bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of murine PVSRIPO plus anti-PD-1 immune checkpoint inhibitor (ICI) in a melanoma tumor model.
Authors: Neighbours Lauren , McKay Zachary P , Gromeier Matthias , Nichols Garrett , Kelly Andrea True , Corum Daniel , Brown Michael
Published: June 2021

2560

Background: Most patients with advanced melanoma (mel) fail/acquire resistance to ICI, including anti-(α) PD-1. PVSRIPO is a novel intratumoral immunotherapy derived from the Sabin type 1 attenuated poliovirus (PV) that targets CD155, widely expressed on solid tumors and antigen-presenting cells (APCs) of the tumor microenvironment. Therapy leads to direct tumor cell death and type I/III interferon-dominant innate inflammation, mediating priming and recruitment of tumor antigen-specific T cells. Inflammation-mediated upregulation of the PD-1/L1 IC suggests greater anti-tumor response could be achieved with PVSRIPO + αPD-1. The aim of this preclinical study was to evaluate the efficacy and safety of murine PVSRIPO (mRIPO) + αPD-1 in an aggressive mel tumor model (B16-F10.9-OVA in human-CD155 transgenic mice [C56BI/6]). Methods: Mice were randomized to 4 groups (G) of 12: (G1 [control]: vehicle [v] + IgG; G2: v + αPD-1; G3: mRIPO + IgG; G4: mRIPO + αPD-1). Tumor cells (5 x 105) were implanted into the right (R) and left (L) flanks. When tumor volume (vol) was ̃25 mm3, 15 µL v or 1 x 107 TCID50 mRIPO was injected into R (Day 1) and L (Day 4) tumors; αPD-1 or IgG (250 µg, 100 µL ip) was given on Days 1 and 4 and q 3 days until termination (Day 13). Weight, hematology, chemistry, and inflammatory cytokines were assessed pre/post-tumor implantation. Tumor vol was assessed every other day, with gross/histologic exam at termination. Results: 47 mice without health issues were euthanized as planned; 1 G1 animal required early euthanasia for tumor ulceration. Microscopic findings: increased mononuclear cell tumor infiltrates (G2 and G4); less severe L tumor growth necrosis in G2, G3, and G4 vs G1. There were no specific treatment-related changes in serum cytokines in G4. See the table below for summary of total tumor vol changes vs control; the most significant reduction was observed in G4. No tumor cells were observed via histopathology at Day 13 in R flanks of 1 mouse in G2; 3 in G3; and 8 in G4; and only G3 (n=1) and G4 (n=5) mice had no evidence of L flank tumor cells, with regression evident before L tumor mRIPO injection (ie, abscopal response). Conclusions: mRIPO + αPD-1 had the greatest overall anti-tumor response, and the combination was well tolerated. These results suggest combination therapy is not associated with untoward immune-mediated toxicity and highlight the potential for enhanced efficacy in injected and uninjected tumors. A phase 2 clinical trial of PVSRIPO ± αPD-1 in unresectable αPD-1 refractory mel is enrolling (LUMINOS-102, NCT04577807).[Table: see text]
Mega- and meta-analyses of fecal metagenomic studies in predicting response to immune checkpoint inhibitors.
Authors: Heirali Alya , Chen Bo , Wong Matthew , Schneeberger Pierre H.H. , Rey Victor , Spreafico Anna , Xu Wei , Coburn Bryan
Published: June 2021

2570

Background: A number of studies have demonstrated that the gut microbiome of responders to immune checkpoint inhibitors (ICI) is compositionally different compared to that of non-responders. However, differences in study design, patient cohorts and bioinformatic analyses make it challenging to identify bacterial species consistently associated with response to ICI across different cohorts and cancer types. Methods: We leveraged the statistical power of mega- and meta-analyses to identify bacterial species consistently associated with response to ICI using data from three published fecal metagenomic studies (Gopalakrishnan et al., Science 2018; Matson et al., Science 2018; Routy et al., Science 2018). Metagenomic data was uniformly processed and analyzed using Metaphlan v2.0. We conducted a two-part modelling approach of bacterial species present in at least 20% of samples to account for both prevalence and relative abundance differences between responders/non-responders. Results: A total of 190 patients (n = 103 responders; n = 87 non-responders) were included from the three studies. Data from Routy et al., was analyzed as subsets based on tumor type for a total of 4 analyzed cohorts. We identified five species including Bacteroides thetaiotaomicron, Clostridium bolteae, Holdemania filiformis, Clostridiaceae bacterium JC118 and Escherichia coli that were concordantly significantly different between responders and non-responders using both meta- and mega-analyses. B. thetaiotaomicron and Clostridium bolteae relative abundance (RA) were independently predictive of non-response to immunotherapy when data sets were combined and analyzed using mega-analyses (AUC 0.59 95% CI 0.51-0.68 and AUC 0.61 95% CI 0.52-0.69, respectively). Conclusions: Despite inter-cohort heterogeneity in tumor type, treatment regimens, and sequencing modalities, meta- and mega analysis of published metagenomic studies identified generalizable bacterial species associated with ICI response or lack thereof. B. thetaiotaomicron and C. bolteae were predictors of non-response to ICI suggesting the clinical potential of narrow spectrum anti-biotics targeting non-response associated bacterial species to improve outcomes in ICI recipients.
A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Ganju Vinod , Cooper Adam , Gao Bo , Wilkinson Kate
Published: June 2021

2577

Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.
Relationship between DICER1 mutations and immunotherapy biomarkers in solid tumors.
Authors: Gao Jie , You Xia , Guo Taiyan , Zhang Qin , Duan Qianqian , Qi Chuang
Published: June 2021

