tbuckley/cabot-search huggingface dataset:
A phase I/II study of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors (iMATRIX-Atezolizumab).
Authors: Birgit Geoerger, Erin E. Karski, Michel Zwaan, Michela Casanova, Lynley V. Marshall, Steven G. DuBois, Matthew Kowgier, Michael Tagen, Antonia Kwan, Meghna Das-Thakur, Tanya Maria Trippett
Journal: Journal of Clinical Oncology (2017)

10524 Background: Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anticancer T-cell response. The iMATRIX-Atezolizumab study (phase I/II, multicenter, open-label; NCT02541604) assessed the safety, pharmacokinetics (PK) and preliminary activity of atezolizumab in pediatric/young adult patients with refractory/relapsed solid tumors. Methods: Patients aged &lt; 30 years with refractory/relapsed non-central nervous system solid tumors received atezolizumab every 3 weeks until loss of clinical benefit ( &lt; 18 years old, 15mg/kg [maximum dose 1200mg]; ≥18 years old, 1200mg). Safety/PK were assessed across tumor types and initial response was assessed by tumor-type cohorts after approximately 10 patients in each cohort had been treated. Results: As of July 19 2016, 74 patients (median age 14 years; range 2–29) were enrolled: osteosarcoma, n = 12; Ewing sarcoma, n = 11; neuroblastoma, n = 11; rhabdomyosarcoma (RMS), n = 10; non-RMS soft tissue sarcoma, n = 10; Wilms tumor, n = 6; Hodgkin lymphoma (HL), n = 5; non-HL, n = 1; other tumor types, n = 8. PK data (n = 48) were similar to that in adults (geometric mean C min , µg/mL [cycle 2, day 1, pre-dose]: 53.6 [2– &lt; 6 years old]; 54.1 [6– &lt; 12 years old]; 62.0 [12– &lt; 18 years old]; 68.0 [adult]). Most tumors, except HL, had &lt; 1% (score 0) tumor cell [TC]/tumor-infiltrating immune cell (IC) PD-L1 expression with overall TC/IC-positive expression rates (≥1%, score 1–3) of 7% and 10%, respectively. All available HL samples had ≥5% (score 2–3) TC/IC PD-L1 expression. 67/71 patients who received atezolizumab (median cycles 2; range 1–10) had ≥1 adverse event (AE; mainly immune-related grade 1–2); 17 patients (24%) had treatment-related grade 3–4 AEs. One AE (grade 3 transaminase increase) led to study drug discontinuation. Common AEs were pyrexia (37%), fatigue (34%) and constipation (32%). 2/5 patients with HL had a partial response (PR); the only patient with atypical rhabdoid tumor (RT) had an unconfirmed PR. Conclusions: The PK and safety profile of atezolizumab in pediatric and young adult patients is similar to that in adults. Preliminary antitumor activity was seen in HL and RT; new cohorts are planned in RT and atypical teratoid RT. Clinical trial information: NCT02541604.
Early postoperative PET-CT in patients with pathological stage III colon cancer may change their outcome: Results from a large single-institution study.
