tbuckley/cabot-search huggingface dataset:
Therapeutic drug monitoring of nivolumab in clinical practice: Preliminary experience.
Authors: Manuel Sureda, Ana Catalán-Latorre, Juan José Mata, Vanesa Escudero, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2019)

e14089 Background: Fixed dose schemes, regardless of body weight, have been accepted by the regulatory agencies for the PD-1 targeting antibodies. Zaho X. and Ratain M. have elucidated that the mean steady state concentrations of nivolumab (N) at flat-doses of 240 mg Q2W or 480 mg Q4W were 57 µg/mL and 47 µg/mL, respectively. These levels are very similar to those observed at the dosage of 3 mg/kg Q2W. Considering the long half-life of N, its mechanism of action and the absence of correlation between exposure and response or toxicity at clinically tested doses, other schemes can be explored. Moreover, therapeutic drug monitoring (TDM) can contribute to individualize and optimize dosage. We determined serum N levels in patients with solid tumors. Methods: The PK profile of N was analyzed in 15 patients with solid tumors who received 3 mg/kg Q2W from May 2017 through January 2019. Eligible patients had non-small-cell lung cancer (n = 7), urothelial cancer (n = 1), gastric cancer (n = 1), breast cancer (n = 1), renal cell cancer (n = 1), colorectal cancer (n = 1), prostate cancer (n = 1), melanoma (n = 1) and sarcoma (n = 1). Free N serum concentrations were determined with a quantitative ELISA capable of detecting ≥ 0.3 µg/mL (Shikari Q-Nivo, Matriks Biotek, Ankara, Turkey). A total of 28 TDM were done after steady state (6th and 26th cycle). Results: For different reasons, 9 patients received N at 3, 4, 5, 6 or 7 week intervals once the steady state was reached. In these patients, a median reduction of 20.8% (6.7% - 43.0%) of the received doses was observed. Mean plasma concentrations of N observed after administration every 2 weeks was 73.5±32.5 µg/mL (n = 9). Once the steady state was reached, mean plasma concentrations at 3, 4, 5, 6 or 7 weeks, were 54.0±1.3 µg/mL (n = 2), 45.1±25.3 µg/mL (n = 7), 42.9±29.5 µg/mL (n = 5) and 24.4±11.7 µg/mL (n = 5), respectively. No statistically significant differences were observed in the serum levels of N between the dosing intervals of 3, 4 and 5 weeks and the standard regimen (Q2W) (p &gt; 0.05). These data are similar to those described by Long G.V. et al. that compared N pharmacokinetic exposure for the 480 mg Q4W schedule simulated in 3817 patients across multiple tumor types with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. Conclusions: The incorporation of the TDM of N in routine clinical practice could help to maintain a therapeutic drug plasma concentration with lower or less frequent doses, adding a financial benefit, without decreasing clinical efficacy. Further randomized trials to explore alternative dosing schemes of N, including personalization through TDM, are warranted
Comparison of enzalutamide versus abiraterone in castration-resistant prostate cancer before docetaxel: Results of a propensity score-matched analysis.
Authors: Marcelle Goldner Cesca, Maysa Tamara Silveira, Natasha Carvalho Pandolfi, Thiago Bueno Oliveira, José Augusto Rinck, Alexandre Andre B. A. Da Costa, Marcelo Corassa, Maria Nirvana Formiga, Aldo A. Dettino
Journal: Journal of Clinical Oncology (2019)

