bluuebunny/crossref_metadata_2025_split huggingface dataset:
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced nonsquamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Thein Wai Lin , Tun Aung , Guevara Elizabeth , Elfiky Aymen , Gasperino James 
Published: July 2019

125 Background: RCTs have tested the role of adding immunotherapy to standard therapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the first-line setting. We conducted a systematic review and meta-analysis of RCTs to assess the efficacy and toxicity of adding immunotherapy in this patient population. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line standard therapy +/- immunotherapy in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 2 & 3 RCTs (Keynote – 021,189 and IMpower – 150) including 1431 patients with advanced non-squamous NSCLC patients were included in the analysis. Keynote 021 & 189 trials did not allow patients with EGFR or ALK mutations, while IMpower 150 trial allowed EGFR or ALK mutations. The study arm used standard regimens in combination with pembrolizumab or atezolizumab while control arm used only standard regimens. The pooled HR for PFS was 0.57 (95% CI: 0.5-0.65; P=0.00001), the pooled HR for OS was 0.61 (95% CI: 0.43-0.87; P=0.006), and the pooled RR for ORR was 1.83 (95 CI: 1.13-2.95; P=0.01). The pooled RRs for all-grade AEs and high-grade AEs were 1 (95% CI: 0.99-1.02; P=0.48) and 1.11 (95% CI: 0.97-1.28; P=0.14), respectively. Conclusions: Pooled data showed significant improvement in PFS, OS & ORR with chemo-immunotherapy compared to the standard treatment regimen for the first-line treatment of advanced non-squamous NSCLC. There was no increase in the risk of all-grade and high-grade AEs.
Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients previously treated with at least one prior systemic therapy.
Authors: Sarnaik Amod , Thomas Sajeve Samuel , Davar Diwakar , Kirkwood John M. , Kluger Harriet M. , Lutzky Jose , Wilson Melissa , Pavlick Anna C. , Curti Brendan D. , Whitman Eric D. , Phan Giao Q. , Ernstoff Marc S. , Takamura Kathryn Toshimi , Barton Debora , Suzuki Sam , Karyampudi Lavakumar , Samberg Nancy Louise , Fardis Maria , Chesney Jason Alan 
Published: July 2019

136 Background: While immunotherapies including checkpoint inhibitors and targeted therapies (BRAF/MEK inhibitors) are options for patients with metastatic melanoma, many patients still develop progressive disease. These patients have few treatment options available including high dose IL-2 and chemotherapy with reported second line response rates of 4-10%. Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma, able to elicit durable and complete responses in even heavily pretreated patients. We provide preliminary data for lifileucel TIL (LN-144) in heavily pre-treated metastatic melanoma patients who progressed on multiple checkpoint and BRAF/MEK inhibitors. Methods: C-144-01 is an ongoing global Phase 2, open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 47) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed at central GMP facilities in a 22-day manufacturing process. The final product was cryopreserved and shipped to sites. Patients received a one week cyclophosphamide/fludarabine preconditioning lymphodepletion regimen, a single lifileucel infusion, followed by up to 6 doses of iv IL-2 (600,000 IU/kg). Results: Patients with Stage IIIC/IV melanoma had 3.3 mean prior therapies (range: 1-9) and high baseline tumor burden, reflected by a mean sum of diameters of target lesions of 112 mm. Preliminary efficacy results: ORR = 38% (1 CR, 13 PR, 4 uPR), DCR = 77%, and median DOR 6.4 mo (range: 1.3 to 13.7) with median follow-up 6.0 mo. Longer follow-up led to improved responses in some patients including the CR. Frequency of AEs decreased over time, a potentially important benefit of one-time TIL treatment. Conclusions: Preliminary data support lifileucel TIL as an efficacious and well-tolerated therapeutic option for patients with metastatic melanoma who have failed multiple lines of prior therapies including checkpoint inhibitors and BRAF/MEK inhibitors. Clinical trial information: NCT02360579.
Checkpoint inhibitor (CPI) experienced patients (pts) from COSMUS-1: A clinical observational study of talimogene laherparepvec (T-VEC) in United States practice.
Authors: Perez Matthew , Amatruda Thomas , Conry Robert Martin , Ariyan Charlotte Eielson , Desai Anupam M. , Kirkwood John M. , Treichel Sheryl , Ismail Rubina , Raskin Leon 
Published: July 2019

