bluuebunny/crossref_metadata_2025 huggingface dataset:
A severe case of refractory esophageal stenosis induced by nivolumab and responding to personalized treatment.
Authors: Obeid Michel
Published: July 2019

113

Background: The prevalence of esophageal stenosis caused by ICI in the context of induced immune mucositis and esophagitis is extremely rare. Methods: NA. Results: Case presentation: We report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory. Esophagogastroduodenoscopy revealed mucositis with a scar-like stricture immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. A blood sample revealed a discrete increase in the ESR with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent response, allowing the total resolution of the irAEs leading to successful steroid tapering. Conclusions: Herein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory irAEs.
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Tun Aung , Thein Wai Lin , Elfiky Aymen , Gasperino James , Guevara Elizabeth
Published: July 2019

117

Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced 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: Seven phase 2 & 3 RCTs (Keynote-021,189, 407, IMpower-131, 150, checkmate-227, and Govindan et al) including 3785 patients with advanced NSCLC were included in the analysis. IMpower 150 trial allowed EGFR or ALK mutated patients. The study arm used standard treatment regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab, while control arm used only standard treatment regimens. The pooled HR for PFS was 0.65 (95% CI: 0.56-0.77; P=0.00001), the pooled HR for OS was 0.73 (95% CI: 0.59-0.90; P=0.003), and the pooled RR for ORR was 1.45 (95 CI: 1.17-1.8; P=0.0007). The pooled RRs for all-grade AEs and high-grade AEs were 1.1 (95% CI: 1-1.21; P=0.05) and 1.28 (95% CI: 1.13-1.46; P=0.0001), respectively. Conclusions: Adding immunotherapy to standard regimen significantly improves PFS, OS, and ORR for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.
Estimated costs of grade 3–4 all-cause and treatment-related adverse events for stage IV or recurrent non-small cell lung cancer (NSCLC) in the CheckMate 227 (CM-227) trial.
Authors: Stenehjem David D. , Santi Irene , Gupte-Singh Komal , Penrod John R. , Venkatachalam Meena
Published: July 2019

120

Background: In the ongoing phase 3 CM-227 trial, nivolumab + ipilimumab (N+I) showed significantly longer progression-free survival compared to chemotherapy (C) among patients with NSCLC and tumor mutational burden (TMB) ≥10 mutations/megabase (high) by Foundation One CDx. The frequencies of all-cause (AC) and treatment-related (TR) adverse events (AEs) including grade 3–4 AEs were similar between the N+I and C arms, although the types of AEs differed. This study estimated the costs of managing grade 3–4 ACAEs and TRAEs in the first year after treatment initiation in CM-227 patients with high TMB. Methods: The frequency, grade, and attribution of AEs were extracted from CM-227 patient-level data. Costs of managing each grade 3–4 ACAE and grade 3–4 TRAE were estimated using related codes of the International Classification of Disease, 10th Revision, as well as cost information from the Healthcare Cost and Utilization Project National Inpatient Sample data (2015). A sensitivity analysis accounting for treatment duration and a temporal trends analysis were conducted. Results: In patients treated with N+I (n = 135), 157 grade 3–4 ACAEs and 70 grade 3–4 TRAEs were observed compared to 153 and 74 respectively among the patients treated with C (n = 159). The cost of managing grade 3–4 ACAEs per treated patient for N+I was $19,602 and for C was $16,353 (difference $3,249; 95% CI $1,774–$4,723), while the cost of managing grade 3–4 TRAEs per treated patient was $6,921 and $8,925 for N+I and C, respectively (difference $2,004; 95% CI $878–$3,131). An analysis adjusting for treatment duration yielded lower cost per person-month for N+I compared to C for both grade 3–4 ACAEs ($2,886 and $3,521; difference $634; 95% CI $379–$889) and grade 3–4 TRAEs ($1,019 and $1,921, difference $902; 95% CI $696–$1,109). For both N+I and C, the cost of managing grade 3–4 ACAEs and grade 3–4 TRAEs per person-month was highest in the first 3 months and declined thereafter. Conclusions: The cost of ACAEs was somewhat higher for N+I than for C, while the cost of TRAEs was somewhat lower for N+I than for C. Adjusting for treatment duration, N+I had lower costs for both ACAEs and TRAEs compared to C. Clinical trial information: NCT02477826.
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced squamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Tun Aung , Thein Wai Lin , Gasperino James , Elfiky Aymen , Guevara Elizabeth
Published: July 2019

