bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical response and biomarker analysis of a phase II basket trial of toripalimab, a PD-1 mAb in combination with standard chemotherapy as a first-line treatment for patients with solid tumors.
Authors: Ren Chao , Wei Xiao-Li , Xu Nong , Shen Lin , Dai Guanghai , Yuan Xianglin , Chen Ye , Yang Shujun , Shi Jianhua , Hu Xichun , Lin Xiaoyan , Zhang Qingyuan , Feng Jifeng , Ba Yi , Liu Yunpeng , Liu Wei , Shu Yongqian , Xu Rui-hua ,   Shanghai Junshi Biosciences
Published: May 2020

e15083

Background: Platinum based chemotherapy is the standard care for 1st line treatment of metastatic gastric adenocarcinoma (GC), esophageal squamous cell carcinoma (ESSC), nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC). Combinations of PD-1 blockade with chemotherapy have shown promising but mixed results in solid tumors. Predictive biomarkers for chemo-immunotherapy combination as 1st line treatment remain undefined. Methods: Patients (n = 60) included in this analysis were four complete cohorts from a multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in combination with standard chemotherapy for the 1st line treatment of GC, EC, NPC and HNSCC (excluding NPC). Whole exome sequencing (WES), RNA sequencing and immunohistochemistry were performed on tumor biopsy samples. PD-L1 expression and tumor mutational burden (TMB) were evaluated for correlation with clinical efficacy. Results: From Oct 2016 to Feb 2019, 33 GC, 12 ESSC, 12 NPC and 3 HNSCC patients were enrolled and treated with 240mg or 360 mg toripalimab Q3W via IV infusion in combination with Oxaliplatin/Capecitabine (XELOX), Paclitaxel/Cisplatin (PP), Gemcitabine/Cisplatin (GP) and Docetaxel/Cisplatin/5-FU(TPF) respectively. By the data cutoff date of Nov 15, 2019, all patients experienced treatment related adverse event (TRAE). There was one TRAE (heart failure) leading to death. Grade 3-4 TRAEs occurred in 67% patients, mostly attributed to chemotherapy, including 27% neutropenia, 23% thrombocytopenia, 18% leukopenia and 12% anemia. As assessed by investigators according to RECIST v1.1, the ORR/DCR were 54.5%/84.8%, 66.7%/91.7%, 75.0%/83.3% and 33.3%/100% respectively for GC, EC, NPC and HSNCC cohorts. The median duration of response was 8.3, 6.8, 7.7 and 7.1 months respectively. WES showed distinctive patterns of genomic alterations among different cohorts. The clinical response was not correlated with either PD-L1 expression or tumor mutational burden. Conclusions: Toripalimab in combination with chemotherapy as first-line treatments showed promising results for metastatic GC, EC, NPC and HNSCC patients. Two randomized Phase III trials of toripalimab in combination with Paclitaxel/Cisplatin or Gemcitabine/Cisplatin versus chemotherapy alone are ongoing to further evaluate the combination as first-line treatments in metastatic EC and NPC patients. Clinical trial information: NCT02915432 .
Markers of immune checkpoint inhibitor efficacy in the AACR Project GENIE database.
Authors: Yang Yuanchu J , Rubinstein Sam , Warner Jeremy Lyle
Published: May 2020

e15091

Background: Although immune checkpoint inhibitors (ICIs) have been shown to be effective in many tumor types, some highly lethal cancers are not responsive to ICI. Potential biomarkers of ICI response include tumor mutational burden (TMB), which is thought to correlate with increased neoantigen production, and 9p24.1 copy number gain (CNG), which can result in over-expression of programmed death ligand 1 (PD-L1). 9p24.1 CNGs have been described in ICI-sensitive (ICI-S) hematologic malignancies (e.g., Hodgkin lymphoma), but are not well described in solid malignancy. We sought to investigate TMB and 9p24.1 CNG for ICI-S and ICI-resistant (ICI-R) tumor types in the publicly available AACR Project GENIE database, version 7.0. Methods: TMB was calculated by counting somatic mutations with tumor reference allele frequency ≥5% and sequencing depth ≥200X. Samples with < 0.5 MB sequenced were excluded. 9p24.1 CNG was extrapolated from gene-level data. Samples with two or more consecutive gene amplifications in the 9p24.1 region were determined to have 9p24.1 CNG. Samples whose sequencing assay did not include at least two genes in 9p24.1 were excluded. Using an overall response rate (ORR) of ≥10% to define ICI-S, we assessed three ICI-S cancers: hepatobiliary cancer (HBC), melanoma (MEL), non-small cell lung cancer (NSCLC); and two ICI-R types: metastatic breast cancer (MBC) & pancreatic ductal adenocarcinoma (PDAC). Groupwise TMB was compared using Wilcoxon rank-sum and 9p24.1 CNG was compared using Chi-squared. Results: MEL had the highest median TMB but a low 9p24.1 CNG rate; NSCLC had the highest rate of 9p24.1 CNG (Table). PDAC had both the lowest median TMB and 9p24.1 CNG rate. As a group, the ICI-S cancers had higher median TMB (p < .001) and 9p24.1 CNG rate (p < .001). Conclusions: Although rates of 9p24.1 CNG were low across the database as a whole, the NSCLC finding replicates findings described in early stage resected NSCLC (Inoue et al. 2016). Relatively high median TMB in MEL may explain ICI-sensitivity in this cancer type. The combination of low median TMB and low rates of 9p24.1 CNG in PDAC may explain the general lack of efficacy of ICIs in this disease. These findings demonstrate the utility of GENIE as a clinico-genomic database, and also highlight the need to identify better markers of responsiveness to these potentially effective but toxic therapies. [Table: see text]
Long-lasting, irreversible and late-onset immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs): A real-world data analysis.
Authors: Ghisoni Eleonora , Wicky Alexandre M , Latifyan Sofiya , Mederos Alfonso Nuria Neisy , Özdemir Berna C. , Cuendet Michel A , Imbimbo Martina , Marandino Laura , Delyon Julie , Gerard Camille Lea , Tavazzi Erica , Gatta Roberto , Valabrega Giorgio , Aglietta Massimo , Obeid Michel , Coukos George , Peters Solange , Di Maio Massimo , Bouchaab Hasna , Michielin Olivier
Published: May 2020

