tbuckley/cabot-search huggingface dataset:
Clinical outcomes in patients with baseline renal dysfunction in the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors.
Authors: Jonathan R. Strosberg, Edward M. Wolin, Beth A. Chasen, Matthew H. Kulke, David L Bushnell, Martyn E. Caplin, Richard P. Baum, Timothy J. Hobday, Andrew Eugene Hendifar, Laura Ravasi, Kjell E. Oberg, Philippe B. Ruszniewski, Eric Krenning
Journal: Journal of Clinical Oncology (2018)

4102 Background: Might potential nephrotoxicity be a risk for therapy with 177Lu-Dotatate? Among patients randomised in the NETTER-1 study, nephrotoxicity and treatment efficacy were evaluated in the two study arms (177Lu-Dotatate (177Lu) vs. high-dose octreotide (Oct)) according to renal function categories at baseline (no dysfunction eCrClC-G ≥ 60 ml/min vs. mild dysfunction eCrClC-G = 50 – 59.99 ml/min vs. moderate dysfunction eCrClC-G < 50 ml/min). Methods: Changes in renal function were assessed in the two arms per the three baseline categories, and analysed via Fisher’s exact test. The primary endpoint of the NETTER-1 study, progression-free survival (PFS), was evaluated after classifying the patients according to the baseline renal function categories (impaired vs. normal at baseline). Results: There were 93 patients with normal renal function, 11 with mild baseline renal dysfunction and 13 patients with moderate dysfunction in the 177Lu arm. Equivalent numbers were seen in the Oct arm (85 with normal function, 16 with mild and 9 with moderate dysfunction; p = 0.41825 for imbalance between the two study arms). The rates of deterioration of renal function over baseline in the two treatment arms for each of the three categories of baseline renal function, were similar (p = 0.70695; 1.0000; 1.000, respectively). In patients with no renal impairment at baseline, Kaplan-Meier analysis showed a greater PFS (p < 0.0001 log-rank test); HR 0.180 [95% CI: 0.102 – 0.318] within the patients treated with 177Lu vs. those treated Oct. In those with renal impairment at baseline, Kaplan-Meier analysis showed a greater PFS (p < 0.001 log-rank test); HR 0.251 [95% CI: 0.084 – 0.751] among the patients treated with 177Lu (N = 23) compared to those treated with Oct (N = 24). Conclusions: The NETTER-1 study did not show any evidence of nephrotoxicity associated with 177Lu treatment, even in patients with mild to moderate baseline impairment in renal function. Long-term analysis of renal function will be performed at time of overall survival analysis. Treatment with 177Lu resulted in a markedly longer PFS regardless of whether baseline renal function was normal or impaired.
Outcome of KRAS mutated (m) non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (immuneCI).
Authors: Nuria Pardo Aranda, Cristina Viaplana, Jordi Remon, Alex Martinez Marti, Susana Cedres Perez, Alejandro Navarro, Ana Maria Martinez de Castro, Guillermo Villacampa, LLuisa Carbonell, Alberto Hernando, Ana Vivancos, Rodrigo Dienstmann, Enriqueta Felip
Journal: Journal of Clinical Oncology (2017)

e20526 Background: The most frequent genetic alteration in advanced NSCLC is KRASm in ~25% of tumors. This event associates with smoking pattern and high mutational burden, which correlate with the efficacy of CI in NSCLC. There is in silico evidence that coexisting KRASm and TP53m positively impact immuneCI benefit , but this association needs clinical validation. Methods: We retrospectively assess the efficacy of PD-1/PDL-1 CI (atezolizumab, pembrolizumab, nivolumab or durvalumab) in a cohort of NSCLC patients whose tumors were KRASm (with or without coexisting TP53m) as assessed by a next-generation sequencing test. Endpoints were clinical benefit rate (CBR), defined as partial response or stable disease &gt; 4 months (m), and time to progression (TTP) on immuneCI. Fisher-exact test and log-rank test P values are described. Results: 25 pacients were identified, 68% female, median age 54 y (33-75), 95% former/current smoker; 95% adenocarcinoma; 59% with 2 or more metastatic sites; 36% immuneCI as third-line or beyond (median time from first-line to immuneCI of 7.5 m). 20 tumors had KRASm in codon 12, 3 codon 13 and 2 in codon 61. Overall, CBR was 36% (CI95% 19%-57%) and median TTP was 3.7 m (CI95% 2.2-NA). Coexisting KRASm/ TP53m (n = 11) did not associate with higher CB (27% vs 50%, p = 0.56). A trend for lower TTP in the KRASm/ TP53m vs TP53 wild-type was observed (2.1 vs 5.6 m, HR 0.3; p = 0.11). Conclusions: NSCLC patients whose tumors are KRASm can have substantial benefit with immuneCI. In our series, the population with KRASm/ TP53m tumors did not derive higher clinical benefit from this therapeutic intervention
Retrospective analysis of prognostic factors for survival in metastatic castration-resistant prostate cancer patients (mCRPC) treated with abiraterone.