e16540 Background: Metastatic castration-resistant prostate cancer (mCRPC) phenotype involves androgen-receptor signalling mechanisms that support the use of enzalutamide (EZ) and abiraterone (Abi). These therapies improve overall survival (OS) and quality-of-life, with a favourable safety profile. There is no validated data defining the best drug or sequence to be used. Methods: A retrospective cohort of mCRPC patients (pts) was analysed at AC Camargo Cancer Center. The primary objective was to compare progression-free survival (PFS) and OS in patients treated with EZ or Abi as first line (docetaxel naïve pts). Kaplan-Meier, Log-Rank Test and Cox Regression were used for survival analysis. To address unbalanced characteristics between the two treatment groups treatment efficacy was compared in a propensity score matched cohort. Results: From May, 2002 to September, 2017, 120 pts were treated with Abi (84%) or EZ (36%). Median follow-up was 21.2 months. Median age at diagnosis was 66 (48-84), the majority were Gleason score 7 (34%) and median baseline PSA was 14. Median PFS was 17.4 months in EZ and 10.6 months in Abi group (HR = 0.65; 95%CI: 0.39-1.10; p = 0.11). Median OS was not reached and 31.6 months for EZ and Abi, respectively (HR = 0.60; 95%CI: 0.27-1.36; p = 0.22). EZ was associated with a better PSA response in the first 4 months of treatment (p &lt; 0.001). Independent prognostic factors for worse OS and PFS were ECOG ≥ 1, treatment toxicity ≥ G1 and lower PSA doubling time before treatment and for better OS and PFS were PSA response in the first 4 months and alkaline phosphatase and lactate dehydrogenase response at any time. In the propensity score matched cohort including 72 patients PFS was better in EZ group (HR = 0.36; 95%CI: 0.20-0.64; p &lt; 0.001) but there was no difference in OS (HR = 0.66; 95%CI: 0.27-1.63; p = 0.37). Conclusions: EZ was associated with prolonged PFS and better PSA response, with no OS improvement when compared with Abi for mCRPC before docetaxel, in a propensity score matched analysis.
Moving away from the boilerplate: Real-world evidence for clinical trial laboratory criteria.
Authors: David Hadley, William Jeffery Edenfield, Debra A. Kientop
Journal: Journal of Clinical Oncology (2019)

e14581 Background: There is a need to enable as many suitable patients onto clinical trials in oncology, that are also representative of patients seen in clinical practice. Currently, oncology trials often require patients to have minimum laboratory tests for hematology and liver function amongst others. We compared the real-world laboratory results and clinical information in TransMed’s patient repository against the requirements of a set of clinical trials to assess patient eligibility retrospectively. Methods: Industry-sponsored clinical trials for follicular lymphoma which started in 2018 were retrieved from the U.S. National Library of Medicine’s clinical trials website. We aimed to find the most common set of diagnosis inclusion criteria and the range of platelet requirements to those observed from real-world data. TransMed’s patient data was collected from its consortium of 205 clinical sites, which includes a variety of source systems at each site, such as electronic medical record systems and laboratory information management systems among others. Results: There were 16 trials which matched our criteria. The most common trial inclusion criteria were for grades 1-3a, progression after at least one line of therapy, and a platelet count &gt; 75 x10 -9 /L. We found 53 retrospectively-eligible patients who would have met the trial’s main criteria when the patient was between therapies in 2018. At some point within 90 days before starting another therapy, 9% (5/53) of patients failed the requirement for platelet count. Among those, 40% (2/5) were within a 10% drop in the required threshold. Conclusions: We have presented an exemplar combination of cancer diagnosis with a single laboratory test and found patients who could be considered for trials though are deemed ineligible due to a narrowly-missed requirement. Many such tests vary over time, by cancer type, prior treatment, comorbidities and should be considered in the context of other test results. By using real-world evidence at the time of trial design, clinical trials can be optimized to allow improved patient recruitment and expanded availability to patients while ensuring clinical suitability.
The landscape of <i>RET</i> alterations from 56,970 adult patients with cancer: Clinical implications.
Authors: Alexander Andreev-Drakhlin, Jason Roszik, Vivek Subbiah
Journal: Journal of Clinical Oncology (2019)

