bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1B study of avelumab and whole brain radiotherapy (WBRT) in patients with leptomeningeal disease (LMD) from epithelial carcinomas: Final results and molecular analyses with single cell RNA sequencing.
Authors: Pina Yolanda , Chen Ann , Arrington John , Macaulay Robert J , Tran Nam D. , Liu James K , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran A. , Creelan Ben C. , Gray Jhanelle Elaine , Evernden Brittany , Khushalani Nikhil I. , Smalley Inna , Vogelbaum Michael A. , Yu Michael , Smalley Keiran , Forsyth Peter A. J.
Published: June 2023

2598

Background: Leptomeningeal disease (LMD) from epithelial cancer has a dismal prognosis with median overall survival (OS) of 3-4 months (mo) using PD-1 axis blocking therapy. Preclinical studies showed that this combination promotes antigen presentation within the CSF compartment, increases BBB permeability and increases ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab in combination with WBRT in patients with LMD (NCT0371768). Methods: Patients received concurrent Avelumab 800 mg IV q2 weeks for up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy in 10 daily fractions. Primary endpoints were safety/DLTs and 3-month OS. Secondary endpoints included CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6 mo were excluded. Results: 15 patients were enrolled with disease sites that included breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). Patients were 87% female, median age 59 range 32-82. One patient did not complete WBRT. Two of 15 patients had grade 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related <grade 3 AEs, including hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). There were no grade 5 toxicities. Median follow up was 3.7 mo (range, 0.9-36.8 mo; 95% CI 1.3-14.7 mo). The median follow-up time for survival analyses of the study was 19.8 mo. Ten out of 15 patients (66.7%) were alive at 3 mo. Median OS was 10.5 (95% CI 1.2 - 19.8 mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3 mo (95% CI, 0.9-15.2 mo), Fig. 3B. Two patients remain alive and clinically well. ScRNAseq analyses are underway; signatures correlated with outcomes in short versus long term survivors. Conclusions: The combination of Avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short versus long term survivors should be further explored. Clinical trial information: NCT03719768 .
DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab plus tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Keilholz Ulrich , Gauler Thomas Christoph , Stromberger Carmen , Kofla Grzegorz , de Wit Maike , Mette Ramona , Burock Susen , Klinghammer Konrad Friedrich
Published: June 2023

2611

Background: Concurrent platinum-based chemo-RT is the standard treatment for LA-HNSCC, despite of limited efficacy in poor-risk patients and long-term toxicity. Targeting PD-L1 with D has activity in recurrent/metastatic (RM)-HNSCC, and the combination with the CTLA4 targeting agent T was considered to augment the immunotherapy efficacy of a chemotherapy-free regimen. Thus DURTRERAD was designed as a randomized two-arm phase II study to investigate, whether D or DT combined with RT was feasible in the patient population and a 1-year progression free survival rate of 50% was reached. Methods: The phase II study planned to enroll 60 patients in each treatment arm. Key selection criteria were patients with advanced HPV negative unresectable HNSCC planned for definitive radiotherapy. Treatments: First dose of immunotherapy 14 days prior to start of RT (70Gy over 7 weeks). D (1500mg q 3 weeks x 13) or DT (D: 1500mg q 3 weeks x 13 + T: 4 x 75 mg in weeks 5,9,13,17). Planned treatment duration was 51 weeks in both arms. Treatment was considered feasible in case of <10% treatment discontinuations. An interim analysis for feasibility was planned after treatment of 6 patients per arm and a futility analysis was performed after treatment of 18 patients, resulting in premature closure of the trial. Results: Patient accrual in 4 centers in Germany from 9/2018 - 9/2020. The interim feasibility analysis of DT revealed that 5/6 patients stopped treatment due to 1 grade 5 and 1 grade 4 immune related AE and 3 non-immune related AEs, respectively. Thus, the DT arm was prematurely terminated, and only the D monotherapy arm continued. Futility analysis of D monotherapy: One of 12 patients stopped treatment due to immune related toxicity, and 7 patients experienced disease progression on treatment or died within the first year. The median PFS was 39 weeks, the 1 year PFS rate was 42%. Conclusions: Even though D was previously proven as an active agent in RM-HNSCC, and there DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of HPV negative LA-HNSCC. D monotherapy in combination with RT was well tolerated, but revealed a low level of efficacy, when administered in the trial schedule, starting 2 weeks prior to RT. Similar to results in lung cancer, start of immunotherapy after completion of radiotherapy may be of interest. Clinical trial information: NCT03624231 .
MyTACTIC: Afficacy and safety of atezolizumab (atezo) + chemotherapy (chemo) in patients (pts) with advanced unresectable/metastatic solid tumors with high tumor mutational burden (TMB-H) or high microsatellite instability (MSI-H)/deficient mismatch repair (dMMR).
Authors: Spigel David R. , Hussein Maen A. , Zuniga Richard , Mahadevan Daruka , Winn Robert , Darbonne Walter C. , Yoo Bongin , Kim Young , Whitehead Zach , Vanderwalde Ari M.
Published: June 2023

