Metastatic Solid Tumors Research Articles

Hypofractionated radiotherapy combined with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor, and thymosin-α1 in advanced metastatic solid tumors: a multicenter Phase II clinical trial

PurposeThis multicenter Phase II clinical study assessed the efficacy and safety of hypofractionated radiotherapy (HFRT) in combination with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor (GM-CSF), and thymosin-α1 in patients with heavily treated metastatic solid tumors.MethodsPatients were enrolled between September 2022 and May 2024. HFRT was administered to targeted tumors, and GM-CSF was administered for 14 days from day 1 of radiotherapy. Thymosin-α1 was injected concurrently twice weekly until disease progression. Immunotherapy with camrelizumab was started following HFRT and repeated every 3 weeks. GM-CSF was administered daily for 7 days before each cycle of immunotherapy.ResultsBy June 15, 2024, there were 37 study participants. The median follow-up duration was 5.97 months (range 0.40–20.9). Median progression-free survival was 3.5 months (95% confidence interval 2.73–4.23) in the intention-to-treat population. The objective response rate was 23.08%, and the disease control rate was 65.38%. Overall survival data are not yet mature. Abscopal effects were observed in 6 patients (23.08%); four of whom achieved a partial response. Patients who achieved a partial response were significantly more likely to have an abscopal effect( P = 0.025). The group with a lower baseline neutrophil–lymphocyte ratio had a significantly lower risks of distant metastasis and death( P = 0.024). Seventeen adverse reactions were reported, including six grade 3 or 4 adverse events. There were no grade 5 adverse events.ConclusionIn conclusion, the trends in efficacy observed in our study are promising; however, well-designed protocols are essential to validate these findings.

Clinical results of a phase 1 trial evaluating a HER2 directed CAR-T product selective for the tumor microenvironment (TME) in patients with GI and other solid tumor malignancies.

449 Background: A major limitation of CAR-T in solid tumors has been the inability to safely target antigens shared between healthy and malignant tissue. One approach to improving selectivity is to regulate CAR affinity through the unique metabolism of the tumor microenvironment (TME). This first in human trial evaluated an autologous (41BB) CAR-T product encoding a tumor metabolism regulated HER2 CAR. Methods: This Phase 1, dose escalation, basket trial evaluated the safety, tolerability, pharmacokinetics and efficacy in 12 patients (pts) with HER2 IHC 3+ / FISH + Stage IV r/r solid tumor malignancies (gastric, esophageal, colorectal, breast). They had failed multiple lines of therapy (66.7% patients had failed 4~10 lines of therapies previously). Dose cohorts of 3E5 (n=3), 1E6 (n=3), or 1E7 (n=6) CAR-T cells/kg were evaluated with a 28-day in-patient DLT observation period. Cell product was manufactured from whole blood, with a 12-day closed process and release on day 17. Lymphodepletion regimen was 500 mg/m 2 Cy and 30 mg/kg 2 Flu X 3 prior to infusion of CAR-T. Results: Data cutoff 09/16/24. All 12 patients were evaluable for safety and efficacy. No DLTs, ICANS or SAEs were observed. For HER2 positive normal tissues of special concern (e.g. cardiomyocytes), longitudinal functional, biochemical and clinical cardiovascular tests showed no signs of OTOT. One patient experienced Grade 2 CRS and recovered. No AE’s lead to study discontinuation. In one patient, there were two Grade 3 AEs attributed to product (neutropenia and hypoxia); both which resolved. With a median follow-up of 302 days for cohort 3, 12-month survival rate in this cohort is 83.3%, compared to the 12-month survival rate of 33.3% for cohorts 1 and 2 combined. Encouraging signals of efficacy were observed with an ongoing (at 24 wks) deep PR (100% reduction SLD) in a GC patient. The median peak copy number of CAR-T cells in peripheral blood (n=12) was 1,818 copies/µg DNA (range 403 – 10,466). Conclusions: The tumor metabolism regulated HER2 CAR-T product was generally well tolerated, with no DLTs, and evidence of radiologic objective response in patients with gastroesophageal cancer. Combined, the safety and activity observed in this study suggests that a previously challenging solid tumor antigen may be safely targeted by a CAR with affinity regulated by the metabolism of the TME. Enrollment for the study was complete as of 28-Feb-2024 (NCT04511871). Clinical trial information: NCT04511871 .

Peripheral blood PD-1+T lymphocytes as biomarkers in liquid biopsies for solid tumors: Clinical significance and prognostic applications.

