tbuckley/cabot-search huggingface dataset:
A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.
Authors: Huayan Xu, Xinan Sheng, Xieqiao Yan, Zhihong Chi, Chuanliang Cui, Lu Si, Bixia Tang, Lili Mao, BIN LIAN, Xuan Wang, Siming Li, Li Zhou, Xue Bai, Jun Guo
Journal: Journal of Clinical Oncology (2020)

e17113 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefit from the treatment of RC48-ADC.The study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, one-arm, non-randomized phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary objectives were activity (ORR) and safety. Progress-free survival, disease control rate and overall survival will also be assessed. Results: As of February 2020, 8 patients were enrolled in the study. The median age was 65 years old. At baseline, most patients (6/8) had visceral metastasis. 6 (75%) patients had received≥2 lines treatment and 4 (50%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 25% (2/8) and the DCR was 75% (6/8). The ORR was 33.3% (2/6) in patients with visceral metastasis and was 50.0% (2/4) in liver metastasis patients. The ORR was 33.3% (2/6) in patients post to ≥ 2 lines of treatment and 25% (1/4) in patients post to immunotherapy. Common treatment-related AEs were AST increase (62.5%), ALT increase (50.0%), nausea (50.0%), leukopenia (37.5%), fatigue (37.5%), vomiting (37.5%), hypoesthesia (25.0%), alopecia (25.0%), and neutropenia (25.0%). Most of these AE were Grade 1 or 2. The AE of Grade 3 was neutropenia (12.5%). The SAE was CPK increased (12.5%). Conclusions: The study showed that RC48-ADC was safety and the ORR was 25% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. Clinical trial information: NCT04073602.
Adoption and utilization of NGS-based molecular profiling in community-based oncology practices: Insights from Sarah Cannon.
Authors: Andrew McKenzie, Daniel Schlauch, Yasha Sharma, David R. Spigel, Howard A. Burris, Suzanne Fields Jones, Holli Hutcheson Dilks
Journal: Journal of Clinical Oncology (2019)

e18064 Background: As the price of NGS-based sequencing technologies falls, adoption of those technologies is predicted to increase. To date, a survey of the adoption and utilization of NGS-based technologies as a part routine oncology clinical care has not been performed. Thus, a comprehensive analysis of physician adoption and utilization of commercial NGS testing in the community-setting between 2012 and 2018 was performed. Methods: Medical Oncologists in the Sarah Cannon Research Institute network ordered commercially-available NGS-based molecular profiling for their patients as standard of care. Data use agreements were initiated between SCRI, affiliated medical oncology practices, and commercial NGS testing providers, and patient NGS data were subsequently analyzed starting in 2012. Results: Community-based NGS testing rates within the Sarah Cannon network were 5.75/month in 2012 and 440/month in 2018. Plasma-based NGS testing began in 2014 and comprised 4.9% of total testing compared to 40.1% in 2018. The number of oncologists ordering molecular profiles increased from 11 in 2012 to 269 in 2018. Physician test utilization grew from an average of 6 tests/physician to 22 tests/physician in 2012 and 2018, respectively. NGS tests were performed on 34 different tumor types and biopsies were taken from both primary (~40%) and metastatic (~60%) sites . Tissue-based tests averaged 14 mutations/sample while plasma-based tests averaged 4 mutations/sample. There was a 74% decrease in median time between biopsy collection and NGS test results between 2012 and 2018 (131 and 34 days, respectively), indicating a shift toward the use of fresh – non-archival – tissue in recent years. Conclusions: These data establish NGS-based testing trends in community oncology practices and show that NGS-based tumor testing utilization has increased in the community-setting between 2012 and 2018. NGS testing is performed on a wide array of tumor types and oncologists utilize fresher biopsies.
A Phase Ib/II Study of Oprozomib in Patients with Advanced Multiple Myeloma and Waldenström Macroglobulinemia
Authors: Irene M. Ghobrial, Ravi Vij, David Siegel, Ashraf Badros, Jonathan Kaufman, Noopur Raje, Andrzej Jakubowiak, Michael R. Savona, Mihaela Obreja, Jesus G. Berdeja
Journal: Clinical Cancer Research (2019)