e15095

Background: ICIs are effective in many tumors, but can cause severe irAEs, with potential long-term impact. Description of irAEs in literature is often insufficient, especially in terms of irAEs duration, and in terms of incidence of late-onset events. Namely, duration of irAEs and proportion of patients (pts) with toxicity still ongoing at data cut-off were not specified in 52 (89.6%) of 58 publications of trials leading to ICIs approval by US FDA and/or EMA up to August 2019. Real-world data are urgently needed to integrate this information. Methods: We retrieved the medical charts of all pts affected by lung cancer (LC) and melanoma (Mel) treated consecutively with approved ICIs at the Centre Hospitalier Universitaire Vaudoise (CHUV) from Jan 2012 to Dec 2019. We collected the following data: treatment setting, ICIs received, duration of each treatment, incidence of any irAEs of grade (G) ≥ 2 (according to CTCAE v5.0), time to onset and duration of irAEs. Pts with follow-up (FU) ≤ 28 days were excluded. Results: 345 pts were included (166 LC, 179 Mel), for a total of 455 ICIs treatment lines. 33 pts (7%, all with Mel) were treated in the adjuvant setting, while all the others were treated for advanced disease. 228 pts (50%) received anti-PD1, 43 (9%) anti-PD-L1, 56 (12%) anti-CTLA-4, 100 (22%) ICI-ICI combinations and 28 (6%) ICI–chemotherapy combinations. Median FU was 369 days (range 29-2903). Median duration of treatment was 71 days (range 1-1625). 196 pts (57%) experienced at least 1 G≥2 irAE for a total of 277 irAEs (22% skin, 18% gastro-intentinal [GI], 13% pneumonitis, 12% thyroid disorders, 11% hyphophisitis and 8% hepatitis). With 122/277 (44%) irAEs still on-going at our data cut-off, median duration of irAEs was 98 days; 104/277 irAEs (37%) lasted more than 6 month, of them 89% were considered irreversible. Out of 76 pts still on ICIs treatment at 6 months, incidence of G≥2 irAE with onset after 6 months was 51% (26% pneumonitis, 26% endocrine disorders, 15% skin disorders, 8% hepatitis and GI). Out of 32 pts still on ICIs treatment at 12 months, incidence of G≥2 irAE with onset after 12 months was 41% (38% pneumonitis, 23% endocrine and 15% skin disorders, 8% hepatitis and GI). Conclusions: Our real-world analysis shows that long-lasting and late-onset irAEs represent an important issue during ICIs treatment. A better description of toxicities in clinical trials is needed to allow a proper evaluation of treatment value and the impact on patients' quality of life.
Does radiation increase the risk of immunotherapy related pneumonitis in cancer patients with thorax radiotherapy combined immune checkpoint inhibitors: A meta-analysis.
Authors: Jie Yamin , Gu Anxin , Fu Pingfu , Kong Feng-Ming Spring
Published: May 2020

