tbuckley/cabot-search huggingface dataset:
Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC).
Authors: Hiroaki Akamatsu, Hibiki Udagawa, Kentaro Tanaka, Masayuki Takeda, Shintaro Kanda, Keisuke Kirita, Shunsuke Teraoka, Kazuhiko Nakagawa, Yutaka Fujiwara, Ikuko Yasuda, Sumiko Okubo, Masayuki Shintani, Rachel S Leibman, Charity D. Scripture, Tomohide Tamura, Isamu Okamoto
Journal: Journal of Clinical Oncology (2019)

8557 Background: SCLC rapidly recurs after first-line platinum therapy, and while several agents are approved in the relapsed/refractory setting, there is no approved agent or existing standard of care for third-line in Japan. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not in normal tissue. This was the first study evaluating safety, PK, and preliminary anti-tumor activity of Rova-T in Japanese pts. Methods: This was an open label Phase 1, 3+3 dose-escalation study of Rova-T in Japanese pts with advanced recurrent SCLC (NCT03086239). Eligibility: progressive disease after ≥2 prior systemic regimens incl. ≥1 platinum-based regimen; ECOG 0-1. Pts received 0.2 or 0.3 mg/kg Rova-T IV on Day 1 of a 6-week cycle for 2 cycles. Objective was to evaluate safety, tolerability, PK, and preliminary efficacy and expression of DLL3. Antitumor activity was measured by RECISTv1.1, and DOR, PFS, OS were evaluated. Results: 29 pts were treated with Rova-T (6 at 0.2mg/kg, 23 at 0.3 mg/kg). Median age 68 yrs; 76% male; 64% DLL3 high (≥75% expression); 86% DLL3 positive (≥25%). 20 pts (69%) had received ≥3 prior lines of therapy. Similar PK and AEs were seen compared to previous studies in non-Japanese pts. The most frequently reported study drug-related AEs were platelet count decreased, pleural effusion, oedema peripheral, and aspartate aminotransferase increased, the majority Grade 1/2. No DLTs occurred, and both dose levels were tolerated. Three pts previously treated with ≥3 prior lines of therapy had confirmed partial response by investigator (10% of all pts; 17% of DLL3 high pts). For DLL3 high pts, mDOR was 3.0 mos (95% CI: 2.9, 4.1), mPFS was 2.9 mos (1.2-3.6), and mOS was 7.4 mos (4.1-11.9). Individual responses were analyzed in detail and radiographic data with tumor shrinkage will be shown. Conclusions: Rova-T demonstrated a manageable safety profile with promising preliminary efficacy in Japanese SCLC pts, in particular pts with DLL3 high expression. These data support further exploration of Rova-T treatment in Japanese pts with SCLC in global Phase 3 studies. Clinical trial information: NCT03086239.
DC-HIL/Gpnmb checkpoint blockade as a synergistic combination for stereotactic ablative radiation (SAbR).
Authors: Vijay Ramani, Jin-Sung Chung, Masato Kobayashi, Jonathan Schoenhals, Ponciano D Cruz, Raquibul Hannan, Kiyoshi Ariizumi
Journal: Journal of Clinical Oncology (2019)