A shift toward a T cell exhaustion phenotype is associated with the upregulation of expression of programmed cell death protein 1 (PD-1) on T lymphocytes in patients with malignant solid tumors. The interaction between PD-1 and programmed death-ligand 1 (PD-L1) inhibits PD-1+ T lymphocyte function, impacting their anti-tumor immune activity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized the treatment of various solid malignancies, improving therapeutic efficacy and survival outcomes. Peripheral blood analysis of liquid biopsies is being increasingly used to identify populations most likely to benefit from various treatment modalities. PD-1+ T lymphocytes represent the primary cell population responsive to immunotherapeutic interventions for patients with solid malignancies, as evidenced by the altered PD-1 expression levels and proportion of cells comprising the overall population of immunocytes. PD-1+ T cells in peripheral blood exert an associative and reciprocal predictive effect on homologous intratumoral cells. Distinct subpopulations of PD-1+T cells exhibit differential ability to proliferate in the periphery and can be characterized by tumor antigen-specific and exhaustion phenotypes. These characteristics have prognostic implications, aiding in the prediction of the efficacy of antitumor therapy and predicting survival outcomes. We highlight distinct subpopulations of PD-1+T cells, their exhaustion and antigen-specific phenotypes, and their dynamic changes over treatment, providing insights into their utility for tailoring personalized therapies. For the first time, this review discusses the role of peripheral PD-1+T lymphocytes as prognostic biomarkers in liquid biopsies, focusing on their clinical significance, predictive value during therapy, and future research directions.

Practical guide for the diagnosis and treatment of localized and generalized cutaneous pruritus (chronic itch with no underlying pruritic dermatosis).

Itch, also known as pruritus, is one of the most prevalent symptoms observed in dermatological practices. Itch frequently arises from primary pruritic dermatoses, although it may also manifest in the absence of a primary pruritic skin rash. The latter itchy condition is referred to as "cutaneous pruritus" in the Japanese guidelines published in 2020. Cutaneous pruritus can be classified into two categories based on its distribution: localized cutaneous pruritus and generalized cutaneous pruritus. Localized cutaneous pruritus is indicative of a neuropathic cause, whereas generalized cutaneous pruritus suggests underlying systemic disease(s), drug-induced itch, psychogenic itch (also known as functional itch disorder), or chronic pruritus of unknown origin (CPUO). Systemic diseases associated with cutaneous pruritus include disorders of iron metabolism, chronic kidney disease, chronic liver disease (especially cholestasis), endocrine/metabolic diseases, hematological disorders, and malignant solid tumors. CPUO is a term used to describe chronic itch that is often generalized and for which no underlying cause can be identified despite a comprehensive and careful diagnostic workup. A variety of treatment approaches are available for cutaneous pruritus, including device-based physical therapies (such as phototherapy) and medications that act on the itch-perception processing pathway from the skin, peripheral sensory nerves, the spinal cord, to the brain. This review presents an overview of the current knowledge regarding cutaneous pruritus, from its underlying pathophysiologic mechanisms to the diagnostic procedures and treatment approaches that are currently available.

An open-label, phase IB/II study of abemaciclib with paclitaxel for tumors with CDK4/6 pathway genomic alterations.

Disruption of cyclin D-dependent kinases (CDKs), particularly CDK4/6, drives cancer cell proliferation via abnormal protein phosphorylation. This open-label, single-arm, phase Ib/II trial evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, combined with paclitaxel against CDK4/6-activated tumors. Patients with locally advanced or metastatic solid tumors with CDK4/6 pathway aberrations were included. Based on phase Ib, the recommended phase II doses were determined as abemaciclib 100 mg twice daily and paclitaxel 70 mg/m2 on days 1, 8, and 15, over 4-week-long cycles. The primary endpoint for phase II was the overall response rate (ORR). The secondary endpoints included the clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Tissue-based next-generation sequencing and exploratory circulating tumor DNA analyses were carried out. Between February 2021 and April 2022, 30 patients received abemaciclib/paclitaxel (median follow-up: 15.7 months), and 27 were included in the efficacy analysis. CDK4/6 amplification (50%) and CCND1/3 amplification (20%) were common activating mutations. The ORR was 7.4%, with two partial responses, and the CBR was 66.7% (18/27 patients). The median OS and PFS were 9.9 months [95% confidence interval (CI) 5.7-14.0 months] and 3.5 months (95% CI 2.6-4.3 months), respectively. Grade 3 adverse events (50%, 21 events) were mainly hematologic. Genetic analysis revealed a 'poor genetic status' subgroup characterized by mutations in key signaling pathways (RAS, Wnt, PI3K, and NOTCH) and/or CCNE amplification, correlating with poorer PFS. Abemaciclib and paclitaxel showed moderate clinical benefits for CDK4/6-activated tumors. We identified a poor genetic group characterized by bypass signaling pathway activation and/or CCNE amplification, which negatively affected treatment response and survival. Future studies with homogeneous patient groups are required to validate these findings.

Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer, hepatocellular carcinoma, and other locally advanced or metastatic solid tumors.