Authors: Krisztina Biro, Barna Budai, Marta Szonyi, Istvan Bodrogi, Zsofia Kuronya, Fruzsina Gyergyay, Krisztian Nagyivanyi, Lajos Geczi
Journal: Journal of Clinical Oncology (2016)

e16504 Background: The COU-AA-301 trial showed that abiraterone, an oral inhibitor of cytochrome p450 CYP17, improved survival in mCRPC patients progressing after docetaxel. Methods: Our first patient started abiraterone treatment on April 21, 2011 in an early-access protocol trial (NCT01217697). After October 8, 2012 abiraterone became generally available in Hungary. From April 21, 2011 to November 05, 2014 117 patients received abiraterone. 48 patients were treated in the clinical trial until PSA, radiographic, and clinical progression. In the non-clinical trial group (n = 69) the treatment was covered until PSA and radiographic progression. The two groups were statistically homogeneous in every other major aspect. Treatment outcomes and adverse events were evaluated and the groups compared. Results: The mean age was 70.3 (48-90) years. 75 patients received abiraterone as second-line after docetaxel, while 42 patients were treated in third- or forth-line. Median overall survival (mOS) was 18.4 months (95% CI, 11.8-24.2) and 15.8 months (95% CI, 13.6-18) for the trial and non-trial patients, respectively. The difference was statistically significant (P= .021). Other factors that significantly affected mOS were age ( < vs. ≥ 75 years, P= .002), lymphocyte/neutrophil ratio (LNR) ( < vs. ≥ 0.45, P= .003), prior lines before abiraterone (one vs. more, P= .026), PSA decline at 3 months (yes vs. no P= .043). Gleason score, length of hormonal treatment before docetaxel, and presence or absence of visceral metastases had no effect on mOS. With multivariate COX regression analysis LNR (P= .01), lines prior abiraterone (P= .02), and trial vs. non-trial survey (P= .04) were independent factors of mOS. The treatment was well tolerated; drug related grade 3-4 toxicities occurred in 8% of patients. Conclusions: In our retrospective analysis, LNR, number of previous chemotherapy regimens, and treatment beyond PSA and radiographic progression until clinical progression proved to be independent prognostic factor of longer mOS.
A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).
