tbuckley/cabot-search huggingface dataset:
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Wai Lin Thein, Aung Tun, Kyaw Zin Thein, Elizabeth Guevara
Journal: Journal of Clinical Oncology (2019)

e20558 Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemoimmunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through January 31, 2019. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Nine phase 2 &amp; 3 RCTs (Keynote – 021,189, 407, IMpower – 130, 131, 132, 150, checkmate-227, and Govindan et al) including 5042 patients with advanced NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.65 (95% CI: 0.57-0.73; P = 0.00001), the pooled HR for OS was 0.72 (95% CI: 0.61-0.86; P = 0.0003), and the pooled RR for ORR was 1.45 (95 CI: 1.23-1.72; P = 0.0001). The pooled RRs for all-grade AEs and high-grade AEs were 1.03 (95% CI: 0.99-1.07; P = 0.13) and 1.21 (95% CI: 1.1-1.34; P = 0.0001), respectively. Conclusions: The combined chemoimmunotherapy can significantly improve PFS, OS, and ORR compared to standard chemotherapy for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.
Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.
Authors: Francesca Battaglin, Shu Cao, Fotios Loupakis, Sebastian Stintzing, Aparna Raj Parikh, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Martin D. Berger, Hiroyuki Arai, Joshua Millstein, Sara Lonardi, Wu Zhang, Chiara Cremolini, Christoph Mancao, Alfredo Falcone, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

3048 Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( P FDR = 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( P FDR = 0.056), and between SLC6A3 rs6347 and OS ( P FDR = 0.041) and SLC6A3 rs6876890 and TR ( P FDR = 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.
A randomized, multicenter clinical trial to determine the efficacy and safety of pegfilgrastim (GEMA BIOTECH) compared to pegfilgrastim (Roche) for prevention of chemotherapy induced neutropenia in patients with breast cancer.
Authors: Martin Eduardo Richardet, Ruben Dario Kowalyszyn, Mirta Susana Varela, Eduardo Ortiz, Cristian Micheri, Juan Jose Zarba, Susana Kahl, Ezequiel Klimovsky, Andrea Alicia Federico, Luis Enrique Fein, Jorge Horacio Cassini, Gustavo Cortese, Florencia Visintini Jaime, Lucas Cordeiro, Nestor Ruben Lago
Journal: Journal of Clinical Oncology (2019)

3113 Background: Peg-Neutropine, GEMA BIOTECH SAU biosimilar Peg-Filgrastim, is the first Peg-Filgrastim approved in LATAM for prevention of febrile neutropenia in patients treated with myelosuppressive chemotherapy. Methods: Study population: women with stage 2, 3 or 4 of breast cancer scheduled to receive 4 or 6 cycles of chemotherapy (with Taxane) at 3 weeks interval. Stratification was based on breast cancer stage. Study drug was administered subcutaneously in a 6 mg dose. The study was blind to the assessors. The primary endpoint was Duration of Severe Neutropenia (DSN, Absolute Neutrophil Count-ANC &lt; 500/mm3) in the first cycle of chemotherapy. Secondary endpoints were incidence of severe neutropenia (SN), other efficacy measures, and incidence of ADRs. The non-inferiority margin for DSN was estimated in less than 1 day. Results: A total of 120 subjects were randomized 1:1, 58 were treated with Peg-Neutropine and 62 with Peg-Filgrastim (Roche). Efficacy: SN was developed in 52/283 (18,4%) cycles with Peg-Neutropine in 27 patients and 48/297 (16,2%) cycles with Peg-Filgrastim (Roche) in 20 patients (p=0,4836). In the first cycle, 16 patients with Peg-Neutropine and 11 patients with Peg-Filgrastim (Roche) developed SN. In per protocol analysis mean DNS in the first cycle was 0,78 ± 1,53 days for Peg-Neutropine group and 0,53±1,25 for Peg-Filgrastim (Roche) group (95% IC for the difference -0,26; 0,76). Per ITT analysis the mean DSN was 0,90±1,79 for Peg- Neutropine group and 0,50±1,21 for Peg-Filgrastim (Roche) group , (95% IC for the difference -0,15; 0,95). For all the efficacy secondary endpoints the differences were not statistically significant. Safety: 7 ADRs were developed by 3 subjects with Peg-Neutropine and 31 ADRs were developed by 10 subjects with Peg-Filgrastim (Roche). The most common reaction was myalgia, and other ADRs were arthralgia, asthenia, bone pain and acid sensitive syndrome. Conclusions: Based on the non-inferiority margin established we conclude that Peg-Neutropine is biosimilar to Peg-Filgrastim (Roche). Clinical trial information: NCT03404752.
Outcomes of men with prostate cancer managed with active surveillance and tested with clinical cell-cycle risk score.
Authors: Behfar Ehdaie, Sanjeev Kaul, Kirk Wojno, Brent Evans, Ryan Bernhisel, Stephanie Meek, Richard D'Anna, Jeffrey Ferguson, Jeffrey Glaser, Todd Matthew Morgan, Jeremy Lieb, Robert Yan, Steven Stone, Todd Cohen
Journal: Journal of Clinical Oncology (2019)

