorectal cancer (mCRC).
Authors: Hui-Li Wong, Koen Degeling, Azim Jalali, Jeremy David Shapiro, Suzanne Kosmider, Rachel Wong, Belinda Lee, Matthew E. Burge, Jeanne Tie, Desmond Yip, Louise M. Nott, Muhammad Adnan Khattak, Stephanie Hui-Su Lim, Susan Caird, Maarten J Ijzerman, Peter Gibbs
Journal: Journal of Clinical Oncology (2019)

e18061 Background: The wide range of possible combinations and sequences available for mCRC treatment presents a major challenge to clinicians, who need to determine the optimal approach for an individual patient or patient subset. In the absence of clinical trial evidence, real world data are an increasingly valuable resource that can be utilized not only to understand treatment patterns and outcomes in routine practice, but also to define an optimal treatment strategy for individual patients across multiple lines of therapy. Methods: Real world data from an Australian mCRC registry were used to develop an interactive data visualization tool that displays treatment variation, customizable to different levels of detail and specific patient subsets, based on patient and disease characteristics. Next, a discrete event simulation model was developed to predict progression-free (PFS) and overall survival (OS) for first line palliative treatment with doublet chemotherapy alone or with bevacizumab, based on data of 867 patients that were treated accordingly. Results: Of 2694 Australian patients enrolled, 2057 (76%) started 1st line treatment with chemotherapy and/or a biologic agent, 1087 (40%) and 428 (16%) received 2nd and 3rd line therapy, respectively. Combined, these 3 lines of treatment accounted for 733 unique sequences. After recoding treatment to the most intensive chemotherapy and the first exposed biologic, 472 unique sequences remained. In exploratory analyses, the simulation model estimated that median 1st line PFS (95% CI) of 219 (25%) patients could be improved from 175 (156, 199) to 269 days (247, 293) by targeting a different treatment. Conclusions: This was an initial exploration of the potential for data visualization and simulation modeling to inform understanding of practice in mCRC and to guide clinical decision making. Such tools allow clinicians and health system providers to define variation in practice patterns and to identify opportunities to improve care and outcomes. Ultimately, the aim is to improve the delivery of personalized cancer care, where other applications such as conditional survival and cost-effectiveness analyses may be useful.
Impact of antiviral prophylaxis in HSV positive patients treated with concurrent chemoradiotherapy for head and neck cancer.
Authors: Nathalie Letarte, Vincent-T. Taillefer, Céline Marty, Louise Lambert, Francine Aubin, Denis Soulieres, Rahima Jamal, Jean-Philippe Adam
Journal: Journal of Clinical Oncology (2019)

6078 Background: Chemoradiotherapy used for the treatment of locally advanced head and neck cancer (HNC) causes a high incidence of mucositis that may be accentuated by a reactivation of herpes simplex virus (HSV). To date, no study has evaluated the impact of antivirals used as prophylaxis to prevent mucositis or their severity. Methods: This is a retrospective observational study including patients who received at least one cycle of concurrent chemoradiotherapy for the treatment of head and neck cancer between January 2014 and June 2017 at the Centre hospitalier de l’Université de Montréal (CHUM). HSV negative patients were excluded. After approval by the IRB, we compared the incidence and severity of mucositis in HSV positive patients who started an antiviral prophylaxis before cycle 1 or 2 (prophylaxis group) to HSV+/unknown HSV patients who did not receive antiviral prophylaxis (control group). Emergency visits and hospitalizations related to mucositis were collected. Mucositis were assessed regularly by radiation oncologists during the treatment. Results: Of 482 patients who received concurrent chemoradiotherapy for HNC, 75 were HSV negative and 407 were included in this study. In the group with (n = 94) and without prophylaxis (n = 313), patients received carboplatin and 5-FU (77% vs 62%) and cisplatin (23% vs 38%) with concurrent radiation respectively. The rate of all grade mucositis in patients with and without prophylaxis (99% vs 96%; p = 0.19) was not statistically significant. The rate of grade 3 and 4 mucositis (42% vs 49%; p = 0.29), the rate of emergency visit (29% vs 28%; p = 0.91) and hospitalization (9% vs 8%; p = 0.80) were not statistically significant between each group. However, in a subgroup of patient receiving carboplatin and 5-FU, antiviral prophylaxis seems to decrease significantly the rate of grade 3 (49% vs 63%; p = 0.04). Conclusions: The addition of antiviral prophylaxis in HSV positive in patients undergoing concurrent chemoradiotherapy for locally advanced HNC didn’t decrease the rate of all grade mucositis. In the subgroup of patients receiving carboplatin and 5-FU mainly of oropharynx origin, HSV prophylaxis decreased the severity of mucositis.
Dipeptidyl peptidase inhibitor BXCL701 synergizes with immunomodulatory agents in a preclinical model of colorectal cancer (CRC) by altering the function of various components of the immune system.
Authors: Veena Agarwal, John MacDougall, Dimple Bhatia, Snigdha Gupta, Zeenia Jagga, Nirmal Keshava, Subhendu Seth, Hemant Banga
Journal: Journal of Clinical Oncology (2019)