e14129 Background: The combination of radiotherapy (RT)/immunotherapy holds a promise as an innovative cancer treatment. Expansion of myeloid-derived suppressor cells (MDSC) dampens cancer immunity, and DC-HIL receptor is a potent mediator of the suppressor function. We examined whether DC-HIL blockade is useful as a synergistic combination for SAbR using mouse model and human clinical samples. Methods: After tumor-irradiation on mice with subcutaneous (sc) RM9 prostate cancer (PC), tumor-infiltrating lymphocytes were phenotypically analyzed. Mice with sc tumor were injected i.v. with RM9-GFP cells (lung mets); 4 d later tumor-irradiated and treated with Ab (6 x 200 μg/shot). Tumor growth was measured by volume or GFP + cells. PC (n = 22, stages II-III) patients were treated with SAbR, and blood samples collected at week (w) 0, 2, 8 and assayed for % monocytic (m) and granulocytic (g) MDSC and their expression of DC-HIL vs. PDL1. Suppressor function of MDSC was assayed by fall in T cell IFN-γ response. Results: Tumor-RT increased MDSC by 40% on day 8; the most expanded subset Gr1 hi Ly6C lo gMDSC expressed DC-HIL highly but PDL1 lowly. Combination of anti-DC-HIL/RT inhibited tumor growth in RT-irradiated sc tumor and non-irradiated lung mets and converted tumor microenvironment from the suppressive to the competent milieu. PC patients (17/22 cases) showed elevated MDSC blood levels at w2, but markedly varied at w8 among individuals (2.7 ± 7.3%). DC-HIL + MDSC levels were also upregulated. gMDSC showed small changes after RT, and DC-HIL (but not PDL1) expression was markedly upgraded by ~90% (n = 3). SAbR decreased the suppressor ability of both MDSC: ~93% T cell suppression at w0 down to ~56% at w8 by mMDSC; and ~76% to ~49% by gMDSC. However, anti-DC-HIL Ab reversed the suppressor ability of MDSC at w8 more than those at w0 (~59% reversal to ~89%), showing that SAbR increased the criticality of DC-HIL pathway in their function. Five cases showed a high rise in DC-HIL expression at w8, with no significant fall in PSA levels at ~13 mons, and one with a noticeable fall in both levels. Conclusions: DC-HIL blockers may amplify the therapeutic effects of SAbR for PC treatment. DC-HIL expression may be a predictive marker for PC response to SAbR.
Acupuncture: Real-world patient-reported outcomes of treatment-related symptoms in breast cancer survivors.
Authors: Jacqueline Zayas, Kathryn Jean Ruddy, Janet E. Olson, Fergus Couch, Brent Bauer, Molly Mallory, Ping Yang, David Zahrieh, Charles L. Loprinzi, Elizabeth Jane Cathcart-Rake
Journal: Journal of Clinical Oncology (2019)

e23111 Background: Acupuncture has been shown to reduce aromatase inhibitor-induced arthralgias, as well as possibly hot flashes and fatigue, but research has been limited. The purpose of this study was to evaluate real world perceived benefit of acupuncture for commonly experienced symptoms among breast cancer survivors. Methods: Breast cancer survivors who had used acupuncture for cancer- or treatment-related symptoms were identified using an ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR) cohort. In addition, Mayo Clinic electronic health records (EHR) were queried to identify additional participants. All identified patients were mailed a survey with acupuncture-related questions. Respondents were also asked to recall their severity of arthralgia, myalgia, post-surgical pain, hot flashes, nausea/vomiting, fatigue, depression, anxiety, insomnia, lymphedema, headache, and neuropathy from 1 to 5 (1 = mild, 5 = severe) before and after acupuncture treatment. Results: Acupuncture use was reported among 413 participants in MCBDR (12% of all enrollees) and 73 patients were identified in the Mayo EHR. 241 eligible women returned surveys (median age at diagnosis 50 yrs). Mean symptom severity scores decreased from before to after acupuncture by at least 1 point for all queried symptoms (Table). Conclusions: Acupuncture is frequently used by patients for a variety of breast cancer-related symptoms. Those who do pursue acupuncture usually perceive few toxicities and substantial benefits. Cost may be a barrier to treatment for some. [Table: see text]
Response by Mann et al to Letter Regarding Article, “Effects of Liraglutide Versus Placebo on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease: Results From the LEADER Trial”
Authors: Johannes F.E. Mann, Vivian Fonseca, Ofri Mosenzon, Itamar Raz, Bryan Goldman, Thomas Idorn, Bernt Johan von Scholten, Neil R. Poulter
Journal: Circulation (2019)
Improving health with programmatic, legal, and policy approaches to reduce gender inequality and change restrictive gender norms
Authors: Jody Heymann, Jessica K Levy, Bijetri Bose, Vanessa Ríos-Salas, Yehualashet Mekonen, Hema Swaminathan, Negar Omidakhsh, Adva Gadoth, Kate Huh, Margaret E Greene, Gary L Darmstadt, Gary L Darmstadt, Margaret Eleanor Greene, Sarah Hawkes, Lori Heise, Sarah Henry, Jody Heymann, Jeni Klugman, Ruth Levine, Anita Raj, Geeta Rao Gupta
Journal: The Lancet (2019)
Low-fat dietary pattern and breast cancer mortality by metabolic syndrome degree: Secondary analyses of the Women’s Health Initiative (WHI) Dietary Modification randomized trial.
Authors: Kathy Pan, Aaron K Aragaki, Marian L Neuhouser, Michael S. Simon, Juhua Luo, Bette Caan, Snetselaar Linda, Joanne E. Mortimer, JoAnn E Manson, Candyce Kroenke, Dorothy Lane, Kerryn Reding, Thomas E Rohan, Rowan T. Chlebowski
Journal: Journal of Clinical Oncology (2019)

