tbuckley/cabot-search huggingface dataset:
Therapeutic and prognostic impact of genetic alterations identified in nationwide genome screening for squamous cell lung cancer (LC-SCRUM-Japan).
Authors: Tomohiro Sakamoto, Shingo Matsumoto, Eri Sugiyama, Kiyotaka Yoh, Nobuaki Kobayashi, Takuma Yokoyama, Masato Shingoji, Terufumi Kato, Hiromi Aono, Satoshi Hara, Shunichi Sugawara, Akimasa Sekine, Koichi Goto
Journal: Journal of Clinical Oncology (2018)

9074 Background: A variety of genetic alterations have been identified in squamous cell lung cancer (SqLC), but the clinical relevance of them remains poorly understood. We have prospectively analyzed advanced SqLC patients for multi-gene alterations and have followed up clinical course of the patients, establishing a large-scale clinico-genomic database in our nationwide genome screening project (LC-SCRUM-Japan). Methods: Since March 2015 to December 2017, 3316 advanced non-small cell lung cancer patients from 251 institutions had been enrolled in the LC-SCRUM-Japan, and 470 of them were histologically SqLC. Submitted tumor samples were subjected to a next-generation sequencing system, Oncomine Comprehensive Assay, enabling the analysis of < 160 cancer-related genes. Results: Among 409 available SqLC samples, potentially targetable gene alterations were detected in 196 (48%). Based on the gene alterations, the patients were categorized into 4 types, consisting of 40 (10%) with genetic alterations of FGFR family (FGFR type; 26 FGFR1 amp, 12 FGFR1/2/3/4 mut, 1 FGFR3 amp and 1 FGFR3 fus), 67 (16%) with those of the PI3K pathway (PI3K type; 46 PIK3CA mut/amp, 18 PTEN mut and 3 AKT mut), 49 (12%) with other oncogene alterations (AdC-like type; 24 EGFR mut/amp, 14 KRAS mut, 6 ALK mut/fus and 5 ERBB2 amp) and others. Mutations in TP53, CDKN2A, STK11 and RB1 were also detected in 57/13/7/5%, respectively, but these were not significantly correlated between the 4 types. The overall survival (OS) of the patients with FGFR type tended to be shorter than that of PI3K and AdC-like types (median OS, 8.8 vs 18.8 months; p = 0.09). The efficacy of platinum-containing chemotherapies or immune checkpoint inhibitors was not significantly different among the 4 types in the current follow-up data. Conclusions: Through the nationwide screening, a series of genetic alterations have been identified in advanced SqLC and FGFR gene alterations were related to poor prognosis. Our large-scale integrative clinico-genomic database enables us to elucidate the clinical significance of genetic alterations, contributing the development of genotype-directed therapeutic strategy for SqLC patients.
mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer m(CRC): A randomized phase II VOLFI trial of the AIO (AIO- KRK0109).
Authors: Michael Geissler, Jorge Riera-Knorrenschild, Andrea Tannapfel, Jobst Greeve, Axel Florschütz, Swen Wessendorf, Thomas Seufferlein, Stephan Kanzler, Swantje Held, Volker Heinemann, Anke C. Reinacher-Schick, Uwe Marc Martens
Journal: Journal of Clinical Oncology (2018)

3509 Background: Triple chemotherapy with an anti-EGFR reported promising activity with some safety concerns in single arm phase II trials. This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. Methods: Prospective 2:1 randomized, multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Cohort 1: irresectable mCRC; cohort 2: chance of secondary resection of metastatic lesions. Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 85.7% in arm A and 54.5% in arm B (p = 0.0013, OR 5.000; 95%-CI 1.870-13.370). DCR was 96.8% in arm A and 78.8% in arm B (p = 0.0071, OR 8.212). ORR in Arm A was 90.6% versus 60.0% (p = 0.0288, OR 6.400) and in Arm B 60.0% versus 50% (p = n.s.) for left and right located CRC, respectively. ORR between arms A and B comparing left and right sided CRC was 90.6% versus 60.0% (p = 0.0039, OR 6.400; 95%-CI 1.889-21.679) and 60.0% versus 50.0% (p = n.s.), respectively. Secondary resections in cohort 2 were 60% (n = 12) and 36.4% (n = 4) in arms A and B, respectively. Treatment related serious adverse advents grade 3-5 occured in 32.8% and 12.1% in arms A and B, respectively (p = 0.0297). Nevertheless, no differences in global health status, functional scales, and symptom scales were reported. Conclusions: mFOLFOXIRI plus Panitumumab results in significantly higher response rates compared to FOLFOXIRI in RAS wild-type mCRC. Strong effectivity was observed also in right sided and BRAF mutated CRC. High secondary resection rates could be achieved. Although toxicity (treatment related SAEs) was increased, QL reporting was similar in both arms. Final PFS, AEs, and dosing data will be presented at the meeting. Clinical trial information: NCT01328171.
Temsirolimus-induced interstitial lung disease as an on-target effect in patients with metastatic renal cell carcinoma.
Authors: Masatoshi Eto, Takanobu Motoshima, Yutaka Sugiyama, Kiyohide Fujimoto, Chikara Ohyama, Koji Mita, Naoya Masumori, Toshiyuki Kamoto, Koichiro Matsumoto
Journal: Journal of Clinical Oncology (2017)