2612

Background: MyTACTIC (NCT04632992) is a phase II, non-randomized, multi-arm basket study evaluating targeted therapies as single agents or combinations in pts with advanced solid tumors with specific biomarkers. We present the efficacy and safety of arm E from MyTACTIC: atezo + chemo in pts whose tumors have TMB-H and/or MSI-H/dMMR. Methods: Enrolled pts were ≥18 years old, with histologically/cytologically confirmed advanced unresectable/metastatic solid tumors with TMB-H (TMB≥10 mut/Mb) and/or MSI-H/dMMR and ECOG PS ≤2; those with symptomatic/actively progressing CNS metastases were excluded. Pts received intravenous atezo 1200 mg every 21 days and physician’s choice chemo (docetaxel; paclitaxel; capecitabine) until progressive disease (PD), toxicity or death. Primary endpoint: investigator-assessed confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR; confirmed complete response [CR] + partial response [PR] + stable disease [SD] or non-CR/non-PD for ≥70 days), duration of response (DOR), progression-free survival (PFS) and safety. Results: At data cutoff (May 16, 2022), 25 pts with 10 tumor types had received atezo + chemo. Median age was 69 years (range 37–83), 88% of pts had ECOG PS ≤1 and 20 pts with metastatic disease had a median of 1 prior line of therapy (range 1–4). Twenty-three pts had TMB-H (2 missing), 7 had MSI-H and 7 had dMMR (12 missing); 7 pts had TMB-H and MSI-H/dMMR. cORR was 28.0% (7/25; 95% CI 12.1–49.4), including 1 CR (colon cancer) and 6 PRs. Responses were observed in 6/10 tumor types studied. cORR was 12.5% in pts with TMB-H alone (2/16) and 71.4% (5/7) in pts with TMB-H and MSI-H/dMMR. DCR was 32.0% (8/25; 95% CI 14.9–53.5). Median DOR and median PFS were 7.4 months (95% CI 7.4–not estimable) and 3.9 months (95% CI 2.2–8.4), respectively. The safety profile of atezo + chemo was consistent with previous reports for this combination. The most common treatment-related adverse events (TRAEs) were diarrhea (60%) and fatigue (32%). Grade 3/4 TRAEs occurred in 32% of pts and there were no serious or grade 5 TRAEs. Conclusions: In this small cohort, treatment with atezo + chemo demonstrated clinical activity in pts with advanced solid tumors with TMB-H and/or MSI-H/dMMR. Responses were observed in different tumor types and were numerically higher in pts whose tumors had both biomarkers vs those with TMB-H alone. Further analyses with a larger cohort and longer follow-up will be required to confirm these results. Clinical trial information: NCT04632992 . [Table: see text]
High transferrin receptor expression marks tumors with increased immune-effector infiltration and expression of targetable checkpoint molecules: Results of a multi-cancer analysis in solid tumors.
Authors: Trabolsi Asaad , Arumov Artavazd , Gandhi Nishant , Farrell Alex Patrick , Kang Irene , Hoon Dave S. B. , Wei Sam , Radovich Milan , Sledge George W. , Liu Stephen V. , Ma Patrick C. , Schatz Jonathan Harry
Published: June 2023

2613

Background: The cell-surface transferrin receptor, TFR1, encoded by TFRC, imports iron-bound transferrin into cells to drive tumor proliferation. We have found worse prognosis with high TFRC expression across multiple tumor types. The mechanism by which TFRC drives tumor cell- intrinsic oncogenesis is multifactorial, but its interaction with the tumor microenvironment (TME) has not been studied. Here, we assessed TME infiltration by immune effector populations and immune checkpoint expression. Methods: Tissue samples underwent comprehensive molecular profiling at Caris Life Sciences: Next-gen sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA- seq (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. RNA deconvolution analysis by the Microenvironment Cell Populations (MCP)-counter method quantified immune populations to assess T cells, B cells, natural killer cells (NK) and myeloid dendritic cells (MDC). Analyses compared quartiles of TFRC mRNA expression between Q4 ( TFRC-H) high and Q1 ( TFRC-L) low expressors. Results: Among 27,607 patients with non-small cell lung cancer (NSCLC), 5,332 with prostate cancer (PC), and 14,287 with colorectal cancer (CRC), TFRC-H tumors were associated with high tumor mutational burden (TMB-high, ≥10 mutations/MB), and TP53 mutation (q<0.05). Multiple immune checkpoint genes showed significantly higher expression in TFRC-H relative to TFRC-L in all tumor types, including CD274 (PDL1), LAG3, PDCD1LG2 (PDL2), and CTLA4 (Table; All values are statistically significant: q<0.05). Moreover, TME assessment by MCP-counter showed significantly increased infiltration by total T cells, CD8+ cells, B cells, NK cells, and MDCs in TFRC-H (Table). Finally, among patients who received Check-point inhibitors (CPI), TFRC-L had improved survival (HR=0.807 (95% CI 0.76 – 0.85) p<0.00001) in NSCLC but no difference was found in CRC or PC. Conclusions: Our study is the first to reveal the TME characteristics associated with TFRC expression in a variety of solid tumor types. We found TFRC-H tumors have increased infiltration by immune effector populations but also express significantly higher levels of immune checkpoint molecules, highlighting immune exhaustion. Altered iron metabolism has been shown to promote tumorigenesis and here we identify a new role for TFRC in remodeling the TME. TFR1- targeting therapeutic agents are in clinical development and warrant further investigation in combination with CPIs. [Table: see text]
Genomic landscapes to characterize mismatch-repair deficiency (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers stratified by tumor mutation burden (TMB).
Authors: Wang Jingyuan , Xiu Joanne , Farrell Alex Patrick , Battaglin Francesca , Arai Hiroyuki , Millstein Joshua , Soni Shivani , Zhang Wu , Shields Anthony F. , Grothey Axel , Weinberg Benjamin Adam , Marshall John , Lou Emil , Khushman Moh'd M. , Sohal Davendra , Hall Michael J. , Oberley Matthew James , Spetzler David , Lenz Heinz-Josef
Published: June 2023