2603

Background: Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. DICER1 is the core caner-intrinsic CTL-evasion gene, especially positive correlate with innate anti-PD-1 resistance signature or IPRES signature and hERV expression which involved in sensitivity and resistance to ICIs. Nevertheless, the association between mutations in DICER1 and the Chinese patients, the relationship between DICER1 mutations with immunotherapy biomarkers are unknown. Methods: NGS and clinical data were collected from 10953 Western pan-cancer patients (TCGA cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 3514 Chinese pan-cancer patients (Chinese cohort). Both DICER1 mutation ratio and TMB were calculated on the two cohorts following the same criteria.DNA NGS testing (MSI-high vs low/stable (MSS)) in Chinese cohort were included. NGS data of 3514 patients who also detected PD-L1 expression from Chinese clinical dataset were analyzed to explore the association with mutation and PD-L1. The survival information was collected from 1661 pan-cancer patients to analyze the association between DICER1 mutation and efficacy of immunotherapy (MSKCC cohort). Results: In total, 2.91% (319/10953) patients in TCGA harbored DICER1 mutation; in the Chinese cohort, the DICER1 mutation ratio (2.67%, 94/3514) was similar to TCGA. The top 5 mutant DICER1-associated cancer types in Chinese cohort were lung cancer, colon adenocarcinoma, liver cancer, uterine corpus endometrial carcinoma, melanoma. In both cohorts, TMB level of mutation group was significantly higher than wild-type group (p < 0.001). The ration of mutation group in MSI-H (50%) and MSI-L (23.53%) was significantly higher than wild-type group in Chinese cohort (2.17%) (p < 0.001). In addition, the ratio of PD-L1 positive expression (≥1%) in mutation group (48.94%, 46/48) was significantly higher than wild-type in Chinese cohort (38.48%,1316/2104) (p < 0.05). The survival probability of mutation group was significantly longer than wild-type group in immunotherapy. Conclusions: The results indicated that DICER1 mutation was associated with a higher TMB, MSI-H and PD-L1 expression level in Chinese patients. Patients with DICER1 mutations may benefit more from ICIs.
Awareness and utilization of tumor mutation burden (TMB) as a biomarker for administration of immuno-oncology (I-O) therapeutics by practicing community oncologists in the United States (U.S.).
Authors: Savill Kristin M. Zimmerman , Zettler Marjorie E. , Feinberg Bruce A. , Jeune-Smith Yolaine , Gajra Ajeet
Published: June 2021

2608

Background: TMB, a measurement of the number of mutations carried by tumor cells, is emerging as a biomarker for the identification of patients who may benefit from certain I-O-based therapies. TMB-high (TMB-H) tumors, defined by the detection of ≥10 mutations/megabase (mut/Mb) in tumor cells using a tissue-based assay such as the FoundationOneCDx (F1CDx) assay (Foundation Medicine, Inc.), may be more likely to respond to some I-O therapies. Higher neoantigen loads of TMB-H tumors have been proposed to contribute to increased responsiveness of TMB-H tumors to certain I-O therapeutics. Pembrolizumab was approved by the FDA on June 16, 2020 for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H tumors, as determined by F1CDx, based on results from the KEYNOTE-158 trial (NCT02628067), which demonstrated that 50% of patients with TMB-H tumors had response durations of ≥24 months, with objective response rates in TMB-H vs. non-TMB-H patients of 29% and 6%, respectively (Marabelle et al, The Lancet Oncology, 2020). This survey-based study aimed to evaluate awareness and utilization of TMB as a biomarker for I-O therapeutics among practicing community oncologists in the U.S. Methods: Questions related to awareness and utilization of TMB as a biomarker for I-O therapeutics were developed by two medical oncologists (AG and BF) and presented to community oncologists in a web-based survey prior to virtual meetings held between October and November 2020. Descriptive statistics were used to analyze the results. Results: Of the 193 participating providers geographically distributed across the U.S., 15% reported being unaware of either the concept of TMB in I-O therapy or how to use the information clinically. 39% of these providers reported testing ≤25% of patients with advanced cancer for TMB, including 8% who do not test for TMB at all. Misconceptions regarding TMB identified among participating providers included the belief that high TMB is considered to be > 5 mut/Mb among 20% of providers, that TMB is essentially the same as MSI-high among 8% of providers, and that there are no therapies with FDA approval based on TMB among 15% of providers. Further, 37% of the participants did not identify pembrolizumab as an agent approved for the treatment of solid tumors based on TMB-H status. Conclusions: These findings demonstrate that there is a knowledge gap regarding the definition of TMB, testing for TMB, as well as implementation of TMB status in clinical decision making. Education directed towards community oncology providers regarding TMB and its use as a predictive biomarker for I-O therapy may improve its utilization and adoption in solid tumors to improve patient outcomes.
Comprehensive genomic and transcriptomic profiling (CGTP) to predict pembrolizumab (P) benefit in patients (pts) with advanced solid tumors (STs).
Authors: Rhodes Dan , Hovelson Daniel H , Safa Malek M. , Burkard Mark E. , Yang Eddy Shih-Hsin , Edenfield William Jeffery , Reeder Travis , Vakil Hana , Kwiatkowski Kat , Mitchell Khalis , Johnson Bryan , Tomlins Scott A.
Published: June 2021