e16086 Background: An inhibitor for mammalian target of rapamycin (mTORi), temsirolimus, has been used for metastatic renal cell carcinoma (mRCC) pts with poor risk. mTOR is known to regulate proliferation of lymphocytes, which has been rationale of applying mTORi for preventing graft rejection in transplantation. However, nobody knows the immune status of mRCC pts treated with temsirolimus. In addition, accumulation of clinical practices of temsirolimus has revealed a variety of AEs including interstitial lung disease (ILD). The underlying mechanisms of ILD by mTORi remain uncertain. Moreover, the clinical impact of ILD on the clinical response to mTORi remains unknown. So, we have conducted a prospective clinical trial investigating immune parameters in mRCC pts treated with temsirolimus. This project was denominated in Japanese m-TOR Immune Modulation trial (J-TORIM) (UMIN000009662). Methods: J-TORIM was a prospective observational study recruited pts at 25 hospitals in Japan with a targeted sample size of 30. The primary objective was to evaluate whether administration of temsilorimus has consistent effects on immune parameters collected from the peripheral blood before and 3-to-5 weeks after the beginning of temsirolimus therapy. The secondary objectives were to evaluate the associations of immune parameters or ILD with ORR, PFS, and OS, and the associations of immune parameters with ILD. Immune parameters include PBMC culture with con A or lipopolysaccharide (LPS), PBMC flow cytometry with anti- CD4, CD8, CD3, PD-1, PD-L1, CD25, Foxp3 mAbs. Results: Twenty-eight patients were enrolled in the study. ORR of temsirolimus was 10.7% (1 CR and 2 PR). The most commonly reported treatment-related AEs were ILD (28.5%) and stomatitis (28.5%). There were no significant changes after temsirolimus therapy for any immunological parameters. Interestingly, a significant correlation between ILD development and ORR was observed (p &lt; 0.01). In addition, a significant increase of regulatory T cells was also observed after the recovery of ILD (p &lt; 0.05). Conclusions: This is the first prospective study demonstrating that ILD development can be predictive for response to temsirolimus in mRCC pts. Clinical trial information: 000009662.
Phase II trial of SurVaxM combined with standard therapy in patients with newly diagnosed glioblastoma.
Authors: Manmeet Singh Ahluwalia, David A. Reardon, Ajay P Abad, William T. Curry, Eric T. Wong, Ahmed Belal, Jingxin Qiu, Kathleen Mogensen, Cathy Schilero, Danielle Casucci, Laszlo Mechtler, Erik J Uhlmann, Michael J Ciesielski, Robert Fenstermaker
Journal: Journal of Clinical Oncology (2018)