3106 Background: Activating receptor-tyrosine kinase rearranged during transfection ( RET) mutations and fusions have been recognized as potent drivers of oncogenesis. Recent identification of highly potent and selective RET inhibitors holds great promise in the management of RET-dependent tumors. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Methods: We analyzed 59,347 samples from 56,970 patients available from AACR Project GENIE (Cancer Discov. 2017) database for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types. Results: A total of 1414 RET alterations were detected, including 91 fusions (6.4%), 1166 missense mutations (82.5%), 136 truncating mutations (9.6%), and 21 in-frame mutations (1.5%). RET fusions were observed in 0.15% of tumor samples and were most commonly identified in non-small cell lung cancer, thyroid cancer, colorectal cancer, prostate cancer, and gastric cancer (62.6%, 18.6%, 5.5%, 4.4%, 3.3% of identified RET fusions, respectively). RET fusions were significantly co-altered with MAPK3/ERK1 (p=0.045), SETD2 (p=1.36E-07 ), and EIF4E (p=0.045), while there was a negative association between RET fusions and EGFR (p=0.009634) , TP53 (p=0.02267), and KRAS (p=2.53E-05) alterations. Most common RET gene upstream partners were KIF5B, CCDC6, and NCOA4 (42.9%, 24.2%, 7.7% of identified RET fusions, respectively). RET missense mutations were found in 2.0% of tumor samples; 136 (11.7%) of identified missense mutations, including 8 RET gatekeeper V804M/L mutations, were characterized as likely oncogenic, 12 (1.0%) as likely benign, and 1018 (87.3%) as variants of unknown significance using OncoKB database. RET amplifications occurred in 1.5% of tested samples. Conclusions: While RET fusions represent extremely rare events in multiple cancers, RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted. MAPK pathway co-alterations in patents with RET fusions may present a strategy for future therapeutic combinations.
A phase II study of lenvatinib in patients with metastatic colorectal cancer refractory to standard chemotherapy: LEMON study (NCCH1503).
Authors: Hirokazu Shoji, Satoru Iwasa, Aya Kuchiba, Gakuto Ogawa, Mamiko Kawasaki, Kenichi Nakamura, Mikio Mori, Yoshitaka Honma, Atsuo Takashima, Ken Kato, Narikazu Boku, Natsuko Okita, Yasuhide Yamada
Journal: Journal of Clinical Oncology (2019)

3538 Background: Although regorafenib significantly improved overall survival compared with placebo for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies in the global phase III CORRECT trial, regorafenib is often discontinued due to toxicity. Lenvatinib is an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptors α, RET, and KIT, showing receptor inhibition profile and kinetics different from regorafenib. This phase II study was conducted to evaluate the efficacy and safety of lenvatinib in patients with mCRC refractory to standard chemotherapies. Methods: mCRC patients with measurable lesions, PS 0-1, and refractory to standard chemotherapies including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab (if RAS wild-type), and TAS-102 (trifluridine/tipiracil) were eligible. Prior treatment with regorafenib was not allowed. Patients received lenvatinib orally at a dose of 24 mg once daily in 28-day cycles until unacceptable toxicity or disease progression. The primary endpoint was disease control rate (DCR) assessed by independent central review. Secondary endpoints included safety, response rate, progression-free survival (PFS), and overall survival. The planned sample size was 30 patients to expect a DCR of 60% with a threshold DCR of 35%, one-sided alpha of 5% and power of 80%. Results: Between October 2016 to January 2018, 30 patients were enrolled. All had received prior chemotherapy; 14 (47%) and 16 (53%) had received 3 or ≥ 4 prior lines for advanced disease, respectively. The median number of lenvatinib cycles was 4 (range 1-13). Two patients achieved partial response and 19 patients had stable disease, resulting in a response rate of 6.7% and DCR of 70.0% (95% CI: 50.6-85.3%). Median PFS was 3.6 months (95% CI: 2.6-3.7). The most common grade ≥ 3 adverse events were hypertension (53%), elevated serum aspartate aminotransferase (13%), thrombocytopenia (10%), and anorexia (7%) without unexpected safety signals. Conclusions: Lenvatinib showed promising antitumor activity with acceptable toxicity for patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000023446.
Inflammatory biomarkers as pronostic factors of mortality in critical ILL oncology patients at ICU.
Authors: Carlos Aliaga Macha, Thanya Runciman, Carlos F. Carracedo
Journal: Journal of Clinical Oncology (2019)