e15099

Background: Thorax radiotherapy (TRT) combined with immunotherapy has shown promising results. However, it remains unclear whether TRT would increases the risk of immunotherapy related pneumonitis (IRP). Here, we performed a meta-analysis to compare the rates of IRP in patients treated with TRT to patients treated without TRT. Methods: A meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Two individual researchers conducted the platform searches on the PubMed upto Nov. 4th, 2019. Quality of studies was assessed independently by two researchers using the Cochrane Collaboration's tool for randomized clinical trials, and the Newcastle-Ottawa Scale for cohort studies. Any disagreements encountered were settled through senior authors. The single rate of pneumonitis along with the corresponding 95% confidence interval (CI) was estimated. The odds ratio (OR) and its 95% CI were computed using random-effects model after checking the heterogeneity across studies using the Cochran Q chi-square test and the I2 statistic. Data analyses were performed using R version 3.6.2, meta and metafor packages. Results: A total of 62 studies including 14648 patients on IRP were first selected. Thirteen studies had two arms data, 501 patients were in TRT arm, 1185 patients were in non-TRT arm. Two studies including 557 patients were treated with immunotherapy and concurrent/sequential TRT. The remaining 47 studies had no TRT patients or TRT data were unavailable. The pooled rate of any grade IRP of all 62 studies (14648 patients) was 6% (95% CI: 5%-8%). All grades IRP was significantly higher among patients treated with immunotherapy and TRT arm when compared to the non-TRT arm (OR = 1.44, 95% CI: 1.04-2.00, P = 0.030). In the subgroup analysis, no significance difference in IRP rate was found between patients with various cancer types or various types of immune checkpoint inhibitors (p = 0.7033, p = 0.7522, respectively). The rate of IRP in all TRT patients was 18% (95% CI: 13%-24%), comparing to 5% (95% CI: 4%-6%) in control group. Conclusions: This meta-analysis demonstrates that TRT combined immunotherapy had an elevated incidence of IRP compared to non-TRT (OR = 1.44, 95% CI: 1.04-2.00, P = 0.030). There remains a lack of data on risk factors of IRP in TRT patients, and future large-scale studies are warranted. To our knowledge, this is the first comprehensive meta-analysis of IRP for TRT patients.
Impact of body mass index on survival rates in patients receiving immune checkpoint inhibitors.
Authors: Maslov Diana , Tawagi Karine , Simenson Victoria , Yuan Helen , Parent Cameron , Bamnolker Adi , Goel Richa , Blake Zoe , KC Madhav , Matrana Marc Ryan , Johnson Daniel H.
Published: May 2020

e15108

Background: Obesity is associated with 13 different cancer types, accounting for 40% of all cancers1. A few studies have linked a higher Body Mass Index (BMI) with longer Progression Free Survival (PFS) and Overall Survival (OS) from immune checkpoint inhibitors (CPI)s in patients with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma2,3,4. Our study evaluates CPI efficacy in patients with multiple tumor types in relation to Body Mass Index (BMI). Methods: We retrospectively collected data from patients treated with CPIs alone who also received steroids during their treatment from a single institution. This data included demographics such as age, sex, and BMI. Response and progression were defined per RECIST v1.1. The association of BMI and PFS was assessed by exact chi-square test. Kaplan Meier and Cox proportional hazard regression methods were used to estimate the survival probability and hazard ratios. Results: We identified a total of 129 overweight or obese patients (49%) with stage IV cancer who received CPI therapy. CDC guidelines define overweight as BMI > 25 and obese as BMI > 30. There was a significant relationship between PFS and BMI. Median PFS for those overweight was 287 days and 479 days for obese. Those with BMI 18.5-25 (normal), median PFS was 128 days and 103 days for those underweight (BMI < 18.5), (p = .0024). There was also a significant relationship between OS and BMI. Median OS for those obese was 751 days, for those overweight was 462 days. Median OS for those normal weight was 281 days and those underweight was 273 days (p = .0005). Obese patients had a 48% reduced risk of progression of disease/death as compared to those who had normal BMI (Hazard Ratio 0.52, p = .019). Overweight had a 31.5% relative risk reduction (HR 0.685, p = .05). Overall Response Rate was not significant between the two groups but there was a strong trend (p = .087). Conclusions: Higher BMI was associated with improved PFS and OS in patients with metastatic cancer across 20 different tumor types. Further investigation into the immune mechanisms behind this may lead to improvement in CPI efficacy for all patients.
Phase I pilot study of RRx-001 + nivolumab in patients with traditionally non-checkpoint inhibitor-responsive cancers (PRIMETIME).
Authors: Carter Corey , Caroen Scott , Oronsky Bryan , Quinn Mary Flanagan , Williams Jeannie , Brzezniak Christina E.
Published: May 2020

e15119

Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received > 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of > SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .
Results of a phase Ib study investigating durvalumab in combination with eribulin in patients with metastatic HER2-negative breast cancer and recurrent ovarian cancer.
Authors: Landry Chrystal Ann , Ru Meng , Hickson Christopher , Klein Paula , Fasano Julie , Bhardwaj Aarti , Shapiro Charles L. , Irie Hanna , Shao Theresa , Selkridge Isaiah , Tiersten Amy
Published: May 2020