2041 Background: To determine 6-month progression-free survival (PFS-6), 12-month overall survival (OS-12) and immunologic response in newly diagnosed glioblastoma (nGBM) treated with concurrent temozolomide (TMZ) and radiation, followed by adjuvant TMZ and survivin-targeted immunization with SurVaxM (SVN53-67/M57-KLH). Methods: A single-arm, multi-center phase II trial was conducted in 63 evaluable patients with nGBM with HLA-A*02, -A*03, -A*11 and -A*24 haplotypes and Karnofsky performance status ≥70. Patients (Pts) underwent craniotomy with near-total resection ( < 1 cm3 residual contrast enhancement), followed by chemoradiation (Stupp) were eligible. Pts received 4 priming doses of SurVaxM (500 mcg) with Montanide and sargramostim (100 mcg) every 2 weeks, followed by adjuvant TMZ and maintenance SurVaxM every 12 weeks until progression. Immunogenicity of SurVaxM was assessed using expansion of survivin-specific CD8+ T-cells (dextramers) and survivin antibody (IgG) levels. Results: Interim analysis of the first 55 pts. Pts ranged in age from 20-82 yrs (median = 60), male:female = 32:23 with survivin tumor expression of 1-40% (median = 12%) by immunohistochemistry. PFS-6 was 96.3% (+2.8, -10.3)(n = 55) measured from diagnosis and 62.8% (+12.5, -16.2)(n = 43) from first immunization. OS-12 was 90.9% (+6.1, -16.5)(n = 33) from diagnosis and 70.8% (+14.1, -22.4)(n = 24) from first immunization. Median time to first immunization was 3.0 mo (1.9-4.0 mo). The regimen was generally well tolerated and immunization-related adverse events were mild with no serious adverse events attributable to SurVaxM. The drug was highly immunogenic and produced survivin-specific antibody (IgG) titers and CD8+ T-cells detectable by survivin dextramers. IDH-1, MGMT methylation status, HLA class I haplotype, survivin expression levels, and the relationship of these variables to survival will be presented. Outcomes will be compared to historical patients receiving Stupp regimen, and Stupp plus Optune. Conclusions: Standard therapy plus SurVaxM appears promising in nGBM compared to standard therapy alone. The use of SurVaxM is safe in nGBM. A randomized, prospective trial of SurVaxM in glioblastoma is planned. Clinical trial information: NCT02455557.
Development and external validation of a novel risk score to identify insignificant prostate cancer.
Authors: Lorenzo Dutto, Jorn H. Witt, Katarina Urbanova, Christian Wagner, Andreas Schuette, Mustafa Addali, John D Kelly, Senthil Nathan, Timothy Philip Briggs, Ashwin Sridhar, Stefania Gori, Amar Ahmad, Gregory Shaw
Journal: Journal of Clinical Oncology (2017)

5073 Background: Active surveillance is increasingly used for insignificant prostate cancer (PCa). In order to identify suitable patients, risk scores have been developed which use pre-operative factors. We evaluated the accuracy of 9 separate tools developed to identify patients harbouring insignificant PCa in 2613 patients who underwent radical prostatectomy for Gleason 3+3 PCa. We have developed and validated a novel risk score to correctly identify insignificant PCa for use in unscreened patient cohorts using non-dichotomised clinical predictors. Methods: 2799 patients who would have been candidates for AS (Gleason score 6 only) patients underwent robotic radical prostatectomy between 2006 and 2016 at a tertiary referral center. The volume and grade of tumour in the resected prostate was analysed. Inignificant PCa was defined as Gleason 3+3 only, index tumour volume &lt;1.3 cm3 , total tumour volume &lt;2.5 cm3 (updated ERSPC definition). 2613 patients were included in the final analysis. We computed the accuracy (specificity, sensitivity and area under the curve (AUC) of the receiver operator characteristic) of 9 predictive tools. Multivariate logistic regression with elastic net regularisation was used to develop a novel tool to predict insignificant prostate cancer using age at diagnosis, baseline PSA, TRUS volume, clinical T-stage, number of positive cores and percentage of positive cores as predictors. This tool was validated in an external cohort of 441 unscreened patients undergoing surgery for Gleason 6 PCa. Results: All of the predefined tools rated poorly as predictors of insignificant disease as none of them reached the required AUC threshold of 0.7. The new tool performed well in training and validation cohorts. Conclusions: Pre-existing predictive tools to identify indolent PCa have a poor predictive value when applied to an unscreened cohort of patients. Our novel tool shows good predictive power for insignificant PCa in this population in training and validation cohorts. The inherent selection bias due to analysis of a surgical cohort is acknowledged. [Table: see text]
Faster approvals?: Trends in the use of FDA’s expedited approval programs for oncology medications.
Authors: Lisa Ambrosini Vadola, Monique A Pond, Ann Winter-Vann, Robin Whitsell
Journal: Journal of Clinical Oncology (2017)