142 Background: T-VEC, a modified oncolytic herpes virus, is an intralesional therapy for unresectable advanced melanoma. COSMUS-1, a recently presented observational chart review study from 7 US academic sites, described metastatic melanoma treatment (tx) patterns and safety of T-VEC in the real-world setting (Perez et al, SMR 2018). In this analysis, we evaluated T-VEC use in pts after prior CPI use or with CPI from COSMUS-1. Methods: Of 76 pts treated with T-VEC (first dose 27Nov2015-15Dec2016), 33 pts had received pembrolizumab, nivolumab and/or ipilimumab (ie, CPI) prior to or with T-VEC and were analyzed for demographics, clinicopathologic characteristics, outcomes, and adverse events. Two groups were identified: Group A, CPI then T-VEC only and Group B, CPI with T-VEC. Results: There were 21 pts in A and 12 pts in B; in B, all received TVEC + CPI with (1) prior CPI, n = 5, (2) prior CPI and additional CPI after combination, n = 1, (3) as combination only, n = 4, or (4) as combination followed by CPI only, n = 2. In A and B, respectively, mean age was 72 yrs and 63 yrs; 12 (57%) and 9 (75%) were men; 17 (81%) and 9 (75%) had ECOG 0-1,10 (48%) and 4 (33%) had Stage IIIB-IVM1a, and 11 (52%) and 7 (58%) had Stage IVM1b/c. Two pts (both in B) remained on T-VEC by study end. 21 (100%) pts in A and 10 (83%) pts in B discontinued T-VEC (most common, respectively: 10 pts and 3 pts due to disease progression, 4 pts and 2 pts due to physician decision). 2 pts had no injectable lesions left (in A) and 1 pt (in A) had pathologic complete response (CR). Adverse events of interest were reported in 7 pts (33%) in A and 6 pts (50%) in B; most common events in A and B, respectively, were immune-mediated events (n = 3 and 6) which included flu-like symptoms (fever, chills, rigor; n = 2 and 5) and injection site complications (n = 5 and 2). No herpetic infections were reported in pts. Conclusions: These real-world data suggest that T-VEC is well tolerated and can be administered in pts previously treated with a CPI, both those who switched to T-VEC or those where T-VEC was added on. One pt achieved a pathologic CR.
Antibiotic treatment prior to immune checkpoint inhibitor therapy as a tumor-agnostic predictive correlate of response in routine clinical practice.
Authors: Pinato David James , Howlett Sarah , Ottaviani Diego , Urus Heather , Patel Aisha , Mineo Takashi , Brock Cathryn , Power Danielle , Hatcher Olivia , Falconer Alison , Ingle Manasi , Brown Anna , Gujral Dorothy M. , Partridge Sarah , Sarwar Naveed , Gonzalez Michael , Bendle Maggie , Lewanski Conrad R. , Newsom-Davis Thomas , Bower Mark 
Published: July 2019

147 Background: Antibiotic therapy (ATB) may impair efficacy of immune checkpoint inhibitors (ICPI) through modulation of gut microbiota. Evidence is however limited to trial participants with non-small cell (NSCLC) and renal cell carcinoma (RCC). In this multi-centre study, we validated the impact of ATB in patients (pts) treated with ICPI in routine practice, irrespective of tumour site. Methods: We analysed a prospective dataset of pts treated with ICPI in 2 centres. We documented timing and duration of ATB administered within 1 month prior to ICPI treatment (pATB) or concurrently (cATB) until ICPI cessation. We evaluated response and overall survival (OS) across ATB+/-. Results: We enrolled 196 pts with NSCLC (n=119), Melanoma (n=38) and other histotypes (n=39). Most pts were male (n=137, 70%) with performance status 0-1 (n=159, 84%) and a median number of 2 metastatic sites (range 0-7). Pts received mostly anti-PD-1/PD-L1 ICPI (n=189, 96%) as first-line metastatic therapy (n=120, 62%). Twenty-nine patients (15%) received pATB with penicillins (n=22, 75%) for ≤7 days (n=26, 89%). Sixty-eight pts (35%) received penicillin-based (n=49, 72%) cATB for ≤7 days (n=39, 88%). Respiratory infections were the commonest indication for both pATB (n=16, 55%) and cATB (n=38, 85%). pATB (p<0.001) but not cATB (p=0.76) was associated with worse OS (26 vs. 2 months, Hazard Ratio 7.4, 95% CI 4.2-12.9) and increased likelihood of primary refractoriness to ICPI (44% vs 81%, p<0.001). pATB consistently worsened OS in NSCLC (26 vs. 2.5 months, p<0.001), melanoma (14 vs 3.9 months, p<0.001) and other tumours (11 vs 1.1 months, p<0.001). In multi-variable analyses pATB (p<0.001, HR 3.4, 95% CI 1.9-6.1) and response to ICPI (p<0.001, HR 8.2, 95% CI 4.0-16.9) predicted for OS independent of histotype, tumour burden, PS. Conclusions: This study suggests pATB to exert an independent detrimental effect on response and survival in unselected pts treated with ICPI in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICPI treatment.
Association between sample characteristics and tumor mutational burden estimated by next-generation sequencing-based multiplex gene panel assay.
Authors: Pham Nguyen Quy , Kanai Masashi , Kou Tadayuki , Kondo Tomohiro , Yamamoto Yoshihiro , Matsubara Junichi , Hiroshima Akinori , Mochizuki Hiroaki , Sakuma Tomohiro , Fukuyama Keita , Matsumoto Shigemi , Muto Manabu 
Published: July 2019

