bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra and perinodular CT delta radiomic features associated with early response to predict overall survival (OS) in immunotherapy-treated non-small cell lung cancer (NSCLC): A multisite multi-agent study.
Authors: Prasanna Prateek , Khorrami Mohammadhadi , Gupta Amit , Patil Pradnya Dinkar , Khunger Monica , Velu Priya , Bera Kaustav , Alilou Mehdi , Velcheti Vamsidhar , Madabhushi Anant
Published: May 2019

2588

Background: None of the current biomarkers for predicting response to checkpoint inhibitors (ICIT) for advanced NSCLC are associated with long-term benefits, such as improved OS. In this multi-agent (nivolumab, pembrolizumab, or atezolizumab) multi-site study (Cleveland Clinic, Univ. of Pennsylvania), we demonstrate that changes in computer-extracted textural patterns, from within and 30mm outside the nodules, between baseline and post-treatment CT following ICIT correlate with RECIST-derived responses, and are prognostic of OS. Methods: CT scans from 139 NSCLC patients both pre-, and post 2-3 cycles of ICIT were acquired from 2 sites. Patients with objective response/stable disease per RECIST v1.1 were defined as ‘responders’, and those with progressive disease were ‘non-responders’. The cohort was divided into a discovery (D1 = 50) and two validation sets (D2 = 62, D3 = 27). 454 intranodular texture (IT) features, and 7426 perinodular features (PT) were extracted from the temporalscans, Relative differences were computed to yield a set of ‘delta-radiomic’ descriptors. In D1, 8 features that evolved the most between baseline and post-treatment CT, and performed the best in identifying responders, were determined. These were then used with a Linear Discriminant Analysis classifier to identify the responders from the non-responders. We then computed a radiomic risk score (RRS) system and tested its prognostic ability in assessing differences in OS. Results: A combination of 5 IT, 3 PT delta radiomic features yielded an AUC of 0.88 ± 0.08 in D1 and a corresponding AUC = 0.85 and 0.81 in D2 and D3, respectively. Multivariate survival metrics are shown in Table. Conclusions: Delta-radiomic features, both from inside and outside the nodules, could be used to identify patients likely to derive clinical benefit from ICIT (eg: OS) beyond anatomic response. [Table: see text]
Can serum IL-6 levels predict sarcopenia and poor outcome in relapsed/refractory gynecologic cancer patients?
Authors: Yoshikawa Tomoyuki , Takano Masashi , Kudoh Kazuya , Miyamoto Morikazu , Aoyama Tadashi , Matsuura Hiroko , Ishibashi Hiroki , Iwahashi Hideki , Kakimoto Souichirou , Asakawa Takayoshi , Kouta Hiroko , Ikeda Sayaka , Kita Tsunekazu , Kikuchi Yoshihiro
Published: May 2019