e15120

Background: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a novel microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary anti-tumor activity of the combination in patients with previously treated HER2-negative MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3-6 patients with HER2-negative MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of dose limiting toxicities (DLTs) during cycle 1 and 2 of therapy. Secondary endpoints: AE rate, Objective Response Rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients [median age 63 (37-77)] with median 4 prior therapies for advanced disease were treated: 5 patients with HER2-negative MBC and 4 patients with ROC. The RP2D of eribulin was 1.4mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs ( > 50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1/2. There was one immune-related AE of grade ≥3 (hepatitis). Three patients discontinued study drug related to toxicity [neutropenia (n = 1), hepatic toxicity (n = 2)]. ORR was 55% (all partial response) and 4 additional patients experienced stable disease; all MBC patients experienced a response to therapy. Median PFS was 6.2 months. Median OS has not been reached. Conclusions: The combination of eribulin and durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early anti-tumor activity observed in this study suggests that further investigation of this combination is warranted. Clinical trial information: NCT03430518 .
A phase I study of APL-501, an anti-PD-1 antibody, in patients with recurrent or advanced solid tumors.
Authors: Voskoboynik Mark , Richardson Gary Edward , Mileshkin Linda R. , McNeil Catriona M. , Horvath Lisa , Benedetti Fabio M. , Choy Gavin S. , Sankar Neil , McCurry Shelly , Zhang Xiaoling , Gao Min , Shah Ajit K. , Millward Michael
Published: May 2020

e15125

Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .
Immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients with WNT pathway mutations (APC/CTNNB1).
Authors: Iranzo Patricia , Callejo Ana , Pedrola Anna , Pardo Aranda Nuria , Navarro Alejandro , Martinez-Marti Alex , Cedres Perez Susana , Ros Javier , Assaf Juan David , Saoudi Nadia , Carbonell Caterina , Amat Ramon , Frigola Joan , Jimenez Jose , Dienstmann Rodrigo , Palmer Hector G. , Vivancos Ana , Felip Enriqueta
Published: May 2020

e15137

Background: APC and CTNNB1 mutations (mut) lead to an aberrant activation of the WNT pathway which has been linked to lack of benefit of immunotherapy in patients (pts) with lung cancer. Our aim is to describe the pts’ characteristics of a NSCLC cohort with APC or CTNNB1 mut and their association with outcomes (Overall survival [OS] and Progression-Free-Survival [PFS]) when treated with ICI. Methods: We selected NSCLC pts with mut in APC or CTNNB1 by targeted NGS (tissue), whole exome sequencing (tissue) or Guardant 360(plasma) between January 2014 and October 2019. Functionality of mut and β-catenin protein expression by immunohistochemistry (IHC) were correlated with outcome. Results: We identified a total of 37 patients with 44 mutually-exclusive mutations in APC (31) or CTNNB1 (6), 25 adenocarcinomas (68%). Of APC mut cohort, 16 had pathogenic mut (52%) and 15 of unknown significance (48%). All 6 CTN NB1 mut were known pathogenic. Median OS (mOS) in metastatic setting was 21.6 months (m) (CI95% 14.9-NR), without differences between APC and CTNNB1 groups (HR 1.5, p = 0.4) or when stratified by mut functionality (HR 1.1, p = 0.8). Globally, 21 pts received treatment with ICI (57%, 19 APC, 2 CTNNB1), median PFS (mPFS) was 5.43m (1.8-21.7), with trend for shorter mPFS in CTNNB1 mut (mPFS 1.7m) vs. APC mut (mPFS 6.6m, HR 1.5, p = 0.1). Among patients treated with ICI, 8 (38%) had coexisting driver targetable alterations ( EGFR, ERBB2 or MET) and 13 (62%) other functional mut were found ( TP53, KRAS, STK11, BRCA2, ATM). mPFS was 3.9m (1.8-NR) in the subgroup with driver mut vs. 6.6m (1.4-NR) for remaining pts (HR 1.36, p = 0.5). In 15 pts β-catenin IHC was performed, being positive in 7 cases (47%), 4 of them received ICI with a mPFS 12.1m. Conclusions: In our experience, benefit with ICI is not influenced by the presence of APC mut, and small numbers of CTNNB1 cohort limit conclusive statements. Additional studies are required to assess WNT pathway activation on top of genomics and correlate with the ICI efficacy.
Tolerability of dual checkpoint blockade with nivolumab and ipilimumab: A meta-analysis.
Authors: Carvajal Alejandro Ramon , Huang Judy , Wu Shenhong
Published: May 2020

e15149

Background: The dual checkpoint blockade of PD-1 and CTLA-4 with nivolumab and ipilimumab have been used extensively for cancer immunotherapy in clinical practice and trials due to its efficacy. A critical concern is the tolerability of the combination due to the increased risk of severe immune-mediated adverse events. A meta-analysis of clinical trials was performed to assess the treatment tolerability measured as discontinuation due to adverse events. Methods: A search through PubMed as well as abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until December 2019 was performed to identify clinical trials in which the combination of nivolumab and ipilimumab was given to cancer patients. Eligible clinical trials reported a discontinuation rate due to adverse events for the groups of patients receiving nivolumab and ipilimumab. A random or fixed effects model was used to determine summary incidences, relative risks, and 95% confidence intervals. Results: Seven clinical studies which included a total of 3,213 patients (combo: 1746, control: 1467) with various cancers were selected. Overall, the intolerability of nivolumab and ipilimumab measured as the summary incidence of discontinuation due to adverse events was 25.1% (95% CI: 17.8-34.1%). The rate varied significantly with the type of cancer (P < 0.001). The lowest discontinuation rate was in uveal melanoma, with a rate of 11% (95% CI: 2.9-34.2%), and the highest discontinuation rate was in melanoma at 46.3% (95% CI: 36.6-56.4%). In comparison with chemotherapy controls from randomized controls, the intolerability was significantly higher with an relative risk of 2.1 (95% CI: 1.78-2.84) for the combination. Conclusions: There is a substantial risk for intolerability in cancer patients receiving the combination nivolumab and ipilimumab. Further studies are needed for risk mitigation.
Overall survival in high and very high PD-L1 expressing patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors in a real-world data setting.
Authors: Zhang Chenan , Sweetnam Connor , Wolf Frank , Walters Sheetal , Hirsch Jonathan , Brown Thomas D.
Published: May 2020