The oral proteasome inhibitor oprozomib has shown preclinical antitumor activity. Here, we report phase Ib/II study results investigating single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.The primary objectives were to determine the MTD, safety, and tolerability of oprozomib (phase Ib) as well as overall response rate (ORR; phase II). Oprozomib was administered once daily on days 1, 2, 8, and 9 (2/7 schedule) or days 1 to 5 (5/14 schedule) of a 14-day cycle.In patients with multiple myeloma or Waldenström macroglobulinemia (n = 71), the determined MTDs were 300 mg/day (2/7 schedule) and 240 mg/day (5/14 schedule). Median oprozomib treatment duration for patients with multiple myeloma was 11.4 weeks (2/7 schedule, 240/300 mg/day), 5.4 weeks (5/14, 240 mg/day), and 10.1 weeks (5/14, 150/180 mg/day). For patients with Waldenström macroglobulinemia, these values were 34.6 weeks (2/7 schedule, 240/300 mg/day) and 8.1 weeks (5/14 schedule, 240 mg/day). The most common grade ≥3 adverse events (AE) in phase Ib included gastrointestinal and hematologic AEs. Three AE-related deaths in phase II prompted enrollment into 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). In phase II, ORRs in 95 response-eligible multiple myeloma patients were 41.0%, 28.1%, and 25.0% in the 2/7, 240/300-mg/day; 5/14, 150/180-mg/day; and 5/14, 240-mg/day cohorts, respectively. ORRs in 31 response-eligible Waldenström macroglobulinemia patients were 71.4% and 47.1% for the 2/7 and 5/14 cohorts, respectively.This study demonstrated promising efficacy of single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.
Oncolytic HSV and PI3K inhibitor BKM120 synergize to promote killing of prostate cancer stem-like cells.
Authors: Lei Wang
Journal: Journal of Clinical Oncology (2019)

e16503 Background: Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence and are important therapeutic targets. Methods: We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium, and characterized stem-like properties of clonogenicity and tumorigenicity in vivo. The efficacy of two different oHSVs (G47∆ and MG18L) in PCSCs was tested alone and in combination with radiation, chemotherapy, and inhibitors of PI3K, Wnt, and NOTCH in vitro, and G47∆ with BKM120 in a PCSC-derived tumor model in vivo. Results: PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing in vitro, while the combination was synergistic. In contrast, oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, combination intra-tumoral G47∆ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals, and exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. Conclusions: oHSV synergizes with BKM120 in killing PCSCs in vitro and the combination markedly inhibits tumor growth even inducing regression in vivo.
First-in-human phase I and pharmacological study of TAS-119, a selective Aurora A (AurA) kinase inhibitor, in patients (pts) with advanced solid tumors.
Authors: Debbie Robbrecht, Ferry Eskens, Emiliano Calvo, Xiaomin He, Hiroshi Hirai, Nital Soni, Natalie Cook, Afshin Dowlati, Angelica Fasolo, Victor Moreno, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