2592

Background: Cancer cachexia occurs in more than half of cancer patients and can be the primary cause of death for at least 20% of all patients. Cancer cachexia also lowers quality of life in cancer survivors due to a severe loss of skeletal muscle mass. Although a multitude of cytokines have been implicated in facilitating a cachectic state, the correlation of serum IL-6 and cancer-induced muscle wasting in gynecologic cancer patients has not been elucidated. Methods: The correlation between serum level of IL-6 and skeletal muscle volume in the patients with gynecologic cancers that received multiple lines of therapy was retrospectively evaluated. We used the psoas muscle index [PMI (cm2/m2)], the psoas major muscle area at the fifth lumber level divided by the height squared, measured using digital axial CT images, for the value of skeletal muscle volume. The level of IL-6 cut-off for elevation was defined as more than 12.0 pg/mL. The comparison of the survival distributions from the day of IL-6 measuaments was made using a log-rank test. Results: A total of 74 cases were assessed for the serum IL-6 and PMI: 32 cases with Mullerian cancers, 24 cases with endometrial cancers, 13 cases with cervical cancers, and 5 patients with others. The group with elevated IL-6 were associated with the lower PMI (t-test, p = 0.0154). The patients with IL-6 elevation had significantly worse survival compared with those with normal IL-6 (1y-OS; 31% vs. 80%, p < 0.0001). In 28 patients with more than two-point measurements of IL-6, the patients with the decrease to the level of IL-6 cut-off had favorable survival compared with those without the decrease (6m-OS; 100% vs. 52%, p = 0.0069). Conclusions: Serum level of IL-6 could be a sentinel biomarker for cancer-induced sarcopenia in the patients with gynecologic cancers. Additionally, IL-6 could be a biomarker to determine further continuation of aggressive chemotherapy for the patients that had received multiple lines of chemotherapy.
Balixafortide (a CXCR4 antagonist) + eribulin in HER2-negative metastatic breast cancer (MBC): Survival outcomes of the phase I trial.
Authors: Kaufman Peter A. , Pernas Simon Sonia , Martin Miguel , Gil-Martin Marta , Gomez Pardo Patricia , Lopez-Tarruella Sara , Manso Luis , Ciruelos Eva , Perez-Fidalgo Jose Alejandro , Hernando Cristina , Ademuyiwa Foluso Olabisi , Weilbaecher Katherine N. , Mayer Ingrid A. , Pluard Timothy J. , Martinez Garcia Maria , Vahdat Linda T. , Barker Debra , Romagnoli Barbara , Cortes Javier
Published: May 2019

2606

Background: Balixafortide (B) is a potent antagonist of the chemokine receptor CXCR4. Preclinical evidence suggests that disrupting CXCR4 dependent pathways prevents development of breast cancer metastases, enhances the cytotoxic effect of chemotherapy and immunotherapy, and counteracts tumor cell evasion of the immune system. Encouraging safety and efficacy data were published recently from the ongoing Phase 1 trial investigating B + eribulin (E) in patients with HER2 negative MBC (Pernas S. et al. Lancet Oncol. 2018; 19: 812−24). The objective response rate, median progression free survival and median overall survival (OS) for the expanded cohort (EC) and the overall efficacy population (OEP) were 37.5% and 29.6%, 6.2 months and 4.5 months, and 18 months and 16.8 months, respectively. Here we report the 18 and 24 months landmark OS data from this trial. Methods: This trial enrolled 56 patients with HER2-negative, CXCR4-positive MBC, previously treated with 1−3 chemotherapy regimens for MBC. A 3+3 dose escalation design was used, followed by an EC. All cohorts received E on days 2 and 9, and B on days 1−3 and 8−10 of 21 day cycles. The association between various baseline biomarkers and treatment outcomes including OS is currently being investigated in a multivariate analysis (MVA). Results: Landmark survival data for the trial are shown in the table. Clinical trial information: NCT01837095. Conclusions: Landmark 18 months and 24 months OS data are consistent with the positive trend of all efficacy read-outs observed in this study and safety information is consistent with what was previously reported. Although inter-trial comparisons should be interpreted with caution, these survival rates, especially for the EC, are higher than those reported for eribulin monotherapy in similar MBC populations. These promising results suggest that B + E could potentially provide a new treatment option in heavily pre-treated patients with HER2 negative MBC and this is currently being investigated in a pivotal, randomized trial.[Table: see text]
Phase I study of KN035, the first subcutaneously administered, novel fusion anti-PD-L1 antibody in patients with advanced solid tumors in China.
Authors: Xu Jian-Ming , Qin Shukui , Zhang Yun , Zhang Yaoyue , Jia Ru , Liu Rongrui , Zhang Gairong , Zhao Chuanhua , Lu Ni , Liu Huilong , Xu Wenlian , Fu Meng , Cao Walt , Lu Haolan , Liu David , Dong Ruiping , Wang Xiaoxiao , Wang Pilin , Xu Ting , Gong John
Published: May 2019