e16566 Background: The indolent nature of many prostate cancers (PC) makes some men eligible to undergo active surveillance (AS) rather than immediate definitive treatment. Accurate risk classification is critical for selection of appropriate candidates for AS. The clinical cell-cycle risk (CCR) score, a combined clinical and molecular score, provides improved prognostic information about tumor aggressiveness over clinical parameters alone. This study aimed to evaluate the clinical outcomes of men with low-risk PC by NCCN guidelines and CCR score who selected AS. Methods: This study retrospectively reviewed men with localized PC who received CCR testing (2013-2017) and had low-risk disease according to NCCN guidelines and CCR score (N = 664). Low-risk by CCR score was defined as having a risk of disease-specific mortality &lt; 3.2%. Men selected AS (no definitive treatment within 6 months of diagnosis) or underwent immediate definitive treatment. Durability of AS was evaluated beginning from diagnosis. Clinical outcomes were determined by reporting adverse events (biochemical recurrence (BCR), progression to metastasis as confirmed by radiographic imaging, prostate cancer specific mortality). Results: In this study, 547 men (82%) selected AS (median follow-up time 2.2 years [1.5, 3.1]). Of those managed by AS, two (0.4%) men experienced an adverse event. One man experienced BCR 3.7 years after diagnosis, and the other experienced metastasis 0.9 years after diagnosis. There were no reported cases of disease-specific mortality. The probability of remaining on AS for 3 years was 69.6%. Common reasons for exiting AS were patient choice (27.1%), increase in Gleason score (23.3%), and change in prostate specific antigen (PSA) (10.5%). Of those patients that left AS due to change in PSA (N = 14), only 4 exhibited a clinically significant increase in PSA ( &gt; 10 ng/mL). Conclusions: The majority of men with molecularly-confirmed (CCR), NCCN low-risk PC selected AS in both academic and community settings. The incidence of metastatic disease or BCR after definitive treatment for disease progression was rare. The majority of men who selected AS remained on AS for the duration of the study.
Use of a clinical trials screening tool in the NCI Community Oncology Research Program (NCORP) to enhance accrual and promote disparities research.
Authors: Diane C. St. Germain, Troy Budd, Worta J. McCaskill-Stevens
Journal: Journal of Clinical Oncology (2019)

e14587 Background: Despite the identification of multiple patient, clinician, and health systems barriers, accrual to a new generation of cancer clinical trials continues to present challenges. It may be that barrier data is not sufficiently granular. A clinical trial screening tool was developed for use in NCORP to collect trial- and site-specific information as well as broadened demographic data to determine factors that may impact accrual. Methods: The tool was developed with stakeholder input and the NCI Oncology Patient Enrollment Network was used for data input and analyses. Results: From February 2016 to December 2019, 14,340 entries were made in the screening tool. Eighty-two percent of participants consented to participate. Participants screened were female (77%), married (64%) and Caucasian (85%). Fourteen percent of the participants were racial minorities (1% not reported) and 5% were Hispanic or Latino. The mean age was 60 (range 1-95). Thirty-six percent were employed, ≥ 32 hours per week followed by 35% retirees. Income did not vary significantly ( &lt; $25,000(16%), $25,000 - $50,00 (20%), $51,000 - $10,000 (26%), and &gt; $100,000 (19%), and 19% of participants refused to provide income data. Four percent of the participants were uninsured at diagnosis. Seventy-two percent (8,501) of participants screened enrolled in a clinical trial. Of those not enrolled, 49% were ineligible and 48% were eligible but declined to participate. The most common reasons for ineligibility included concurrent disease, abnormal lab or other tests, and patient could not comply with eligibility criteria. The most common reasons eligible participants declined to participate were perception that toxicities were too great and social issues (child care, transportation). Further analysis of the data will include correlation of race/ethnicity, age, income and co-morbidities with enrollment status. Conclusions: The majority of participants approached agreed to participate in the screening tool protocol. Approximately half of the participants were eligible for a trial but declined to participate. These issues will be addressed within the network to enhance accrual. The data collected will also provide opportunities for investigators within the network to develop research questions focused on disparities and clinical trial accrual.
Effect of oligometastatic disease management with stereotactic body radiation therapy on survival in patients with metastatic lung cancer.
Authors: Luis E. Raez, Ana Botero, Miguel Castillo, Ignacio Castellon, Brian Hunis, Aaron Falchook
Journal: Journal of Clinical Oncology (2019)