e14535 Background: Inflammatory markers have been used as prognostic factors in multiple malignancies.In cancer patients, critically ill, the utility of these have limited data.The aim of our study is to determine whether neutrophil lymphocyte ratio (NLR) or lymphocyte platelet ratio(PLR) are prognostic factors for mortality in critically ill patients. Methods: We retrospectively analyzed data of 79 patients with solid tumors admitted to ICU at Sanna-Aliada Clinic between January 2018 to December 2018. Inflammatory markers results were obtained from laboratory tests performed during the first 24h of admission to ICU. Receiving operating characteristic (ROC) curves were constructed and the sensitivity, specificity, predictive values and probability indicators for the NLR and PLR. Results: A total of 79 patients were assessed, 39 women and 40 men. The average age was 60.28 years, median of 61 ( 18 to 91). 51.9% had metastatic disease. The most frequent places were lung 12 (15.2 %) and brain 9 (11,4%) . The main cause for admission to ICU was infectious disease (40.5%). The analysis of normality (Kolmogorov-Smirnov test) indicates that the variables age, hemoglobin, leukocytes, platelets, neutrophils, lymphocytes, have a normal deviation while the other variables: lactate, PCR, neutrophil to lymphocyte ratio (NLR) , Platelet to lymphocyte ratio (PLR) are not distributed normally. Regarding mortality, 44 patients were alive at 30 days (66.7%), and 30 (45.5%) were alive at 90 days. The average stay in the ICU was 8.43 days, with a median of 6, (SD 7.17, 1 to 40 days), 22.8% died in the ICU. The evaluation of PLR and NLR as a mortality marker is significant for the group of patients admitted to the ICU due to a noninfectious pathology, generating an area under the curve (AUC) of 0.706 for NLR (95% CI, 0.535 - 0.876, p-value = 0.035) and 0.767 for PLR (95% CI, 0.615-0.918; p-value = 0.006); the optimal cut point by Youden’s index for NLR was 8.29 and 267.94 for PLR (Sensitivity: 76%, Specificity: 67%). In contrast, the group with infectious pathology, the AUC was 0.47 for NLR (p = 0.78) and 0.42 for PLR (p = 0.44). The relationship of the biomarkers with stay in ICU was also evaluated, finding a statistically significant association with the lactate value (p = 0.024, Kruskal-Wallis) Conclusions: Inflammatory markers are useful as predictive markers of mortality in critically ill patients due to non-infectious causes. The lactate value serves as a predictive factor of stay in the ICU for all the patients. We suggest carrying out prospective studies to confirm the validity of our findings.
Evaluating the impact of cancer awareness months in Mexico using internet search engine analytics.
Authors: Jorge Humberto Hernandez-Felix, Mónica Isabel Meneses Medina, Edgar Omar Martos Armendariz, Mauricio Rivera Aguilar, Vanessa Rosas Camargo, Fidel David Huitzil Melendez
Journal: Journal of Clinical Oncology (2019)