2609

Background: P is approved in many ST types, however predictive biomarkers and the proportion of pts who benefit vary widely. Biomarkers beyond PD-L1 immunohistochemistry and comprehensive genomic profiling (CGP) based tumor mutation burden (TMB) may improve benefit prediction. We determined if treatment data and CGTP collected in an ongoing observational trial (NCT03061305) could predict pan-ST P benefit. Methods: Eligible advanced ST pts had QC-passing TMB and expression data from multiplex PCR based tissue CGTP on FFPE tissue (StrataNGS and an investigational test) and documented P treatment > 1 month. Real-world time to next treatment (TTNT) was defined as time in months from therapy start to new therapy start (after stopping initial therapy) or death. TMB and gene expression biomarker association with P TTNT was evaluated. Backward stepwise regression was performed to fit a multivariate Cox proportional hazards model; pts were assigned to four score groups (IRS 1-4) based on overlapping TTNT curves from 8 equal bins. P TTNT were compared between IRS groups by log-rank test. A chemotherapy (C) comparator cohort was established from C TTNT for pts in this cohort. Results were stratified by ST type, P mono vs. C combo, and TMB status. Results: 610 pts (254 [41.6%] NSCLC; 356 [58.4%] from 23 other ST types) with CGTP and P treatment were identified; P TTNT was highly correlated to overall survival (n=146; Pearsons r2=0.75). By univariate analysis of TMB and 9 expression biomarkers, TMB, two independent PD-L1 expression amplicons, and PD-L2 expression were significantly associated with P TTNT (all p ≤ 0.002). The most significant multivariate model included 5 variables, with 1) increasing TMB, PD-L1, and PD-L2, and 2) decreasing TOP2A (proliferation) and GZMA as P TTNT predictors. Median P TTNT, but not C TTNT (345 courses from 254 pts), differed significantly by IRS group (Table). Median P TTNT by IRS group did not significantly differ by non-small cell lung vs. other ST type or P mono vs. C combo (both p > 0.05); excluding TMB-high patients, median P TTNT was still significantly longer in IRS groups 3/4 vs. 1/2 (p = 5.0e-4). Across 19,623 total evaluable pts in NCT03061305, 12.2% were in IRS groups 3/4 and outside of P approved ST types/TMB-low. Conclusions: CGTP in an observational trial cohort demonstrated that TMB, PD-L1 and PD-L2 independently predicted pan-ST P benefit as assessed by OS-validated TTNT. A multivariate CGTP signature predicted P benefit relative to C across ST types. If further validated, such a signature may enable improved P benefit prediction. P versus C TTNT by IRS group. Clinical trial information: NCT03061305. [Table: see text]
Adverse effects of COVID-19 vaccination among cancer patients: Results from an Internet-based survey.
Authors: Loew Brian , Tsai Richard , Hervey John , Hoffman Kathleen D. , Novack John , Johnson Jennifer , Dizon Don S. , Goldberg Stuart L.
Published: June 2021

2621

Background: The rapid development of safe and effective vaccines against SARS-CoV-2 may stem the global COVID-19 pandemic. However, since individuals with cancer were under-represented during clinical vaccine trials, experience with COVID-19 vaccines among cancer patients is limited. Methods: An internet-based survey was conducted January 15 - February 10, 2021 among members of the Inspire online health community. The 63-item survey was emailed to members of the Inspire community who had opted-in for research. Results: Out of 19,152 respondents, 4895 (25%) self-reported a cancer diagnosis. Of these, 1337 (27%) were receiving active therapy. Cancer respondents were 66% female, 77% white, 44% college educated, with a median age range 55-65 years. 88% had solid tumors and 12% hematologic malignancies. 241 (5%) had prior COVID-19 and 148 (3%) thought they had had it but were not tested. Among cancer patients with COVID-19 approximately 30% reported ongoing late symptoms. At the time of survey, 1335 (27%) cancer patients had received a COVID-19 vaccine (Moderna 51% Pfizer-BioNTech 46%, Astra-Zeneca 3%, Other/unknown >1%). Following the first injection, 63% had local adverse events (AEs): injection site pain (51%), swelling (8%), redness (6%), and itching (4%). 34% reported systemic AEs including myalgia (32%), fatigue (18%), headache (12%), joint pain (5%), and chills (5%). 199 (15%) had received the second (booster) vaccination. 76% reported local AEs including pain (69%), swelling (14%), itching (8%), and redness (7%). 67% reported systemic AEs including fatigue (49%), myalgia (30%), headache (29%), chills (23%), fever (16%), joint pain (15%), and nausea (12%). AEs were comparable to the clinical trial results obtained from the general population (fda.gov/media/144245/download & 144434/download). Conclusions: In this internet-based survey drawn from the Inspire online health community 1335 cancer patients reported receiving COVID-19 vaccinations. By self-report the vaccines were well tolerated with AEs patterns mimicking clinical trial results conducted in the general population. These safety results should be reassuring to cancer patients although attention to COVID-19 vaccine efficacy is required (and will be studied during follow-up surveys).[Table: see text]
Risk factors for immune mediated adverse events with immune checkpoint inhibitors.
Authors: Pelcovits Ari , Mistry Hetal , Chudasama Rani , Andrea Sarah , Khurshid Humera
Published: June 2021