2608

Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc fragment, formulated for subcutaneous (SC) injection. Methods: The escalation phase followed a modified 3+3 design with a 28-day DLT evaluation period and 8 dose levels were planned at 0.1, 0.3, 1.0, 2.5, 5 and 10 mg/kg SC weekly. One patient each was enrolled at 0.1 and 0.3 mg/kg dose levels. Additional dose levels followed traditional 3+3 design. Response was assessed per RECIST 1.1 every 12 weeks. Results: As of 11/2/2018, 17 patients were enrolled in the escalation phase (urothelial carcinoma (n=2), hepatic cell carcinoma (n=2), intrahepatic cholangiocarcinoma (n=2), thymic carcinoma (n=2), colorectal cancer£¨n=2£©£¬renal cell carcinoma (RCC, n=3), Squamous-cell lung carcinoma (n=1) and ovarian cancer (n=1)). The majority of subjects had advanced disease stage, stage IV (15/17) and stage III (2/17). A total of 7 subjects received radiotherapy, 16 subjects received surgery, and 13 subjects received systematic anti-cancer therapies from previous treatment. None had received prior checkpoint inhibitor treatment. Planned maximum dose of 10 mg/kg was reached (n=3) without DLT occurred. There was only one Grade 3 drug related Treatment Emergent Adverse Event (TEAE) occurred at 0.3 mg/kg dose level, which was immune related dermatitis and resolved later. All other drug related TEAEs were either Grade 1 or 2, with the most common events as elevated ALT (5/17) and elevated AST (4/17). Among all enrolled subjects, three subjects had confirmed PR, including one RCC subject at 2.5 mg/kg and one Intrahepatic cholangiocarcinoma subject at 5 mg/kg, and one cholangiocarcinoma subject at 10 mg/kg. Conclusions: KN035 exhibits a favorable safety profile and promising preliminary anti-tumor activity in patients with advanced malignancies. Clinical trial information: NCT03101488.
Immunological impact of canerpaturev (C-REV, formerly HF10), an oncolytic viral immunotherapy, with or without ipilimumab (Ipi) for advanced solid tumor patients (pts).
Authors: Nakayama Takayuki , Yamashita Makiko , Suzuki Toshihiro , Shimomura Manami , Nakatsura Tetsuya , Aoki Kazunori , Yamamoto Noboru , Yamazaki Naoya , Isei Taiki , Uhara Hisashi , Kiyohara Yoshio , Uchi Hiroshi , Saruta Hiroshi , Inozume Takashi , Tanaka Maki , Kitano Shigehisa
Published: May 2019