3063 Background: AurA is a serine threonine kinase regulating cell division and cell cycle progression and has a role in carcinogenesis. This clinical trial investigated safety, pharmacokinetics and -dynamics and antitumor activity of the selective oral AurA kinase inhibitor TAS-119. Methods: Pts with advanced solid tumors were enrolled into 6 dose escalation cohorts (70-300 mg BID 4 days on/3 days off; every 3 out of 4 weeks; or the same schedule in a continuous weekly schedule). In the expansion phase (intermittent schedule), pts with small-cell lung cancer (SCLC), breast cancer, or MYC-amplified/B-catenin mutated (MT) tumors were enrolled, and pts with other solid tumors in a basket cohort. Results: Overall, 34 pts were enrolled to the escalation (median age 67 years; 45.3% &gt; 2 prior therapies); DLT was observed in 5 (16.1%) of 31 DLT evaluable pts; 1/10 at 150 mg, 1/6 at 200 mg, 1/5 at 250 mg, and 2/2 at 300 mg BID (fatigue, nausea, dry eyes, corneal epithelial microcysts). The maximum tolerated dose (MTD) was 250 mg BID and recommended Phase 2 dose (RP2D) was 200 mg BID. The most frequent treatment-emergent adverse events were diarrhea (28.3%), eye disorders (27%), fatigue (22.9%), and decreased appetite (14.8%). Grade 3 ocular toxicity were corneal epithelial microcysts in 1 pt (300 mg cohort) and punctate keratitis (expansion breast cancer cohort) in 1 pt. Toxicity grade ≥ 3 in ≥ 10% of pts were diarrhea (escalation part only), and increased lipase. Plasma exposure was dose-proportional and accumulation ratio was low. Pharmacodynamic data demonstrated target inhibition. Overall, 40 pts were enrolled to multiple expansions (10 SCLC, 9 breast cancer, 13 MYC-amp/B-cat MT tumors, 8 other; median age 60 years; 72.5% &gt; 2 prior therapies). Median delivered relative dose intensity was 89.1% (47.9% - 100%). Stable disease was reported in 37.8% of patients but no complete or partial responses. Conclusions: TAS-119 demonstrated favorable safety and tolerability. Low-grade eye toxicity was a dose-dependent toxicity. Preliminary anti-tumor activity of monotherapy TAS-119 is limited. A Phase 1 trial combining TAS-119 with paclitaxel was conducted in parallel. Clinical trial information: NCT02448589.
Clinical outcomes of EGFR+ NSCLC pts treated with immune checkpoint inhibitors (ICI).
Authors: Zofia Piotrowska, Rosemary G. Cobb, Mandeep Banwait, Nicolas Marcoux, Meghan Mooradian, Ibiayi Dagogo-Jack, Jessica Jiyeong Lin, Rebecca Suk Heist, Alice Tsang Shaw, Justin F. Gainor, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2019)

9069 Background: ICIs have limited efficacy in EGFR+ NSCLC with ORR ~10% if PDL1 &gt; 25% in ATLANTIC, yet ICIs are often used in later lines of therapy as pts and providers feel there may be little risk. The impacts of ICI in this setting are poorly understood. We describe our institutional experience of ICI use in EGFR+ NSCLC. Methods: MGH pts with advanced EGFR+ NSCLC treated with ICI (any line) were retrospectively reviewed for demographics, PDL1, treatment duration and patient outcomes. Disease flare was defined as hospital/hospice admission due to progression or death (Chaft CCR 2011) within 30d of ICI. Results: 40 pts with EGFR+ NSCLC (22 del19, 11 L858R, 5 ins20, 2 other) received ICI between 7/2012-12/2018. 13 were on a clinical trial. 4 had SCLC transformation. Median # of prior therapies = 3 (range, 0-8). Of 16 with PDL1 quantified, 8 had PDL1 &gt; 25%. ICI regimens were: nivolumab (nivo; n = 16), pembrolizumab (pembro; 9), atezolizumab (atezo; 3), ipilimumab/nivo (7), carboplatin/pemetrexed (pem)/pembro (3), pem/pembro (1), paclitaxel/atezo (1). 18 pts stopped TKI ≤21d prior to ICI start. Median duration of treatment (DOT) was 25 days (range, 1-1482). DOT was &gt; 1 yr for 2 pts (5%), treated with 1 st -line nivo/erlotinib (erlo) and 3 rd -line nivo. All 8 pts with PDL1 &gt; 25% had DOT &lt; 2 mos. Disease flare within 30d of ICI occurred in 16/40 (40%) overall, 8/18 (44%) who stopped TKI ≤21d of ICI start, and 14/26 (54%) who received ICI in 4 th line or later. 8 pts had concurrent TKIs (4 erlo/nivo, 2 erlo/pembro, 1 erlo/atezo, 1 osimertinib (osi)/nivo); 3/8 discontinued ICI for toxicity (all 3 treated first-line). 5 pts received osi immediately post-ICI. There was no pneumonitis on osi post-ICI; 1 pt developed gr3 LFTs and gr4 hypoNa. Conclusions: In this real world cohort of EGFR+ NSCLC, clinical benefit from ICI (assessed by DOT) was rare, including pts with high PDL1. 5% had durable benefit (both pts received ICI in earlier lines of therapy). A previously underappreciated negative outcome of ICI is that admission to hospital, hospice or death within 30d of ICI occur in up to 54% pts. This may be related to disease flare or hyperprogression and suggests that use of ICI in heavily pretreated EGFR+ NSCLC may negatively impact outcomes at end-of-life and should be used with caution.
Correlation of methylthioadenosine phosphorylase (MTAP) loss with response to anti-folate therapy in urothelial bladder carcinoma (UBC).
Authors: Omar Alhalabi, Jianfeng Chen, Matthew T Campbell, Rebecca Slack Tidwell, Guangchun Han, Wei-Lien Wang, Jian H. Song, Sumankalai Ramachandran, Lidia Lopez, Anh Hoang, Arlene O. Siefker-Radtke, Mark Anton Titus, Charles Guo, Gary Gallick, Pavlos Msaouel, Eleni Efstathiou, Christopher Logothetis, Thai Huu Ho, Linghua Wang, Jianjun Gao
Journal: Journal of Clinical Oncology (2019)