2622

Background: Immune checkpoint inhibitors (ICIs) are associated with unique toxicity - immune-related adverse events (irAEs). irAEs are common, occurring in nearly 30 % of patients (pts) in clinical trials. Risk factors for irAEs remain largely unknown, with limited evidence to guide risk stratification for these pts. Methods: In this historical cohort study, we identified 400 pts receiving ICIs at our institution between 1/1/2015 - 12/31/2019 and followed them until progression, death, or study end date. Using modified Poisson and multinomial logistic regression we assessed irAEs (yes/no; none/grade 1-2/grade 3-4) as a function of independent risk factors in separate models. These included age, PDL-1%, steroid use in the 2 weeks (S2wks) prior to ICI, concurrent chemotherapy, combination ICI use, and pre-ICI creatinine (Cr) and absolute lymphocyte count. We constructed sample weights using sociodemographic and clinical factors to account for confounding by indication and mortality-related censoring. Results: 367 pts (median age: 68 yrs) had complete data for analysis comprising 55% men and 89% white. 111 (31%) experienced an irAE during the study period (median time to first event: 81 days). Risk was greatest for the youngest and oldest pts on ICI. In weighted models, Pts ≤59 yrs were 3 times as likely to experience an irAE relative to those aged 60-68 (95% CI: 1.18,7.41; Table). Additionally, for each 1 unit increase in Cr, risk of irAE increased by 19% (95% CI: 1.08,1.28). Precision of weighted estimates was impacted by limited pt comparability across factors of interest and overall sample size. While not statistically significant (RR: 2.04;95% CI:0.92,4.53) 70.6% of pts on combination ICIs experienced an irAE compared with 20.3% on one ICI. Similarly, while not statistically significant, 15.4% of pts with PDL-1 >49% experienced a grade 3/4 irAE compared with 7.7% of pts with PDL-1<1%. Conclusions: In this real-world analysis of irAEs, younger age and elevated creatinine were risk factors for development of irAEs. Further research leveraging larger data sources is needed to examine PDL-1% as a potential risk factor of irAE.[Table: see text]
Initial findings of the first-in-human phase I study of AGEN2373, a conditionally active CD137 agonist antibody, in patients (pts) with advanced solid tumors.
Authors: Tolcher Anthony W. , Carvajal Richard D. , El-Khoueiry Anthony B. , Ortuzar Feliu Waldo , Zang Hong , Ancukiewicz Marek , Shapiro Irina , Strauss James Fredric
Published: June 2021

2634

Background: CD137 is a member of the tumor necrosis factor receptor superfamily that functions as a potent co-stimulator of both adaptive and innate immune cells, thus making it an attractive target for cancer immunotherapy. The development of first-generation anti-CD137 antibodies has been hampered by limited clinical activity or dose-limiting hepatotoxicity. AGEN2373 is a novel, conditionally active CD137 agonist antibody designed to selectively enhance tumor immunity while mitigating side effects associated with systemic activation of CD137. Here we report the initial findings from the first-in-human evaluation of AGEN2373 in pts with advanced solid cancers. Methods: Pts received AGEN2373 on day 1 of a 28-day cycle (Q4W dosing), with cycles repeated until progression, intolerable toxicity or investigator/patient decision. Dose-escalation followed a standard 3+3 scheme, with planned dosing of 0.03, 0.06, 0.3, 1.0, 2.0, and 3.0 mg/kg. The primary objective was to determine the safety, tolerability, and dose-limiting toxicity (DLT) of AGEN2373 as monotherapy. Secondary objectives included pharmacokinetics (PK) and preliminary clinical activity. Adverse events (AEs) were reported per CTCAE v5.0 and DLTs evaluated within a 28-day window. For PK analyses, serum AGEN2373 concentrations determined using a validated bioanalytical assay and simultaneously analyzed by an NLME model. Antitumor activity was assessed using RECIST v1.1. Results: As of January 21 2021, 19 pts (median age 54.4 years, range 33-74; 11 men, 8 women; 7 with prior immunotherapy) have been treated with AGEN2373 Q4W at escalating doses from 0.03 – 2.0 mg/kg across 5 cohorts. Eleven pts (57.9%) experienced treatment-related AEs; none were grade 3 or higher. The most common events were fatigue (4 pts, 21.1%) and nausea (2 pts, 10.6%). No DLTs have been observed. Importantly, no drug-related elevations in liver transaminases (ALT, AST) or bilirubin beyond 1 grade have been seen. AGEN2373 PK were consistent with linear elimination. Prolonged disease stabilization as best response occurred in 5 pts (26.3%; range, 6-41 weeks); three of which were seen in heavily pretreated pts with metastatic leiomyosarcoma, including one who had progressed on prior combination checkpoint immunotherapy. Enrollment into the 3.0 mg/kg cohort is continuing. Conclusions: AGEN2373 demonstrates good tolerability in pts with advanced solid tumors, with a safety profile characterized by a lack of hepatotoxicity frequently observed with CD137-targeting antibodies. These findings underscore the suitability of AGEN2373 as a potential partnering agent for other immunomodulatory agents, including planned expansion as combination therapy with balstilimab (anti-PD-1). Clinical trial information: NCT04121676.
Late immune-related adverse events with immune checkpoint inhibitors.
Authors: Ip Andrew , Wang Shuo , Cheruku Divya , Krishnamurthy Kanchi , Weber Melinda , Sinclaire Brittany , Gourna Paleoudis Elli , Alaoui Adil , lev-Ari Shaked , Serzan Michael T , Adams Shari , Kaufman Jordan , Parikh Sahil B. , Tonti Emily , Muller Eric , Williams Aquino , Ahn Jaeil , Pecora Andrew , Atkins Michael B. , Shah Neil J.
Published: June 2021