2610

Background: C-REV, an oncolytic, spontaneous mutant of Herpes Simplex Virus type 1 (HSV-1), is a cancer immunotherapy agent that combine direct tumor cell killing with immune modulation. A phase I study for solid tumors with cutaneous and/or superficial lesions treated with C-REV monotherapy and a phase II study for unresectable or metastatic melanoma treated with C-REV and Ipi combination therapy were conducted. Immune status of cancer pts before and after administration of C-REV with/without Ipi has been unclear. Methods: A phase I study (n = 6) included solid tumor pts with cutaneous and/or superficial lesions treated with C-REV monotherapy (1 x 106 and 1 x 107 TCID50/mL/dose; 4 injections q2-4wk). In phase II study (n = 28), C-REV (1 x 107 TCID50/mL/dose; 4 injections q1wk; then up to 15 injections q3wk) was injected into each tumor for advanced melanoma pts. Four Ipi infusions (3 mg/kg) were administered at q3wk. Immune-monitoring was conducted before and after treatment in tumor microenvironment usingpaired biopsy samples by multiplex immunohistochemistry (mIHC) and in peripheral blood by flow cytometry (FCM). Results: In the phase I study, significant infiltrations of CD8+and CD4+ T cells were observed at tumor local site statistically in three pts (60%) among five pts. In the phase II study, FCM of peripheral blood (n = 10) showed that the responders (irSD, n = 7, 70%) tend to express the higher levels of ICOS on CD4+ T cells as a pharmacodynamic biomarker of ipi monotherapy reported previously (Ng Tang D, et al. Cancer Immunol Res. 2013) and lower levels of PD-L1 on monocyte after two months of treatment. Moreover, mIHC analysis of paired tumor biopsy samples (n = 11) revealed that five pts (45%) among 11 pts were confirmed persistent infection of C-REV at the injected site by qPCR. Disease control rate of pts with the virus DNA detected on Days 85/169 was higher than that without it (100% [n = 5, irPR; 1, irSD; 4] vs. 33% [n = 6, irSD; 2, irPD; 4]). Furthermore, median OS of pts with or without the DNA detected was 342 or 251 days respectively. Conclusions: Our results suggest C-REV injection in the tumor local site have potential to enhance systemic immune response of Ipi. Clinical trial information: NCT03153085.
Response to immune checkpoint inhibition and survival in BRCA-associated recurrent ovarian cancer.
Authors: Liu Ying L , Boland Julia Lindsay , Cadoo Karen Anne , Friedman Claire Frances , Konner Jason A. , O'Cearbhaill Roisin Eilish , Aghajanian Carol , Zamarin Dmitriy
Published: May 2019

2615

Background: Alterations in the DNA mismatch repair pathway increase susceptibility to immune checkpoint inhibition (ICI). Tumors with BRCA-related DNA repair defects may have increased antigenicity, which could drive response to ICI. Responses to ICI in ovarian cancer (OC) have been modest. We seek to evaluate the association of BRCA mutations with response to ICI and survival in recurrent OC. Methods: A single-center, retrospective review identified 103 women with recurrent OC and known BRCA mutation status (90 germline and 33 somatic testing) who received ICI between 1/2013-7/2018 (98 on study). Clinical characteristics and duration of ICI (Long > = 24 vs. Short < 24 weeks) were compared by BRCA status. Kaplan Meier survival analysis was used to calculate progression-free (PFS) and overall survival (OS) from start of ICI, and CoxPH models/logrank test were used to assess survival differences by BRCA status. Results: Deleterious germline (g) or somatic (s) BRCA 1/2 mutations were present in 29 (28%) women (12 g BRCA1, 9 g BRCA2, 3 s BRCA1, 5 s BRCA2, 1 g BRCA1/s BRCA1, 3 g BRCA2/s BRCA2, and 1 g BRCA2/s BRCA1). Patients (pts) with BRCA mutations had more lines of treatment prior to ICI (median 5 vs. 4, p = 0.03) and a longer time from diagnosis to ICI (median 54 vs. 38.5 months (mo), p = 0.01), but there were no significant differences in other variables including histology (86% high grade serous), stage at diagnosis (96% Stage III/IV), and platinum status (83% resistant), p > 0.05. Four pts (15%) with BRCA mutations had long duration of ICI as compared with 20 pts (27%) in those without mutations, p = 0.20. Median PFS was 2.2 mo (95% CI 1.7-2.7) in those with BRCA mutations and 3.4 mo (95% CI 2.1-4.0) in those without mutations, HR 1.22 (95% CI 0.78-1.91, p = 0.38). At a median follow-up of 23.3 mo, median OS was 21.3 mo (95% CI 13.7-31.8) in those with BRCA mutations and 19.8 mo (95% CI 13.8-25.3) in those without. This was not significantly different, HR 1.00 (95% CI 0.54-1.87, p = 0.99), after adjustment for prior lines and time from diagnosis to ICI. Conclusions: In our study of heavily pretreated OC pts receiving ICI, BRCA 1/2 mutations were not associated with improved response or survival. These findings should be validated in larger studies.
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.
Talazoparib beyond BRCA: A phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes.
Authors: Gruber Joshua James , Afghahi Anosheh , Hatton Alyssa , Scott Danika , McMillan Alex , Ford James M. , Telli Melinda L.
Published: May 2019