e18056 Background: Cancer awareness months (CAM) are a health promotion tool that pursues to increase the public knowledge of a specific type of cancer. Awareness campaigns have benefited from the ease of access to the internet and social media. Analysis of internet search data has been used as an indirect tool to determine the information-seeking patterns of people and may reflect the impact of a campaign. We aim to determine national cancer awareness months’ impact on people’s internet search habits focusing on malignancies that have a specific awareness month in Mexico: breast, colorectal and prostate. Methods: We used Google Trends (GT) to obtain search volume indexes (SVIs), a term designed by GT scaled from 0 to 100 based on total searches during a specified period, of malignancies with an awareness month in Mexico from January 2008 to December 2018. Terms were consulted in Spanish: "cáncer de mama" (breast cancer), "cáncer de colon + cáncer colorrectal" (colon + colorectal cancer), "cáncer de próstata" (prostate cancer). We compared mean SVIs from each cancer awareness month to mean SVIs from the rest of the year using two-tailed two-independent sample T-tests. For prostate and colorectal, SVI’s were compared from the year its CAM was nationally instituted. Results: For breast cancer, mean SVI from October, its awareness month was 54.18 vs 12.09 for the rest of the year (p &lt; 0.001). For colorectal cancer, mean SVI from its awareness month March, was 65.0 vs 55.5 for the rest of the year (p = 0.34). For prostate cancer, mean SVI from November, Mexican prostate awareness month, was 72.0 vs 35.52 for the rest of the year (p = 0.44). Conclusions: Google’s search volume for breast cancer was significantly higher in its awareness month compared to the rest of the year, which proves the impact of its CAM on modifying online activity. For more recently instituted CAMs on prostate and colorectal cancer, search volume didn’t change significantly between their CAM and the rest of the year. There are perhaps lessons to be learned from the breast cancer awareness month campaign which might usefully be adapted for the highest incident malignancies in Mexico.
Mucosal melanoma of the female genital tract: Operation modalities.
Authors: Xuan Wang, Chuanliang Cui, Bin Lian, Li Zhou, Zhihong Chi, Lu Si, Xinan Sheng, Yan Kong, Lili Mao, Xieqiao Yan, Bixia Tang, Jun Guo
Journal: Journal of Clinical Oncology (2019)

e21060 Background: Primary melanomas originating from the female genital tract are rare and aggressive. There are still no established guidelines for its primary surgery , so we analyzed the effect of the surgical approach on its relapse free survival (RFS) and overall survival (OS ) based on a phase 3 randomized trial (NCT03435302). Methods: Mucosal melanoma patients with female genital tract primary which were stageⅠ-Ⅲ and completely resected were enrolled as part of the multicenter, randomized, controlled, phase 3 trial for the comparison of adjuvant chemotherapy (TMZ plus DDP 6 cycles) vs. High-dose interferon group (HDI, 1 year).The RFS and OS was compared between local and extensive excision group. Results: Seventy eight female genital tract primary melanoma patients were enrolled from Feb 2014 to Jun 2016, Surgical approach was chosen by the surgeon, 39.2% (29/74) took local excision and 60.8% (45/74) extensive excision. The average age was 52.3 years. Of all these patients 46.2% were vulvar primary, 53.8% vaginal, and 85.3%stage I/II, 14.7% stage III. Primary ulceration was found in 68.1% lesions, 7 cases harbored with BRAF mutation. 57.7% patients randomized to adjuvant chemotherapy and 42.3% in HDI group. All these factors showed no difference in local excision and extensive excision group. At a median follow-up of 31.2 months (range: 5.3-60.0m), 64.4% got metastases and 23.1% showed local recurrence. RFS (8.0m vs. 11.4m, p = 0.523) and local recurrence rate (13.8% vs.31.1%, p = 0.105 ) did not show significant difference between local excision group and extensive excision group. OS in whole cohort was 28.9 months, it also did not show significant difference between two groups(local 25.5m vs. extensive 40.1m, p = 0.653). In univariate analysis there was also no relation between surgical approach and OS in this cohort. Conclusions: Based on this trial, for resectable female genital tract primary mucosal melanoma, there was no difference of local control rate, RFS and OS between local excision and extensive excision group. Local excision might be adequate for the primary leision. Still more prospective data are needed for this subtype of melanoma. Clinical trial information: NCT03435302.
Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.
Authors: Lisa Butler, Swati Irani, Margaret Centenera, Natalie Ryan, Neil Pegg, Anthony Nigel Brooks
Journal: Journal of Clinical Oncology (2019)

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of &gt; 90% compared to vehicle control; p &lt; 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.