e15156

Background: Clinical trials show improved survival for advanced non-small cell lung cancer (aNSCLC) patients whose tumors are positive for PD-L1 expression when treated with immune checkpoint inhibitors (ICI), including pembrolizumab (Pb) and nivolumab (Nb). It is unclear whether relatively higher PD-L1 expression by tumor proportion score (TPS) is associated with better response to treatment, and whether this can be generalized to a real-world setting. Methods: We assessed overall survival (OS) across categories of PD-L1 expression levels among aNSCLC patients who received ICI monotherapy in the advanced/metastatic setting (stages IIIB or IV, or documented metastatic disease at diagnosis). Sub-analyses were performed based on first, second, or subsequent lines of treatment, as well as for patients receiving only Pb. The patient population is a sample from community health systems based in the United States, with data derived from electronic medical records and supplemented with molecular data integration from diagnostics labs. Results: 874 aNSCLC patients received ICI in the advanced/metastatic setting in the first line (n = 246, 28%), second line (n = 456, 52%), or third or later lines (n = 172, 20%). ICI-treated patients in any line with TPS of 1-49% (n = 148), 50-89% (n = 124), and 90-100% (n = 97) had OS of 6.9, 11.5, and 11.7 months, respectively. Pb-treated patients in any line with TPS of 1-49% (n = 38), 50-89% (n = 104), and 90-100% (n = 72) had OS of 5.5, 10.1, and 11.7 months, respectively. ICI-treated patients in the 1st line with TPS of 1-49% (n = 10), 50-89% (n = 80), and 90-100% (n = 59) had OS of 3.7, 8.0, and 7.4 months, respectively. Pb-treated patients in the first line with TPS of 1-49% (n = 7), 50-89% (n = 80), and 90-100% (n = 58) had OS of 3.7, 8.0, and 9.5 months, respectively. Conclusions: Results suggest OS benefit for real-world ICI-treated aNSCLC patients with PD-L1 TPS ≥50%, consistent with observations in clinical trials. The data further suggest additional benefits in the highest TPS category of 90-100% among Pb-treated patients, while the evidence is weaker for all ICI-treated patients, although comparisons did not reach statistical significance. A similar trend was seen in analyses of both patients treated in first-line only and in any line. Further analyses, to include comparison to clinical trial results, are warranted.
Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors.
Authors: Qin Qian , Patel Vaibhav G. , Wang Bo , Mellgard George , Gogerly-Moragoda Mahalya , Zhong Xiaobo , Parikh Anish B , Leiter Amanda , Gallagher Emily J. , Galsky Matt D. , Oh William K. , Tsao Che-Kai
Published: May 2020

e15160

Background: Development (DV) of immune-related adverse events (IRAEs) to immune checkpoint inhibitor (ICI) have been associated (asso/) with (w/) favorable treatment (tx) response, but heterogeneity in clinical presentation remains a concern. We aim to characterize the type, timing, and risk factors asso/ w/ IRAE DV in ICI-treated solid tumor (ST) patients (pts). Methods: The characteristics (char), tx course, and clinical outcomes of ST pts who received at least 2 ICI doses at our institution from 1/1/2011 to 4/29/2017 were reviewed. IRAEs were identified and graded (GR) based on CTCAE (v.4.0). Fisher’s exact test and multivariable regression analyses (MVA) were performed to study the differences between pts w/ versus without (w/o) IRAE. Results: Of the 344 pts identified, 111 pts (32%) had IRAE(s) w/ 145 total events (GR 1: 31%, GR 2: 57%, GR 3: 12%), of which 45% required systemic steroids (SS), 27% lead to ICI discontinuation (DC), and 17% lead to hospitalization (HP, Table). Median time to any IRAE was 12 weeks (w, range 1-149.5w). The most common IRAEs were endocrine (30%), gastrointestinal (GI, 28%), and skin (24%) related. On univariable analysis, antibiotic use, melanoma, and combination ICI use were asso/ w/ IRAE DV; melanoma remained significant on MRA (odds ratio, OR: 3.58 [1.68, 7.64], p = 0.0010). Pts w/ IRAE had higher disease control rate (complete/partial response + stable disease) than pts w/o IRAE (OR: 2.20 [1.29, 3.75], p = 0.0038). Conclusions: Our real-world data showed higher IRAE incidence when compared to those reported in trials, although no GR 4/5 IRAEs occurred. Melanoma was asso/ w/ IRAE DV on MRA, possibly due to the type, dose, and combination of ICIs. These findings warrant further investigation to better identify those at the highest risk to develop clinically significant IRAE. [Table: see text]
Comparative quantitative safety profiles of PD-1 and PD-L1 checkpoint inhibitor monotherapies: A Bayesian model-based meta-analysis.
Authors: Shulgin Boris , Smirnova Alexandra , Kosinsky Yuri , Helmlinger Gabriel , Peskov Kirill
Published: May 2020