1539 Background: The WHI Diet Modification (DM) trial randomized 48,835 postmenopausal women with no prior breast cancer to a low-fat dietary intervention or comparison group. After 16.1 years follow-up, the intervention was associated with an 18% reduction in risk of death after breast cancer (P =0.01), with greater reduction (29%) in those with waist circumference≥88 cm (J Clin Oncol 2017). To extend these findings, we examined the influence of the dietary intervention on breast cancer mortality in subgroups defined by number of metabolic syndrome (MS) components with 19.6 years median cumulative follow-up. Methods: WHI DM has been previously described. Four MS components were determined at entry: 1) waist circumference≥ 88 cm, 2) high blood pressure or anti-hypertensive use, 3) high cholesterol history and 4) diabetes history, with women categorized as having 0 (n=10,639), 1-2 (n=30,948), or 3-4 (n=4,246) MS components. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomized group assignment and number of MS components. Results: Women with 3-4 MS components were more likely to be Black, be obese (BMI ≥30), and have diabetes (all P &lt; 0.001). Breast cancers in women with 3-4 MS components were less likely to be local stage (P = 0.005) or well differentiated (P = 0.03). The magnitude of reduction in deaths from breast cancer in the dietary intervention vs comparison group increased as the number of MS components increased (interaction P = 0.01). Hazard ratios (HR) and 95% confidence intervals (CI) for death from breast cancer for intervention vs comparison groups for women with 0 MS components was 1.09 95% CI, 0.63-1.87, with risk low in both randomization groups (0.028% and 0.026%, respectively); for women with 1-2 MS components, HR 0.80 95% CI 0.62-1.02; and for women with 3-4 MS components, HR 0.31 95% CI, 0.14-0.69, with risk in the intervention group reduced to 0.026%. Conclusions: Adoption of a low-fat dietary pattern had a greater effect on reducing deaths from breast cancer in women with more MS components, suggesting that this is a high risk group more likely to benefit from the dietary intervention. Clinical trial information: NCT00000611.
Phase (Ph) I/II study of pembrolizumab (P) with gemcitabine (G) in patients (pts) with previously-treated advanced (Adv) non-small cell lung cancer (NSCLC).
Authors: Rachel E. Sanborn, Regan M. Duffy, Brenda K Fisher, Kelly Shea Perlewitz, Herschel D. Wallen, Rui Li, William L Redmond, Yoshinobu Koguchi, Bernard A. Fox
Journal: Journal of Clinical Oncology (2019)

e20652 Background: P has demonstrated improved survival alone or with chemotherapy in untreated adv NSCLC. G may increase antigen cross-presentation and prime CD8 T cell response via tumor apoptosis. This study evaluated P + G in pts with previously-treated adv NSCLC naïve to anti-PD1. Methods: The study included ph 1 (previously reported), then single arm ph II, 1-3 prior therapies, regardless of PD-L1 status. Treatment: G, 1250 mg/m2, Days (D) 1 &amp; 8 + P 200 mg D 1; 21-day cycles. G given max 6 cycles, P max 2 years. Tumor tissue was collected for PD-L1 (22C3). Immune response via whole blood immunophenotyping and ProtoArray was conducted. Results: 16 pts enrolled. Male/Female: 8/8; Age 53-75 (Median 64.5); ECOG 0/1: 2/14 pts, respectively. Median prior therapies: 1 (Range (R) 1-3). Median cycles: 4 (R 1-24). Primary reason for discontinuation: progression. Toxicity was primarily attributed to G, including Gr 3: neutropenia (5), leukopenia (3), anemia (2); lymphopenia, URI, hyponatremia (1 each). Gr 4: 1 hypoxia attributed to intrapulmonary hemorrhage from G. Other toxicities attributed to both G and P included dyspnea (2), pneumonitis (2) (Gr 3). Progression free survival (PFS): 3.2 months (m) (R 0.6-18.5 m). Overall survival (OS) is not yet mature (4 pts in follow up). 14/16 pts were evaluable for response. Stable disease (SD): 9 (56%); partial response (PR): 2 (13%); progression (PD): 3 (19%). 2 pts discontinued prior to first evaluation (1 pulmonary hemorrhage; 1 clinical progression). 1 pt had SD as best response for 18.5 m before PD. Disease control rate (DCR; CR + PR + SD): 56%. 12 pts were PD-L1 evaluable (central). 2 pts had PD-L1 testing through alternate source (22C3). Of the 14 pts with PD-L1 result: PD-L1 0%: 8 (50%); PD-L1 10-40%: 3; ≥50%: 3 (19% each) PFS of 0% PD-L1: 3.75 m (1 PR, 6 SD; DCR 88%). PFS ≥50% PD-L1: 3 m (1 SD, 0 PR). Exploratory immune profiling showed late peripheral immune activation in 3 of 6 pts with Cycle 6 samples (all SD; PFS 5.8 m). ProtoArray analysis is pending. Conclusions: P+G was a feasible combination, without unexpected toxicity. The majority of pts had 0% PD-L1 expression. PFS was not associated with PD-L1 level. PFS did not differ from G or P alone. OS pending. Clinical trial information: NCT02422381.
The impact of routine ESAS use on overall survival: Results of a population-based retrospective matched cohort analysis.
Authors: Lisa Catherine Barbera, Rinku Sutradhar, Craig Earle, Nicole Mittmann, Hsien Seow, Doris Howell, Qing Li, Thiruchelvam Deva
Journal: Journal of Clinical Oncology (2019)