e13582 Background: Overall survival (OS) of metastatic non-small cell lung cancer (NSCLC) patients (pts) is improving with the development of targeted therapies (TARGET) and immunotherapy (IMMUNO), however is limited by disease progression (PD) which necessitates a change in systemic therapy. Stereotactic body radiation therapy (SBRT) can allow NSCLC pts to stay longer with the same therapy by eliminating oligometastatic progression (OMP) improving progression free survival (PFS) and OS. Methods: 100 pts with metastatic NSCLC undergoing chemotherapy (CHEMO), IMMUNO or TARGET that had OMP defined as less than 4 sites of metastasis and underwent SBRT were evaluated for PFS and OS. PFS1: Time between initiation of systemic therapy and development of OMP. PFS2: Time between OMP treated with SBRT and development of further PD requiring a change in systemic therapy. Pts received IMMUNO for second line and beyond. Robotic SBRT was delivered in 1-5 fractions on consecutive days or every other day. SBRT doses were determined based on the disease site and dose tolerance of the adjacent organs. Results: Brain metastasis (BM) were seen in 45 pts and 55 pts had extracranial metastasis (EM). 34 pts were receiving CHEMO, 34 Target and 32 IMMUNO at the time of OMP. Main endpoints (m) are shown (Table) Pts with BM that received SBRT were able to continue the same therapy for a period of 6.5-9 extra months due to the control of BM. Pts with EM that have developed PD were able to continue the same therapy 17-21 extra months due to the ablation of OMP by SBRT. Overall PFS was: 16.5m for BM and 34m for EM and the OS were: 31m and 53m respectively. Conclusions: Substantial prolongation was observed in PFS/OS compared with historical controls thanks to the use of SBRT in pts that develop OMP while on systemic therapy. SBRT allowed patients to continue with the same systemic treatment. Our CHEMO cohort is composed of long term survivors under therapy and may not represent the average PFS/OS of pts on CHEMO. Survival data from prospective trials will be essential in determining the value of this resource-intensive treatment.[Table: see text]
Impact of invasive regional lymph node examination (IRLNE) and time to radiation on overall survival for patients with stage I NSCLC treated with SBRT- a NCDB analysis.
Authors: Pradnya Dinkar Patil, Wei (Auston) Wei, Nathan A. Pennell
Journal: Journal of Clinical Oncology (2019)

e20041 Background: SBRT is the standard of care for patients (pts) with early stage NSCLC who are not surgical candidates due to co-morbidities. Current NCCN guidelines state that IRLNE prior to definitive treatment for stage IA NSCLC is optional. Performing SBRT without IRLNE may increase the risk for occult nodal metastasis that could lead to regional recurrences and impact survival, however small retrospective studies have failed to demonstrate any benefit of IRLNE. Prior studies have also shown that delay in time to surgery impacts survival in stage 1 NSCLC pts, and due to co-morbidities SBRT pts are more likely to have a delayed time to radiation. However, the impact of time to radiation on OS in such pts is not well defined. Methods: We queried the NCDB for pts with stage 1 NSCLC treated with SBRT diagnosed from 2004 to 2014. We identified whether regional lymph nodes were examined for these pts. In addition, we obtained data regarding other clinicopathologic and treatment associated variables. Kaplan Meier method was used for survival analysis. Cox proportional hazards model was used to assess the impact of the co-variates on OS. Results: We identified 15,338 pts with stage 1 NSCLC treated with SBRT. Of these, 943 pts had IRLNE. Median age was 75 years (range 26-90) and Charlson-Deyo score was ≥ 1 in 6,427 pts. Median OS was 35.4 months (95% CI 34.6-36.2 months). The median time to radiation from diagnosis was 57 days. In a multivariate analysis, there was no impact of IRLNE on OS. Other clinicopathologic variables that impacted OS are listed in the table. A delay in initiation of radiation was associated with significantly worse OS. Conclusions: Invasive staging prior to SBRT for stage I NSCLC does not impact OS. A delay in initiating definitive radiation adversely affects survival in this population and the risk is incremental per week delay. [Table: see text]
The 55 STAR study: Prognostic and predictive value of the 55-gene classifier (55GC) in stage III colon cancer.
Authors: Toshiaki Ishikawa, Eiji Oki, Eiji Shinto, Mototsugu Shimokawa, Shigeki Yamaguchi, Megumi Ishiguro, Seiji Hasegawa, Yasumasa Takii, Hideyuki Ishida, Tetsuya Kusumoto, Masaru Morita, Naohiro Tomita, Manabu Shiozawa, Masafumi Tanaka, Heita Ozawa, Yojiro Hashiguchi, Shinobu Ohnuma, Sachiyo Tada, Tomoko Matsushima, Kazuo Hase
Journal: Journal of Clinical Oncology (2019)