e15167

Background: Anti-cancer therapies with immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis, to compare safety profiles of PD-1 and PD-L1 checkpoint inhibitor monotherapies. Methods: We performed an exhaustive search through PubMed and TrialTrove databases, ASCO and ESMO abstracts to identify relevant ICI safety data. A Bayesian meta-analysis (BMA) was performed for all-grade and high-grade (Grades 3-4) treatment-related AEs (trAEs) and immune-mediated AEs (imAEs). The analysis was performed for total AEs and individual AEs affecting different organs: dermatological (rash, pruritus), gastrointestinal (diarrhea, colitis), hepatic (AST, ALT), respiratory (pneumonitis), and endocrine (hyperthyroidism, hypothyroidism). Software STAN along with the brms package in R software were used for the BMA. Results: A total of 145 articles were identified, covering 30,737 patients in 153 cohorts treated with anti PD-1 and anti PD-L1 monotherapies. For total all-grade and grade 3&4 trAEs, anti PD-L1 demonstrated lower AE rates vs. anti PD-1 (65% vs. 69% and 12% vs. 16%, respectively). Results were similar for total all-grade and high-grade imAEs (19% vs. 26% and 4% vs. 7%, respectively). The analysis of all-grade individual trAEs showed that anti PD-L1 exhibited lower AE rates vs. anti PD-1 for rash (8% vs. 10.5%), pruritus (9% vs. 12%), diarrhea (8.5% vs. 11%), colitis (1.0% vs. 1.6%), AST (3.0% vs. 5.5%), ALT (3.5% vs. 5.6%), pneumonitis (3.0% vs. 3.9%), hyperthyroidism (0.8% vs. 4.0%) and hypothyroidism (6.0% vs. 8.0%). For grade 3&4 trAEs, differences between anti PD-L1 and anti PD-1 were: 0.6% vs. 1.3% for diarrhea, 0.7% vs. 1.4% for colitis, and 0.9% vs 1.6% for pneumonitis. All-grade imAEs were less frequent for anti PD-L1 vs. anti PD-1 for: rash (6.5% vs. 10%), colitis (1.0% vs. 2.0%), AST (3.5% vs. 3.9%), ALT (2.9% vs. 4.0%), pneumonitis (2.0% vs. 4.0%), hyperthyroidism (2.5% vs. 4.0%) and hypothyroidism (5.5% vs. 9.0%). Similar results were obtained for grade 3&4 imAEs incidences: rash (0.5% vs. 0.9%), diarrhea (0.5% vs. 1.5%), colitis (0.5% vs. 1.1%) and pneumonitis (0.9% vs. 1.4%). Conclusions: Significant differences in trAEs and imAEs rates were shown for anti PD-L1 vs. anti PD-1 monotherapies. Anti PD-L1 demonstrated more favorable safety profiles for total and individual AE rates. Notably, AE rates for pneumonitis and colitis were twice as high for anti PD-1 vs. anti PD-L1 therapies.
Correlation between TMB and MSI in patients with solid tumors.
Authors: ZHAO ZHENG , Li Wentao , Zhang Xing , Ge Minhui , Song Chao
Published: May 2020

e15169

Background: Both oftumor mutational burden (TMB) and microsatellite instability (MSI) are promising predictive biomarkers for immunotherapy in cancer treatment. However, the association between TMB and MSI with solid tumors was not well investigated especially in East Asian patients. Herein, the relationships for characterizing TMB and MSI in major cancer types were made. Methods: TMB and MSI were measured by 539 genes panel via NGS in tumor tissues. The TMB were calculated as the numbers of synonymous and nonsynonymous mutations, and InDels per megabase in coding regions. MSI was the gain or loss of nucleotides from repetitive DNA and the criteria of MSI-H were defined as above 10% positive of the 195 tested microsatellites sites, and this method was totally consistent with conventional MSI-PCR testing in Research and development sample verification. The relationships between TMB and MSI of 874 patients with solid tumors including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases were performed by Spearman rank correlation analysis via SPSS v22.0. Results: There was no significant correlation between TMB and MSI in total patients with solid tumors (r = 0.061, p = 0.073). Significantly correlations were observed in patients with colorectal cancer (r = 0.248, p = 0.006) and pancreatic cancer (r = 0.397, p = 0.040). Meanwhile, no significant correlations between TMB and MSI were identified in patients with liver cancer (r = -0.016, p = 0.830), bile duct cancer (r = 0.325, p = 0.070), gastric cancer (r = 0.209, p = 0.130), melanoma (r = -0.057, p = 0.757), glioma (r = 0.009, p = 0.967) and lung cancer (r = 0.015, p = 0.758). Interestingly, total eleven cases were confirmed as MSI high in patients with colorectal cancer, glioma and lung cancer all presented phenotypes of TMB high. Conclusions: We demonstrated the presence of tumor-specific properties correlations between TMB and MSI and provided new insights to use them as biomarkers in immunotherapy. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Comparison of tumor mutational burden across eight types of human cancer.
Authors: Chen Peng , Zhang Cuicui , Meng Zhaoting , Zhang Xing , Ge Minhui , Qin Huijuan
Published: May 2020