TPS322 Background: Wnt/B-catenin pathway activation, which is frequently present in most colorectal cancers and a variety of other solid tumors, is associated with poor prognosis and resistance to immunotherapy. FOG-001 is a Helicon peptide that competitively inhibits the interaction between β-catenin and the T-cell factor (TCF) family of transcription factors. Experiments in patient-derived-xenograft (PDX) models of colorectal cancer (CRC) and hepatocellular carcinoma (HCC) have demonstrated that FOG-001 can inhibit tumor growth and promote tumor regression when administered as monotherapy or in combination with immune checkpoint inhibitors or standard of care therapies, including bevacizumab and 5-FU. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Part 1) and dose-expansion (Part 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of FOG-001 as monotherapy and in combination with other anti-cancer therapies. Eligible patients must have received at least one prior systemic anti-cancer therapy and either progressed on, not responded to, or be unfit for available therapies. In Part 1, FOG-001 is administered intravenously, either weekly or every other week, at escalating dose levels evaluated sequentially in a standard 3+3 design as monotherapy in patients with: (1a) microsatellite stable (MSS) CRC or any solid tumor with a documented Wnt/b-catenin pathway activating mutation (WPAM) and (1c) HCC with WPAM. Part 1b will evaluate PD effects in cohorts of approximately six patients with MSS CRC. Upon selection of the preliminary recommended Phase 2 dose from Part 1a for weekly dosing, combination dose escalation (1d) evaluates the safety/tolerability, PK and anti-tumor effects of FOG-001 in CRC patients combined with FOLFOX+bevacizumab, anti-PD-1/PD-L1 (also includes other solid tumors with known WPAM), or trifluridine/tipiracil+bevacizumab. Part 2 dose expansion evaluates FOG-001 monotherapy in MSS CRC, HCC, and other solid tumors with documented WPAM. Combination dose expansion evaluates the combinations initially evaluated in Part 1d. Primary endpoints are safety/tolerability and preliminary anti-tumor effects (objective response rate). Secondary endpoints are PK, PD, and other anti-tumor responses (e.g., best objective response, duration of response, and progression free survival). Enrollment in Parts 1 and 2 is ongoing in the USA. Clinical trial information: NCT05919264 .

Preclinical and phase 1/2 data of the CHK1 inhibitor BBI-355 in development for esophageal and gastric cancers (EGC) with EGFR or FGFR2 amplifications.

TPS517 Background: High-copy number amplifications of oncogenes (e.g., EGFR , FGFR2 ) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. While targeted therapies have improved survival for patients with oncogene mutations, they have limited activity in oncogene amplified cancers. In Barrett’s esophagus-associated esophageal adenocarcinoma (EAC) ecDNA can be found early in the transition from high-grade dysplasia to EAC. In EAC and gastric cancer (EGC), ~7% and ~3% have EGFR and FGFR2 amplifications, respectively, with possibly >50% occurring on ecDNA. Tumor cells with oncogene amplifications, particularly on ecDNA, have increased DNA replication stress and are sensitive to inactivation of checkpoint kinase 1 (CHK1). We developed BBI-355, an oral, potent, and selective small molecule inhibitor of CHK1, which is in Phase 1/2 clinical development. Methods: BBI-355-101 is a first-in-human Phase 1/2 study of BBI-355 alone or in combination with targeted therapies for advanced or metastatic solid tumors with oncogene amplification (NCT05827614). Part 1 is dose escalation of BBI-355 (PO Q2D). In Parts 2 and 3, patients with EGFR or FGFR 1-3 amplifications are treated with BBI-355 in combination with the EGFR inhibitor erlotinib (150 mg PO QD) or the FGFR inhibitor futibatinib (20 mg PO QD). While this study is enrolling all tumor types, EGC are some of the most likely to harbor ecDNA amplifications. Amplification-driven cancers rarely contain driver oncogene mutations or fusions, and so are excluded. Results: Preclinical: Tumors that harbor oncogene amplifications on ecDNA can evade targeted therapeutic pressure via ecDNA-based resistance mechanisms. BBI-355 in combination with agents targeting the amplified oncogenes ( FGFR2 or EGFR ) prevented resistance to targeted therapies in multiple ecDNA+ gastric cancer CDX and PDX models. Clinical: Safety and PK data of BBI-355 alone and in combination with erlotinib or futibatinib will be presented. The most common drug-related TEAEs, SAEs, and DLTs were hematologic (i.e., leukopenia, neutropenia, lymphopenia and thrombocytopenia) which are on target for CHK1 inhibition and generally well managed. Dose escalation is ongoing and the RP2D/MTD has not been determined. PK showed dose-dependent increase in exposure of BBI-355. Target engagement as determined by pCHK1 IHC as a PD biomarker was observed at all dose levels of BBI-355. Conclusions: The first ecDNA directed therapy, BBI-355, demonstrated significant synergistic anti-tumor activity in combination with targeted therapies in multiple ecDNA+ oncogene amplified EGC models. BBI-355 alone and in combination with erlotinib/futibatinib was well tolerated. Clinical testing in patients with EGFR and FGFR2 oncogene amplifications is ongoing with a strong rational for EGC. Clinical trial information: NCT05827614 .