148 Background: Tumor mutational burden (TMB) measured via next-generation sequencing (NGS)-based gene panel testing is a promising biomarker for response to immune checkpoint inhibitors (ICIs) in solid tumors. However, little is known about the characteristics of tissue sample that can affect the TMB score. Methods: Data of 199 patients with solid tumors who underwent NGS-based gene panel assay were reviewed. Associations between the TMB score and sample characteristics, including sample DNA quality, sample type, sampling site, and storage period, were analyzed. Clinical outcomes of patients with a high TMB score (≥10 mutations/megabase) who received anti-PD-1 antibodies (n = 22) were also analyzed. Results: TMB score was significantly higher in samples that yielded a DNA library concentration of < 5 nM and in samples obtained from formalin-fixed paraffin-embedded tissue (FFPE) compared to fresh frozen tissue. The sample storage period was also positively correlated with TMB score. Of the 22 patients with a high TMB score, partial response and stable disease were observed in two (9.1%) and five (22.7%) cases, respectively. Among 15 non-responders, 11 (73.3%) had a low DNA library concentration, thereby indicating that a high TMB score might be attributable to false positive mutation calls. Conclusions: Our results suggest that the TMB score estimated via NGS-based gene panel assay could be affected by the DNA library concentration, sample type and storage period.
Hyperprogressive disease on immune checkpoint therapy in advanced solid malignancies: A systematic review.
Authors: Wei Xiao X. , Chanza Nieves M. , Ko Eric Chi-Ching , Mita Carol , Krajewski Katherine M. , Choueiri Toni K. , Rahma Osama E. , Harshman Lauren Christine 
Published: July 2019

154 Background: Immune checkpoint therapy has changed the treatment landscape for many malignancies. As these agents are rapidly being incorporated into clinical practice, a subset of patients appear to have an accelerated tumor growth rate (TGR) after treatment initiation, a phenomenon termed hyperprogressive disease (HPD). Methods: A systematic search of original articles published between January 2000 and June 2018 was performed using PubMed, Embase, and Web of Science. Studies were eligible for inclusion if they reported on HPD in adult patients with advanced solid malignancies treated with checkpoint inhibitors and provided a specific HPD definition. Abstracts from ASCO, ESMO, and IASLC meetings were also included. Prespecified outcomes of interest included criteria used to define HPD, incidence of HPD, and association between HPD with baseline clinical or molecular characteristics and survival outcomes. Results: Of 700 studies screened, 12 retrospective studies were eligible, 3 of which evaluated patients treated in the context of clinical trials. Lung cancer and melanoma were the most common of the diverse histologies represented. The most common treatment was anti-PD1/PD-L1 monotherapy. A variety of criteria were utilized to define HPD, including TGR, RECIST progression, and time to treatment failure. HPD incidence ranged from 2% to 29%, and the only clinical factor significantly associated with HPD in more than one study was increased age. MDM2/4 and EGFR alterations appear to be associated with a higher incidence of HPD. HPD was significantly associated with poor overall survival in 3 studies. Conclusions: It remains unclear whether HPD reflects worsening disease caused by immunotherapy or is simply a manifestation of unfavorable, treatment unresponsive disease biology. There is a need to establish a consensus definition for HPD, and to examine HPD in prospective cohorts with appropriate comparison arms.
Evaluating the value of checkpoint inhibitor therapy using the ASCO and ESMO frameworks.
Authors: Feng Sophie , Cao Yanshuo , Amir Eitan , Chen Eric Xueyu 
Published: July 2019