Authors: Phuoc T. Tran, Ryan Phillips, William Shi, Su Jin Lim, Emmanuel S. Antonarakis, Steven P. Rowe, Ashley Ross, Michael A. Gorin, Curtiland Deville, Stephen C. Greco, Channing Judith Paller, Theodore L. DeWeese, Daniel Y. Song, Hao Wang, Michael Anthony Carducci, Kenneth J. Pienta, Martin Pomper, Adam P. Dicker, Mario A. Eisenberger, Maximilian Diehn
Journal: Journal of Clinical Oncology (2020)

116 Background: Mounting evidence supports metastatic ablation for oligometastatic prostate cancer (OMPC). Importantly, biomarkers to determine patients who benefit most from complete ablation are unknown. We hypothesize that stereotactic ablative radiation (SABR) will improve oncologic outcomes in men with OMPC. Methods: In this phase II randomized trial, men with recurrent hormone-sensitive OMPC (1-3 radiation fields) were stratified by primary management (radiotherapy vs surgery), PSA doubling time, and prior androgen deprivation therapy and randomized 2:1 to SABR or observation (OBS). The primary endpoint was progression at 6 months by PSA (≥ 25% increase and ≥ nadir + 2 ng/mL), conventional imaging (RECIST 1.1 criteria or new lesion on bone scan), or symptomatic decline. Tissue, liquid and imaging correlatives were analyzed as biomarkers. Results: From 5/2016-3/2018, 54 patients were randomized. Progression at six months occurred in 19% of SABR patients and 61% of observation patients [p=0.005]. SABR improved median PFS (not reached vs 5.8 months, HR 0.30, p = 0.0023). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at six months (16% vs 63%, p = 0.006). No toxicity ≥ grade 3 was observed. T-cell receptor sequencing identified increased clonotypic expansion (p = 0.03) following SABR and correlation between baseline clonality and progression with SABR only. Analysis of circulating tumor DNA (ctDNA) and germline mutations identified a mutation profile that was associated with benefit from SABR. Conclusions: SABR for OMPC improves outcomes and is enhanced by total consolidation of disease identified by PSMA-targeted PET. SABR induces a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates. Clinical trial information: NCT02680587.
Abstract 19585: Overestimation of Functional Cardiomyopathy Disease Variants in the Human Gene Mutation Database
Authors: Kian Huat Lim, Richard Aplenc, Joseph Rossano
Journal: Circulation (2015)

Introduction: Dilated cardiomyopathy (DM), hypertrophic cardiomyopathy (HCM), and arryhmogenic right ventricular dysplasia (ARVD) have been associated with germline genetic variants. However, uncertainty exists regarding the functional impact of specific variants described in the literature. Hypothesis: We hypothesized that a substantial fraction of presumed casual variants would be identified as non-disease causing in a normal patient population. Methods: Missense variants associated with three main subtypes of cardiomyopathy were extracted from Human Gene Mutation Database Professional (HGMD). To assess the prevalence and pathogenicity of these potential disease-causing alleles, the population frequency of each variant was screened in a recently published large-scale exome database of over 60,000 whole exomes (ExAC). In addition, PolyPhen-2 was used to predict the functional impact of amino acid substitution for each missense variant. Results: In the HGMD, 1,405 missense variants were associated with cardiomyopathy, of which 25% were found in 2 or more samples in the ExAC database. Specifically 121 of 422 (28.7%) DM associated variants, 201 variants of 900 (22.3%) HCM associated variant, and 40 of 83 ARVD (48.2%) associated variants were observed in the ExAC database. Polyphen predicted 331 (23.9%) of variants as benign, 290 (20.6%) as possibly damaging, and 784 (55.8%) as probably damaging. Table 1 presents disease specific Polyphen results. Conclusions: We observed that a large proportion (25-45%) of cardiomyopathy-associated missense variants predicted as being damaging were indistinguishable from the background in ExAC. Using stringent cutoffs derived from these observations, we estimated more than 50% of previously associated cardiomyopathy variants may be non-functional or non-monogenic causes of cardiomyopathy.
Assessing outcome differences in the second line treatment of metastatic colorectal cancer (mCRC): An ARCAD analysis comparing sequence after first line trials (SAFL) and dedicated second line trials (DSLT).