2618

Background: TMB is a predictive biomarker for immune checkpoint inhibitor treatment in dMMR/MSI-H cancers. We aimed to characterize specific molecular features of a large cohort of dMMR/MSI-H GI tumors with a range of TMB levels. Methods: A total of 2272 GI tumors tested as dMMR/MSI-H were analyzed using Next-generation sequencing (NGS) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. TMB-H were defined using differing TMB cutoffs (10, 20, 50 mutations/Mb). Molecular features were compared in four groups (TMB < 10 vs 10-20 vs 20-50 vs ≥50mutations/Mb) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. The impact of TMB on tumor immune environment was analyzed using a TCGA cohort. Significance was determined by adjusted (adj) P < 0.05. Results: Tumors with TMB over 10, 20, 50 mutations/Mb were observed in 95.38%, 86.05% and 14.47% respectively in the dMMR/MSI-H GI cohort. Compared to other groups, dMMR/MSI-H GI tumors with TMB over 50 mutations/Mb exhibited the highest mutations rates in RNF43, MSH6, KMT2D, BRCA2 and ASXL1 (Top 5, all Padj< 0.0001). Among the four MMR genes, only MLH1 mutation had no association with higher TMB. The rates of CNNE1 amplification (i.e. the Cycle E1 gene) and HER2 overexpression were the highest in tumors with TMB below 10 mutations/Mb (all Padj< 0.05). The association between PD-L1 positivity and TMB levels was only observed in gastroesophageal cancers ( P= 0.03). The lymphocyte infiltration signature score, IFNγ response and M1 macrophage infiltration were significantly lower, while fraction of genome alterations was significantly increased in dMMR/MSI-H tumors with TMB below 10 mutations/Mb, compared to other subgroups (all P< 0.05). Neoantigens were significantly enriched in those with TMB over 50 mutations/Mb, compared to other subgroups ( P< 0.0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of dMMR/MSI-H GI cancers with different degrees (magnitude) of TMB. These data may inform our understanding of the efficacy of ICB in dMMR/MSI-H GI tumors.
Spatial distribution of B cells and lymphocyte clusters for the treatment of non-small cell lung cancer.
Authors: Ramos Corinne , Gerstenberg Amandine , Boute Melodie , Ponzoni Adele , Stauber Jonathan
Published: June 2023

2622

Background: The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers including non-small cell lung cancer (NSCLC). However, the relationship between TLS spatial organization and the treatment response remains unknown in NSCLC who received ant-PD-1 antibody. The purpose of this study was to evaluate the effect of the various stages of the spatial organization of the TLS from locally concentrated aggregates of immune cells, through clearly defined B cell follicles to mature follicles in NSCLC and its relationship with the tumor microenvironment on anti-PD1 treatment response. Methods: Frozen sections from retrospectively collected surgically resected NSCLC tumors treated with adjuvant pembrolizumab therapy were used. The TLS in tumor tissues was detected by high-plex imaging mass cytometry staining and the difference in TLS spatial organization was compared to the features of the tumor microenvironment and the objective response rate of the patients. Results: TLS identified and characterized according to their spatial organization within or adjacent to the tumor showed that the presence of tumor-associated TLS (TA-TLS) correlated with favorable response to anti-PD-1 therapy. The abundance and the spatial distribution of B cells allowed for a better definition of the correlation between B cell subsets with clinical outcomes showing that the heterogeneity in these TA-TLS influences the predictivity significance to anti-PD-1 therapy. Conclusions: Identifying the phenotypic heterogeneity of intratumor B cells and their functional connection to CD8 T cell helps optimally guide the anti-PD-1 treatment strategy. This spatial mechanistic insight also provides an exciting opportunity for translation of B cell-based immunotherapies into clinics complementary to existing T cells centric strategies.
Clinical and biological activity of FLX475, an oral CCR4 antagonist, in advanced cancer.
Authors: Brockstedt Dirk G. , Grant Adam , Adamik Juraj , Trujillo Damian , Goyal Rakesh Kumar , Ho William , Ikeda Shoji , Zhu Qingfeng , Anders Robert A. , Sabouri Mohsen , Kassner Paul D
Published: June 2023