First-in-human, phase 1a, dose escalation study of BGB-B167, a CEA x 4-1BB bispecific antibody, as monotherapy or combined with tislelizumab (anti-PD-1), in patients with selected advanced or metastatic solid tumors.

123 Background: BGB-B167 is potentially a first-in-class IgG-based bispecific antibody that targets CEA, a tumor-associated antigen overexpressed in many cancers, and 4-1BB, a key T-cell co-stimulatory receptor expressed on activated CD4+/CD8+ T lymphocytes. Preclinical data suggest BGB-B167 binds to these target proteins with high specificity/affinity, inducing T-cell activation and antitumor activity, with potential for mitigating strong AEs, eg CRS and hepatoxicity. We present results of a first-in-human, phase 1a, open-label, multicenter trial of BGB-B167 given as monotherapy (Part A [A]) or with tislelizumab (TIS) (Part B [B]) (NCT05494762). Methods: Eligibility: ≥18 y with unresectable/metastatic CRC, CEA+ GC or CEA+ NSCLC previously treated with standard systemic therapy or for whom treatment is unavailable; pts with CRC and known MSI-H/dMMR status must have received prior ICI, if available. Primary objectives: safety/tolerability; MTD and RP2D for BGB-B167 ± TIS; key secondary objective: antitumor activity (RECIST v1.1). Results: As of July 7, 2024, 54 pts were enrolled (31 in A, 23 in B) with BGB-B167 dose ranges of 5–1200 mg IV QW assessed in A and 50–600 mg IV QW in B. In A and B, respectively, 29/31 (93.5%) and 18/23 (78.3%) had CRC, 2/31 (6.5%) and 3/23 (13%) had GC, 0/31 (0%) and 2/23 (8.7%) had NSCLC; 19/31 (61.3%) and 18/23 (78.3%) had liver metastases; 20/31 (64.5%) and 14/23 (60.9%) received ≥3 lines of prior therapy. TEAEs occurred in all pts (Table). Most common treatment-related TEAEs were nausea (4/31; 12.9%) and fatigue (3/31; 9.7%) in A and pruritus (5/23; 21.7%) and diarrhea (4/23; 17.4%) in B; there were no treatment-related TEAEs indicative of hepatotoxicity or CRS. There was a single DLT (gr 3 SJS) in a pt who received 600 mg BGB-B167 + TIS (resolved after treatment discontinuation). MTD was not reached. 3 pts (1 with CRC [A]; 1 with CRC and 1 with GC [B]) had confirmed PRs. DoR was ≥5.6 mo for the pt in A and ≥5.6 mo and ≥6.9 mo for the pts in B; all remained on treatment with ongoing responses as of the data cutoff date. DCR (95% CI) was 33.3% (17.3–52.8) in A and 40.9% (20.7–63.6) in B. Serum exposure of BGB-B167 increased dose dependently from 150 to 1200 mg. Conclusions: Overall, BGB-B167 ± TIS was well tolerated and has demonstrated limited antitumor activity in pts with advanced/metastatic CEA+ solid tumors. Clinical trial information: NCT05494762 . Safety. Part ABGB-B167 monotherapy(N=31) Part BBGB-B167 + TIS(N=23) Any TEAE 31 (100.0) 23 (100.0) Any treatment-related TEAE 17 (54.8) 15 (65.2) Gr ≥3 4 (12.9) 1 (4.3) Serious 0 (0) 2 (8.7) Leading to death 0 (0) 0 (0) Leading to treatment discontinuation 0 (0) 1 (4.3) Any imAE 2 (6.5) 5 (21.7) IRRs 4 (12.9) 6 (26.1) Patients with multiple adverse events (AEs) are counted once. All AEs are listed as n (%). imAE, immune-mediated AE; IRR, infusion-related reaction; TEAE, treatment-emergent AE.

Nutritional Status in Locally Advanced or Metastatic Solid Cancer Patients Treated With Chemotherapy, Radiotherapy, and Immunotherapy in Spanish Outpatient Oncology Units.