e15170

Background: Tumor mutational burden (TMB) is an impressive predictive biomarker for immune checkpoint inhibitors therapy, and immunotherapy is one of the most promising methods for cancer treatment. However, the profile of TMB in various types of cancers was still poorly understood. Methods: In this study, genomic profiling of DNA was performed using next generation sequencing from a 539 genes panel in tumor tissues. The TMB was defined as the numbers of SNVs including synonymous and nonsynonymous mutations, and InDels per megabase in coding regions of sequenced genome. TMB-H was defined as highest mutation load quintile (top 20%) in each cancer type. The values of TMB of 874 patients were compared among eight main tumor types including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases by multiple independent samples nonparametric Kruskal-Wallis H test via SPSS v22.0. Results: The median values of TMB in liver cancer, bile duct cancer, gastric cancer, colorectal cancer, pancreatic cancer, melanoma, glioma and lung cancer were 10.29, 8.09, 11.03, 10.29, 5.88, 7.35, 5.88 and 7.35 Muts/Mb, respectively. The cut-off values of TMB-H in corresponding eight solid tumors were 16.18, 19.12, 19.85, 16.18, 10.29, 13.24, 10.29 and 18.38 Muts/Mb, respectively. Based on nonparametric Kruskal-Wallis H test, there were significant differences of median TMB values across eight independent tumor types (χ2 = 26.752, p = 3.693×10−4). Significant differences between patients with colorectal cancer and pancreatic cancer ( p = 0.005) or lung cancer ( p = 0.011) were observed via pairwise comparisons. Conclusions: Our study proved the presence of significant differences across eight cancer types, deepened the knowledge of the cancer-specific of TMB, provided useful information in immunology therapy for East Asian patients with solid tumors. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Integration of TMB and tumor heterogeneity identify an immunologic subtype of melanoma with favorable survival.
Authors: Yang Chunhe , Zhao Guodong , Wang Jianfei , Wang Lingyu , Jin Ge , Lin Rongbo , Yang Yadong
Published: May 2020

e15183

Background: Tumor mutational burden (TMB) has been reported a predictive marker of response to immune checkpoint inhibition (ICI) therapy in previous clinical trials. However, TMB alone is not sufficient to accurately predict immunotherapy benefit. Additional biomarkers are needed for better stratification of immunotherapy sensitive patients. Methods: Here we combined TMB with tumor heterogeneity for evaluating response to ICI treatment. Mutation and clinical data were collected from several melanoma immunotherapy studies, including cohort treated with Ipilimumab and anti-PD-(L)1/anti-CTLA-4 (VanAllen_2015, n = 110; Miao_2018, n = 151) and a cohort treated with Nivolumab (Riaz_2017, n = 60). Tumor heterogeneity was estimated with mutant-allele tumor heterogeneity (MATH) or clone number. Benefit score was defined as ratio between TMB and tumor heterogeneity and the most significant critical values were selected to group patients. Besides, we calculated clonal TMB and investigated its correlation with TMB and tumor heterogeneity. Statistical analyses were performed using R software. Results: Benefit score was tested in several cohorts as a marker of ICI therapy response. In VanAllen_2015 and Miao_2018 cohort, TMB/MATH score significantly improved the performance of stratifying the overall survival (OS) of patients with ICI treatment compared with TMB alone as predictor (p = 0.0068 vs. p = 0.1 and p = 0.028 vs. p = 0.042). In Riaz_2017 cohort, we used clone number to calculate the benefit score due to the unavailability of the raw data. In this cohort, benefit score is also positively associated with higher overall survival (p = 0.056), which outperforms TMB alone with a significance of p = 0.57. Moreover, clonal TMB showed positive correlation with TMB (R > 0.3) and negative correlation with tumor heterogeneity (R < -0.3) in one melanoma cohort (Miao_2018). Conclusions: Tumor heterogeneity, combined with TMB showed superior efficacy in predicting response of ICI therapy. This may further help delineating the mechanisms of immunotherapy in melanoma patients.
Utilizing quantitative multiplex immunofluorescence to characterize paracrine interactions within the tumor-immune landscape of metastatic melanoma.
Authors: Maus Rachel L. , Leontovich Alexey , Moore Raymond , Nevala Wendy Kay , Flotte Thomas J. , Geyer Susan , Guo Ruifeng , Schimke Jill , Dicke Betty Ann , Markovic Svetomir
Published: May 2020