4521 Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2 nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.
Can smoking duration alone replace pack-years to predict the risk of smoking-related oncogenic mutations in non-small cell lung cancer (NSCLC)?
Authors: Koichi Ogawa, Tomoya Kawaguchi, Yasuhiro Koh, Shun-Ichi Isa, Akihito Kubo, Masahiko Ando, Hideo Saka, Naoki Yoshimoto, Akihide Matsumura, Hiroyasu Kaneda, Akihiro Tamiya, Yoshihiko Taniguchi, Kenji Sawa, Yoshiya Matsumoto, Motohiro Izumi
Journal: Journal of Clinical Oncology (2019)

e20017 Background: P has widely been used for the risk assessment of lung cancer and chronic obstructive pulmonary disease (COPD). We previously reported that mutations in KRAS, TP53, and EGFR were also associated with P from a prospective multicenter molecular epidemiology study (JME study; Kawaguchi T, J Clin Oncol 2016). Recently, D alone has been reported to provide stronger risk estimates of COPD than P. Here, we show the comparison of these two indices in predicting the risk of smoking-related oncogenic mutations in NSCLC, utilizing the database from the JME study including detailed smoking information and the mutational profile by next generation sequencing. Methods: In 439 ever- and 437 never-smokers, the frequency of mutations in KRAS, TP53 and EGFR were 9.4, 26.8 and 42.5%, respectively, and smoking-related cytosine to adenine base substitution (C &gt; A) was observed in 12.7 % of cases. AUC values (area under the ROC curves) for logistic regression determined from P and D to predict the mutations or C &gt; A change were compared, considering gender, age, stage and histology as covariates. Results: The median of P and D were 43 (1-189) and 41 (years, 1-65) in smokers, respectively. The AUC values in EGFR and KRAS were numerically higher than others, suggesting stronger association with smoking. There was no significant difference in AUC values between P and D in TP53, EGFR and C &gt; A, and P was a significantly better estimate of KRAS mutations (table). Conclusions: P remains the standard method to evaluate the risk of oncogenic mutations in NSCLC. D, however, warrants further investigation as a simpler alternative to P.[Table: see text]
Community and academic partnerships: Moving a new generation of clinical trials in NCI Community Oncology Research Program (NCORP) into community oncology practices.
Authors: Worta J. McCaskill-Stevens, Ann M. Geiger
Journal: Journal of Clinical Oncology (2019)