Malnutrition is a prevalent condition in cancer patients that significantly impacts patients' clinical outcomes and health-related quality of life (HR-QoL). The outcome was to characterize the nutritional status by describing the prevalence of malnutrition (mild, moderate, or severe) and its risk in outpatient cancer patients. Multicenter, prospective, cross-sectional, descriptive, two-cohort study conducted on consecutive adult patients with locally advanced or metastatic solid tumors (stages III-IV). The study was conducted in 10 Spanish hospitals distributed all over the Spanish geography, with a recruitment period of 5 months (between April and September 2020). Study patients were divided into two groups according to their cancer therapy: group A, patients who underwent immunotherapy, and group B, patients who received combined therapy (immunotherapy plus chemotherapy and radiotherapy). A total of 585 patients were included. The proportion of patients at risk of malnutrition was notably more significant in the combination group (chemotherapy and/or radiotherapy) than in the immunotherapy-only group (28.3% versus 58.5%, respectively, P < .0001). According to this evaluation the highest proportion of patients at risk were those with pancreatic cancer (51 patients; 89.5%), followed by large intestine cancer (52 patients; 55.3%) and lung cancer (56 patients; 29.3%), P < .0001. Patients treated with only immunotherapy seemed to have better nutritional status, which indicated health-related quality of life improvement. Additionally, there was a trend associating nutritional status with tumor location. Treatment strategy, treatment duration, performance status, and treatment location were independently associated with malnutrition. Integrating nutritional assessment into routine clinical practice will improve the quality of life of oncology patients. An integrative approach to health improves overall results in terms of nutritional status and improved quality of life and shows that daily living activities are more satisfactory for patients with nursing interventions. Nursing interventions are consistent with an educational approach to patients as long as the interventions described in international guidelines are detailed in the framework of the patient care.

Blood-based prognostic scores and early dynamics under immunotherapy to select patients with metastatic solid tumors for continuing immune check-point inhibition: a prospective longitudinal study

IntroductionImmune check-point inhibitors (ICI) were a major breakthrough in cancer care, but optimal patient selection remains elusive in most tumors.MethodsOverall 173 adult patients with metastatic solid tumors candidates to ICI in clinical trials at our Institution were prospectively recruited. Blood samples were collected at cycle 1 (C1D1) and 2 (C2D1) and until the occurrence of progressive disease (PD). C1D1 LIPI, RMH, PMHI, NLR, dNLR, PIPO and GRIm prognostic scores were calculated. The primary endpoint was identifying the best score to predict rapid PD (≤ 4 months) with ICI using logistic regressions accounting for tumor type, and receiving operators characteristics (ROC) with area under curve (AUC), accompanied by an extensive comparison of the score performances in the prediction of overall survival (OS), progression-free survival (PFS), overall response rates (ORR) and durable clinical benefit (DCB). Secondary objectives included describing study cohort outcomes and studying the association between the selected score at C1D1, C2D1 and its dynamics with OS and PFS.ResultsC1D1 LIPI was the best predictor of rapid PD, OS and PFS, regardless of cancer type, compared to other scores. No score was associated to ORR and only RMH to DCB. Baseline LIPI detected three categories of patients with significantly different OS (p < 0.001) and PFS (p = 0.013). The same was observed at C2D1 for OS and PFS (both p = 0.020). Significant LIPI class shifts were observed in the overall population (p < 0.001), rapid progressors (p = 0.029) and non-rapid progressors (p = 0.009). Retaining a good LIPI or experiencing a shift towards a better prognostic class was associated to improved OS (p = 0.009) and PFS (p = 0.006). C2D1 LIPI, but not C1D1, remained significantly associated to rapid PD in multivariable analysis.ConclusionsLIPI may improve patient selection for ICI and guide treatment adjustments according to on-treatment dynamics in a pancancer context.

Colorectal cancer metastatic dMMR immunotherapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer 9NRG-GI004/SWOG-S1610).

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

Global, regional and national burden of neuroblastoma and other peripheral nervous system tumors, 1990 to 2021 and predictions to 2035: visualizing epidemiological characteristics based on GBD 2021.

Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, accounting for >15 % of cancer-related deaths in children. We analyzed the epidemiological statistical indicators of neuroblastoma and other peripheral nervous system tumors patients from 1990 to 2021 in Global Burden of Disease (GBD) 2021 database, aiming to provide valuable insights for public health interventions and clinical practices. Based on the GBD 2021 database, this study analyzed the incidence, mortality, prevalence, and Disability-Adjusted Life-Years (DALYs) of neuroblastoma and other peripheral nervous system tumors from 1990 to 2021, stratified by sociodemographic development index (SDI) and geographic regions. Cross-country inequalities analysis was conducted to quantify the SDI-related inequality of disease burden across countries. In addition, the average annual percentage change (AAPC) and Age-Period-Cohort (APC) model were used to evaluate the trend of disease burden, while the global burden of disease to 2035 was predicted by Bayesian Age-Period-Cohort (BAPC) model. This study reported the disease burden of neuroblastoma and other peripheral nervous system tumors in GBD 2021 database for the first time. Globally, the incidence and mortality of neuroblastoma have increased year by year from 1990 to 2021, especially in regions with low SDI, such as South Asia and sub-Saharan Africa, where the burden of disease has increased significantly. Regions with high SDI, such as North America and Western Europe, have seen a reduction in disease burden due to higher levels of medical care and earlier diagnosis. The age distribution shows that children under 5 years of age are mainly affected, especially in low- and middle-income areas. In addition, the incidence is slightly higher in men than in women. The BAPC model predicts that the global incidence, mortality, and DALYs of neuroblastoma will continue to increase until 2035. Significant regional and population variation in neuroblastoma and other peripheral nervous system tumors worldwide, with a particularly high disease burden in low SDI areas with limited medical resources. This trend highlights the urgent need for global public health interventions and resource allocation, particularly in low-income countries. Future research should focus on improving early diagnosis, risk stratification and target therapy in order to reduce the global burden of disease and improve patients' prognosis. This study was supported by National Natural Science Foundation of China (No. 82293662, No 82172357 and No 81930066), Key project of Shanghai "Science and Technology Innovation Action Plan (22JC1402304) and Research fund of Shanghai Municipal Health Bureau (No. 2019cxjq03).