2635

Background: Immune Checkpoint Inhibitors (ICIs) are associated with unique immune-related adverse events (irAEs). IrAEs can occur at any timepoint of ICI treatment. Late irAEs are not well reported in the literature. Herein, we attempt to characterize irAEs that occur 6-month, one year and two years after ICI treatment initiation. Methods: We identified patients treated with ICIs (anti-CTLA-4, anti-PD(L)-1 either alone or in combination or with chemotherapy) across Hackensack Meridian Health hospital and MedStar Georgetown University Health systems from 12011 to 4/2018. Patients' baseline demographics, treatment history, and irAEs were collected from EHR. CTCAE V4.03 was used to grade irAEs. Results: We identified 1332 patients treated with 1443 unique ICIs. The ICI therapies were nivolumab 38% (543), pembrolizumab 23% (332), ipilimumab plus nivolumab 12% (180), ipilimumab 11% (161), Atezolizumab 3% (47) and others 13% (180). Tumor types were lung cancer 34% (496), melanoma 27% (389), GI cancers 6% (92), kidney cancer 6% (87), and other cancers 26% (379). The median age was 66 (21-87), age >75 37% (541), Caucasian 67% (970). We identified a total of 911 any grade irAEs among 37% (552) therapies. Among, 911 irAEs, grade 1-2, grade ≥3 and unknown grade irAEs were 39% (572), 12% (182) and 11% (157), respectively. The most common any grade irAEs were skin rash 22% (202), colitis 13% (120), and hepatitis 12% (108). 84% of all irAEs and 85% of ≥ Grade 3 irAEs occurred within 6 months of treatment initiation. Of the 350, patients on active treatment at six months, 37 % (132) and 7% (26) developed any grade and grade ≥3 irAEs, respectively. irAEs that had > 10% of their occurrences after six months were skin rash and colitis 14% each. Other common irAEs were hypothyroidism, hepatitis, joint pain, pruritis and pneumonitis at 7% each. Among 170 patients on active treatment at one year, 37% (62) and 7% (12) developed any grade and grade ≥3 irAEs respectively. irAEs with >10% incidence after one year of treatment were rash 19% and hepatitis 13%. Conclusions: Our RWE findings suggest although 85% irAEs occurs within the first six months of treatment, late irAEs can occur with ICI treatment. The incidence and pattern of late irAEs appears similar to early irAEs, (e.g., skin rash, colitis, hypothyroidism and hepatitis) with pneumonitis being a notable exception. It is uncertain if these results will be influenced by changing patterns of ICI use (e.g. different diseases and/or regimens) over time.[Table: see text]
Infections in cancer patients treated with immune checkpoint inhibitors: Data from randomized trials.
Authors: Solinas Cinzia , Morelli Anna Maria , Luciani Andrea , Ghidini Antonio , Petrelli Fausto
Published: June 2021

2637

Background: Febrile neutropenia and infections are well studied complications of chemotherapy (CT) and some targeted agents employed in oncology. Less is known about the risk of infection associated with the use of immune checkpoint inhibitors (ICIs) in cancer patients. The present systematic review and meta-analysis was performed to address this question in patients diagnosed with solid tumors enrolled in randomized trials employing ICIs as experimental treatment. Methods: The Cochrane Library, EMBASE, and Pubmed databases were searched from inception through December 1st, 2020. Randomized clinical trials comparing any ICI alone, with CT, or with other agents vs CT, placebo, or other agents in patients with solid tumors were included. Two independent reviewers used a standardized data extraction and quality assessment form. Discordant cases were discussed with a third independent investigator. The following information was extracted: baseline study characteristics, including the primary tumor, author, year of publication, type of trial, type of disease, and the type of therapy (experimental and control arms); and the incidence of any-grade (grades [G] 1–5), low-grade (G1–2), and high-grade (G3–4), fatal event (G5) infections, and type of event. Random or fixed-effect models were used according to the statistical heterogeneity. Results: 36 randomized clinical trials were deemed eligible. The total population reached 21451 patients. In the pooled analysis, the use of ICIs was associated with a similar risk of all-grade infections (relative risk, RR = 1.02; 95% CI 0.84–1.24; P = 0.85) compared to non-ICI treatments (G1-5 events: 9.6 vs. 8.3%). When the ICIs alone arms were compared to CT, the experimental arms were associated with a 42% less risk of all-grade infections (RR = 0.58, 95% CI 0.4–0.85; P = 0.01; N = 18 studies). Compared to CT, the combination of ICIs and CT increased the risk of all-grade infections (RR = 1.37, 95% CI 1.23–1.53; P < 0.01; N = 13 studies) and severe infections (RR = 1.52, 95% CI 1.17–1.96; P < 0.01; N = 12 studies). Fatal infections were similar in the experimental and control arms (0.5%). Conclusions: In patients with advanced solid tumors, when ICIs were administered with CT, the risk of all-grade and G3-5 infections was significantly increased. Compared to CT alone, ICIs were safer and their use should be recommended for frail patients. Further studies are required to identify high-risk patients and evaluate the need for CT dose reduction or prophylactic myeloid growth factors use.
Pseudoprogression and cancer immunotherapy: A seven year retrospective study of rate, temporal course, and predictive markers in an Irish tertiary referral center.
Authors: McKendry Kate , Desmond Fiona , Ward Cian , Duffy Austin G
Published: June 2021