2551 Background: NCORP is a model program that bridges academic and community oncology practices and research. Over the past decade, community cancer investigators have adopted new technology, encountered new treatment sequalae, and faced rising cost of care with its financial toxicity imposed upon individuals seeking care. Opportunities are abundant for community investigators to assess feasibility and uptake of research advances into community practice settings, yet these opportunities are met with the challenges of dynamic changes in types of organizations delivering cancer care and diversity of populations within their catchment areas. Little information is shared about how and to what extent the health environment influences this partnership and the implementation of a broad cancer research portfolio. Methods: This abstract reports on the continued interest and participation of community oncologists in research which is demonstrated by 987 practices with over 4000 investigators in NCORP. Since 2014, over 30,000 individuals enrolled in symptom management, screening, surveillance, quality of life, and treatment trials. An additional 4500 patients and clinicians have enrolled in care delivery studies. Results: NCORP has been central in evaluating the most effective strategies for investigators to effectively communicate to patients the science of genomically-driven trials. It has also provided ways of bringing the pediatric and AYA patients access to the most up-to-date treatment strategies and new therapies in their community. This creates the least disruption on family structure/dynamics, diminished traveling requirements/costs, and reduced the financial burden. NCORP promotes involvement of treating oncologists in research activities. This also improves care for patients not enrolled in clinical trials. Therefore, NCORP serves as a laboratory to determine the most effective strategies for co-management of cancer patients and survivors. Conclusions: Several questions however remain to be addressed using this clinical trial model. These include: how to continue to reduce disparities in cancer care and clinical trial participation; and, what are the best strategies for fostering implementation of cancer care models in community practice.
Comprehensive transcriptome analysis reveals link between epigenetic dysregulation, endogenous retrovirus expression and immunogenicity in metastatic colorectal carcinoma.
Authors: Shehara Ramyalini Mendis, James Thomas Topham, Emma Titmuss, Laura Williamson, Erin D. Pleasance, Luka Culibrk, Joanna Karasinska, Shiru Lucy Liu, Michael Lee, John Aird, Richard A Moore, Andrew J. Mungall, Janessa J. Laskin, Steven J. M. Jones, Marco A. Marra, David F. Schaeffer, Daniel John Renouf, Jonathan M. Loree
Journal: Journal of Clinical Oncology (2019)

3535 Background: Endogenous retrovirus (ERV) elements represent genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated increases in ERV mRNA as a result of DNA hypomethylation, and ERV transcription has been associated with increased immunogenicity in metastatic renal cell carcinoma. We performed comprehensive bioinformatics analysis of ERV transcription in metastatic colorectal carcinoma (mCRC), to identify novel links between ERV transcription, epigenetic dysregulation and immunogenicity in metastatic colorectal carcinoma (mCRC). Methods: Tumour samples from 63 patients with mCRC were subjected to RNA sequencing as part of the Personalized OncoGenomics program (POG; NCT02155621) at BC Cancer. Patients were enrolled between 07/2012-07/2017. ERV transcription was quantified across 702,533 distinct loci. Tumors were classified ERV-hi if their total ERV expression (RPKM) was greater than the mean across all samples. High antiviral gene expression tumors (AVG-hi) were designated as having a mean expression of IFIH1, DDX58, TLR3, TANK, TBKBP1, TBK1, IRF3 and IRF7 that was greater than the mean across all samples. All pairwise comparisons of gene expression were subjected to multiple hypothesis correction. Results: Median age was 59 years, with 34 (54%) male and 1 tumor microsatellite unstable. ERV-hi tumors showed increased expression of DNA demethylators TET2 ( q=0.0045) and TET3 ( q&lt;0.0001). Significant overlap existed between ERV-hi and AVG-hi tumors (18/27, p=0.016). Tumors both ERV-hi and AVG-hi trended towards increased PD-L1 expression (p=0.055) and showed a significant increase in survival compared to tumors with high antiviral expression in the absence of high ERV transcription (p=0.0043). Conclusions: Our results suggest DNA demethylation drives increased ERV transcription and ERV-associated immunogenicity in mCRC. Moreover, we provide novel insight into the impact of ERV transcription on the biology of mCRC, highlighting ERV transcription as a potential biomarker and target for precision immunotherapy. Clinical trial information: NCT02155621.