bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of the combination of the heat shock protein-90 inhibitor onalespib (AT13387) and the cyclin-dependent kinase inhibitor AT7519M in patients with advanced solid tumors.
Authors: Do Khanh Tu , Hays John L. , Liu Stephen V. , Chen Alice P. , O'Sullivan Geraldine , Supko Jeffrey G. , Beebe Kristin , Neckers Len , Trepel Jane B. , Lee Min-Jung , Gannon Courtney , Muzikansky Alona , Campos Susana M. , Downey Elizabeth , Wolanski Andrew , Hedglin Jennifer , Arnaldez Fernanda Irene , Doroshow James H. , Shapiro Geoffrey 
Published: May 2019

2619 Background: The 90kDa heat shock protein (HSP90) participates in the folding, stabilization, activation, and proteolytic turnover of aberrant proteins that contribute to the growth and survival of cancer cells. HSP90 inhibition leads to degradation of these aberrant proteins through the ubiquitin-proteosome pathway, allowing for simultaneous targeting of multiple pathways. Inhibition of HSP90 alone stimulates a compensatory upregulation of HSP70. The transcriptional induction of HSP70 has been linked to the activity of CDK9. Combined inhibition of onalespib-mediated HSP90 inhibition and AT7519-mediated CDK9 inhibition has demonstrated synergistic anti-tumor activity in preclinical models at NOAEL doses, justifying a Phase 1 study. Methods: We conducted an open-label phase 1 study following a 3+3 trial design. Patients received a 1-week lead-in of onalespib alone (C0), followed by onalespib/AT7519M on days 1,4,8, and 11 of a 21-day cycle. Pharmacokinetic samples were obtained on C0D1 after onalespib alone, and on C1D1 and D11 with the combination. HSP70 protein levels were analyzed in PBMC and plasma samples collected at baseline, after onalespib alone, and after the combination, in order to demonstrate AT7519-mediated suppression of HSP70 expression. Patients enrolled to the expansion phase underwent optional paired tumor biopsies for assessment of proof-of-mechanism demonstration of modulation of client proteins. Results: Twenty-eight patients have been treated, 10 of whom were enrolled to the expansion cohort with optional tumor biopsies. The MTD is DL2: onalespib 80 mg/m2 IV + AT7519M 21 mg/m2 IV on days 1,4,8, and 11 of a 21-day cycle. At DL3, DLTs included Grade 3 troponin elevation and mucositis. Drug-related adverse events occurring in ≥ 30% of patients include diarrhea, fatigue, mucositis, nausea, and vomiting, consistent with known toxicities of these agents. Two patients with colorectal and endometrial cancer, respectively, remained on study for 10 cycles with SD as the best response. Modulation of HSP70 were demonstrated in patient plasma samples. Conclusions: The combination of onalespib and AT7519 is tolerable, although the doses of both agents were below the monotherapy MTDs. Prolonged disease stabilizations were observed. Pharmacokinetic and pharmacodynamic analyses are ongoing, including assessment of HSP70 expression in plasma and tumor. Clinical trial information: NCT02503709.
Non-small cell lung cancer (NSCLC) next generation sequencing (NGS) using the Oncomine Comprehensive Assay (OCA) v3: Integrating expanded genomic sequencing into the Canadian publicly funded health care model.
Authors: Perdrizet Kirstin , Stockley Tracy , Law Jennifer H. , Shabir Muqdas , Zhang Tong , Le Lisa W , Lau Anthea , Tsao Ming Sound , Pal Prodipto , Cabanero Michael , Ko Hyangmi , Schwock Joerg , Kamel-Reid Suzanne , Liu Geoffrey , Sacher Adrian G. , Bradbury Penelope Ann , Shepherd Frances A. , Leighl Natasha B. 