2651

Background: Immunotherapy is a relatively new treatment strategy which has achieved unprecedented clinical efficacy in many advanced malignancies. However, the pattern of tumour response to immunotherapy is distinct from other therapies and poses major challenges to clinicians. One such challenge is pseudoprogression. The aim of this study was to assess the current management of patients on immunotherapy with radiological evidence of disease progression at first restaging imaging in an Irish cancer centre, and to determine the rate, time course, and predictive markers of pseudoprogression in those patients treated beyond progression (TBP). Methods: Patients treated with immunotherapy for metastatic malignancy in MMUH between March 2013 and September 2020 were retrospectively drawn. Inclusion required follow-up restaging imaging every 4-12 weeks for the duration of treatment. Patterns of response during immunotherapy were established from radiology reports and categorized as stable (SD), response (R), mixed disease (MD), or progressive disease (PD). Pseudoprogression was defined as progression/ mixed disease at first restaging compared to baseline followed by subsequent response/stable disease. Results: The cohort of 228 patients was comprised of 80 NSCLC, 74 melanoma, 25 RCC, 19 gynaecological, 14 gastrointestinal, 6 breast, 1 ESSCLC, and 9 other cancer patients. Median age was 61.16 (IQR 49.47-69.44). Therapeutic agents were anti-PD1 alone (176) or in combination with targeted therapy (6) or CTLA4 (13), CTLA4 alone (15), and anti-PD-L1 alone (13) or in combination with chemotherapy (5). At first restaging, the number (%) classified as SD, R, MD, and PD, respectively, was 29 (12.8), 62 (27.2), 16 (7), and 76 (33.3). Treatment was stopped prior to restaging in 44 (19.3) cases. Of the 92 patients with mixed/ progressive disease, 41 were TBP and 51 were not treated beyond progression (NTBP). Evidence of radiological progression and worsening performance status (PS) were the most common reasons given by clinicians for NTBP. Of those TBP, 20 had subsequent response/stable disease, occurring at a median of 105.50 (range 58.0-420) days after the initial restaging scan and giving an overall pseudoprogression rate of 8.8%. At one year, 100% of the pseudoprogression group was alive. The neutrophil-lymphocyte ratio (NLR) was significantly lower in the pseudoprogression group compared to those with true progression (p = 0.006). There was no significant difference in performance status between the two groups. Conclusions: Pseudoprogression on cancer immunotherapy is real but uncommon, with an overall incidence of 8.8%. It can occur any time up to 420 days after initial progression and indicates a high likelihood of > 1 year survival. A low NLR may be a useful predictor of pseudoprogression but a technological solution is likely needed.
Genes copy number as a marker of low-invasive assessment of rectal tumors radiotherapy effectiveness.
Authors: Gusareva Marina A. , Kosheleva Natalia G , Fatkina Natalya B. , Solntseva Anna A. , Rozenko Lyudmila Ya. , Donskaya Aliya K. , Vasilieva Ekaterina O. , Karnauhova Elena A. , Krokhmal Julia N. , Gabrichidze Peter N. , Dontsov Vladimir A. , Gaziev Umar M. , Legostaev Vladislav M. , Shlyakhova Olga V. , Lyman Natalia A. , Balitsky Gennady V. , Nosov V. A. , Kravchenko A. B. , Kutilin Denis S.
Published: June 2021

3025

Background: Radiotherapy (RT) is a key component of rectal cancer (RC) treatment, however, nonresponsiveness in patients to preoperative RT is very common, usually due to the tumor cells radioresistance, mediated by their molecular characteristics, such as gene expression. The features of mRNA rapid degradation in extracellular environment make this indicator unsuitable for low invasive diagnostics. The solution to this problem is possible by switching to a more stable marker - the copy number variation (CNV), which can be determined in the extracellular DNA (cfDNA) circulating in the blood plasma. Therefore, the aim of the study was to identify the relationship between the level of genes CNV in the cfDNA of blood plasma with the effectiveness of rectal tumors RT. Methods: We used cfDNA preparations from blood plasma obtained before RT from 200 patients with RC, as well as from blood plasma of 50 apparently healthy donors (AHD, without cancer). RT was carried out on a linear accelerator Novalis TX (SFD = 2.4 Gy, TFD = 54.0 Gy). Blood samples were separated into plasma and cell fraction by centrifugation. Isolation of cfDNA from blood plasma was performed using the phenol-chloroform method. Determination CNV of 5 genes (BRCA2, H2AX, CASP9, RBBP8 and BCL2) was performed using Real-Time qPCR method. Differences were assessed using Mann-Whitney test; the Bonferroni correction was used to correct multiple comparisons. Results: RT results for 200 patients allowed them to be divided into 2 groups. After RT, 120 patients showed complete tumor regression (group 1), 50 patients showed insignificant tumor regression and 30 patients did not regress (group 2). In cfDNA of group 1 patients was found CNV decrease (p < 0.05) of H2AX and RBBP8 genes by 2.5 and 2.0 times, respectively, relative to AHD group. In the cfDNA of group 2patients an increase (p < 0.05) of BRCA2, H2AX, RBBP8 and BCL2 genes CNV was found by 2.0, 2.2, 2.0 and 2.0 times, respectively, relative to AHD group. Only 2 genes CNV differed in group 1 from group 2: the CNV of H2AX and RBBP8 was 5.4 and 4.0 times less respectively (p < 0.005). Conclusions: Thus, it has been found that increased CNV of genes BRCA2, H2AX, BCL2, RBBP8 in blood plasma cfDNA is associated with low efficiency of RT. At the same time, the CNV of H2AX and RBBP8 genes in cfDNA of patients with RC has the greatest potential as a marker of the RT effectiveness.
Correlation between different levels of HER2 expression in circulating tumor cells (cHER2 ratio) and metastatic behavior in stageIVaggressive breast cancer.
Authors: D'Amico Paolo , Reduzzi Carolina , Gandini Sara , Gerratana Lorenzo , Qiang Wenan , Zhang Qiang , St-Pierre Frederique , Zhang Youbin , Shah Ami N. , Davis Andrew A. , Jacob Saya , Vagia Elena , Wehbe Firas Hazem , Behdad Amir , Curigliano Giuseppe , Cristofanilli Massimo
Published: June 2021