3006

Background: Talazoparib, a PARP inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 is unknown. We conducted a single institution phase II trial to evaluate talazoparib in patients (pts) with advanced HER2-negative breast cancer or other solid tumors with a germline (g) or somatic (s) alteration in HR pathway genes not including BRCA1/2. Methods: Eligible pts had measurable disease, lacked a germline or somatic mutation in BRCA1/2, received at least one prior therapy for advanced HER2-negative breast cancer or other solid tumor and had a HR pathway gene mutation: PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL. Pts with no progression on or within 8 weeks of their last platinum dose were eligible. Pts were treated with talazoparib 1 mg po daily until disease progression. Response was assessed every 8 +/- 1 weeks. If 2 or more responses were observed in 10 pts in stage I, the study would proceed to stage II and enroll 10 additional pts. The null hypothesis of a ≤ 5% objective response rate would be rejected if at least 3 of 20 respond. Results: Twenty pts were enrolled; 13 breast cancer (12 HR+/HER2-, 1 TNBC) and 7 non-breast cancer (pancreas, colon, uterine, testicular, parotid salivary). Median age was 54 years. Of 12 response evaluable pts with breast cancer, 3 had a RECIST response (ORR = 25%, 2 g PALB2, 1 g CHEK2/g FANCA/sPTEN) and 3 additional pts (g PALB2, s ATR, s PTEN) had SD ≥ 6 months (CBR = 50%). No responses were seen in non-breast tumors; 2 (g CHEK2 testicular, g ATM colon) had SD ≥ 6 months. Talazoparib was well tolerated; 5 patients required dose reduction for hematologic toxicity. Results of tumor HR deficiency status assessment from metastatic biopsies and serial ctDNA profiling will be presented. Conclusions: In this proof-of-concept phase II study, single agent talazoparib demonstrated activity in HER2-negative advanced breast cancer pts with a HR pathway mutation beyond BRCA1/2. Further evaluation of talazoparib in this population is warranted. Clinical trial information: NCT02401347.
A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.
Authors: Kumthekar Priya , Rademaker Alfred , Ko Caroline , Dixit Karan , Schwartz Margaret A. , Sonabend Adam M. , Sharp Laura , Lukas Rimas Vincas , Stupp Roger , Horbinski Craig , McCortney Kathleen , Stegh Alexander H.
Published: May 2019

3012

Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated with a corona of densely packed, highly oriented siRNA oligonucleotides targeted to the GBM oncogene BCL2L12, represent a novel class of blood-brain and blood-tumor barrier-permeable nanomedicinal conjugates, for suppressing gene expression in the tumors of GBM patients. Methods: This is a single-arm, open-label, “window of opportunity” phase 0 first-in-human trial to determine the safety and bioavailability of a novel nanotherapeutic compound, NU-0129. Enrolled patients were treated with intravenous NU-0129 at the dose of 0.04mg/kg. This treatment dosing was considered microdosing defined as 1/50ththe NOAEL (no observed adverse event level) from non-human primate studies. Treatment was followed by tumor resection 8-48 hours later. Primary outcome patient safety and toxicity was monitored weekly for 3 weeks post-infusion. Secondary objectives included biodistribution of NU0129 in tissue, evaluation of pharmacokinetics of NU0129 and the feasibility of NU0129 administration. Exploratory objectives included Bcl2L12 expression and post treatment apoptotic markers as well as progression free survival and overall survival rates. Results: 8 patients were enrolled, treated and subsequently underwent surgical resection. No significant treatment related toxicities were seen. Severe ( > grade 3) adverse events were observed in two patients: hypophosphatemia (one grade 3, one grade 4) and one patient with grade 3 lymphopenia, all were considered as “possibly related” by treating oncologists. In 6 of the 8 patients sufficient tumor tissue was available for analysis of gold accumulation by ICP-MS (inductively coupled plasma-mass spectrometry), and gold accumulation was seen in the tumor tissue of all 6 of these patients. Conclusions: Macrodosing of the nanotherapeutic NU-0129 was well tolerated in glioblastoma patients with no unexpected adverse effects and showed initial evidence of crossing blood brain barrier. Immunohistochemistry for Bcl2L12 expression, apoptotic markers, and PK studies are pending. The demonstration of gold nanoparticles in the tumor tissue validates this approach for drug delivery. Clinical trial information: NCT03020017.
Design and development of the molecular analysis for Therapy Choice (NCI-MATCH) Designated Laboratory Network.
Authors: Tricoli James V. , Zane Linda , Harrington Robin , Yee Laura , Harper Kneshay N. , Chang Ting-Chia , Harris Lyndsay , Chen Alice P. , Flaherty Keith , O'Dwyer Peter J. , Conley Barbara A. , Winter Cynthia , Lee Jennifer , Williams Paul M. , Sklar Jeffrey , Patton David , Tsongalis Gregory J. , Hamilton Stanley R. , Iafrate A. John , Karlovich Chris Alan ,   The NCI MATCH Designated Laboratory Network
Published: May 2019