6509 Background: The study objective was to examine the impact of routine Edmonton Symptom Assessment System (ESAS) use on overall survival among adult cancer patients. We hypothesized that patients exposed to ESAS would have better overall survival rates than those who didn’t have ESAS. Methods: The effect of ESAS screening on survival was evaluated in a retrospective matched cohort study. The cohort included all Ontario patients aged 18 or older who were diagnosed with cancer between 2007 and 2015. Patients completing at least one ESAS assessment during the study were considered exposed. The index date was the day of their first ESAS assessment. Follow up time for each patient was segmented into one of three phases: initial, continuing, or palliative care. Exposed and unexposed patients were matched 1:1 using hard (birth year ± 2 years, cancer diagnosis date ± 1 year, cancer type and sex) and propensity-score matching (14 measures including cancer stage, treatments received, and comorbidity). Matched patients were followed until death or the end of study at Dec 31, 2015. Kaplan-Meier curves and multivariable Cox regression were used to evaluate the impact of ESAS on survival. Results: There were 128,893 pairs well matched on all baseline characteristics (standardized difference &lt; 0.1). The probability of survival within the first 5 years was higher among those exposed to ESAS compared to those who were not (73.8% vs. 72.0%, P-value &lt; 0.0001). In the multivariable Cox regression model, ESAS assessment was significantly associated with a decreased mortality risk (HR: 0.49, 95% CI: 0.48-0.49) and this protective effect was seen across all phases. Conclusions: ESAS exposure is associated with improved survival in cancer patients, in all phases of care. To the extent possible, extensive matching methods have mitigated biases inherent to observational data. This provides real world evidence of the impact of routine symptom assessment in cancer care.
A multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for <i>EGFR</i> mutation-positive non-squamous non-small cell lung cancer: TORG1833.
Authors: Yoshiro Nakahara, Terufumi Kato, Reiko Isomura, Nobuhiko Seki, Naoki Furuya, Katsuhiko Naoki, Takeharu Yamanaka, Hiroaki Okamoto
Journal: Journal of Clinical Oncology (2019)

TPS9120 Background: Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways are shown to be interrelated in several preclinical studies. Furthermore, recent clinical studies have shown the adding effect of an anti VEGF monoclonal antibody with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Thus, osimertinib plus ramucirumab would be the promising candidate for the new standard treatment in EGFR mutation positive NSCLC. Methods: This study is an investigator initiated trial. Previously untreated EGFR mutation positive advanced non squamous NSCLC patients aged 20 years or older with a performance status of 0 or 1 are randomized at a 1:1 ratio to receive osimertinib (80mg) every day either without or with ramucirumab (10mg/kg) every 2 weeks until evidence of disease progression or development of unacceptable toxicity. The primary endpoint of the study is progression free survival (PFS) assessed by the central image reviewer. Secondly endpoints include PFS (assessed by an attending physician), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), safety and toxicity profile. Stratification factors are gender and the type of EGFR mutation (exon 19 deletion, Leu858Arg point mutation in exon 21). We determined that, with a sample size of 120 patients (60 in each arm), the trial will have 80% power to show a hazard ratio for disease progression or death of 0.667 at a one-sided alpha level of 0.2 (as calculated on the basis of 80 such events) for comparison between the two arms with 1.5-year accrual and 2-year follow-up periods. Study enrollment began in November 2018 and is continued for 3.5 years among 20 sites of Thoracic Oncology Research Group (TORG). Seven patients were enrolled at time of submission. Clinical trial information: 184146.
Safety results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma (ESO-Shanghai 2).
Authors: Dashan Ai, Yun Chen, Qi Liu, Xiangpeng Zheng, Yunhai Li, Shihong Wei, Jinjun Ye, Jialiang Zhou, Qin Lin, Hui Luo, Jianzhong Cao, Jiancheng Li, Guang Huang, Kailiang Wu, Min Fan, Huanjun Yang, Zhengfei Zhu, Weixin Zhao, Ling Li, Kuaile Zhao
Journal: Journal of Clinical Oncology (2019)