17 Background: The advent of checkpoint inhibitor therapy (CIT) has dramatically changed the oncology landscape, but is associated with significant costs. A positive randomized clinical trial (RCT) may not translate to meaningful outcomes for patients. The American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) have developed frameworks to quantify the value of cancer treatment. We applied these frameworks to RCTs involving CIT in order to explore the relationship between trial outcomes and magnitude of clinical benefit. Methods: A literature search was conducted to identify CIT RCTs. Data extracted included study characteristics, pre-specified estimated hazard ratios (eHR) and observed HR (oHR). ASCO Value Framework version 2016 and ESMO Magnitude of Clinical Benefit (MCB) scale v1.1 were applied to each publication by 2 authors independently. Results: 30 RCTs (3 adjuvant, and 27 advanced setting) using CIT were identified between January 2010- October 2018. The majority of trials were in lung cancer (37%) and melanoma (36%). The eHR was 0.71±0.06 (range: 0.55-0.78), and oHR was 0.76±0.15 (range: 0.49 – 1.11). 54% RCTs did not achieve eHR, with a difference of 0.16±0.12 (range: 0.01 – 0.41). ASCO framework scores ranged -24.0 to 71.3, far below the maximum potential score of 180. 18 RCTs formed the basis for FDA approvals. The mean ASCO framework score was 45.6 ± 16.6 (range: 14.4 - 71.3) for FDA approved indications, and 14.0 ± 18.4 (range: -24 – 49) for non-FDA approvals (p < 0.001). All FDA approvals scored grade 4 or 5 on the ESMO MCB scale, indicating a meaningful clinical benefit. Many non-FDA approved RCTs did not receive an MCB grade as they were negative trials. There was no difference in the ASCO framework scores between MCB grade 4 and 5 RCTs. 3 adjuvant RCTs had an ASCO framework score ranging from 20.5 to 38.7 despite an MCB Grade A. Conclusions: Many trials did not meet the pre-specified eHR. FDA approval had statistically significantly higher NHB scores than non-FDA approvals, and they were deemed to have a meaningful clinical benefit according to the ESMO MCB scale. ASCO framework scores may require re-calibration since the highest score achieved in CIT RCTs was only 40% of the maximum score.
The effect of adoptive transfer of ex vivo activated T cells on the efficacy and tumor penetrance of intravenously-administered CD3-engaging bispecific antibody.
Authors: Gedeon Patrick C. , Suryadevara Carter M. , Choi Bryan D. , Sampson John H. 
Published: July 2019

30 Background: Activated T cells are known to traffic throughout the body including past the blood-brain barrier where they perform routine immune surveillance. Whether activated T cells can be used to enhance the efficacy and delivery of intravenously-administered, immunotherapeutic antibodies has yet to be explored. Methods: To examine efficacy, T cell migration and antibody delivery in vivo, the invasive murine glioma, CT-2A-EGFRvIII, was implanted orthotopically in human CD3 transgenic mice. Cohorts of mice were given vehicle or 1x107 non-specifically activated, syngeneic T cells intravenously. Beginning the subsequent day, groups were treated with daily intravenous infusions of human-CD3-binding, tumor-lysis-inducing bispecific antibody (hEGFRvIII-CD3 bi-scFv) or control bispecific antibody. To block T cell extravasation, cohorts received natalizumab or isotype control via intraperitoneal injection every other day beginning on the day of adoptive cell transfer. T cell migration was assessed using whole body bioluminescence imaging of activated T cells transduced to express firefly luciferase. Bispecific antibody biodistribution was assessed using PET-CT imaging of iodine-124 labeled antibody. Results: Following intravenous administration, ex vivo activated T cells tracked to invasive, syngeneic, orthotopic glioma, reaching maximal levels on average four days following adoptive transfer. Administration of ex vivo activated T cells enhanced bispecific antibody efficacy causing a statistically significant increase in survival (p = 0.007) with 80% long-term survivors. Treatment with the T cell extravasation blocking molecule natalizumab abrogated the increase in efficacy to levels observed in cohorts that did not receive adoptive transfer of activated T cells (p = 0.922). Pre-administration with ex vivo activated T cells produced a statistically significant increase in tumor penetrance of radiolabeled bispecific antibody (p = 0.023). Conclusions: Adoptive transfer of non-specifically activated T cells enhances the efficacy and tumor penetrance of intravenously-administered CD3-binding bispecific antibody.
Long-term clinical outcomes and transcriptional analysis following partial and complete tumor SBRT plus pembrolizumab.
Authors: Bhave Sandeep Ramesh , Luke Jason J. , Lemons Jeffrey , Zha Yuanyuan , Carll Timothy C. , Krausz Thomas , Liang Hua , Janisch Linda A. , Hseu Robyn D. , Khodarev Nikolai , Weichselbaum Ralph R. , Pitroda Sean , Chmura Steven J. 
Published: July 2019