Authors: Alexis Diane Leal, Fang-Shu Ou, Levi Pederson, Alberto F. Sobrero, Mace L. Rothenberg, Eric Van Cutsem, Marc Peeters, Henry C. Pitot, Cornelis J. A. Punt, Dirk Arnold, Bruce J. Giantonio, Christophe Tournigand, Shaheenah Dawood, Aimery De Gramont, Daniel J. Sargent, Axel Grothey
Journal: Journal of Clinical Oncology (2017)

3554 Background: There is considerable variability in the outcomes between second line (SL) trials in mCRC. The aim of this analysis is to compare the outcomes of patients (pts) with mCRC treated either on SAFL, with protocol defined SL treatment, or DSLT. Methods: Individual pt data was available on pts with mCRC enrolled in 1 of 10 trials (7 DSLT, 3 SAFL) in the ARCAD database. Regimens included FOLFIRI, FOLFOX, and irinotecan (IRI), since pts did not receive biologic agents in SL on SAFL. For pts on a SAFL, PFS and OS were defined as time from initiation of SL treatment to second progression (SP)/death and death, respectively. Descriptive statistics and multivariable Cox models were used to assess differences in PFS and OS. Results: 5,076 pts were included; 63% were male; median age was 62. See Table for treatment details. Pts treated on SAFL had shorter OS (0.7-1.5 months (mos&gt;) shorter) and PFS (0.6-2.6 mos shorter), compared to those treated on DSLT. These findings were statistically significant and differences in OS did not attenuate after adjustment for age, gender, and prior treatment. PFS differences in FOLFOX became insignificant after multivariable adjustment. Conclusions: There are modest differences in both PFS and OS between pts with mCRC treated on SAFL and those on DSLT, suggesting differences in these pt populations. Caution is needed when applying these data to pts, as we were unable to control for potential confounders (ECOG PS, number and sites of metastases) at initiation of SL in SAFL, which may impact outcomes. [Table: see text]
Pre-clinical assessment of rational design immuno-oncology biologics with improved therapeutic indices.
Authors: Margaret Karow, Kurt Jenkins, Miso Park, Parker Johnson, Asaul Gonzalez, Veronica Flesch, Tim Miles, Ulrich Rodeck, John C. Williams
Journal: Journal of Clinical Oncology (2018)

e15096 Background: The clinical anti-tumor immune responses demonstrated by immune checkpoint antagonists and cell-based therapies are unprecedented. However, the challenge with these therapeutic approaches is the systemic activation of the immune system leading to dose limiting immune related adverse events (irAEs). Focusing the activity of immuno-oncology agents to the tumor microenvironment is expected to overcome the limitations on dosing and efficacy posed by irAEs. We have developed and demonstrated a rational approach to efficiently design immuno-therapeutics that are locally activated by proteases in the tumor microenvironment and exhibit reduced systemic activities. Our approach, which we have termed Aklusion™, has the potential to improve the safety and efficacy of immuno-oncology therapeutics. Methods: We used anti-mouse CTLA4 antibody 9D9 and anti-mouse PD1 antibody J43 to demonstrate the benefits of localizing pharmacological activity to the tumor microenvironment. In vivo activity was characterized with syngeneic MC38 tumors in C57Bl/6 mice using tumor regression as a measure of efficacy. The potential for improved therapeutic index was evaluated using a Fluorescent Activated Cell (FAC) analysis of tumor and splenic T cell populations for anti-CTLA4. Induction of diabetes in NOD mice versus tumor eradication was used to evaluate expanded therapeutic index for the anti-PD1. Cleavage was assessed for anti-CTLA4 using mass spectrometry, whereas anti-PD1 cleavage was assessed by western blotting. Results: Akluded antibodies led to tumor reduction similar to the parental antibodies that was dependent on protease activity. Critically, the Akluded antibodies exhibit reduced levels of systemic activity compared to their parental antibody. In vivo cleavage indicates a fraction of the molecules in circulation have been cleaved. Conclusions: The data from these studies indicate the potential of Aklusion to improve the therapeutic index of immunomodulatory antibodies and biologics, enabling more efficacious dosing.