121

Background: Squamous Non-small cell lung cancer (NSCLC) accounts for ~30% of lung cancers, and long-term survival remains poor for advanced disease. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced 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 3 RCTs (Keynote – 407, IMpower – 131, and Govindan et al) including 1991 patients with advanced squamous NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, or atezolizumab, while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.71 (95% CI: 0.56-0.9; P = 0.005), the pooled HR for OS was 0.84 (95% CI: 0.68-1.04; P = 0.11), and the pooled RR for ORR was 1.19 (95 CI: 0.9-1.56; P = 0.22). The pooled RRs for all-grade AEs and high-grade AEs were 1.17 (95% CI: 0.99-1.39; P = 0.07) and 1.36 (95% CI: 1.19-1.56; P = 0.0001), respectively. Conclusions: The combined chemo-immunotherapy improves PFS without significant improvement in OS & ORR compared to standard chemotherapy for the first-line treatment of advanced squamous NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.
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]
Paradoxical effect of regulatory T-cell density in the invasive margin on colon cancer disease-free survival.
Authors: Lombardo Jamie , Messersmith Lynn , Williams Grant , Hickerson Annelies , Campf Jessica , Collins Ryan , Brady Robert , Peoples George Earl , Clifton Guy T.
Published: July 2019

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Background: Increased numbers of FoxP3+ regulatory T cells (Treg), an immunosuppressive T cell subpopulation, in the tumor microenvironment (TME) has been associated with decreased recurrence risk in colon cancer. We assessed the association of Treg levels and disease-free survival (DFS) to confirm correlation with recurrence risk and to evaluate the impact on DFS in patients with colon cancer. Methods: Cases of colonic adenocarcinoma with endoscopic biopsies who had curative resection were collected from 2006-2016. The tissue sections were stained with FoxP3 immunohistochemical stain. FoxP3+ cells (Tregs) were counted with a digital imager software program and reported as cells per square mm. DFS from time of surgery was determined with a retrospective chart review. FoxP3 levels were compared with a Man-Whitney U test and DFS was compared with a Spearman’s test and regression. Results: 109 matched endoscopic biopsy colonic adenocarcinoma specimens were gathered. 94 cases had at least 4 months of follow up and were analyzed. The recurrence rate was 21.3% (20/94) with a median recurrence time of 13.5 months. The median time to follow up in patients with no recurrence was 39 (range 4-116) months. Tregs in those that recurred had a mean density of 152 (range 9-1267) at the invasive margin compared to 251 (range 15-485) in the cases that did not yet recur (p = 0.005). The same association was observed with Treg density in the center of the tumor (p = 0.03). In the cases that had a recurrence, there was a moderate, inverse correlation between Tregs at the invasive margin and time to recurrence (Spearman’s correlation coefficient = -0.46, p = 0.04.) A logarithmic inverse relationship between Tregs at the invasive margin and time to recurrence was observed (Correlation coefficient -0.63, p = 0.003). Conclusions: Treg density in endoscopic biopsies in colon adenocarcinoma is associated with recurrence risk, consistent with previously reported observations. Paradoxically, in patients who did recur, higher Treg density was associated with shorter time to recurrence. This discordant relationship of Treg density and colon cancer prognosis warrants further investigation.
Modeling of prognostication based on genomic expression in the tumor microenvironment of muscle invasive urothelial carcinoma via machine learning.
Authors: Lee Sunyoung S. , Lee Dong Eun , Baird Andrew , Lee Seongwon , Park Shinyoung , Dolan Jillian , George Saby
Published: July 2019

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Background: Stroma in the tumor microenvironment (TME) influences prognosis and response to therapy. Few mathematical models exist to prognosticate patients (pts), based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 401 pts with muscle invasive urothelial carcinoma were obtained from TCGA. Expressivity of 191 genes enriched in cellular and structural elements of TME and clinical data were analyzed by Kaplan-Meier (KM) analysis, correlation analysis, and multivariate nonlinear regression assisted by machine learning to achieve confined optimization with model-data minimization among multiple distribution functions. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in stage 2-4 (Table, stage 1 data not available from TCGA). P/G is the ratio of genes associated with poor (19 genes) to good (11) prognosis (refer to presentation). Based on RS, pts in each stage were clustered into 2 groups (high and low RS), showing 2 KM curves with p < 0.01 in each stage, confirming the validity of RS modeling. Analysis of immune profiles in these 2 groups shows that regardless of stage, expression of genes associated with Desmoplasia, Angiogenesis, and Epithelial-mesenchymal transition (DAE) is higher in high RS groups. Furthermore, expression of DEA genes in stage 4 correlated more strongly with poor prognosis than observed in stage 2-3 as evidenced by smaller p-value. Among stage 4 tumors, expression of genes related to IFN response, NK cells, and T1 helper cells is higher in low RS groups. In stage 2 and 3, genes related to immune activation and inhibition have no association with prognosis (p > 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis show that genes related to immune activation are associated with better prognosis, while DAE genes correlate with poorer prognosis among advanced stages. RS enables prognostication of pts encountered in the clinic, given genomic profiles. [Table: see text]
Relationship between tumor burden to growth rate and treatment outcomes of nivolumab for patients with head and neck squamous carcinoma.
Authors: Suzuki Chiaki , Kiyota Naomi , Imamura Yoshinori , Rikitake Junpei , Sai Satoshi , Koyama Taiji , Hyogo Yasuko , Nagatani Yoshiaki , Funakoshi Yohei , Toyoda Masanori , Otsuki Naoki , Nibu Ken-ichi , Minami Hironobu
Published: July 2019