e18270 Background: With the importance of speed-to-market and addressing unmet needs, pharmaceutical companies have sought accelerated approvals through the Food and Drug Administration (FDA). Introduced with the FDA Safety and Innovation Act (FDASIA) of 2012, Breakthrough Therapy Designation (BTD) has become an important mechanism for approval of serious and life-threatening conditions that do not have adequate therapies. Notably, these pathways have been ill-understood by both pharmaceutical companies and health care providers. This study assessed how BTD and other FDA designations have played a role in the approval of oncology drug marketing applications and evaluated trends in the use of these regulatory pathways. Methods: We analyzed publicly available data on novel oncology drug approvals by the FDA from 2012-2016, including the 4 expedited programs for serious conditions (BTD, Accelerated Approval, Fast Track, and Priority Review). Results: Of the 43 novel oncology drugs approved by the FDA between 2012-2016, 42 used at least 1 of the expedited approval programs, including 65% that used ≥2 programs and 35% that used ≥3 programs. The BTD has been used by 15 of the 43 (35%) approved novel oncology drugs since 2012. The use of the BTD, Accelerated Approval pathway, and Priority Review designation among approved oncology drugs has generally increased each year from 2012-2016, while the use of the Fast Track designation has decreased over the same time period. Conclusions: Companies seeking oncology approvals often use more than one expediting strategy. Alone or in combinations, the BTD, Accelerated Approval, and Priority Review have been shown to play an increasingly important role in oncology drug development. Data collected between 2012-2016 suggest that use of BTD is growing more common, while use of the Fast Track designation has decreased among approved oncology drugs. Additional expedited approval programs have remained steady or increased since the FDA introduced BTD. Based on these observations, we anticipate use of the BTD, Accelerated Approval, and Priority Review designation will grow in future oncology drug applications.
Retrospective claims analysis of patient factors affecting multi-line treatment patterns in multiple myeloma (MM).
Authors: Safiya Abouzaid, Kejal Parikh, Chi-Chang Chen, Catherine Balderston McGuiness, Rolin L. Wade, Ajai Chari
Journal: Journal of Clinical Oncology (2016)

8041 Background: We sought to generate novel real world evidence on how patient factors affect therapy patterns in MM. Methods: US Claims data from PharMetrics Plus was used to identify patients (pts) with a MM-therapy claim (index date), between 1/1/2009 and 3/31/2014 with ≥ 2 MM diagnoses (ICD-9 203.0x). Regimens were defined as all MM treatments (Tx) observed within 60 days of index. Tx progression was defined as the addition of a new agent > 60 days from index, or Tx restart following a > 90 day therapy gap. Results: A total of 2,454 pts were identified of which 994 received autologous stem cell transplant (ASCT). Mean (SD) age was 57.3 (7.2) years in ASCT vs. 65.3 (10.4) in non-ASCT (p < 0.001). The prevalence of cardiovascular, metabolic and renal disorders at index was lower in ASCT patients, as was mean age-adjusted Charlson Comorbidity Index score: 5.0 vs. 6.4 for non-ASCT (p < 0.001). Common first line (1L) Tx regimens consisted of doublet or triplet therapy with lenalidomide and/or bortezomib (ASCT doublet n = 508, triplet = 355; non-ASCT doublet = 956, triplet = 357). At index, non-ASCT pts receiving doublet Tx were significantly older and with less hypercalcemia versus those receiving triplet Tx. In both ASCT and non-ASCT pts, those receiving doublet therapy had a lower prevalence of pathologic fracture and hematologic disorders at index. In ASCT pts, the mean (SD) 1L Tx duration was 9.8 (9.7) months with more doublet pts progressing to second line (2L) compared to triplet pts (40.0% vs. 24.8%, p < 0.0001). However, mean (SD) time to 2L was similar for doublet and triplet pts [7.3 (8.2) vs. 7.0 (7.7) months] as was the mean (SD) duration of 2L Tx [10.0 (11.0) vs. 11.1 (12.0) months]. In non-ASCT pts, mean (SD) 1L Tx duration was 11.9 (11.6) months, and 722 (46.6%) were followed to 2L Tx, with a mean (SD) time from index to progression of 10.9 (9.7) months. Mean (SD) Tx duration in 2L was 9.7 (9.9) months and 278 were followed to third line Tx with a mean (SD) of 10.3 (9.6) months. Conclusions: This analysis of treatment patterns with ASCT, doublet or triplet Tx in MM found patient factors such as age and disease severity strongly influenced the choice of therapy. Patients progressing to 2L and 3L treatment did so relatively rapidly.
Effect of statins on risk of pancreatic cancer: A meta-analysis of randomized controlled trials (RCTs) and observational studies (OS).
Authors: Ahmad Cheema, Hafeez Hassan, Waqas Qureshi, Mariam Shakeel, Wasif M. Saif
Journal: Journal of Clinical Oncology (2016)