Decreased PSA nadir as a result of dose-escalated stereotactic body radiation for patients with low- and intermediate-risk prostate cancer.
Authors: Zaker Hamid Rana, Louis Potters, Lucille Lee, Brett W Cox
Journal: Journal of Clinical Oncology (2018)

e17076 Background: Prostate cancer (CaP) is characterized by a low a/b ratio relative to surrounding normal tissue, and consequently a therapeutic gain could be achieved with dose escalation. The purpose of this study was to report the clinical outcomes, PSA kinetics, and toxicities in patients with low and intermediate-risk CaP treated on a prospective, Phase I/II, IRB approved dose-escalated SBRT trial. Methods: From 2011 to 2016, 26 patients with low and intermediate-risk CaP received 40, 45, and 50 Gy in five fractions to the prostate and seminal vesicles in cohorts of 9, 10, and 7 patients (pts). Self-reported QOL was prospectively measured from the Expanded Prostate Cancer Index Composite (EPIC) and International Prostate Symptom Score (IPSS) at baseline and intervals of every 3 months for the first two years followed by every 6 months thereafter. Common Toxicity Criteria for Adverse Events v. 4.03, data was collected to observe acute and late toxicities. No pts received androgen deprivation therapy. Results: Median follow-up was 4.8 years. A PSA nadir < 0.5 ng/ml was seen in 22%, 80%, and 71% of patients receiving 40, 45, and 50 Gy, and < 0.2 ng/ml in 11%, 50%, and 71% of patients after 3 years. After 5 years, a PSA nadir < 0.5 ng/ml was achieved in 100% of patients receiving 45 Gy compared to 33% receiving 40 Gy. PSA nadir was significantly reduced when comparing cohorts receiving 45 or 50 Gy to 40 Gy one to five years following treatment (p < 0.02). There was an acute increase in EPIC and IPSS scores followed by a return to baseline over two years. There were no Grade 3 or higher toxicities. Univariate analysis revealed that Grade 2 toxicity was associated with prostate size > 60 cc (p < .01). One biochemical failure was observed in the 40 Gy arm after 3.6 years resulting in a freedom from biochemical failure rate of 96% at 5 years. Prostate cancer specific survival was 100% and actuarial overall survival was 96%. Conclusions: This small prospective dose-escalation study identified that higher doses of 45 and 50 Gy, respectively are associated with improved PSA nadir without increased risk of GU or GI toxicity. Further follow-up is needed to assess PSA freedom from recurrence and late toxicity.
Implementation of molecular testing for EGFR mutations and ALK rearrangement in lung adenocarcinoma in Brazil.
Authors: Sofia Palacio, Gilberto Lopes, Edna Prado
Journal: Journal of Clinical Oncology (2017)

e18002 Background: Lung cancer is the leading cause of cancer death worldwide. In Brazil, cancer is the second most common cause of death and there were an estimated 27,330 new cases of lung cancer in 2014. Targeted therapies have changed disease prognosis and current clinical guidelines advocate for EGFR/ALK molecular testing for all patients with advanced-stage lung adenocarcinoma. Access to this testing is often limited in the developing world. In the case of Brazil, there is limited data regarding the frequency of testing and the changes in patterns of testing overtime. Methods: De-identified data was obtained from a commercial database that surveys approximately 2,000 cancer physicians in Brazil regarding practice patterns. On average 300 physicians responded to the survey, which is conducted every 6 months, and provided information on about 18,000 patients. Subsequently, we identified patients with lung cancer and calculated the frequency of testing for EGFR mutations and ALK rearrangement from 2011 to 2016. Results: 11,684 patients with lung adenocarcinoma were analyzed from 2011 to 2016. The frequency of testing for EGFR mutations increased significantly: 12.8% (287/2,228) in 2011, 34.4% (738/2,142) in 2012, 39.2% in 2013 (822/2,092), 43.9% in 2014 (866/1,972), 53.3% (1165/2,184) in 2015, and 58% (626/1,066) for the first semester of 2016. Testing for ALK rearrangement also increased noticeably over the same period: 0% in 2011 (0/2,228) and 2012 (0/2,142), 0.9% (19/2,092) in 2013, 2.99% (59/1,972) in 2014, 5.5% (121/2,184) in 2015, and 4.8% (52/1,066) for the first semester of 2016. Conclusions: To our knowledge this is the largest data analysis regarding changing practice patterns of molecular testing for lung adenocarcinoma over time in Brazil and Latin America. The frequency of testing for EGFR mutations and ALK rearrangement has increased over the last 5 years but is still below the current guidelines recommending that all patients with advanced disease be tested. Further understanding of the barriers to testing, will hopefully lead to national strategies for universal implementation of molecular testing.