2625

Background: FLX475 is a potent and selective CCR4 antagonist, designed to block the recruitment of immunosuppressive regulatory T cells (Treg) into tumors without affecting healthy tissues. Blocking migration of Treg into the tumor microenvironment (TME) has the potential to restore antitumor immunity and synergize with a variety of conventional and immunotherapy-based approaches to overcome immune resistance and broaden clinical efficacy. In a recent interim clinical update from the ongoing FLX475-02 Phase 1/2 trial, evidence of monotherapy and combination activity were reported. FLX475 monotherapy induced complete responses in two of the six evaluable subjects enrolled with EBV+ NK/T cell lymphoma. In checkpoint inhibitor naïve non-small-cell lung cancer (NSCLC), 4/13 subjects (31%) had confirmed partial responses (PRs) following treatment with the combination of FLX475 and pembrolizumab. In this analysis we present biomarker data from patients with broad range of tumor types treated with FLX475 monotherapy. We provide evidence to substantiate the mechanism of action and support the combination of FLX475 with pembrolizumab. Methods: Flow cytometry was used to measure relative proportions of Treg in the periphery. CD8 and FOXP3 positive cells in tumor biopsies were quantified by immunohistochemistry (IHC).Gene set enrichment analysis and immune deconvolution methods were used to interrogate RNAseq data derived from tumor biopsies. Results: FLX475 monotherapy results in a small but significant increase in proportion of circulating CD25+CD127-/low CD4+ Treg by day 8 of treatment. IHC analysis revealed a trend towards increased CD8:FOXP3 ratio in the TME of patient biopsies. Transcriptomic profiles from tumor biopsies of FLX475 monotherapy treated patients exhibited significant changes in immune pathways likely to benefit the antitumor response. Using global gene expression analyses we identified that FLX475 monotherapy altered the transcriptome of tumors to resemble those from patients with favorable clinical outcome to anti-PD(L)-1 treatment. Consistent with the proposed mechanism of action, immune deconvolution identified that FLX475-treated patients experienced a decrease in Treg cell populations. Conclusions: FLX475 monotherapy results in beneficial changes in the TME consistent with our proposed mechanism of action. FLX475 monotherapy is modifying the tumor microenvironment toward a phenotype associated with response to anti-PD-1/anti-PD-L1. Clinical trial information: NCT03674567 .
Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting fusion protein, in combination with atezolizumab in patients with advanced solid tumors.
Authors: Saeed Anwaar , Bashir Babar , Luke Jason J. , Chantre Reuven , Amsili Shira , Tabakman Rinat , Shwartz Yaffa , Foley-Comer Adam , Jimeno Antonio
Published: June 2023

2632

Background: DSP107 is a bi-functional fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BB ligand (4-1BBL). The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and anchoring trimeric 4-1BBL to the tumor, which interacts with 4-1BB expressed on activated immune cells. This results in proliferation and conditional activation of effector cytotoxic T-cells in the tumor microenvironment. Thereby, DSP107 triggers both innate and adaptive immune responses. Phase 1 monotherapy dose escalation data demonstrated an excellent safety profile with no binding to red blood cells and no dose limiting toxicities (DLTs), hematological or hepato-toxicities. Here we describe data from the completed DSP107 plus atezolizumab combination dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (1, 3 or 10 mg/kg; N = 6-7 patients/dose cohort) and atezolizumab (1200 mg) Q3W during 3-week treatment cycles. The primary objective was to determine the safety and tolerability of DSP107 in combination with atezolizumab. Restaging imaging was performed every two months and evaluated by RECIST v1.1 criteria. Results: In 19 patients, DSP107 with atezolizumab was well tolerated with no DLTs. Grade 1-2 treatment related adverse events (AEs) were observed in 68% of patients (13/19). The most frequent AEs included diarrhea (21%), fatigue (21%), infusion related reaction (IRR; 16%), nausea, decreased appetite, arthralgia, myalgia and Grade 1 anemia (11% each). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. Stable disease (SD) as best response was observed in 8/19 (42%) patients with treatment duration currently up to 10.5 months. At the highest dose of DSP107 (10 mg/kg), 3/7 patients had SD (1 microsatellite stable-colorectal cancer (MSS-CRC) patient with KRAS mutation had 16% target lesion shrinkage and no progression for 7 months). An additional 2 patients with advanced MSS-CRC (with BRAF and KRAS mutations, respectively) demonstrated deep and durable responses (-73 and -76% reduction in target lesions) including disappearance of pulmonary and hepatic target lesions in one patient. These patients currently continue to receive treatment after > 8 and > 6 months, respectively. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. These Phase 1 data suggest that the combination of DSP107 with PD(L)1 blockade may have anti-tumor activity in cold tumors such as MSS-CRC. Clinical trial information: NCT04440735 .
A phase I study of nelmastobart (hSTC810), an anti-BTN1A1 antibody, in patients with advanced solid tumors.
Authors: Lee Soohyeon , Shin Sangjoon , LoRusso Patricia , Rolfo Christian Diego , Jung Hyunjin , Yoo Stephen Sunghan , Hong David S.
Published: June 2023