e15751 Background: Statins (HMG-CoA reductase inhibitors) are widely prescribed for prevention of coronary artery disease and treatment of dyslipidemias. Several pre-clinical studies have suggested the chemopreventive potential of statins through their anti-proliferative and apoptotic effects on cancer cells. However, the results of clinical studies evaluating the relationship of statin use and risk of pancreatic cancer (PC) have been inconsistent. To better understand this association, we conducted a meta-analysis of original studies pertaining to this subject. Methods: A comprehensive literature search was carried out for articles published up to December 2015. Eligible studies were RCTs and OS that assessed the effect of statin use on the risk of pancreatic cancer, compared with placebo or no treatment. Studies had to report odd ratio (OR), Relative Risk (RR), or Hazard Ratio (HR) estimates with 95% confidence interval (CI), or provide sufficient data for their calculation. Pooled RRs with corresponding 95% CIs were calculated using random effects model. Results: A total of 18 studies (15 OS and 3 RCTs) contributed to the analysis. A total of 1799157 patients (mean age 59.6 years, 63% males) were included. The mean duration of follow up and statin use in RCTs was 4 years. Whereas, observational studies reported variety of statin types, exposure and follow up periods. The incidence of pancreatic cancer was 0.28% (1834/672905) in the statin therapy group versus 0.54% (6135/1126252) in the group without statin therapy. The overall pooled result for all studies demonstrated a statistically significant reduction in the risk of pancreatic cancer among statin users (HR 0.766, 95% CI 0.621-0.946, p = 0.013), compared to non–statin users. Conclusions: This is the first meta-analysis that demonstrates inverse relationship between statin use and the risk of pancreatic cancer, when statins are taken daily for cardiovascular event prevention. This observation warrants further investigation, especially prospective studies, to confirm the association.
Disease-management indicators to improve gastric and colorectal cancer control in the Colombian National Health System.
Authors: Omaira Valencia, Gilberto Lopes, Patricia Sánchez Quintero, Lizbeth Acuña, Jaime Gonzalez, Diego Lopera, Daniel Uribe, Diana Pulido
Journal: Journal of Clinical Oncology (2017)

e18288 Background: Gastric (GC) and colorectal cancer (CRC) are major health problems worldwide due to their high incidence and lethality associated with late presentation. The aim of this study was to develop a set of clinical, quality and administrative measures, for gastric and colorectal cancer based on evidence to assist health care insurers, providers and policy makers in controlling these diseases in Colombia. Methods: A systematic evidence-based literature search was performed to identify the initial list of indicators, which were then selected and developed using an adaptation of the RAND/UCLA appropriateness method by a panel of multidisciplinary expert panels with expertise in CRC and GC care, quality and public health. The following institutions participated in the study: The Ministry of Health and its High Cost Disease Office, medical professional societies, National Health Institute, Institute of evaluation of technologies in health, health care insurers and providers. A total of 1589 cases of GC and 2025 of CRC from the national administrative cancer registry, representing all new cases of these diseases in the country in 2015, were used to define the viability of the proposed measures, which the involved parties developed taking in consideration the whole disease spectrum from diagnosis to treatment. Results: After reviewing relevant articles and holding an in-person expert discussion the panel generated an initial proposed set of 45 disease-management indicators. A total of 15 disease-management measures for CRC and 16 for GC were developed and approved by the expert panel after two rounds of discussion and voting; these are related to opportunities to improve time between diagnoses to treatment and also include measures assessing clinical outcomes and administrative processes. Conclusions: We developed disease-management indicators for GC and CRC in a consensus with healthcare system stakeholders that are feasible and applicable in Colombia. In time, through continuous efforts towards improving the quality of care provided, these will allow all parties to monitor and decrease the burden of GC and CRC in the country and may serve as a model to other low and middle income countries.