Authors: Assaf Moore, Irit Ben-Aharon, Ofer Purim, Gali Perl, Olga Ulitsky, Limor Amit, Yulia Kundel, Ron Lewin, Nir Wasserberg, Hanoch Kashtan, Baruch Brenner
Journal: Journal of Clinical Oncology (2017)

e15163 Background: Staging of patients (pts) with pathological stage III colon cancer (CC) is currently suboptimal; many pts still recur despite an unremarkable preoperative staging. We previously reported that early postoperative PET-CT can alter the stage and management of up to 15% of pts with high risk stage III CC and later reported also encouraging preliminary results in a larger cohort of consecutive pts with stage III CC, in which staging and management were altered in 14.5%. The aim of the current study was to expand the previous one to a larger cohort and to evaluate the actual impact of early postoperative PET-CT on pts outcome. Methods: A Retrospective study of all consecutive pts with stage III CC who were treated at our institution and underwent early postoperative PET-CT between 2007-2016. Demographic and clinicopathological data were retrieved. Statistical analyses were done using standard methods. Results: 348 pts, 166 (47.7%) males, with a median age of 66 years (range, 29-92), were included. Pathological stage was IIIA, IIIB and IIIC in 21(6%), 254 (73%) and 73 (21%) pts, respectively. The median number of lymph nodes examined and of positive ones were 14 (range, 3-54) and 2 (range, 0-32), respectively. High FDG-uptake was noted in 95 (27.3%) pts, including 23 (6.6%) with clear postoperative changes and 18 (5.2%) with a false positive uptake, of whom 6 underwent invasive diagnostic procedures. PET-CT results modified the management of 52 pts (14.9%) who were found to have true positive findings: 44 (12.6%) with overt metastatic disease and 8 (2.3%) with a second primary tumor. At a median follow-up of 45.6 months, the estimated 5y disease-free survival for true stage III pts was 81.9% and the 6y overall survival of the entire cohort was 76.4%. Interestingly, of the 44 pts found to be metastatic, 12 (27.3%) underwent curative treatments and 8 (66.7%) of those remain free of disease, with a median follow-up of 64.7 months. Conclusions: In this large cohort, early postoperative PET-CT changed the staging and management of 14.9% of pts with resected stage III CC, with encouraging outcome results. We are conducting a prospective trial to further evaluate this strategy.
Final results of a phase Ib study of isatuximab (ISA) plus pomalidomide (Pom) and dexamethasone (dex) in relapsed/refractory multiple myeloma (RRMM).
Authors: Joseph Mikhael, Paul G. Richardson, Saad Zafar Usmani, Noopur S. Raje, William Bensinger, Franck Dubin, Qianying Liu, Olivier Vitse, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2018)

8038 Background: ISA is a monoclonal antibody targeting CD38-expressing tumor cells. We report final data from a Ph Ib dose-escalation/expansion study of ISA + Pom/dex in pts with RRMM (NCT02283775). Methods: Pts with RRMM (≥2 prior MM therapies; includes lenalidomide + a proteasome inhibitor [PI]) received 5, 10, or 20 mg/kg ISA (4 weekly [QW] doses, then every 2 wks until progression/intolerable toxicity), Pom 4 mg (Days 1–21), and dex 40 mg (QW; 20 mg if ≥75 yrs old) in 28-day cycles. Primary objective: recommended dose of ISA + Pom/dex. Secondary objectives included efficacy (IMWG criteria), safety, pharmacokinetics (PK). Results: 45 pts received ISA at 5 (n = 8), 10 (n = 31), or 20 (n = 6) mg/kg. Median age 67 (42–82) yrs. Median 3 (2–10) prior lines; 41 (91%), 37 (82%), and 38 (84%) pts refractory to their last regimen, immunomodulatory drugs (IMiDs), or PIs, respectively. 6 pts had high-risk (HR) cytogenetics. Median treatment time: 9.6 mos; 19 (42%) pts remain on treatment. 2 pts (10 mg/kg) discontinued due to AEs (grade [Gr] 5 intestinal perforation [due to underlying MM]; Gr 3 infusion-associated reaction [IAR]). 1 pt at each dose reported a DLT; MTD not reached. Expansion cohort initiated at 10 mg/kg based on efficacy, safety, and PK data. Most common TEAEs, besides IARs/hematologic AEs: fatigue (62%), upper respiratory tract infection (42%), and dyspnea (40%). Gr ≥3 neutropenia occurred in 83% of pts (Gr 4, 56%); all cases reported as AEs resolved with dose modification/growth factor support. IARs occurred in 19 (42%) pts (Gr ≥3, 1 pt): 18 (40%) pts during 1st infusion, 3 (7%) pts at later infusions. Overall response rate (ORR) was 62%; ORR in HR cytogenetics: 33%; IMiD refractory: 57%; PI refractory: 63%. 12 (27%) pts achieved ≥ VGPR (1 CR; 1 sCR). Median time to 1st response, 0.95 mos; median duration of response, 18.7 mos (95% CI 12.5–NC). Median progression-free survival, 17.6 mos (95% CI 6.8–20.5). ISA PK is unaffected by Pom/dex co-administration. Conclusions: These final results confirm the promising clinical activity and manageable safety profile of ISA + Pom/dex in heavily pretreated RRMM. A Ph III confirmatory trial is ongoing with results expected later in 2018. Funding: Sanofi Clinical trial information: NCT02283775.