3036

Background: The presence of HER2 expressing (HER2+) circulating tumor cells (CTCs) occurs often in metastatic breast cancer (MBC) patients (pts). We have previously showed that the ratio among CTCs expressing high level of HER2 and the total number of HER2+ CTCs (circulating HER2 ratio, cHer2 ratio) has a prognostic role in MBC patients. Here we further investigate the role of the cHER2 ratio in the process of metastatic spread. Methods: Under IRB-approved study we prospectively analyzed blood samples of patients with MBC enrolled before starting a new line of therapy. Samples were collected from pts treated at Northwestern University (Chicago, IL) between 2016 and 2020. CTCs were enumerated through CellSearch (Menarini Silicon Biosystems, Bologna, Italy) and characterized for HER2 expression using the CellSearch CXC Kit. HER2+ CTCs were divided in 3 different categories (1+,2+,3+) leaning on fluorescence intensity. Pts with <5 CTCs (stage IV indolent) were excluded from the analysis. The cHER2 ratio, defined as the sum of 2+ CTCs and 3+ CTCs divided by the total number of HER2+ CTCs, was used to split the remaining pts in 2 different cohorts: cHER2 ratio high (> 0.75) (cHER2high) and cHER2 ratio low (≤0.75) (cHER2low). The frequency of each metastatic site (i.e. liver, lung, central nervous system, bone, lymph nodes, skin/soft tissue, serosa) and the total number of different sites involved (1-7, ≤2 and >2 sites) were compared among the two sub-populations and analyzed through Fisher exact test. Results: Out of 98 pts enrolled, 77 were classified as cHER2low and 21 as cHER2high. We observed a higher frequency of oligometastatic pts (≤2 sites involved) in the cHER2high cohort (16, 76%), compared to only 29 (37%) in the cHER2low (p<0.005). Moreover, the cHER2 ratio was associated with a tropism toward specific sites of disease spread with higher incidence of liver, lung and lymph nodes metastases in the cHER2low cohort (p<0.05). No other statistical associations were observed in respect of specific organ tropism. The frequency of involvement for each metastatic site among the two cohorts are reported in the table. Conclusions: Measuring CTCs enumeration and HER2 expression we identified two cohorts, cHER2high and cHER2low, associated with distinct patterns of metastatic spread. The cHER2low pts were correlated to multiple sites of metastatic involvement, with particular tropism toward liver, lung and lymph nodes. These results confirm the prognostic role of the cHER2 ratio, suggesting a peculiar biological meaning of the HER2+ 1+ CTCs.[Table: see text]
Targeted ctDNA sequencing analysis reveals concurrent genomic alterations and its impact on TKI and immune checkpoint inhibitor therapy in advanced NSCLC from Asian population.
Authors: Wu Wei , Lim Jing Shan , Poh Jonathan , Bivona Trever G.
Published: June 2021

3042

Background: For advanced non-small cell lung cancer (NSCLC), liquid biopsy followed by targeted DNA sequencing is used in the clinical setting for driver-gene identification in circulating tumor DNA (ctDNA), tumor evolution and treatment monitoring. To understand the complexity and diversity of genetic alterations in advanced NSCLC, we examined the genetic landscape of late-stage NSCLC from an Asian population and its association with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) treatment. Methods: Plasma cell-free DNA (cfDNA) from 142 Asian patients with advanced NSCLC underwent real-world testing in a CAP-accredited and CLIA-certified central laboratory. We analyzed genetic alterations in cfDNA using an amplicon-based next-generation sequencing assay that covers 61 NSCLC related genes. 88 patients (62%) had received one or more lines of treatment. A similar cohort from Caucasian NSCLC was used for comparison (Blakely et al. Nat Genet 2017). Systematic co-mutation analysis, functional annotation and pathway enrichment analysis were performed. Results: The top 10 mutated genes in the Asian cohort were EGFR (66.2%), TP53 (48.6%), KRAS (11.3%), BRCA2 (7%), CTNNB1 (6.3%), PIK3CA (6.3%), SMAD4 (5.6%), BRCA1 (4.9%), MET (3.5%) and RB1 (3.5%). EGFR mutations occurred at hotspots in exons 18 – 21, with exon19 deletion, L858R, T790M, C797S, and G719A being the top-ranking alleles, similar to the Caucasian NSCLC cohort. Concurrent KRAS and EGFR mutations were higher in Asian cohort (8.5%) than in Caucasian cohort (0.56%). A rare PD-L1 structural variant (1.1%), reported to be related to immune evasion in other cancers (Kataoka et al. Nature 2016), was detected in the EGFR-mutated subgroup. Within the first line TKI-treated group, responders (CR+PR) harbored more alterations than non-responders (p < 0.017). Among ICI-treated NSCLC patients (anti-PD-1/PD-L1 mono- or polytherapy), responders from 1st line or 2nd line ICI treatment harbored fewer mutations than non-responders, but the distribution of mutational allele frequency (MAF) in responders was shifted to the right (more clonal than subclonal mutations). Functional annotation suggests that concurrent mutated genes and copy number alterations in advanced EGFR-mutant NSCLC were enriched in cell cycle, DNA repair, PI3K-AKT signaling pathways. Conclusions: We characterized the ctDNA-derived genetic landscape of advanced NSCLC from an Asian population and dissected mutated genes with the outcome of TKI or ICI treatment. We also report a rare PD-L1 structural variant in the EGFR mutated subgroup, which could be associated with immune evasion. Our analyses support the occurrence of clonal and subclonal driver co-alterations in EGFR-driven NSCLC, underlining the clinical utility of ctDNA detection for NSCLC diagnosis and treatment selection.
Prediction of adenocarcinoma among other subtypes of lung cancer from CT using deep learning.
Authors: Waterfield Price Noah , Janes Sam , Gleeson Fergus , Massion Pierre P. , Lehman Jonathan
Published: June 2021