2633

Background: Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint that is primarily expressed by tumor cells in a manner that is mutually exclusive with PD-(L)1. BTN1A1 can potentially be targeted to extend new immunotherapeutic treatment options to patients (pts) whose tumors are unresponsive to anti-PD-(L)1 therapy. This phase I study describes the safety and clinical activity of Nelmastobart (hSTC810), a humanized monoclonal antibody targeting BTN1A1, in pts with advanced solid tumors. Methods: Nelmastobart was administered intravenously every 2 weeks across 6 dose levels from 0.3 mg/kg to 15 mg/kg. The primary objectives were to determine the safety profile and maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Using a 3+3 design, dose-escalation cohorts were evaluated for dose-limiting toxicities (DLT) during the first 2 cycles. Backfill cohorts were allowed once a dose was deemed safe. Response was assessed using RECIST 1.1 every 4 cycles (8 weeks). Pts were treated until disease progression or unacceptable toxicity. Results: As of January 30, 2023, enrollment in the dose-escalation cohorts is complete. A total of 39 pts with colon (n=14), lung (NSCLC n=3; SCLC n=2), urothelial (n=3), breast, cholangiocarcinoma, melanoma, ovarian, pancreatic (n=2) each, adrenocortical, anal, esophageal, H&N, PEComa, skin, and thymic (n=1) cancers each were treated in the dose-escalation and backfill cohorts. Median duration of therapy for all pts was 8 weeks (maximum 29 weeks). Most common treatment related adverse events (TRAEs) reported were grade 1-2 fatigue (6%), headache (5.9%), and nausea (4.4%); furthermore, there were no TRAEs ≥ 3. No pts was discontinued or required dose reduction due to TRAEs. There were no DLTs across all dose levels and the MTD was not reached. In evaluable pts, one confirmed partial response was observed in MSI-H colon cancer (3 mg/kg) and 13 pts (colon, H&N, lung, melanoma, ovarian, thymic carcinoma) had a best response of stable disease (SD) across multiple dose levels. Median duration of PR/SD pts on study was 17.5 weeks. Interim pharmacokinetics (PK) analysis demonstrated consistent exposure with linear PK. Pharmacodynamic analysis measuring cytokines and cell-based markers is pending and will be presented. Based on the safety, efficacy, and PK, we recommend 15 mg/kg Q2W as the RP2D. Conclusions: Nelmastobart is well-tolerated without DLTs up to the final dose of 15 mg/kg. Current data show evidence of anti-tumor activity and durable SD. Clinical development planning for a phase Ib/II clinical trial is underway to further characterize the therapeutic dose and efficacy in select solid tumors. Clinical trial information: NCT05231746 .
Association between physical activity, immune-related adverse events, and mortality in patients undergoing immune checkpoint inhibition.
Authors: Verheijden Rik Jasper , Cabane Ballester Anna , van Eijs Mick JM , van Lindert Anne SR , Suijkerbuijk Karijn , May Anne Maria
Published: June 2023

2643

Background: Immune checkpoint inhibitors (ICIs) have improved prospects for some, but not all patients with cancer and frequently induce severe immune-related adverse events (irAEs). While physical activity (PA) has been associated with prolonged survival and diminished toxicity of chemotherapy, its association with ICI efficacy and toxicity is currently unknown. Hence, here we study the association between PA in patients undergoing ICI, and survival and severe irAE occurrence. Methods: Patients with advanced cancer receiving anti-PD-(L)1 based immunotherapy at our academic center were enrolled in the UNICIT cohort. All participants who completed the PA questionnaire (SQUASH) at ICI initiation between 10-2019 and 01-2022 were included in this study. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week and moderate to vigorous sport and leisure time activity. Association of PA with overall survival (OS) was assessed using Cox proportional hazard regression. Association of PA with occurrence of a severe irAE (grade 3 or higher) within one year was assessed using logistic regression in patients with at least one year follow-up. All analyses were adjusted for sex, age, tumor type, treatment intent and ICI type. Results: In total, 251 patients were included, with a median follow-up of 20 months and a median age of 64 years. The majority (153 patients) had melanoma. Median OS was not reached. Compared to low levels of total PA, intermediate and high levels of total MET-hours were associated with prolonged survival (adjusted hazard ratios: 0.56 (95%CI 0.31-1.02) and 0.47 (95%CI 0.26-0.86), respectively; table). Thirty eight out of 209 patients with at least one year of follow-up developed severe irAEs within the first year. Compared to patients with low total PA levels, patients with intermediate or high levels of total PA have a lower odds of developing severe irAEs (adjusted odds ratios: 0.35 (95%CI 0.12-0.90) and 0.19 (95%CI 0.06-0.56), respectively). Similar trends of prolonged OS and reduced odds of severe irAE occurrence were observed in patients who performed more moderate to vigorous sport and leisure time activity. Conclusions: Higher physical activity levels at start of ICI treatment are associated with prolonged survival and lower risk of severe irAEs. Future research needs to elucidate whether inactive patients benefit from increasing PA levels after diagnosis. [Table: see text]
Effect of fecal transplantation on patients’ reported outcome after immune checkpoint inhibitor colitis.
Authors: Wang Yinghong , Varatharajalu Krishnavathana , Shatila Malek , Shen Shu-En , Herrera Mary , Gonzalez Elizabeth , Wang Xin Shelley , Thomas Anusha , Jiang Zhi-Dong , DuPont Herbert L.
Published: June 2023

2645

Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 47 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Forty-seven patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (93.6%) and colitis grade ≥ 2 (91.5%). Ulcerous (23, 49.0%) and non-ulcerous (12, 25.5%) inflammation were the predominant endoscopic findings. 45 (95.7%) patients received corticosteroids, and 43 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 85.1% after FMT with median time to response of 4.5 days. The transient complications rate is 34.0% at 7 days and 17.0% at 30 days. Response rate among the 38 patients without concurrent CDI was 86.8%. Forty-one (87.2%) patients demonstrated clinical remission by the end of the study period. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea during 12 weeks after FMT, along with improved daily physical functioning on working. Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 . [Table: see text]
Edema and serositis as an adverse event in patients with cancer receiving immune checkpoint blockade: Systematic review to evaluate this immune-related adverse event and associated treatment strategies.
Authors: Elias Evelyn , Rohs Nicholas Cole , Koseki Mako , Chesta Fnu , Takaoka Kensuke , Nishimura Yoshito , Fujiwara Yu
Published: June 2023