Clinical and therapeutic impact of family with sequence similarity 83, member B in EGFR gene wild type-lung adenocarcinoma.
Authors: Takumi Yamaura, Naoyuki Okabe, Hironori Takagi, Yuki Owada, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Satoshi Muto, Yuki Matsumura, Takeo Hasegawa, Mika Hoshino, Jun Osugi, Yutaka Shio, Junji Ezaki, Shinya Watanabe, Hiroyuki Suzuki
Journal: Journal of Clinical Oncology (2017)

e23136 Background: We have reported the usefulness of Family with sequence similarity 83, member B (FAM83B) as a novel biomarker for diagnosis and prognosis of lung squamous cell carcinoma. FAM83B expresses not only in lung cancer but also in several types of solid cancer. More recently, novel finding showing FAM83B involve to tumor growth, oncogenesis, and resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in breast cancer cell lines has been shown. EGFR signaling pathway also plays an important role in lung adenocarcinoma, therefore, we hypothesize that FAM83B associates with tumor proliferation in lung adenocarcinoma (ADC), results in resistance to EGFR-TKI and in a novel therapeutic target in a part of lung ADC. Here we show that correlation between FAM83B expression and clinicopathological features. Methods: This study was conducted with approval of ethics committee in our institute, and informed consent was obtained from all the participants. We identified 216 participants underwent for primary lung ADC between 2008 and 2015. Paired tumor and corresponding normal tissue samples obtained from patients were subjected. FAM83B mRNA expression were examined by cDNA microarray, and analyzed relationship between the level of FAM83B and clinicopathological variables including survival analysis. Further, FAM83B knock down study was performed in several types of cancer cell lines (H1975, HLC-1, H2347) to validate whether FAM83B involve to cell proliferation. Results: FAM83B highly expressed in male (p = 0.007), or smoker (p = 0.007), or EGFR wild type tumor (p&lt;0.001). Multivariate analyses also showed that EGFR wild type-tumor correlate with FAM83B expression. In survival analysis, multivariate analysis showed FAM83B correlated with poor outcome in both disease free survival and overall survival (p = 0.011 and p = 0.001), especially stratified by EGFR wild type-tumor (p = 0.017, p = 0.008). Gene silencing with FAM83B siRNA showed growth suppression of HLC-1 and H1975 cell lines. Conclusions: FAM83B could involve to tumor proliferation of lung ADC in part, and expected to be the novel therapeutic target of EGFR wild type-ADC.