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Background: Nivolumab improved overall survival (OS) in the treatment of platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) in a phase III clinical trial. However, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy may have better outcomes with cytotoxic treatment. Here, we explored suitable conditions and candidates of predictive factors for nivolumab for R/M HNSCC. Methods: We retrospectively reviewed the clinical records of 28 consecutive patients with HNSCC from 2014-2018. Tumor size was evaluated by computed tomography according to RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3Log (Dt/D0)/t, where D0 and Dt are the sum of the longest diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1 t defined as the 4-week interval between tumor evaluations. Results: After exclusion of 2 patients with unevaluable responses, 26 patients were included in the study. Median follow-up time for survivors was 9.5 months. Median SumTLs at baseline was 43.2 mm (range, 10.1-135.3). Median Gr was 0.22 (range, 0.05-0.76). Median OS and PFS was 7.9 months (95% CI, 5.8 to 34.5) and 3.7 months (95% CI, 2.1 to 12.9), respectively. Patients with progression within 3 months showed significantly worse survival (HR 6.33, 95% CI 2.08-21.67, p=0.001). Moreover, higher Gr and bigger SumTLs appeared to be associated with poorer outcomes. We therefore explored the association between prognosis and the ratio of SumTLs to Gr (SumTLs/Gr). The cut off value of SumTLs/Gr was calculated by ROC analysis. Pre-treatment SumTLs/Gr > 212 was associated with significantly worse OS (HR 8.87, 95% CI 2.33-58.29, p<0.001) and PFS (HR 2.86, 95% CI 1.10-8.33, p=0.03). Conclusions: Although retrospective with a small sample size, these results suggest that pre-treatment SumTLs/Gr > 212 was significantly associated with inferior OS and PFS in R/M HNSCC patients treated with nivolumab. R/M HNSCC patients with pre-treatment SumTLs/Gr > 212 might be unsuitable for treatment with nivolumab.
Expression of T-cell populations and molecular markers of human myocardium with checkpoint-induced myocarditis.
Authors: Zarifa Abdulrazzak , Kim Peter Y. , Gilchrist Susan , Iliescu Cezar , Suarez-Almazor Maria E. , Lopez-Mattei Juan , Balanescu Dinu Valentin , Donisan Teodora , Palaskas Nick , Upadhyay Ankit , Moudgil Rohit , Zhao Bihong , Buja Maximillian , Durand Jean-Bernard
Published: July 2019

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Background: Checkpoint Inhibitors have become first line therapy for a variety of solid and liquid malignancy. Immunotherapeutic agents predominantly target CTLA-4 and PD-L1. Efficacy has been demonstrated, and toxicities, especially cardiac manifested as myocarditis. The incidence of myocarditis is relatively low, fatality with monotherapy approaches 50% and with dual Immunotherapy is over 75%. No screening biomarkers or cardiac imaging predict a priori whom will develop myocarditis, nor which patients will be at risk. The frequency of these targets are unknown in the human heart. Methods: We present a case study of a patient with a diagnosis of urothelial carcinoma to lung and lymph nodes treated with systemic nivolumab plus NKTR after cycle 2 he presented with one week history of shortness of breath and hemodynamically unstable complete heart block requiring temporary transvenous pacemaker. Initial Troponin = 356, BNP = 2106. Given high suspicion for cardiovascular disease and or myocarditis, a left heart angiogram, right heart catheterization and endomyocardial biopsy of right ventricle were performed. RV biopsies were obtained percutaneously from right internal jugular approach with fluoroscopic guidance. Pulmonary capillary wedge pressure was 23mmHg. Persistent complete heart block was present during weaning attempts from temporary pacemaker and a percutaneous dual chamber pacemaker was implanted. Results: Coronary angiogram showed non obstructive disease, endomyocardial biopsy revealed lymphocytic infiltrate with necrosis based on Dallas Criteria. Immunohistochemistry showed, predominance of CD3,CD4,CD8,CD20,CD68 and PD-L1 staining was grossly positive compared to control samples. The patient was treated with methylprednisone 1mg/kg IV BID, plasmapheresis times 5 cycles, mycophenolate mofetil 500mg IV BID with resolution of symptoms and discharged to home. Conclusions: We present a patient with nivolumab induced myocarditis complicated with myocarditis and complete heart block. The pathological approach of T-Cell phenotyping is unique and identifies a novel approach to precision driven diagnosis, the incidence of PD-L1 expression in the human heart is unknown.
Patient (pt) experiences with avelumab in treatment-naive metastatic Merkel cell carcinoma (mMCC): Qualitative interview findings from a registrational clinical trial.
Authors: Bharmal Murtuza , Lambert Jeremy , Russell Jeffery Scott , Lebbé Celeste , Chmielowski Bartosz , Hennessy Meliessa , Marrel Alexia , D'Angelo Sandra P.
Published: July 2019