4055 Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC) . Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m 2 /d, d1-3, PTX 175 mg/m 2 , d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m 2 , civ 96h, PTX 50 mg/m 2 , d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m 2 , civ 72h, PTX 175 mg/m 2 , d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m 2 , d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m 2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. TP group had a significant higher incidence of acute grade 3/4 neutropenia (59.7% vs. 16.8%(TF) or 32.4%(TC)), thrombocytopenia (12.7% vs. 3.5%(TF) or 6.2%(TC)), anemia (6.4% vs. 4.4%(TF) or 4.4%(TC)), fatigue (10.0% vs. 0.9%(TF) or 0.9%(TC)) and vomiting (5.5% vs. 0%(TF) or 0.9%(TC)) than other two groups ( P &lt; 0.05). TF group had a significant higher incidence of grade 3/4/5 esophagitis (13.1% vs. 1.8%(TP) or 5.3%(TC)) and pneumonitis (4.4% vs. 0%(TP) or 1.8%(TC)) than other two groups ( P &lt; 0.05). One patient in TF group died of acute pneumonitis. One patient in TF group and one in TC group died of acute esophagitis. Conclusions: TP and TF regimen showed different severe AEs in CCR in ESCC patients and TC showed mild AEs. Clinical trial information: NCT02459457.
Association of colon cancer (CC) molecular signatures with prognosis and oxaliplatin prediction-benefit in the MOSAIC Trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer).
Authors: Katherine L. Pogue-Geile, Thierry Andre, Nan Song, Corey Lipchik, Ying Wang, Rim S. Kim, Huichen Feng, Patrick Gavin, Jean-Luc Van Laethem, Ashok Srinivasan, Tamas Hickish, Samuel A. Jacobs, Josep Tabernero, Peter C. Lucas, Aimery De Gramont, Norman Wolmark, Jean-François Flejou, Soonmyung Paik
Journal: Journal of Clinical Oncology (2019)

3503 Background: MOSAIC and C-07 showed that oxaliplatin (OX) added to 5-fluorouracil plus leucovorin significantly improved disease free survival (DFS). However, OX is associated with neurotoxicity and the vast majority of patients do not receive OX-benefit; highlighting the importance of an OX-benefit predictor. In C-07, colon tumors with a CRCA (Colorectal Cancer Assigner) stem-like subtype were associated with a poor prognosis and no OX-benefit, but stage III patients with an enterocyte subtype did. We tested the association of CRCA and CMS molecular subtypes with prognosis and OX-benefit in stage III MOSAIC patients. Also, recombination proficiency scores (RPS) were tested for the same associations. RPS scores quantify the efficiency of DNA-damage repair. Low RPS have been associated with inferior overall survival (OS) in non-small cell lung carcinoma patients treated with surgery alone but better OS for patients who received surgery plus chemotherapy. Methods: Gene expression profiles from 590 stage III pts with follow up were successfully profiled by a custom designed nCounter code set. CRCA subtypes were determined by a locked down algorithm based on a re-estimated centroid using 72 genes (Song et al 2016). CMS subtypes were determined by modified single sample predictor (SSP) using 84 genes. RPS scores were determined as previously described by Pitroda et al (2014). Signature predictions were made while blinded to clinical outcome and signature performance was evaluated while blinded to gene expression. Results: The stem-like subtype was associated with a very poor prognosis (Stem-like vs others HR=1.56, p&lt;0.01) and no OX-benefit. CRCA and CMS subtypes did not associate with OX-benefit. Using a median cut point, stage III patients with low RPS scores received significant OX-benefit (HR=0.67, p=0.033, N=290) and patients with high RPS scores did not (HR=1.2, p=0.32, N=300) with significant interaction p=0.025. Conclusions: The observation in C-07, that the stem-like subtype has the poorest prognosis and did not receive OX-benefit, was validated in MOSAIC, identifying patients who need new therapies. RPS scores may help to identify the subset of patients with OX-benefit in stage III CC, confirmation of this observation is currently being investigated in C-07. Support: PA DoH; NSABP; Sanofi.