Published: May 2019

2620 Background: Standard of care (SOC) molecular diagnostics for stage IV NSCLC patients in Ontario, Canada includes publicly reimbursed EGFR/ ALK, and selected BRAF and ROS-1 testing. Other genomic alterations are not tested routinely; however, enhanced molecular testing may broaden treatment options for patients. This study evaluated costs, identified actionable targets, and determined clinical trial eligibility as a result of using the OCAv3 NGS in stage IV NSCLC patients. Methods: In a prospective study of stage IV NSCLC out-patients at Princess Margaret Cancer Centre (Toronto) without EGFR/ALK/KRAS/BRAF alteration (unless failure of prior targeted therapy), diagnostic samples were tested by OCAv3 (ThermoFisher; 161 genes: hotspots, fusions, and copy number variations). Primary endpoints were incremental actionable targets and clinical trial opportunities as a result of broader OCAv3 testing. Secondary endpoints include feasibility and cost from the Canadian public healthcare perspective, and treatment outcomes. Results: Of 65 enrolled patients (Feb 2018-Jan 2019; 40 (62%) completed/14 (21%) screen fail/ 11 (17%) pending), median age of completed cohort was 65, 60% (N = 24) female, never/light smokers 68% (N = 27), Asian 38% (N = 15), previously treated 33% (N = 13). Actionable targets beyond SOC were identified in 33% (N = 13): ERBB2 (N = 8), BRAFV600 (N = 3), NRG fusion (N = 1), MET exon 14 (N = 1). New clinical trial options were identified in 70%. Failure of NGS was secondary to insufficient tissue [91% (N = 10) of screen failures; usually due to tissue exhaustion from prior SOC molecular testing]. Incremental costs per case beyond EGFR/ALK are estimated at $540 CAD. If ROS-1 and BRAF testing were publicly reimbursed at current rates, the incremental profiling cost with OCAv3 would be $90 CAD per case. Conclusions: Although a key barrier to implementation is lack of funding for NGS in the Canadian publicly funded system, the OCAv3 consolidates genomic testing, identifies additional actionable targets, and substantially increases clinical trial eligibility for patients at a small incremental cost. Clinical trial information: NCT03558165.
Tumor mutational burden (TMB) profile of K-RAS/TP-53 co-mutation in metastatic non-small cell lung cancer (m-NSCLC).
Authors: Naqash Abdul Rafeh , Walker Paul R. , Muzaffar Mahvish , Feldman Rebecca , Hafiz Maida , Liu Stephen V. , Mamdani Hirva , Patel Anokhi , Borghaei Hossein , Sharma Nitika , Nieva Jorge J. , Boumber Yanis , Vanderwalde Ari M. , Ma Patrick C. , Eldessouki Ihab , Portnoy David Craig , Spira Alexander I. , Yang Li V. , Abdel Karim Nagla Fawzy 
Published: May 2019

2626 Background: Early data suggests that co-occurring genetic events define biological heterogeneity in K-RAS mutant NSCLC, with K-RAS/ TP-53 (KP) co-mutated subset having potential therapeutic vulnerabilities to immune checkpoint blockade (ICB). To explore the immunological basis for these findings, we evaluated the immune biomarker profile (TMB/PD-L1) in KP mutant m-NSCLC using a large next-generation sequencing (NGS) dataset. Methods: Caris life sciences NGS dataset consisting of 1317 m-NSCLC tissue samples from 2016-18 was queried. PD-L1pos was defined as ≥ 1% staining using 22c3 Dako assay. TMB was measured by counting all somatic non-synonymous missense mutations using targeted NGS (592 genes). TMB-high (H) was defined as ≥ 10 mutations/Megabase (mut/Mb). P-values were calculated using Chi-square and Mann-Whitney test. Results: K-RAS mutations were identified in 28.7% (378/1317). Within this K-RAS mutant group, KP subset constituted 49.4% (187/378), remaining were K-RAS mutated/ TP-53 wild type (K-Pwt). 72.2 % (135/187) of KP had PD-L1pos with 51.9% (97/187) having PD-L1 ≥ 50%. KP had higher median TMB vs. K-Pwt (14.5 vs. 9.0 mut/Mb, p<0.001) and higher % of TMB-H vs. K-Pwt (79.9 vs. 45.1%, p<0.001; Table). Even in the PD-L1neg group, KP had higher % of TMB-H vs. K-Pwt (86.5 vs. 41.5%, p<0.001). K-RAS or TP-53 exon-subtypes had no difference in median TMB or % of TMB-H. Across metastatic sites, brain tissue had the highest % of KP subset (38.3%, 68/187) followed by bone (28.9%, 54/187). Within KP subset, brain tissue had higher median TMB vs. bone (16 vs. 11 mut/Mb, p<0.01) as well as greater % of TMB-H vs. bone (86.5 vs. 68.5%, p=0.01). Conclusions: This is the largest dataset to date highlighting the unique immune profile of KP mutant m-NSCLC. Our results show that KP subset has a significantly higher TMB than K-Pwt, especially in the PD-L1neg subgroup. Metastatic site-specific variations in TMB were also observed for the KP subset. These findings could have therapeutic implications in guiding patient selection for ICB and merit prospective investigation.[Table: see text]
Impact of prior chemotherapy or radiation therapy on tumor mutation burden in NSCLC.