e15184

Background: Clinical responses to anti-PD1 immunotherapy in patients with metastatic melanoma (MM) remain challenging to predict. This clinical heterogeneity is also reflected in the tumor-immune microenvironment among patients and within a single tumor lesion. With the emergence of multiplex imaging platforms, defining complex phenotypes at single cell resolution has become possible. Here, we sought to objectively quantify paracrine tumor-immune interactions contributing to the variable clinical responses observed in patients receiving anti-PD1 therapy. Methods: Excisional lymph node (LN) biopsies were obtained from treatment-naïve patients with MM who underwent subsequent anti-PD1 therapy. A single 5µm section of LN tissue was used to assess a 42 analyte panel by multiplex immunofluorescence. From 30 LN samples, 418 fields of view (FOVs) were selected resulting in 14,360 high-resolution images of 4 anatomical subregions: tumor core, tumor-immune interface, tumor infiltrate and adjacent immune stroma. Following image processing, we developed an adaptive classification for tumor-centric cellular neighborhoods (TCCN) to identify and quantify critical paracrine interactions within the tumor-immune microenvironment. Results: Stratification based on responsiveness to anti-PD1 therapy resulted in 4 complete responders (CR) and 12 non-responders (NR) at 12-week follow-up. From 126 FOVs, we defined the cellular composition of 197,865 TCCN across patients based on clinical response and LN subregions. Overall, the percentage of TCCN devoid of any T cells, B cells or macrophages was significantly higher in NR compared to CR irrespective of subregion. However, other markers differentiated TCCN based on subregion. Specifically in CR, tumor core regions were enriched for CD8 T cells, while enrichment for B cells and endothelial cells was demonstrated at the tumor-immune interface. Strikingly, tumor infiltrate regions demonstrate robust immune reactivity with enrichment for M1 polarized macrophages, NK cells and B cells in CR compared to NR. Complete data from the 30 patient cohort across 418 FOVs will be presented. Conclusions: Taken together, this data suggests cellular composition of TCCN across subregions of the LN is dynamic within a single metastatic site. In this small cohort, we introduce a formalized stratification to quantify and classify critical paracrine interactions within the immune-tumor microenvironment with the potential to inform clinical responsiveness to therapy.
The role of TGF-β pathway in immune regulation as a potential biomarker of immunotherapy across pan-cancer.
Authors: Yin Yongmei , Liang Yan , Zhao Zhengyi , Zhang Yuzi , Zhao Jing , Cui Longgang , Wang Guoqiang , Bai Yuezong , Cai Shangli
Published: May 2020

e15187

Background: The transforming growth factor beta (TGF-β) signaling pathway has been reported to be involved in both tumor suppression and tumor promotion. However, the role of TGF-β pathway in immune regulation for cancer patients and its influences on immunotherapy efficacy have not been systematically investigated. Methods: Available data of whole-exome sequencing, mRNA expression, baseline characterization and prognosis information of 10,912 pancancer patients were adopted from The Cancer Genome Altas (TCGA) to explore the role of TGF-β pathway in immune regulation. Formalin-fixed, paraffin-embedded tissue samples from 6,717 Chinese patients with over 17 tumor types were assayed by next-generation sequencing with a panel with 381 cancer related genes as a validation cohort (3DMed cohort). Datasets from the public MSK cohort (N = 1,610) was used to explore the association of TGF-β pathway in patient survival. Results: The highest prevalence of single nucleotide variation (SNVs) in TGF-β pathway fell in digestive system tumors in both TCGA and 3DMed cohorts, including colon adenocarcinoma pancreatic adenocarcinoma, rectum adenocarcinoma, and stomach adenocarcinoma. TGF-β pathway SNVs was significantly correlated with high microsatellite instability, high tumor mutational burden (TMB-H) status and high neoantigen burden (TNB-H) ( p< 0.001) across all tumor types. Notably, the correlation of pathway alternation and TMB or TNB remained significance in microsatellite stable patients ( p< 0.001). Alternations of the pathway genes were associated with significant different expression patterns of immune-related genes such as the up-regulation of CD28, CD40, and CCL5, etc. Consistently, significant higher levels of CD8 ( p< 0.001), dendritic cells ( p< 0.001), and neutrophil cells ( p< 0.001) were observed in the pathway mutated samples. Patients with TGF-β pathway mutations exhibited significant worse prognosis than the wild-type patients regardless of interventions (overall survival, HR 1.20, 95% CI 1.08-1.33; p= 0.001). However, when treated with immune checkpoint inhibitors, superior survival benefit was observed in patients in the mutation group versus the wild-type group (overall survival, HR 0.73, 95% CI 0.61-0.88; p= 0.001). Conclusions: Our study has provided clues for the role of TGF-β pathway in immune regulation in patients with solid tumors and revealed the potential predictive role of TGF-β pathway alternation in cancer immunotherapy.