3597 Background: Patient prognosis can be predicted based on cancer subtypes classified according to DNA microarray results. The most robust classification system involves the consensus molecular subtypes, which uses over 600 genes for classification. To simplify this classification, we recently constructed a 55-gene classifier (55GC) to classify colon cancer (CC) into three subtypes with different recurrence rates: “microsatellite instability (MSI)-like,” “chromosomal instability (CIN)-like,” and “stromal” colon cancers. The 55GC has been reported to be a useful and reproducible grading system for stage II CC recurrence risk stratification. This study aimed to explore the usefulness of 55GC for classifying stage III CC patients. Methods: We retrospectively identified stage III CC patients aged 20-79 years who underwent curative surgery and received adjuvant chemotherapy with or without oxaliplatin (OX) between 2009 and 2012 from 15 institutions. Propensity score matching was used to adjust for the number of lymph node metastases, tumor location, sex, and age. Results: Among 938 eligible patients, 203 and 201 cases involving adjuvant chemotherapy with and without OX were selected, respectively, using propensity score matching. Ninety-five cases each from groups were analyzed after exclusion of cases involving low-quality specimens and those involving chemotherapy for &lt; 3 months. The 5-year relapse-free survival (RFS) in patients receiving adjuvant chemotherapy with and without OX were 77.1% and 73.7%, respectively. Classification of the stage III CC according to 55GC and related 5-year RFS rates were as follows: stromal (N = 60), 66.6%; CIN-like (N = 78), 80.5%; and MSI-like (N = 52), 78.4%. The HRs for 5-year RFS for adjuvant chemotherapy with and without OX in each subtype were as follows: stromal, HR = 0.791 (95% CI = 0.329-1.901); CIN-like, HR = 1.241 (95% CI = 0.465-3.308); and MSI-like, HR = 0.495 (95% CI = 0.145-1.692). Conclusions: The stromal subtype showed poor prognosis in stage III as well as stage II patients. Oxaliplatin had a good additive effect in adjuvant chemotherapy for MSI-like subtype. The 55GC is useful for predicting the efficacy of adjuvant chemotherapy for CC.
Expression of tryptophan metabolizing enzymes (TMEs) and its transporter, LAT1, in metastatic melanoma (MM): Prognostic and therapeutic implications.
Authors: Dimitri G. Trembath, Paul B. Googe, Jill S. Frank, Madeline H Kowalski, Marcus Spearman, Taylor Marie Lagler, Jennifer Ashley Ezzell, Nancy E. Thomas, David W. Ollila, Stergios J. Moschos
Journal: Journal of Clinical Oncology (2019)

e21014 Background: The ECHO-301/KEYNOTE-252 trial failed to show clinical benefit of adding epacadostat to pembrolizumab in PD-1 inhibitor-naïve MM. We reasoned that the expression of other TMEs and/or LAT1 by melanoma cells plays a more important role. Methods: Melanoma tissues from stage III/IV pts were stained for the 4 TMEs (TPH1, TPH2, TDO2, IDO1) and LAT1 by single-color immunohistochemistry. Tissues were scored for the status of tumor-infiltrating lymphocytes (TILs) and the expression of 5 proteins separately in melanoma cells and TILs (if present). Association between protein expression, TIL status, and melanoma-specific overall survival was performed. Results: Tissues from 87 pts (stage IV, n = 25) were available. Expression of all 4 TMEs and LAT1 was significantly higher in melanoma cells compared to TILs ( p&lt; 0.001); TPH1, TPH2, and TDO2 expression in melanoma cells was significantly higher than IDO1 (p &lt; 0.001). Lower TPH1 expression in melanoma cells was associated with presence of TILs. Multivariate analysis using a Cox proportional hazards model that included expression of the 5 proteins in melanoma cells showed that high IDO1 was a favorable and high LAT1 expression was an adverse prognostic factor. Conclusions: Expression of TMEs and LAT1 by melanoma cells may have more important role in metastatic melanoma by depleting an essential amino acid from the tumor microenvironment. Pharmacologic targeting of TPH1/TPH2 (e.g. telotristat) may be more clinically relevant in MM as opposed to IDO1 inhibition.