BEST OF: A phase III study assessing the best of radiotherapy (Intensity Modulated RadioTherapy, IMRT) compared to the best of surgery (Trans-Oral Surgery, TOS) in patients with T1-T2, N0 oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Christian Simon, Carmela Aves Caballero, Catherine Fortpied, Mererid Evans, Petri Koivunen, Jean-Jacques Stelmes, Maria Urbanowicz, Jean Bourhis, Frank Zimmermann, Jens Peter Klussmann, Andreas Dietz, Giuseppe Spriano, C. Rene Leemans, Susanne Singer, Inge Tinhofer, Joanne Patterson, Silvana Quaglini, Keith Hunter, Vincent Gregoire
Journal: Journal of Clinical Oncology (2018)

TPS6098 Background: The incidence of OPSCC has increased dramatically in the last 15 years. The standard treatment for early stage disease is either surgery or radiotherapy, both with comparable high tumor control rates but with different side effect profiles and technical constraints. Treatment choice is generally based on expert or center experience. It is still unclear whether they differ in terms of functional outcome. To clarify this, we proposed a randomised trial with the primary objective to assess and compare the patient-reported swallowing function over the first year after randomisation to either IMRT or TOS among patients with early stage OPSCC. Clinician and patient-reported outcomes will be used to assess treatment. Methods: This is a phase III randomised trial (NCT02984410) that will primarily assess the MD Anderson Dysphagia Inventory (MDADI) score reported by the patients at months 4.5, 6, 9, and 12 after randomisation. MDADI is composed of 19 questions on emotional, functional, and physical aspects, all related to swallowing, wherein scores range between 20 (poorest function) and 100 (best function). BEST OF is powered to detect a clinically significant difference in MDADI score at each of these time points: 4.5, 6, 9, and 12 months with a planned sample size of 170 patients. Key secondary endpoints include treatment response at 6 months after randomization, oncologic outcomes at year 1 and 5, toxicities based on CTCAE, quality of life (QOL) based on QLQ-C30 and HN43 and out-of-pocket costs. QOL domains will be ranked based on patient's priorities. Eligible cases are resectable T1 or T2, N0, M0 OPSCC assessed by a multidisciplinary team. The EORTC quality assurance program (QA) for surgery and pathology (SURCARE) and radiotherapy (RTQA) was implemented in the study. This integrated QA will be the model for future EORTC Head and Neck Cancer trials. BEST OF was opened for recruitment since December 2017 in Belgium and Switzerland and will soon open in France, UK, Germany, Poland, Italy and Portugal through a collaboration with EORTC HNCG and ROG, SAKK, NCRI, GORTEC, and IAG-KHT. Clinical trial information: NCT02984410.
TCT-83 Lactate and Cardiac Power Output Measurements at 12-24 Hours Reliably Predict Outcomes in Cardiogenic Shock: Insights from the National Cardiogenic Shock Initiative
Authors: Mir Basir, Iyad Isseh, Theodore Schreiber, Amir Kaki, John Finley, David Lasorda, Malcolm Foster, Behnam Tehrani, Alexander Truesdell, Thomas Lalonde, Michael Green, Yasir Akhtar, Simon Dixon, William O'Neill
Journal: Journal of the American College of Cardiology (2018)
TAGS, a randomized, double-blind, phase 3 study evaluating TAS-102 plus best supportive care vs placebo plus best supportive care in patients with metastatic gastric cancer refractory to standard treatments.
Authors: David H. Ilson, Josep Tabernero, Kohei Shitara, Robert Winkler, Ali Nasermoaddeli, Cliff Ding, Toshihiko Doi
Journal: Journal of Clinical Oncology (2016)

TPS4141 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, at a molar ratio of 1:0.5. The global phase 3 RECOURSE trial demonstrated a significant prolongation of overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (pbo) in patients (pts) with metastatic colorectal cancer who had been treated with ≥ 2 lines of prior standard chemotherapy. A phase 2 study conducted in Japan that evaluated efficacy and safety of TAS-102 in pts with metastatic gastric cancer who had failed 1 or 2 lines of standard chemotherapy demonstrated that TAS-102 was well tolerated, and TAS-102 treatment led to an OS of 8.7 months and disease control rate of 65.5%. The present study will investigate efficacy and safety of TAS-102 plus best supportive care (BSC) vs pbo plus BSC in pts with metastatic gastric cancer refractory to standard treatments. Methods: This phase 3, double-blind, placebo-controlled multinational study (NCT02500043) will randomize ~500 pts with metastatic gastric cancer who previously received ≥ 2 prior regimens for advanced disease. Eligible pts will be randomized 2:1 to TAS-102 plus BSC or pbo plus BSC, and stratified by region, ECOG performance status, and prior treatment with ramucirumab. TAS-102 or pbo 35 mg/m2/dose will be administered orally twice daily on days 1-5 and 8-12 of each 28-day cycle until discontinuation criteria are met. Primary endpoint is OS; secondary endpoints are PFS, quality of life (QoL), and safety. Computed tomography scans are performed every 8 weeks and QoL assessments every 4 weeks. One interim analysis for efficacy and futility is planned after approximately half of the total target events (384 deaths) are observed. If the primary endpoint is met and a favorable benefit/risk ratio is demonstrated for TAS-102, pts in the pbo arm who meet study eligibility criteria will be offered the option to cross over to open-label TAS-102. As of January 2016, no pts were randomized and recruitment is ongoing. Clinical trial information: NCT02500043.