Pembrolizumab (pembro) plus epacadostat or placebo for locally advanced or metastatic urothelial carcinoma (UC) after failure of first-line platinum-containing chemotherapy: KEYNOTE-698/ECHO-303.
Authors: Thomas Powles, Joaquim Bellmunt, Daniel Peter Petrylak, Lawrence Fong, Hiroyuki Nishiyama, Cora N. Sternberg, Mei Chen, Lei Pang, Mihaela Munteanu, Yufan Zhao, David C. Smith
Journal: Journal of Clinical Oncology (2018)

TPS4586 Background: Pembro has shown clinical efficacy as monotherapy in locally advanced or metastatic UC in first-line (1L) cis-ineligible and second-line (2L) postplatinum settings. Combination of pembro and epacadostat, a potent and highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, in the ongoing ECHO-202/KEYNOTE-037 phase 1/2 study (NCT02178722) showed increased ORR compared with data from pembro monotherapy and durable responses in 1L and 2L advanced UC patients. Further evaluation of this combination in a phase 3 randomized trial in advanced/metastatic UC is warranted. Methods: KEYNOTE-698/ECHO-303 (NCT03374488) is a global, phase 3, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety of pembro plus epacadostat versus pembro plus placebo in patients with locally advanced or metastatic UC that progressed after prior platinum-containing chemotherapy. Eligibility criteria include age ≥18 years; confirmed transitional cell or predominantly transitional cell histology; progression or recurrence of UC after 1 prior platinum-containing chemotherapy regimen for advanced or metastatic UC or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; measurable disease per RECIST v1.1, ECOG 0-1, and good organ function at baseline; and provision of tumor sample for PD-L1 analysis. Eligible patients will be stratified by Bellmunt score (0, 1, ≥2) and PD-L1 expression (combined positive score [CPS] ≥10 or CPS < 10), and randomly assigned 1:1 to receive pembro 200 mg IV Q3W plus epacadostat 100 mg orally twice daily (continuously) or pembro plus matching placebo. Study treatment will continue until disease progression, unacceptable toxicity, or completion of 35 pembro infusions. Imaging will be performed every 9 weeks for the first 12 months and every 12 weeks thereafter until disease progression. Primary end points include OS and PFS (RECIST v1.1) by investigator assessment. Secondary end points include ORR, patient-reported outcomes, and safety. Approximately 648 patients will be enrolled. Clinical trial information: NCT03374488.
Parallel selection on a dormancy gene during domestication of crops from multiple families
Authors: Min Wang, Wenzhen Li, Chao Fang, Fan Xu, Yucheng Liu, Zheng Wang, Rui Yang, Min Zhang, Shulin Liu, Sijia Lu, Tao Lin, Jiuyou Tang, Yiqin Wang, Hongru Wang, Hao Lin, Baoge Zhu, Mingsheng Chen, Fanjiang Kong, Baohui Liu, Dali Zeng, Scott A. Jackson, Chengcai Chu, Zhixi Tian
Journal: Nature Genetics (2018)