Authors: Jonna Sushma , Vanderwalde Ari M. , Nieva Jorge J. , Poorman Kelsey Anne , Saul Michelle , von Buttlar Xinyu , Hu John Y. , Liu Stephen V. 
Published: May 2019

2627 Background: Higher non-synonymous tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) is associated with a higher likelihood of response to checkpoint inhibitors. Tissue samples subject to TMB analysis may be obtained after exposure to cytotoxic chemotherapy or radiation therapy – both of which introduce somatic mutations in DNA and can influence the number of identified mutations. The role of TMB as a potential predictive marker for immunotherapy is evolving, and the impact of prior therapy on TMB could influence interpretation. Methods: Eligible cases were from patients with confirmed NSCLC, available clinical annotation and tumor molecular profiling including TMB analysis at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) using the Illumina NextSeq platform. TMB was calculated using only missense mutations that had not been previously reported as germline alterations. Treatment history was obtained for each patient under an IRB approved protocol to determine whether patients had had received chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. Data analysis was performed using the chi-square test of deviance to evaluate whether TMB was statistically significantly different between groups, correcting for smoking status. Results: Out of 1,118 patients identified, 459 cases met all eligibility criteria and were evaluated. 76 patients (17%) received either chemotherapy or radiation prior to tissue collection. Samples acquired prior to any therapy had a median TMB of 10 mut/Mb vs. 11 mut/Mb in samples acquired after any therapy. After adjusting for smoking, there was no significant difference in TMB between these cohorts (p = 0.41). Secondary pair wise analysis showed no statistically significant difference in TMB from chemotherapy-naïve and chemotherapy-treated samples (p = 0.28). The same was true for radiation (p = 0.75). Collection of clinical data is ongoing and further analysis, including additional cases will be presented. Conclusions: Though cytotoxic chemotherapy and radiation therapy can introduce somatic mutations, prior exposure to either was not associated with a significant difference in TMB.
Quantitative MHC II protein expression levels in tumor epithelium to predict response to the PD1 inhibitor pembrolizumab in the I-SPY 2 Trial.