e14253 Background: The oral DPP8/9 and FAP inhibitor BXCL701 in combination with a checkpoint inhibitor anti-PD-1 antibody (aPD-1) has demonstrated inhibition of tumor growth as well as up-regulation of immuno-stimulatory cytokines and tumor-infiltrating immune cells in animal models [ASCO 2018]. In the present study, BXCL701 was evaluated for its potential to improve synergistically the survival of animals when combined with anti-CTLA-4 antibody (aCTLA-4), an immune checkpoint blocker, and galunisertib, a transforming growth factor (TGF) β type I receptor inhibitor that counteracts the immunosuppressive influence that TGF β signalling has in the tumor microenvironment. Methods: In vivo studies were conducted utilizing the syngeneic colon cancer model (MC38) in C57BL/6 mice. BXCL701 was administered at the dose of 20 µg qd, p.o, while aPD-1 and aCTLA-4 were administered at the dose of 5 and 10 mpk q2w, i.p. respectively. Finally, galunisertib was administered at 75 mpk bid. Dosing was carried out for 4 weeks and median survival of the animals was calculated. Results: BXCL701 demonstrated a significant improvement in the survival of animals when combined with aCTLA-4. The median survival of animals treated with combination of BXCL701 and aCTLA-4 was significantly increased to 51.5 days in comparison to 40 days observed in BXCL701-treated animals (p &lt; 0.001). Furthermore, in a separate study, addition of BXCL701 to the double combination of aPD-1 and aCTLA-4 resulted in a median survival of 51 days in comparison to 37 days for aPD-1 and aCTLA-4-treated animals (p &lt; 0.05). Similarly, addition of BXCL701 to the combination treatment of aPD-1 and galunisertib increased the median survival to 40.5 days in comparison to 28 days observed in animals treated with galunisertib and aPD-1 combination (p &lt; 0.05). Conclusions: BXCL701, an innate immune activator, synergistically combines with aCTLA-4 and a combination of aPD-1 with galunisertib to improve survival response likely by turning cold tumors to hot tumors. The present study advocates for a clinical evaluation of BXCL701 in combination with these immunomodulators in solid tumors.
The developmental origins of high grade serous ovarian cancer.
Authors: Pietro Lo Riso, Carlo Emanuele Villa, Gilles Gasparoni, Raffaele Luongo, Anna Manfredi, Andrea Vingiani, Annemarie Jungmann, Annalisa Garbi, Michela Lupia, Giancarlo Pruneri, Giuseppe Viale, Nicoletta Colombo, Ugo Cavallaro, Davide Cacchiarelli, Jörn Erik Walter, Giuseppe Testa
Journal: Journal of Clinical Oncology (2019)

e17063 Background: The still persistent uncertainty in the identification of the cell of origin of high grade serous ovarian cancer (HGSOC), with two candidate originating tissues identified in the distal tract of the fallopian tube (FI) and the surface epithelium of the ovary (OSE), has hampered the identification of clinically relevant molecular features for this disease to be targeted for therapy. This resulted in only a negligible improvement in patient’s care since the introduction of carboplatin-based treatments. Methods: To solve this issue, here we show an innovative method based on the identification of a cell of origin-specific DNA methylation print (OriPrint) that allows the reliable stratification of human primary HGSOC in FI and OSE-originated tumors. Results: We show that this approach is robust to alternative clustering methods and can discriminate tumors derived from each of the two origins across different datasets. Also, we translated these findings on a well-characterized retrospective cohort, showing that the cell of origin significantly impacts patient’s prognosis. Finally, through RNAseq, we unveil origin-specific transcriptional networks compatible with the differential impact on patient’s survival, mainly involved in inflammatory response and cell survival, movement and signaling. Conclusions: Our approach proves for the first time in human primary samples that both origins can give rise to HGSOC, paving the way to a finer molecular characterization of this disease and to the development of more effective therapeutic regimens for improved care for patients.
An exploratory analysis based on tumor location of REACHIN, a randomized double-blinded placebo-controlled phase II trial of regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tract tumors.
Authors: Anne Demols, Ivan Borbath, Marc Van Den Eynde, Ghislain Houbiers, Marc Peeters, Raphaël Maréchal, Thierry Delaunoit, Jean Charles. Goeminne, Stéphanie Laurent, Stephane Holbrechts, Marianne Paesmans, Jean-Luc Van Laethem
Journal: Journal of Clinical Oncology (2019)