2649

Background: Immune checkpoint blockade (ICB) is a standard therapeutic option for certain patients with solid tumors, often leading to durable responses. Immune-related adverse events (irAEs) can impact treatment duration and patients' quality of life. The mechanism of irAEs is proposed to be an inflammatory response triggered by blocking immune checkpoints, and nonspecific symptoms like edema and fluid accumulation can occur. We performed a systematic review to summarize reported studies evaluating edema and serositis to explore edema and serositis as an irAE and management strategies. Methods: We performed a database search in Medline, Embase, and Web of Science for studies reporting the incidence and outcome of immune-related generalized edema (irGE) including peripheral edema, capillary leak syndrome, serositis, pleural/peritoneal/pericardial effusion, and anasarca as an irAE among patients with solid tumors treated with ICB. Two independent reviewers analyzed the eligibility of each article. Those that did not report outcomes related to irGE were excluded. The number of patients, cancer type, name and type of ICB, type of irGE, treatment of irGE, and treatment outcome for irGE were extracted from each article to summarize the characteristics of irGE. Results: 662 articles were identified, and 80 studies were included (65 case reports/series, 8 cohort studies, 3 phase 1/2 clinical trials) that described clinical characteristics and treatment outcomes for AEs from 196 patients, and 259 irGE incidences reported. The median age was 62 (Interquartile range: 55-68). 35.9% of cases were female (n=28/78). Commonly reported irGEs were pericardial effusion (n=115, 44.4%), pleural effusion (n=58, 22.4%), peripheral edema (n=40, 15.4%), and ascites (n=19, 7.3%). PD-1 blockade was utilized in 75.8% of cases, followed by PD-L1 blockade (14.9%) and dual ICB (CTLA4 and PD-1 blockade, 4.6%). Common cancers where irGE occurred were: lung cancer (63.9%), malignant melanoma (17.0%), and urothelial carcinoma (3.1%). We classified irGEs into primary irGE (n=84, 42.9%), secondary to other irAEs (n=41, 20.9%), secondary to pseudoprogression (n=14, 7.1%), and cancer progression (n=13, 6.6%). Glucocorticoid was used to manage irGEs in 91 patients (46.4%); 48 cases (24.5%) required the prednisone-equivalent dose of > 1 mg/kg/day. ICB discontinuation was confirmed in 96 cases (49.0%) among which 53 (27.0%) permanently stopped ICB use due to irGEs. Conclusions: irGE is an important irAE among patients with solid tumors receiving ICB. Most cases required glucocorticoid therapy along with discontinuation of ICB, which could result in poorer quality of life and potentially impact outcomes. The pathophysiology, incidence and clinical outcomes of irGE need to be accurately described in further studies.
Real-world data: Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in Veteran Health Administration.
Authors: Alkadimi Munaf , Lucero Kana , Boyle Lauren Diaz , Fierro Maria Elena , Franklin Kathleen , Nooruddin Zohra , Mader Michael
Published: June 2023

2651

Background: Advanced Hepatocellular carcinoma (HCC) is an aggressive tumor, and most patients have a poor prognosis. Recent clinical trials have demonstrated improved survival with molecularly targeted treatment and immunotherapy. Atezolizumab plus Bevacizumab (A+B ) is the recommended first-line treatment for advanced HCC based on the phase 3 IMbrave 150 trial. However, in a real-life setting, many patients do not meet the inclusion criteria of this landmark trial. This study proposes a retrospective review of outcomes of advanced HCC patients receiving A + B in Veterans Health Administration (VHA). Methods: Patients with advanced HCC receiving 1st line systemic therapy with A+ B at the VHA between Dec 1, 2019, to Mar 1, 2022, were selected from the electronic medical records (EMR) using ICD-9 and ICD-10 codes. Abstractors reviewed EMR and followed from their index date of A+ B initiation until death or their last VHA visit, with the study period ending on Jan 31, 2023. The Chi-Squared test was used to compare rates, and the Mann-Whitney test was used to compare medians. Results: A total of 332 patients met the study criteria. The median age was 67 yrs., 99% were males, 63% non-Hispanic White, 26% were Black, 66 % had ECOG ≥ 1, 84% had CPS class A, 16% had CPS class B and C, 62% had grade 2 ALBI score, 56% had viral hepatitis-caused HCC, 80 % had cirrhosis, and 67% had prior local therapies. The outcomes are shown. Conclusions: In our real world, despite having similar PFS as the phase 3 IMbrave 150 trial, our OS at 12 months was lower (52% vs. 67%), given that we had more elderly patients with moderate liver dysfunction and 40% were non-white. This study provides actual outcomes in clinical practice where patients do not match the study population of the pivotal trial. [Table: see text]
Safety and efficacy of immune checkpoint inhibitors (ICIs) in patients (pts) with cardiac metastases (mets) from solid tumors.
Authors: Nassar Amin , Abou Alaiwi Sarah , El Zarif Talal , Denu Ryan Austin , Hayek Salim S. , Goodman Rachel S , Woodford Rachel , Neilan Tomas G. , Haykal Tarek , Kojima Yuji , Trevino Alexandra , Hui Gavin , Tandon Ankita , El-Am Edward , Mittra Arjun , Baena Javier , Choudhary Arrush , Grynberg Shirly , Choueiri Toni K. , Naqash Abdul Rafeh
Published: June 2023