34 Background: Preclinical models support a combinatorial role of high-dose irradiation with immunotherapy. Multi-site stereotactic body radiotherapy (SBRT) with pembrolizumab (P) has been demonstrated as safe in advanced solid tumors. Here, we report extended follow-up of treated metastasis control (TMC), progression-free survival (PFS), overall survival (OS) and describe transcriptional changes associated with TMC, PFS and OS. Methods: Patients (pts) with AST received 3-5 SBRT doses (30-50 Gy total dose) to 2-4 metastases based on anatomic location. Pembrolizumab (200 mg IV Q3W) began one week following the final SBRT. Mets >65cc received partial-tumor SBRT. Response was measured by RECIST principles. TMC, PFS, and OS were estimated by Kaplan-Meier method. Pre- and post-SBRT biopsies from 24 pts were assayed via RNA microarray. Results: 68 pts (140 mets) were enrolled. 18 pts (21 mets) received partial tumor SBRT. Median volume of partially irradiated tumors was 121cc vs 7cc of fully irradiated (p=0.001). Median follow-up was 8.4 months (mo; range 1.1-24.2). 1-year TMC was 89.6%. At 12 mo TMC of partial versus full tumor irradiation was not significantly different (p=0.09). On multiple Cox regression, metastasis size, histology, volume of irradiated tumor and PD-L1 status were not predictive of TMC, PFS or OS. However, irradiated metastasis response predicted OS (HR = 0.37; 95% CI, 0.19-0.71; p = 0.003). Pts with irradiated met PR or CR had 17.8 mo median OS vs 9.1 and 3.4 in pts with mixed response or PD, respectively (p=0.005). Unsupervised transcriptional analysis of tumor biopsies demonstrated that the magnitude of DNA repair and innate/adaptive immune pathways induced in irradiated mets following SBRT was significantly associated with irradiated met response (p=0.009) and OS (p=0.007) to SBRT+P. Conclusions: Partial tumor SBRT+P approximates full tumor SBRT+P despite major differences in tumor volume. Transcriptional changes and clinical response of irradiated mets to SBRT+P are highly predictive of OS. Further research is needed to optimize immuno-radiotherapy. Clinical trial information: NCT02608385.
Optimized intratumoral delivery of a STING agonist results in improvements in local tumor immune activation.
Authors: Sheth Rahul , Munoz Nina , Dupuis Crystal , Williams Malea , Dixon Katherine , Maldonado Kiersten , Murthy Ravi , Tam Alda , Avritscher Rony 
Published: July 2019

38 Background: There has been a renaissance in the concept of promoting the immune-responsiveness of the tumor immune microenvironment via intratumoral (IT) delivery of immunostimulatory agents. As with any invasive intervention, though, outcomes following intratumoral drug delivery depend on procedural technique. We have previously shown that multi-sidehole needles (MSHNs) provide a 3-fold improvement in intratumoral drug delivery and retention relative to conventional end-hole needles (EHNs). The purpose of this study was to characterize how variations in drug delivery affect drug efficacy by evaluating immune activation following the IT delivery of a STING agonist using conventional end-hole needles (EHNs) versus multi-sidehole needles (MSHNs). Methods: Syngeneic McArdle RH-7777 (ATCC) hepatoma cells were implanted in the flank of Buffalo rats (n=20). Once tumors reached 15-20 mm in size, a STING agonist (50 ug ML RR-S2 CDA, Sigma Aldrich) vs saline (control) was injected under ultrasound visualization using either a 22G EHN or a 21G MSHN (ProFusion, Cook Regentec). Tumor tissue was harvested at 24 and 48 hours post-injection. Immune profiling was performed using flow cytometry and single cell RNA sequencing (scRNAseq). Results: There was a significant increase in tumor necrosis with MSHN injections compared to EHN or control injections (tumor viability 32%, 54%, and 82% at 48 hours, respectively). Gene expression profiling demonstrated a significant increase in interferon sensitive genes as well as STING-TBK1-IRF3 axis genes within dendritic cells with MSHN injections compared to EHN or control injections (Table). This signaling upregulation was greater at 24 hours than at 48 hours. MSHN injected tumors also exhibited fewer macrophages with immunosuppressive gene signatures and fewer T cells with exhaustion gene signatures relative to EHN or control tumors. Conclusions: Variations in IT delivery technique have a significant impact on subsequent immune activation following the injection of a STING agonist in an animal model of HCC. [Table: see text]