e15622 Background: The REACHIN trial met its primary endpoint of improving PFS for patients with biliary tract cancer (BTC) treated with regorafenib (R) as compared to placebo (P): Median (m) PFS for R was 3.0 months (mo) (95% CI: 2.3-4.9) and 1.5 mo (95% CI : 1.2-2.0) for P with an HR= 0.49 (95% CI: 0.29-0.81), p=0.005 (Demols A et al, ASCO-GI 2019, Abstr 345). We exploratory analyzed the benefit of R according to tumor location: intra-hepatic (ICC), extra-hepatic (ECC), gallbladder (GB) or peri-hilar (PH). Methods: Tumor locations were recorded at randomization of patients in REACHIN (NCT02162914), a multicenter double-blinded P-controlled randomized phase II study to evaluate the safety and efficacy of R in patients with locally advanced (non resectable) and metastatic histologically proven BTC, progressing after gemcitabine-platinum. We analyzed mPFS according to tumor location and their respective 95% CI. Results: 66 patients were randomized and the mPFS data are summarized in the table. Conclusions: Most of the patients had ICC location (64%). The mPFS in the P arm is similar according to the tumor location. Despite its exploratory value and the small number of patients per tumor location, R seems superior to P in ICC, GB and PH. Data in ECC are not conclusive. Additional biomarkers (FGFR, NGS analysis) are ongoing and will be presented at the meeting. Clinical trial information: NCT02162914. [Table: see text]
Overcoming acquired osimertinib-resistance in EGFR<i>-</i>mutant advanced non-small lung cancer mediated by activating BRAF V600E mutation.
Authors: Diana S.Y. Abdulla, Matthias Scheffler, Carsten Kobe, Thorsten Persigehl, Matthias Schmidt, Jana Fassunke, Sabine Merkelbach-Bruse, Sebastian Yves Friedrich Michels, Lucia Nogova, Sophia Koleczko, Rieke Nila Fischer, Richard Riedel, Alexander Drzezga, Reinhard Büttner, Juergen Wolf
Journal: Journal of Clinical Oncology (2019)

e20682 Background: There is growing insight in the mechanisms underlying resistance to the 3 rd generation EGFR inhibitor osimertinib. Unlike resistance to 1 st generation inhibitors, these mechanisms not necessarily lead to sequential targeted therapy approaches. Here we report on the treatment of two patients with acquired resistance to osimertinib with a new detected BRAF V600E mutation as resistance mechanism. Methods: We identified two patients with EGFR-T790M-mutant advanced NSCLC with progression on osimertinib and detection of a new BRAFV600E mutation in a tumor rebiopsy by next-generation sequencing (NGS). No other known resistance mechanism beside T790M loss in one patient was found. Osimertinib was discontinued and BRAF-targeted combination therapy with dabrafenib and trametinib at standard dose was initiated. We monitored the clinical course with sequential 18 F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) / computed tomography (CT) assessing maximum standard uptake value (SUVmax), sequencing based liquid biopsies and tumor marker assessment. Results: Patient (1) with EGFR del19 (E746_A750del), preserved T790M mutation and acquired BRAF V600E mutation showed reduction in FDG uptake of 18% after 2 weeks of dabrafenib/trametinib that demonstrated a slight increase of 12% in a FDG-PET/CT scan 4 weeks thereafter and combination treatment has been continued. Patient (2) with EGFR del19 (E746_A750del), T790M loss and new BRAF V600E mutation showed continuous metabolic (+8% and + 39%, respectively) and morphologic progression after 2 and 4 weeks of dabrafenib and trametinib. A tumor rebiopsy showed no additional molecular changes. We changed the treatment to osimertinib and dabrafenib combination and observed an impressive metabolic response (-33%) after 2 weeks by FDG-PET/CT. Conclusions: BRAF V600E mutation has recently been described as a novel molecular resistance mechanism in osimertinib-resistant EGFR-mutant NSCLC. We describe one patient where combined BRAF/MEK inhibition with no additional EGFR-inhibition resulted in a preliminary feasible tumor control, but confirmatory CT staging is pending. In a second patient, co-inhibition of EGFR and BRAF pathway with osimertinib and dabrafenib was needed to overcome BRAF-mediated osimertinib resistance resulting in an impressive early tumor response that was not observed to either single-target inhibition of EGFR or BRAF. FDG-PET/CT was able to monitor tumor dynamics. Updated data will be presented.