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Background: MCC is a rare, aggressive skin cancer with a poor prognosis. Avelumab is the only anti–PD-L1 monoclonal antibody approved for treatment of mMCC. This qualitative research embedded in a clinical trial aimed to explore pt experiences on treatment with avelumab. Methods: All treatment-naive pts with mMCC entering the registrational, open-label, multicenter trial to investigate the clinical activity and safety of avelumab were invited to participate in optional, semistructured, 30-min phone interviews at baseline (prior to study drug administration) and at weeks 13 and 25. Interviews were conducted by trained professionals, audio-recorded, transcribed, and analyzed using a qualitative software package, ATLAS.ti V7. Key concepts identified from the baseline interview for each pt were assessed during follow-up interviews. Results: A total of 29 pts (mean age, 71 y; 76% male) completed the baseline interview; 19 pts (6 in USA, 4 in France, 5 in Italy, 3 in Germany, 1 in Australia) had ≥1 follow-up interview. The baseline interviews revealed the negative psychological burden on pts living with a symptomless disease and the hope for avelumab to be a successful therapy. Over the course of the trial, most pts reported an increased or continued sense of hope and willingness to fight MCC. Pts who self-reported their disease to be improved (n=12) also reported being stable or experiencing improvements in their ability to do their daily activities and in their physical well-being and having more energy than before starting avelumab. They also reported worrying less and being optimistic. Six pts among the 7 who reported their condition as stable (n=4) or worsened (n=3) reported a worsening of their physical well-being. Nine pts reported fatigue/tiredness on the day of and the day after receiving the avelumab infusion. The reported baseline and longitudinal experiences were similar across pts from all countries. Conclusions: This qualitative study alongside a registrational trial showed that pts experienced perceptible benefits in their physical and psychological well-being following treatment success with avelumab in mMCC. Clinical trial information: NCT02155647 part B.
Smoking history and PD-1/PDL-1 pathway blockade: Predicting response to treatment in metastatic cancer.
Authors: Sullivan Caitlin Marie , Lu Jonathan , Kucharczyk John Ross , Vesselinovitch Diana , Khurana Neharika , KC Madhav , Matrana Marc Ryan
Published: July 2019

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Background: Identifying patients who will benefit from immune-checkpoint inhibitor therapy is a challenge as proven predicative indicators remain to be elucidated. High tumor mutational burden (TMB) represents a possible biomarker for response to PD1 blockade such as in nivolumab or pembrolizumab. Genomic analyses have shown that patients with heavy smoking history are more likely to have high TMB. However smoking status alone has not been examined independently in relation to treatment response. We sought to determine whether a relationship existed between smoking history and response to treatment in metastatic non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mMelanoma). Methods: A retrospective analysis was conducted of Ochsner Health System patients with mRCC, mMelanoma, and NSCLC receiving a minimum of two cycles of nivolumab or pembrolizumab between 12/2014 and 01/2018. Pre- and post-treatment target lesions were analyzed using RECIST criteria to calculate best response to treatment. Patient demographic information was gathered including age, sex, smoking history, and performance status pre and post treatment. Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) outcomes. Results: Heavy smokers (>10 pack-years) had a higher response to immunotherapy than light (< 10 years) and never smokers (p = 0.0500). Heavy smokers with NSCLC treated with immuno-therapy also had significantly improved OS compared to light smokers with NSCLC (p=0.003). mRCC immuno-therapy patients with heavy smoking history showed increased PFS compared to light/never smokers (p=0.026). Conclusions: In summary, in response to PD-1 blockade heavy smokers showed improved survival compared to light and never smokers suggesting smoking history may represent a potential predictor of treatment response to PD-1 inhibitor therapy.[Table: see text]