3016

Background: NCI-MATCH is a precision medicine trial that assigns treatment to refractory cancer patients by tumor mutation profile rather than by histology. After screening fresh tumor biopsies from nearly 6000 patients many treatment arms did not meet accrual due to the low prevalence of the eligible variants. NCI MATCH developed an approach to identify patients for the remaining arms utilizing a network of academic and commercial CLIA-certified labs that perform NGS assays as routine care at MATCH participating sites. Methods: Candidate labs were recruited through a notice in the Federal Register and posted on the NCI and ECOG ACRIN web sites. Twenty-seven labs (17 academic/10 commercial) submitted applications. After acceptance each lab analyzed a common set of 10 DNAs extracted from 8 cell lines and 2 clinical samples for concordance with the central NCI-MATCH NGS assay. Results: For the 17 labs with concordance results, a median of 8 (range 2 – 58) copy number variants (CNVs) were evaluated by the NGS assay of each DL, with the number evaluated depending on each lab’s clinical assay panel content. CNV concordance between central and DL assays, as measured by positive percent agreement (PPA), averaged 98.7% (range 87.5% - 100%) with the central assay as referent and 94.1% (range 77.8% – 100%) with the DL assay as referent. For single nucleotide variants (SNVs) and Insertion/deletions (Indels) combined, a median of 19 variants (range 11 – 26) were evaluated by each DL for concordance. PPA between central and DL assays averaged 98.0% (range 87.5% – 100%) and 98.6% (range 90.0% – 100%) with central and DL assay as referents, respectively. Strong correlations were observed between central and DL assays for both CNVs (median r = 0.93; 0.33 – 1.00) and SNV/Indels (median r = 0.98; 0.67 – 0.99). Conclusions: Our results suggest that different NGS assay platforms using diverse strategies for target enrichment and data analysis may still achieve high concordance if pre-analytical variables are minimized and the common genomic regions interrogated by each assay are well-understood. The designated lab network allows for a wider search for rare variants in tumors and provides a model for conducting future clinical trials. Clinical trial information: NCT02465060.
Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials.
Authors: Siena Salvatore , Doebele Robert Charles , Shaw Alice Tsang , Karapetis Christos Stelios , Tan Daniel Shao-Weng , Cho Byoung Chul , Kim Dong-Wan , Ahn Myung-Ju , Krebs Matthew , Goto Koichi , Garrido Lopez Pilar , Farago Anna F. , Loong Herbert H. F. , Tosi Diego , Barve Minal A. , Simmons Brian P. , Ye Chenglin , Eng Susan , Drilon Alexander E.
Published: May 2019

3017

Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]