2653

Background: Given underlying differences in the tumor microenvironment across metastatic sites, ICIs demonstrate variable efficacy depending on sites of met involvement. Data on the safety and outcomes of pts on ICIs with cardiac mets are limited. Methods: In an international multi-center retrospective study, pts with solid tumors and baseline mets to the heart who had received ≥1 cycle of ICIs were included. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Objective response rates (ORR) were evaluated by RECIST1.1 when available. Median overall survival (mOS) and median progression-free survival (mPFS) were calculated from time of ICI initiation using the Kaplan-Meier method. Results: 110 pts across 20 institutions were identified with a median follow-up of 36 (95% CI 26-51) months. Melanoma (38%, n=42) and non-small cell lung cancer (NSCLC, 24%, n=26) were the most common cancers. Median age at ICI initiation was 65 (IQR: 59-75) years and 29% (n=26) received combination ICI therapy with anti-PD1 and anti-CTLA4. Overall, 62% (n=68) received ICIs as 1st line. The mets were mostly located in the atria (37%, n=41) and ventricles (35%, n=39). At ICI initiation, 21% (n=23) had a cardiac thrombus. Of 78 pts with available echocardiographic data at time of ICI initiation, the mean ejection fraction was 61+/- 7.1%. Cardiology referrals and cardiac MRIs since time of cancer diagnosis were completed on 53% (n=58) and 47% (n=52) of pts, respectively. Overall, 36.4% (n=40) of pts had cardiac complications from the mets, including arrhythmias (13%, n=14), arterial/venous emboli (3.6%, n=4), and cardiac tamponade (2.7%, n=3). For NSCLC, ORR, mPFS (95% CI), and mOS (95% CI) were 23%, 4.4 months (3.0-7.5), and 9.9 months (5.9-14.7), respectively. For melanoma, ORR, mPFS, and mOS were 35.7%, 9.1 months (5.2-20), and 29 months (14-58), respectively. Cardiac met ORRs for NSCLC and melanoma were 27% and 43%, respectively. 74% (N=71/96) of pts with evaluable response data had concordant response in the burden of overall disease and cardiac disease. IrAEs are shown. Conclusions: Although cardiac mets are frequently associated with cardiac complications, ICIs demonstrate meaningful efficacy with no overtly concerning safety signals. Close to three-quarter of pts have concordant response in the overall disease and cardiac disease burden. Multi-disciplinary approach involving cardiologists and oncologists need to be implemented to appropriately manage pts with cardiac mets. [Table: see text]
Pan tumor outcomes to immune checkpoint inhibitors in patients of Native American origin in the United States: The multicenter POINT-US study.
Authors: Phan Minh Duc , El Tomb Paul Antoine , Khreis Tariq , Meissner Tobias , Elsey Rachel , Xu Bing , Arshad Junaid , Rozell Umbreen Arshad , Tjong Elysia , Florou Vaia , Puri Sonam , Khan Arsalan , Rhoades Dorothy , Aljumaily Raid , Ayanambakkam Adanma , Burtman Anthony , Bigbey Mark , Sjoquist Michael , Williams Casey B. , Naqash Abdul Rafeh ,   OUHSC
Published: June 2023

2654

Background: Despite receiving identical standard-of-care therapies, epidemiological data indicate that Native American (NA) patients (pts) with cancer have worse outcomes vs. White pts. ICIs have revolutionized the treatment of certain tumors, however pts from certain racial and ethnic groups, including NA pts, are underrepresented in ICI trials. Methods: This is an ongoing multi-center retrospective study across four U.S. academic cancer centers that serve a high volume of NA pts. We included pts with self-reported race as NA in electronic medical records. We evaluated clinical outcomes and immune-related adverse events (irAEs) of 71 NA pts age ≥18 years with various solid tumors treated with ICI-based therapies between 2015 to 2021. IrAEs were defined based on the Common Terminology Criteria for Adverse Events (version 5.0) or RECIST 1.1. as available, was used to determine objective response rate (ORR). Kaplan Meier log-rank method was used to generate median progression free survival (mPFS) and median overall survival (mOS). Results: Median age (range) at ICI initiation was 62 (24 -81) years; 43 (60%) were males, with 26 (37%) females, 2 pts with missing gender data. 55 (77%) of pts had ECOG performance status 0. The distribution of top six tumor types included (number of pts [%]): non-small cell lung cancer (NSCLC) 22 (31%), renal cell carcinoma (RCC) 16 (23%), melanoma 7 (10%), small cell lung cancer (SCLC) 4 (6%), hepatocellular carcinoma 4(6%); colorectal adenocarcinoma, head and neck squamous cell carcinoma, cervical squamous cell carcinoma each had 3 pts (4%). Most pts (51 [72%]) received single agent ICI, 12 (17%) had dual ICI, 4 (6%) had chemotherapy+ ICI, and remaining had either ICI + tyrosine kinase inhibitor or ICI + study drug (4 [6%]). 55% of pts with NSCLC underwent tumor next-generation sequencing (NGS) while <30% of patients with renal cell carcinoma or melanoma had tumor NGS performed. Among 71 pts, 17 (24%) had any grade (G) irAE, 4 (6%) were reported to be ≥G3. The median time to irAE onset was 18 weeks and 3 (4%) pts discontinued ICI due to irAEs. The mPFS, mOS and ORR for the most frequent tumors (N ≥5) are shown. Conclusions: Although limited by sample size, our emerging data provides new insights into ICI efficacy and irAEs in NA pts that have been unknown to date. To our knowledge, this is the first and only attempt to date evaluating ICI outcomes in NA pts. Updated clinical data and tumor genomics will be presented at the meeting. [Table: see text]
A comprehensive pan-cancer analysis of PD-L1 expression using clone E1L3N in Chinese patients with cancer.
Authors: Lu Huangbin , Huang Zhan , Ge Huijuan , Wang Hongyu , Ruan Li , Zheng Frank
Published: June 2023