3057

Background: Determination of histological subtype is a crucial step in the management of patients with lung cancer as it informs prognosis and management. The identification of adenocarcinoma (AC) is particularly important with new targeted treatments becoming available. Although the gold standard for diagnosing histological subtype is pathological analysis of tissue samples, interventions can present a risk of complication. Imaging-based, computational approaches to distinguishing malignant from benign lesions have shown promising results. A similar approach may also be applied to determining histological subtype, which could provide an early, non-invasive alternative or complimentary method to biopsy. Here, we investigate an imaging and machine learning method to predict the subtype of a malignant lung lesion. Methods: A dataset of 1493 primary lung cancer patients was collected, of which 943 were diagnosed with AC. The histological subtypes of the non-AC patients were, squamous-cell carcinoma (158), large-cell carcinoma (69), small-cell carcinoma (33), other subtypes (27), or unreported non-AC subtype (253). This consists of retrospectively collected CT images and demographic data from both screening and clinical settings, across 41 academic and community centres from the USA (35 centres), and Europe (6 centres). All patients included were aged ≥ 18 with no history of cancer in the last 5 years. Each CT was manually curated. Given a CT-image of a lung nodule, a Convolutional Neural Network (CNN) was trained to classify nodules as AC or non-AC, using 8-fold cross-validation. A logistic-regression model based on clinical parameters was also trained using the same data and cross-validation. Classification performance was evaluated using the Area-Under-the-ROC-Curve (AUC), sensitivity, and specificity. Confidence intervals and P values were calculated by nonparametric bootstrapping. Results: The median age of AC patients was 66 yr (non-AC 67 yr) and 62.3% of them were male (non-AC 57.8%). The median pack years for AC patients was 38.4 p.yr (non-AC 50.0 p.yr). For AC tumours, the median diameter was 14.0 mm (non-AC 14.0 mm) and the mean diameter was 15.0 mm (non-AC 16.4 mm). The AC-classification results are tabulated below. The CNN classification performance is significantly better than the logistic-regression baseline across all three measures of performance P <.001. AC classification results. All values are given in % with 95% confidence interval bounds in parentheses. Conclusions: We find that the CNN significantly outperforms a logistic model in identifying AC from other histological subtypes. With further development, this algorithm could prove a useful tool to aid management of lung cancer patients.[Table: see text]
Safety profile and disease stabilization in late stage, heavily pretreated, solid tumor patients in a first-in-human (FIH) study of ATX-101, a drug targeting proliferating cell nuclear antigen (PCNA).
Authors: Lemech Charlotte Rose , Kichenadasse Ganessan , Marschner Jens-Peter , Alevizopoulos Kostas , Otterlei Marit , Millward Michael
Published: June 2021

3067

Background: PCNA is a conserved scaffold protein orchestrating DNA replication, repair or bypass pathways as well as cellular signaling and apoptosis. More than 500 protein-PCNA interactions have been identified which are mediated via two binding motifs, the PIP-box and APIM. Cellular stress, to which cancer cells and cells of tumor microenvironment are exposed, increases the affinity of the APIM motif. APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 is a cell penetrating peptide containing APIM. It inhibits protein binding via APIM, resulting in cancer cell death and altered cellular signaling. Anticancer effects of ATX-101 have been demonstrated in vitro and in vivo. Methods: A FIH study using a 3+3 dose escalation design was conducted. Patients with late-stage solid tumors received weekly infusions of 20, 30, 45 and 60 mg/m² over 6 weeks. Primary objective was safety, secondary objectives were PK and efficacy. Patients with stable disease (SD) after 6 weeks could continue treatment in a long-term follow-up (LTFU) study. Results: As of January 2021, 22 patients have been treated. All patients received in average 3.8 [1-9] prior treatment lines, all but one had progressive disease at study entry and 80% were refractory to the last therapy. No dose limiting toxicity or death and no treatment related Grade 3/4 or serious adverse events were reported. The maximum tolerated dose was not reached. Mild to moderate infusion related reactions (IRR) were observed in 73% of patients. They were not dose dependent and resolved completely after treatment interruption and/or symptomatic treatment. IRRs occurred despite premedication and could cause infusion interruptions with extended infusion duration. Experiments in dogs indicate that transiently increased histamine levels may cause IRRs. However, elevated histamine and tryptase levels could not be measured in patients so far. ATX-101 exposure was dose-dependent. Cmax was reached either at the middle or at the end of infusion. ATX-101 disappeared quickly from plasma and was not detectable 5 - 60 minutes post infusion. 13 patients finished the FIH study, 10 had SD after 6 weeks. 9 of 10 patients moved into the LTFU study. The treatment duration in the LTFU study varied from 2.1 to 15.6 months (median 4.2 months). Conclusions: ATX-101 is well tolerated at all dose levels with IRRs being the most frequent AEs. Drug exposure is dose dependent with rapid plasma clearance, which confirms in vivo data demonstrating the quick uptake by cells of all organs. The observed duration of SD may be attributed to ATX-101 activity. Proof of concept combination studies are being initiated. Clinical trial information: 375262.