Real-world outcomes of metastatic cancer patients hospitalized at initial diagnosis: ONIRIS, a national study.

Therapeutic management of metastatic cancer patients who are hospitalized at the time of initial diagnosis because of impaired performance status and/or severe symptoms is challenging for clinicians. This study aims to describe their outcome. METHODS: In this prospective multicentric study, we included all adult, inpatients with newly diagnosed metastatic solid tumors between November 2021 and May 2022. Patients were followed for 3months.. Our primary objective was to describe overall survival (OS). Secondary objectives included assessing SANT effectiveness in specific subgroups, identifying baseline factors associated with SANT initiation, and assessing usual prognostic tools and factors associated with response. 107 patients were included. Seventy-four (69%) initiated a SANT. Among them, 39 patients were alive at 3months. Median overall survival was 1.7months for the entire cohort. Thirty-seven patients (55%) died in the unit where they were first admitted. Patients with chemo-sensitive tumors, such as testicular non-seminomatous germ cell tumors (100% OS at 3months), or those receiving targeted therapies or hormone therapies (80% OS at 3months), showed numerically better outcomes. Factors associated with the initiation of a SANT were young age (OR = 0,94 [0,90; 0,98]), low Charlson Comorbidity Index (OR = 0,56 [0,42; 0,73]), and patient's or caregiver's request for treatment (respectively, OR = 0,07 [0,02; 0,17] and 0,17 [0,06; 0,42], compared to the respective reference category (no request)). Metastatic cancer patients hospitalized at the time of diagnosis share a similar poor survival. Despite the notable exception of chemo-sensitive tumors and specific molecular alterations, the high mortality observed in both groups suggests that SANT has a limited impact on their outcomes. Best supportive care can be reasonably considered for these patients. The benefit of SANT in this altered population should be assessed in larger prospective studies.

Abdominal Bloating Following a Diagnosis of Aplastic Anemia: Correlation or Red Herring?

Aplastic anemia (AA) is a bone marrow failure disorder resulting in peripheral pancytopenia and marrow hypoplasia. An alternative diagnosis of hypoplastic myelodysplastic syndrome (MDS) can overlap this diagnosis but is differentiated by the presence of dysplastic progenitor cells. Since AA can be characterized as an autoimmune disease directed against hematopoietic stem cells, its presence can potentially increase susceptibility to alternate malignancies. Hypoplastic MDS, however, can present itself in an extramedullary fashion solely or as a relapse of acute myeloid leukemia resulting in symptoms similar to those described in this case study. Solid tumor malignancies may also result in abnormal blood counts, creating a wide differential diagnosis. This manuscript presents a case of untreated AA in a patient presenting later with severe abdominal bloating.

P-1165. Factors Associated with Initial Antifungal Choice for Invasive Candidiasis

Abstract Background The Infectious Disease Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Disease (ESCMID) recommend an echinocandin (EC) for first line initial therapy for candidemia. No randomized clinical trial has demonstrated superiority for any antifungal (AF) over another for invasive candidiasis (IC). The EC have become preferred agents due to their favorable side effect profile and early fungicidal activity. Despite current recommendations, there are variabilities in prescribing practices of AF in children with IC. Our goal was to investigate factors influencing initial choices of AF for children with IC. Methods We performed retrospective analysis of de-identified data collected as part of the Pediatric Antifungal Comparative Effectiveness Study (PEACE), a collaborative effort by the International Pediatric Fungal Network, conducted 2014 to 2017. 750 patients from 35 centers were included. We looked at demographics, clinical features, risk factors (underlying diagnosis, neutropenia, immunosuppressive medications, stem cell or organ transplant, parenteral nutrition etc) which determine the initial choice of AF within the first 72 hours of IC. Results Males comprised 55.6% and White race 58.3%. Majority were non-Hispanic ethnicity (67.7%). Triazoles (TZ) (40.1%) were the most used initial AF followed by EC (33.7%) and amphotericin B (AmB) (17.9%). When EC use was compared to other AF, there was no difference in age or gender. Multivariate logistic regression showed that patients with prior steroid use were more likely to receive AmB than EC. However, patients who had solid tumor malignancy, gastrointestinal insufficiency, neutropenia, prior steroid use and on vasopressors were more likely to receive EC than TZ. Patients who identified as Black were more likely to receive combination AF than an EC alone (OR 2.36, 95% CI 1.03-5.43, P=0.016). The most common reason for changing AF from the initial therapy was for step-down therapy followed by treatment failure. Conclusion Combination AF use was higher in Black patients. Though overall use of TZ was higher among children with IC, presence of risk factors like steroid use, underlying solid tumor malignancy, neutropenia or vasopressors was associated with EC use. AmB use was not as common as anticipated. Disclosures All Authors: No reported disclosures