2656

Background: Immune checkpoint inhibitors (ICIs) benefit patients with multiple cancer types, and the expression of programmed death ligand 1 (PD-L1) protein assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 ICI therapies in several cancer types. IHC assay with E1L3N clone is currently approved by the NMPA for PD-L1 detection in non-small cell lung cancer (NSCLC), but its performance in other cancer types needs to be further validated. Thus, we performed this study to examine the prevalence of PD-L1 expression in a wide variety of tumor types in Chinese pan-cancer patients using the E1L3N antibody clone. Methods: From 2019 to 2022, a total of 13,647 patient across multiple tumor types were analyzed. Tumor tissue samples were subjected to IHC. PD-L1 expression was tested using the E1L3N PD-L1 IHC assay (Amoy Diagnostics, Xiamen, China), and scored with the tumor proportion score (TPS) and combined positive score (CPS). PD-L1 expression status was identified as positive and negative according to TPS or CPS. For NSCLC: negative (TPS < 1%), low expression (TPS 1-49%), and high expression (TPS ≥ 50%). For gastric/gastroesophageal junction carcinoma (GC/GJC): negative (CPS < 1), low expression (CPS 1-5), and high expression (CPS ≥ 5). For other cancer: negative (CPS < 1), low expression (CPS 1-10), and high expression (CPS ≥ 10). Results: In total, 14 cancer types were enrolled in the present study, including 68.2% NSCLC, 6.9% colorectal carcinoma (CRC), and 3.8% GC/GJC, and the remaining 21.1% include esophageal cancer (EC), breast cancer, cervical cancer (CC), biliary tract cancer (BTC), pancreatic cancer (PC), ovarian cancer, renal cancer, small cell lung cancer, urothelial carcinoma (UC), bladder cancer, head and neck squamous cell carcinoma (HNSCC), etc. PD-L1 positivity by TPS was observed in 52.5% NSCLC patients, similar to the frequency of PD-L1 expression in Chinese NSCLC patients detected using 22C3 clone. 76.0% and 36.7% of GC/GJC patients with PD-L1-positive tumors at a CPS cutoff of ≥ 1 and ≥ 5, respectively. PD-L1 positive expression frequency was higher than that in western GC/GJC patients detected using 22C3 and 28-8 clone (as reported from previous research: PD-L1 positivity with CPS ≥ 1 was 45.5% using the 22C3 assay and 49.1% using the 28-8 assay). 73.6% and 17.5% of CRC patients with PD-L1-positive tumors at a CPS cutoff of ≥ 1 and ≥ 10, respectively. In addition, 8 tumors (EC, CC, breast cancer, PC, BTC, UC, HNSCC, and bladder cancer) had the prevalence of PD-L1 CPS ≥ 1 greater than 50%. Conclusions: E1L3N can be used as a reliable alternative antibody clone to evaluate PD-L1 expression status not only in NSCLC patients but also in other cancer types.
Factors associated with severe immune checkpoint inhibitor-induced pneumonitis.
Authors: Abu-Sbeih Hamzah , Moodabagil Meghana , Peng Jing , Ma Jianing , Easterling Robert , Viveiros Matthew , Li Mingjia , Secor Austin , Goodyear Evelyn , Kendra Kari Lynn , Otterson Gregory Alan , Presley Carolyn J , Donnelly Edwin , Meara Alexa Simon , Owen Dwight Hall , Ho Kevin
Published: June 2023

2658

Background: Immune checkpoint inhibitor (ICI) induced pneumonitis (ICIp) can be severe and even fatal, but risk factors for severe ICIp remain poorly characterized. In this abstract, we characterize ICIp and assess factors associated with severe disease. Methods: This is a retrospective study of consecutive patients who received ICI therapy and developed ICIp at the Ohio State University (2013-2020). Patients with ICIp were identified from a pharmacy database using ICD-10 codes followed by chart review to confirm diagnosis. ICIp was graded based on the CTCAE v5.0 criteria. Laboratory values were collected at the onset of ICIp. A thoracic radiologist reviewed chest imaging for pattern and severity. Survival probabilities were estimated with Kaplan-Meier curve and compared with log rank test. Results: Of 2963 patients who received ICI, we identified 119 patients (4%) with ICIp: 75 (63%) were males; 79 (66%) received PD-1 inhibitor monotherapy; and 71 (60%) had lung cancer. ICIp was severe (grade 1-2) in 69 patients (58%) and mild (grade 3-5) in 50 (42%). 74 patients (62%) were hospitalized. 63 patients (53%) needed oxygen supplementation. ICI therapy was held in all patients except one. ICI was rechallenged in 26 patients; 6 of them (23%) had recurrence of ICIp symptoms. All but 2 patients received steroids for the treatment of ICIp. 10 patients received non-steroidal medications (7 IVIG, 2 infliximab, 1 rituximab, 1 abatacept, 1 cyclophosphamide). Steroids were tapered in 6 patients of those who received non-steroidal medications. 3 of the patients who received IVIG had improvement of symptoms. Factors associated with severe ICIp. 21 patients (18%) died while hospitalized for ICIp are shown. Patients with severe ICIp had shorter overall survival than those with mild ICIp (P < 0.001). Conclusions: ICIp is a serious adverse event that limits ICI treatment and can lead to hospitalization and death. Factors associated with severe ICIp in our study include lower lymphocyte and eosinophil counts, lower albumin levels, finding of consolidation or bronchiectasis on imaging, and lower predicted FVC and TLC. Prospective studies are merited to validate our findings and to investigate the appropriate treatment of ICIp. [Table: see text]