Authors: Wulfkuhle Julia Dianne , Yau Christina , Wolf Denise M. , Gallagher Rosa Isela , Brown Swigart Lamorna , Hirst Gillian L. , Campbell Michael , Nanda Rita , Liu Minetta C. , Pusztai Lajos , Esserman Laura , Berry Donald A. , van 't Veer Laura , Petricoin Emanuel ,   I-SPY 2 Investigators
Published: May 2019

2631 Background: Response to immune checkpoint inhibitors has been associated with immune activation and mutational load within a tumor. Previous results in other tumors have implicated MHC II protein tumor cell expression as a response predictor to immune checkpoint inhibitors. In the I-SPY 2 TRIAL, the anti-PD1 therapeutic antibody pembrolizumab (P) was available to HER2-negative subtypes and graduated in both the HR+/HER2- and TNBC signatures. Pre-specified biomarker analysis was performed to test tumor MHC II expression as a predictor of response to P in the I-SPY 2 TRIAL based on its central role in tumor antigen presentation. Methods: 156 patients (P: 67, controls: 89) had RPPA and pCR data. RPPA-based quantitative data for pan-MHC II protein isotypes HLA-DR/DP/DQ/DX and HLA-DR protein isotype was obtained from LCM-enriched tumor epithelium, and protein levels were assessed for association with pCR in the P and control arms separately using the Wilcoxon Rank Sum test (p < 0.05). Analysis was also performed in the HR+ and HR- subgroups. Markers were analyzed individually; p-values are descriptive and were not corrected for multiple comparisons. Results: Across all P- treated patients, the HLA class II molecules –DR and -DR/DP/DQ/DX had a positive association with response to P (p = 0.014 and p = 0.001). Expression of HLA-DR/DP/DQ/DX also had a positive association with response to P in HR+ tumors. Neither of these associations were seen in the control arm samples. Conclusions: The observation of elevation of MHC II protein expression in HER2- responding patients treated with P suggests that activation of antigen peptide exchange facilitated by these molecules in T and B cells may enhance response to P treatment.
Evaluation of TMB estimates for the prediction of response to immune checkpoint blockage.
Authors: Budczies Jan , Allgäuer Michael , Litchfield Kevin , Rempel Eugen , Christopoulos Petros , Kazdal Daniel , Endris Volker , Thomas Michael , Fröhling Stefan , Peters Solange , Swanton Charles , Schirmacher Peter , Stenzinger Albrecht 
Published: May 2019

2632 Background: Tumor mutational burden (TMB) is an emerging biomarker in immuno-oncology (IO). Panel sequencing (PS) is a promising approach for its implementation in clinical practice. Methods: We analyzed TMB as predictor of IO response in a multi-cancer cohort published by Miao et. al. The performance of three large panels (Illumina TSO500, Qiagen TMB [QIAseq] and Oncomine TMB [OTMB]) and two small panels (Illumina TST170 and Oncomine Comprehensive Assay [OCAv3]) was compared to WES by in silico simulations. Separation of responders (PR/CR) from non-responders (PD) was analyzed in the multi-cancer cohort (n = 193), in the lung cancer (n = 36) and in the melanoma (n = 125) subcohort. We also simulated PS in the TCGA pan-cancer cohort. Results: In lung cancer, TMB was strongly predictive for IO response (area under ROC curve [AUC] 0.78-0.94). WES performed (borderline)-significantly better than PS for all five panels (OCAv3: p = 0.011, TST170: p = 0.01, QIAseq: p = 0.048, OTMB: p = 0.063, TSO500: p = 0.11). For the cut-point of 199 mutations, misclassification rates compared to WES (16.7%) were borderline-significantly higher for the small panels OCAv3 (33.3%, p = 0.087) and TST170 (36.1%, p = 0.054), but not for the large panels. In melanoma, TMB was moderately predictive (AUC 0.58-0.63) and WES performed (borderline)-significantly better than the OCAv3, TST170, QIAseq and TSO500 panels. In the multi-cancer cohort, WES did not perform better than PS. TBM estimates from PS include an inherent fuzziness originating from restriction to a limited part of the coding sequence. Based on a random mutation model, we derived a mathematical formula for the coefficient of variation (CV) of TMB: The CV decreases inversely proportional with both the square root of the TMB level and with the square root of the panel size. We showed that the mathematical law is valid for real-word mutation data. Conclusions: Small panels (size < 1 Mpb) performed imprecise in diagnostic TMB estimation. Even using the largest commercially available panels it can be challenging to capture the full predictive information of TMB. The detrimental effect of small panel size can be addressed by using larger panels, but halving the CV of TMB necessitates quadruplication of the panel size.