P-798. Non-Tuberculosis Mycobacterial Infections at a National Cancer Institute-Designated Comprehensive Cancer Center in Florida

Abstract Background Non-tuberculous mycobacteria (NTM) are environmental organisms which become opportunistic pathogens in certain patient populations. NTM prevalence has increased globally, thought to be due to the increased diagnostic testing and availability of population-based studies. This is especially true in Florida, where we have previously documented more cases of Mycobacterium abscessus group compared to M. avium Complex (MAC) group. Current literature of NTM infections in oncology patients is minimal and represents a unique area for study. Here we present our epidemiological and clinical presentation of NTM infection cases at a National Cancer Institute-designated comprehensive cancer center.Figure 1.Patient Characteristics Methods Retrospective, Institutional Review Board-approved, single-center cohort study, of adult patients with microbiologically proven NTM infections who presented from 2020 to 2023. Demographic, laboratory, and susceptibility data were retrieved from the electronic medical record system and evaluated to show institutional patterns.Figure 2.Microbiological Characteristics for Overall Population Results Ninety-three cases of NTM infection met assessment criteria. Baseline characteristics are shown in Figure 1. A large proportion were female (71%) and white (90%). Many had a past or active cancer (80%), with skin (23%), lung (22%), and breast (13%) most prevalent. MAC (52%) and M. abscessus group (31%) were the most common NTM isolates (Figure 2). The majority were pulmonary infections (81%), with the integument accounting for most non-pulmonary sites (78%). Positive cultures were most frequently obtained via bronchoalveolar lavage (62%) followed by sputum (13%). Figure 3 offers insight into infection/culture site and cancer type stratified by organism, while susceptibility patterns are summarized in Figure 4.Figure 3.Site of Infection/Culture and Type of Cancer Stratified by Organism Conclusion NTM infections at our institution were primarily caused by MAC or M. abscessus group and were typically pulmonary in nature, isolated via bronchoalveolar lavage. Most occurred in patients with a solid tumor malignancy. Further research is needed to delineate prevalence patterns, microbiological characteristics, and treatment approaches of NTM infections in our site’s population. Susceptibility by Organism Disclosures All Authors: No reported disclosures

P-2037. Epidemiology, Clinical Features and Outcomes of COVID 19 Patients Post Evusheld Therapy Among Immunosuppressed Patients

Abstract Background Evusheld® is a combination of two monoclonal antibodies, Tixagevimab and Cilgavimab. It was developed for the pre-exposure prophylaxis (PrEP) and treatment of COVID-19 illness for those who are immunocompromised. There is paucity of long-term real-world data on the use of Evusheld among the immunosuppressed patients against the SARS-CoV-2 Omicron variants. Methods A retrospective cohort chart review of patients 18 years and older who received the two dose Evusheld regimen from December 1, 2021 to January 31, 2023 at a community teaching institution was performed to evaluate the effectiveness of Evusheld as PrEP of COVID-19 patients. Evusheld as PrEP was indicated for patients with active solid tumor and hematologic malignancies or those receiving immunosuppressive treatment including CART therapy, biologic agents and high-dose corticosteroids (i.e., ≥ 20 mg prednisone or equivalent per day when administered for ≥ 2 weeks). The following data was collected: patient demographic, development of COVID19 after receiving Evusheld®, intensive care unit (ICU) length of stay (LOS), hospital LOS, ventilation requirement, duration of ventilation, and mortality among these patients within six months of receiving Evusheld therapy. Results Of the 663 patients screened, 459 were excluded primarily for duplicate patients. The mean age of the 204 included patients was 68.3 years and 97 (47.5%) were female. Eighteen (8.8%) patients had a positive COVID-19 test within 180 days of receiving Evusheld. None of the COVID positive patients were admitted to the hospital or required mechanical ventilation. All COVID positive patients survived. Conclusion Our study shows that Evusheld was effective in preventing COVID-19 among the immunocompromised patients during the six-month follow-up period. This study also showed that patients who developed COVID-19 after Evusheld did not develop severe disease or require hospitalization. Disclosures All Authors: No reported disclosures

SMARCA4 deficiency in small cell lung cancer: A case report and narrative review of the literature