Practical applications of “liquid biopsy” in the colorectal cancer treatment.
Authors: Koichi Suzuki, Yuji Takayama, Kosuke Ichida, Taro Fukui, Nao Kakizawa, Tamotsu Obitsu, Yuta Muto, Fumi Hasegawa, Fumiaki Watanabe, Rina Kikugawa, Takaharu Kato, Yuji Kaneda, Masaaki Saito, Shingo Tsujinaka, Kazushige Futsuhara, Yasuyuki Miyakura, Hiroshi Noda, Hirokazu Kiyozaki, Fumio Konishi, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2016)

e23044 Background: A blood-based technology platform tracking circulating tumor DNA, “Liquid biopsy” represents an ideal non-invasive tool allowing multiple testing over time, monitoring real time changes occurring within the tumor and evaluation of therapeutic response. Here, we show its practical applications via monitoring of KRAS mutation in detection of circulating tumor DNA (ctDNA) during treatments. Methods: 238 plasma samples were collected from 57 patients (pts) who underwent chemotherapy for metastatic colorectal cancer. KRAS mutant ctDNA (MctDNA) was determined by digital PCR as a tool of Liquid biopsy. Results: KRAS assessment in tumor tissues showed 19 patients with mutation (MT) and 38 without mutation (WT). Among 19 patients with MT, 12 patients displayed mutant ctDNA at the initial assessment and 7 patients showed no MctDNA. Regardless of KRAS status in tumor tissues, poor response was likely seen in patients with MctDNA. While 38 patients with WT showed no MctDNA before chemotherapy except one patient (Case 1), 4 patients exhibited MctDNA after treatments with various regimens. 1) Prediction of the drug resistance: MctDNA was detectable in blood of these 4 patients prior to radiographic detection of disease progression, suggesting monitoring of ctDNA was a promising molecular biomarker to predict drug resistance. 2) Selection of candidates for treatments: These 4 patients displaying MctDNA in blood are unlikely benefit from the anti-EGFR antibody treatment despite of their KRAS wild status in tumor tissues. 3) Choice of optimal interventions: MctDNA was detected before treatment in Case 2 without KRAS mutation in the tissue, indicating metastatic liver tumor consisted of KRAS mutant clones. Optional interventions can be available such as surgery for liver metastasis and chemotherapy for primary tumor in this patient. 4) Re-introduction of the drug: The KRAS mutant clones declined in blood of Case 1 during treatment with regorafenib and TAS-102, suggesting that drug sensitivity to the anti-EGFR antibody could be recovered and re-introduction of this antibody would be effective. Conclusions: Liquid biopsy provides a circulating biomarker not only for treatment response but decision making of a sequential strategy.
Rates of PD-L1 expression testing in U.S. community-based oncology practices (USCPs) for patients with metastatic non-small cell lung cancer (mNSCLC) receiving nivolumab (N) or pembrolizumab (P).