Final results of a phase I study evaluating INVAC-1, a novel DNA vaccine expressing an inactive form of human telomerase reverse transcriptase (hTERT) in patients with advanced solid tumors.
Authors: Teixeira Luis , Medioni Jacques , Doucet Ludovic , Angelergues Antoine , Culine Stephane , Oudard Stephane , Brizard Mara , Ghrieb Zineb , Adotevi Olivier , Laheurte Caroline , Dragon Durey Marie-Agnès , Laurent-Puig Pierre , Kiladjian Jean-Jacques , wain-Hobson Simon , Doppler Valérie , DeFrance Rémy , Garibal Julie , Huet Thierry , Langlade Demoyen Pierre 
Published: May 2019

2642 Background: INVAC-1 is an optimized DNA plasmid encoding an inactive form of human Telomerase Reverse Transcriptase (hTERT), a universal tumor antigen expressed in most of human tumors with little or no expression in somatic cells. We report here the final results of a First-In-Human Phase I study evaluating INVAC-1 as a single agent in patients (pts) with advanced solid tumors, ended in June 2018. Methods: A two center Phase I trial evaluated INVAC-1 given monthly for a minimum of 3 cycles and up to 9 cycles by intradermal injection followed by electroporation (n = 20) or using a needle-free injection system (n = 6). Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included immune response (assessed by IFN-γ Elispot) and anti-tumor activity. Immuno-monitoring included detection of autoantibodies, lymphocyte phenotyping and inflammatory cytokine levels in blood. Anti-tumor activity was evaluated through RECIST 1.1 adapted to immune response, and plasma circulating tumor DNA (ctDNA). Results: 26 pts with refractory/progressive tumors were enrolled and treated with 3 escalating doses of 100, 400 and 800 µg. 15 pts experienced stable disease according to RECIST. For 11 of them, the treatment was extended, up to 9 months. INVAC-1 was well tolerated with no dose-limiting toxicities. No significant biological signs of autoimmunity were observed. No significant modification in inflammatory plasma cytokines levels was observed after INVAC-1 administration. INVAC-1 triggered de novo or enhanced pre-existing CD4/CD8 specific anti-hTERT response in 63% of pts. This specific anti-hTERT immune response was enhanced ex vivo by adding the immune checkpoint inhibitor nivolumab. ctDNA was evaluated in 17 pts. We observed a ctDNA decrease in 6 cases, a stable level in 5 cases and an increase in 6 cases. Conclusions: Results indicate that INVAC-1 was well tolerated and immunogenic at the doses and schedule tested. Disease stabilization was obtained for the majority of pts (58%) according to RECIST criteria or ctDNA levels. Clinical trial information: NCT02301754.
Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase I study.
Authors: Kim Tae Won , Lee Jeeyun , Shin Sang Joon , Kim Jin-Soo , Kim Yu Jung , Han Hye Sook , Lee Soo Jung , Lim Hyeong-Seok , Hong Yoon-hee , Noh Young Su , Kyoung Yujung , Han Oakpil , Yoon Jiyeon , Lim Jeong Ah , Kim Suk Ran 
Published: May 2019

3000 Background: Belvarafenib (HM95573/GDC-5573) is an oral type II pan-RAF kinase inhibitor which demonstrates selective anti-tumor activity in several non-clinical cancer models and in cancer patients with RAS- or RAF- mutation. Here we present overall safety and efficacy findings of two phase 1 studies, consisting of dose escalation and dose expansion stages. Methods: Patients with advanced solid cancers harboring documented RAS- or RAF- mutation were enrolled. In the dose escalation study, patients were treated with Belvarafenib at a starting dose of 50 mg once daily (QD) to 800 mg BID to assess safety and tolerability and identify the recommended dose (RD). Dose escalation was guided based on pharmacokinetic data and used a traditional 3+3 design. The dose expansion study was comprised of 6 cohorts (according to