SWItch/Sucrose Non-Fermentable (SWI/SNF) is a large protein complex with a central role in chromatin remodeling and genome transcription. The catalytic subunits of the SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2 (SWI/SNF SMARCA2; also called BRM) and SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4; also called BRG1) are encoded by the SMARCA2 and SMARCA4 genes, respectively, and are mutually exclusive. Loss of either SMARCA2 and/or SMARCA4 has been previously reported in several types of malignant solid tumors of the gastrointestinal and genitourinary tract. So far, their absence in non-small cell lung cancer has been observed in a series of studies involving primary tumors and cell lines, where it is associated with loss of differentiation and heightened tumorigenic potential leading to an unfavorable prognosis. SMARCA2 and SMARCA4 deficiency is frequent in solid predominant adenocarcinomas and tumors with low levels of bronchial epithelial markers, including thyroid transcription factor 1. A rare case of SMARCA4 deficiency in small cell lung cancer is described. A 57-year-old male patient, with no medical history of past illness, was admitted to our center for the investigation and management of a space-occupying lesion in the right upper lung lobe with tracheal and mediastinal infiltration. Biopsy of a lymph node in the right supraclavicular region was diagnostic for small cell lung cancer with regional loss of SMARCA4. The patient demonstrated progressive respiratory failure and clinical deterioration and eventually deceased despite intubation and transfer to the intensive care unit. This case indicates that SMARCA4-deficient small cell lung cancer may present with an aggressively deteriorating phenotype with poor outcomes for the patie

Abstract A005: 18F-Fluorthanatrace PARP inhibitor PET tracer: Potential implications for theranostics

Abstract Objective: PARP (poly [ADP-ribose] polymerase) inhibitors are approved for a variety of malignancies including those with a breast, prostate, and ovarian carcinoma, particularly in the setting of a germline or somatic pathogenic BRCA mutation. There is active interest in the development of theranostics including those with a PARP inhibitor backbone. Methods: We evaluate a novel PARP inhibitor (PARPi) PET tracer 18-Fluorine [18F] Fluorthanatrace (FTT). Patients with primary or metastatic solid tumors with measurable disease initiating therapy with a PARP inhibitor monotherapy or in combination with another systemic agent were eligible. Patients underwent 18F-FTT PET/CT prior to initiation of PARPi and a second 18F-FTT PET 2-4 weeks after initiation of a PARP inhibitor. Hematologic toxicity on PARPi monotherapy or combination was assessed using the CTCAEv5.0 criteria. Regions of interest were drawn over the uninvolved bone marrow (usually taken at L3) and normal muscle to obtain the maximum standardized uptake value. Bone marrow to muscle ratio (B/M) was calculated at baseline and on PARPi. Spearman rank correlation coefficient was used. Results: A total of 21 patients were enrolled and underwent 18F-FTT PET. Patients had a median of 0 (range 0-7) prior lines of systemic therapy. The primary disease site included breast (9), ovary (6), primary peritoneal (1), pancreas (1)and other (4). Measurable uptake of 18F-FTT within the tumor and bone marrow was observed in all patients. Median L3 SUVmax at baseline was 4.3 (range 2.1-11.8) vs. 2.33 (range 1.4-2.9) while on PARP inhibitor. Baseline B/M was associated with highest grade hematologic toxicity in patients (n=10) who received talazoparib monotherapy or combination (r=0.65, p=0.042). While B/M was not associated with hematologic toxicity in patients (n=11) who received olaparib monotherapy or combination (r=0.098, p=0.77). Conclusions: 18F-FTT PET can measure target engagement of PARP inhibitors in bone marrow and may have implications for PARP inhibitor-based theranostics and dosing. Results suggest there may be differential impact of different PARPi on bone marrow and should be considered when selecting a backbone for theranostics. Citation Format: Lilie Lin, Mahmoud Hammad, Franklin Wong, Timothy A. Yap. 18F-Fluorthanatrace PARP inhibitor PET tracer: Potential implications for theranostics. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A005.

Phase 2 Open-Label Trial of Brentuximab Vedotin with Pembrolizumab in PD-1 Pretreated Metastatic Non-Small Cell Lung Cancer and Metastatic Cutaneous Melanoma.

Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells (Tregs) that express CD30 and re-sensitize tumors to anti-(PD-1) therapy. This study evaluated responses to BV+pembrolizumab post PD-1 and explored corresponding biomarkers. 55 patients with metastatic non-small cell lung cancer (NSCLC) and 58 with metastatic cutaneous melanoma received ≥1 dose of BV+pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1-7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor. For the secondary refractory metastatic NSCLC cohort (RECIST v1.1), ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (iRECIST), ORR was 24%, median iPFS was 4.44 months, and median OS was 21.9 months. Overall, median duration of OS follow-up was 17.2 months (95% CI 14.62, 22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in Tregs. Paired tumor biopsies from baseline and Cycle 3 Day 1 showed a trend of increased CD8 T cell infiltration, especially in responding patients. BV+pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.