Authors: Sean Khozin, Amy Pickar Abernethy, Nathan C. Nussbaum, Jizu Zhi, Melissa Curtis, Melisa Tucker, Shannon E Lee, Dave Light, Gideon Michael Blumenthal, Richard Pazdur
Journal: Journal of Clinical Oncology (2017)

11596 Background: FDA approved N for previously treated squamous mNSCLC in 3/2015 and non-squamous mNSCLC in 10/2015 regardless of PD-L1 expression. P was approved for previously treated mNSCLC in 10/2015 for patients whose tumors express PD-L1 as determined by an FDA-approved companion diagnostic (CoDx). Post-FDA approval treatment patterns of N and P, including PD-L1 testing patterns, remain unclear. Methods: We conducted a retrospective analysis using de-identified patient-level electronic health record (EHR) data aggregated from USCPs by Flatiron Health in accordance to an institutional review board approved protocol. Data was abstracted using both structured and unstructured EHR content with 10% duplicate abstraction to confirm data quality. All patients in the database with clinically-confirmed mNSCLC diagnosed from 1/1/11 to 3/31/16 and documented order or administration of N or P were included in the analyses. PD-L1 expression testing results were abstracted from unstructured data in EHR documents. Results: Within the first year of FDA approval, 1,362 mNSCLC patients received N or P (96.2% N; 3.3% P, 0.5% N+P). The median duration of treatment was 113 days. Overall, 11.3% of patients were tested for PD-L1 expression, 42.2% of whom tested positive. PD-L1 expression testing increased quarterly (Q) from 3.0% in Q2 2015 to 12.8% in Q1 2016. An FDA-approved CoDx was used 30.5% of the time. Among patients who received N, 90.5% were not tested for PD-L1 expression, 3.2% tested positive, and 4.7% tested negative for PD-L1. Among patients who received P, 32.7% were not tested for PD-L1 expression, 50.0% tested positive, and 1.9% tested negative. Conclusions: We observed low rates of PD-L1 expression testing in USCPs for patients with mNSCLC receiving N or P. Testing rates increased quarterly following FDA-approval. The majority of patients were not tested using FDA-approved CoDx. Most patients who were not tested for PD-L1 expression or tested negative received N. Clinician education will be important as data on optimal PD-L1 testing strategies guiding immunotherapy treatment decisions accumulates.
FAP-related desmoid tumours treated with low dose chemotherapy: Results from a multicentre retrospective analysis.
Authors: Bruno Vincenzi, Salvatore Provenzano, Antonella Brunello, Giuseppe Badalamenti, Margherita Nannini, Toni Ibrahim, Peter Hohenberger, Silvia Gasperoni, Andrea Napolitano, Marianna Silletta, Marco Vitellaro, Angelo Paolo Dei Tos, Daniele Santini, Giuseppe Tonini, Elena Palassini
Journal: Journal of Clinical Oncology (2018)

11556 Background: Desmoid tumours (DTs) are monoclonal neoplasms with fibroblastic-myofibroblastic differentiation and they represent the most common extra-intestinal manifestation of familial adenomatosis polyposis (FAP). DTs are often multifocal and, even in the absence of a metastatic potential, they represent the first cause of death in FAP patients after colectomy. Data on the activity of chemotherapy in FAP-associated DTs are limited. We specifically examined the activity of chemotherapy with low-dose methotrexate (MTX) + vinca alkaloids. Methods: We retrospectively reviewed data from all patients treated with MTX + vinca alkaloids for FAP-associated DTs in 5 reference centres and cases included into the National rare cancer network were also reviewed and included if sufficiently informative for the study purposes. Radiological responses were assessed using both RECIST and CHOI criteria. Results: We identified 28 patients treated with MTX + vinca alkaloids. All patients had progressive disease before chemotherapy; 17 patients and 9 patients had previously received respectively surgery and/or systemic treatments (i.e. hormone therapy, NSAIDs). Chemotherapy was administered for a median duration of 11 months. According to RECIST criteria (CHOI evaluation is ongoing) complete response, partial response, stable disease, and progressive disease were observed in 1, 17, 10, and 0 patients, respectively. The median progression-free survival (PFS) was 78 months; it was 124 months in responding patients. After chemotherapy withdrawal, MTX + vinca alkaloids rechallenge was offered to 11 patients with progressive disease. In these patients, we obtained a control rate of 100%, resulting in a median second PFS of 64 months. Conclusions: To the best of our knowledge, this is the largest series on the activity of low dose chemotherapy in FAP-related DTs. Our data suggest a tremendous activity of low dose chemotherapy in this very rare subset of patients.