the type of tumor and RAS- or RAF gene mutation) and patients received the RD of Belvarafenib. The primary objective was to explore anti-tumor activity (per RECIST 1.1) and pharmacodynamic effects. Results: The dose escalation study included 72 patients in 9 dose cohorts (cut-off date of 18 Jan 2017). Dose dependent increase in exposures observed up to 650 mg BID. The most common treatment-emergent adverse events that occurred in more than 20% of patients were rash, dermatitis acneiform and pyrexia. A total of 4 DLTs (different kinds of rashes) were reported and included 2 DLTs at the 800 mg BID level. Therefore, 650 mg BID was considered the MTD and 450 mg BID was identified as the RD for Belvarafenib. There were 7 partial responses (3 confirmed PRs) from 200 mg QD to 800 mg BID in NRAS-mutant melanoma, BRAF-mutant melanoma, KRAS-mutant sarcoma, and BRAF-mutant GIST. Four of nine patients with NRAS-mutant melanoma had a PR (ORR 44%). The dose expansion study included 63 patients in 5 indication-specific and basket cohorts administered with 450 mg BID Belvarafenib (cut-off date of 6 Oct 2018). No new safety signal was detected. There were two PRs each in patients with NRAS-mutant melanoma (2/9), BRAF-mutant melanoma (2/6) and BRAF-mutant CRC (2/7), respectively. Conclusions: Belvarafenib was well tolerated and exhibited anti-tumor activity in patients with advanced solid tumors harboring RAS or RAF mutations. Belvarafenib is being further investigated in combination with the MEK inhibitor cobimetinib. Clinical trial information: NCT02405065, NCT03118817.
A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts).
Authors: Pant Shubham , Bendell Johanna C. , Sullivan Ryan J. , Shapiro Geoffrey , Millward Michael , Mi Gu , Yuen Eunice , Willard Melinda D. , Wang Dan , Joseph Sajan , McMillen William T. , Bhagwat Shripad V. , Tiu Ramon Velasquez , Patel Manish R. 
Published: May 2019

3001 Background: LY3214996 is a selective and potent ERK1/2 inhibitor that has demonstrated tumor growth inhibition in several pre-clinical tumor models with BRAF, RAS, or MAP2K1 mutations. This is the first-in-human Phase 1 Study of LY3214996 in adv CA pts. Methods: The goals of this DE study were to determine a recommended Phase 2 dose (RP2D), safety, pharmacokinetic (PK), and preliminary efficacy of LY3214996 (NCT02857270; I8S-MC-JUAB; Eli Lilly & Co.). Pts with adv CA, ≥18 yrs of age, ECOG ≤1, and with adequate organ function were eligible. Pharmacodynamic (PD) biomarkers including pRSK were evaluated in blood and paired tumor tissue. The DE phase evaluated PO doses using the Bayesian model-based toxicity band method. Results: A total of 51 pts with median age of 62 yrs (range: 21-81) received at least 1 dose of LY3214996 with a median of 3 cycles (range: 1-12). Most pts had a mutation in RAS (N = 33) or BRAF (N = 16) and had a median of 4 prior lines of treatment. The DLTs observed in the study include grade (G) 3 cough and fatigue, G3 dehydration, increased creatinine (Cr), G3 increased CPK, G3 rash > 7 days, and 1 pt with renal failure. TRAEs to LY3214996 occurring in ≥10% of pts included nausea, vomiting, diarrhea, dermatitis acneiform, fatigue, pruritus, and blurred vision. LY3214996 exposures increased with dose. Tumor regression was observed in 7 pts with BRAF/non -BRAF mutant CA including 5 pts who failed prior IO/MAPK inhibitors. Four pts achieved stable disease (2 BRAF, 1 RAS and 1 CRAF mutation) that lasted > 4 mos. Up to 100% pRSK decrease from baseline in tumor was observed. Conclusions: LY3214996 had an acceptable safety profile, favorable PK, and potent tumor PD inhibition at RP2D. This supports further exploration of LY3214996 as monotherapy and in combination in CA pts with activating MAPK pathway alterations. Clinical trial information: NCT02857270.