e23127 Background: Early phase clinical trials (EPCTs) assess the safety and toxicity of novel anticancer agents and represent opportunities for patients (pts) to try novel therapies when standard therapies have become ineffective. However, EPCT participants represent a vulnerable population with high financial toxicity and symptoms related to their cancer and previous treatments. EPCTs often require frequent visits and additional procedures which may be burdensome. Pt navigators perform needs assessments and provide guidance to pts as they move through the health care system. Navigation, which has a high level of acceptance among pts with cancer, can improve time from diagnosis to treatment, decrease pt anxiety, and improve participation of minoritized individuals in clinical trials. We hypothesized that EPCT participants would have higher navigation needs than those of non-EPCT participants with cancer. Methods: Utilizing a needs assessment conducted in person or by telephone, pts with cancer treated at Mount Sinai are assessed for 26 individual and systemic social drivers of health (SDoH) barriers by pt navigators at their trial screening visit. EPCT participants were defined as pts participating in a study in the Early Phase Trials Unit. Descriptive characteristics were assessed for all participants regarding demographic characteristics and SDoH barriers. Welch's T-test was used to compare differences in navigation encounters, SDoH barriers and navigator interventions between the EPCT and non-EPCT pt groups. Results: From February to December 2023, 31 EPCT pts and 1145 non-EPCT pts completed the assessment. Median age was 58.9 and 62.4 years, respectively. Racial and ethnic self-identification included 13% vs. 20% Black pts and 19% vs. 20% Hispanic pts. EPCT pts had a mean 5.29 navigation encounters per pt compared to 4.11 in non-EPCT pts (p = 0.27). Pts in the EPCT group were found to have an average of 3.81 SDoH barriers identified, in contrast to 1.7 in the non-EPCT group (p < 0.001). The most common barriers identified in EPCT pts were institutional, knowledge, and psychosocial; in non-EPCT pts, transportation barriers were most common. Furthermore, based on the identified barriers, EPCT pts required an average of 17.23 interventions, compared to 4.57 among those not in the EPCT group (p < 0.001). Interventions most frequently involved coordination with the primary team and education for pts in both groups. Conclusions: EPCT pts had more navigation encounters, SDoH barriers identified, and resultant interventions than non-EPCT pts. Participants in EPCTs are a vulnerable pt population for whom navigation is particularly warranted. [Table: see text]
2559 Background: Tumor-promoting inflammation is a hallmark of cancer pathogenesis and is associated with poor outcomes and treatment resistance. C-reactive protein (CRP) is a routinely measured acute phase reactant whose synthesis is stimulated by cytokines and may thereby represent a surrogate for tumor promoting inflammation. Pre-treatment CRP has been associated with resistance to immune checkpoint blockade (ICB) in several studies. However, whether post-treatment changes in CRP correlate with ICB outcomes has not been systematically examined. Methods: We performed a systematic review to identify cohort studies or clinical trials in solid tumor patients receiving ICB therapy with CRP response comparator pairs (high/low) available. We included studies that had hazard ratio (HR) of overall survival (OS), progression-free survival (PFS), or odds ratio (OR) of objective response rate (ORR) available. We performed a meta-analysis using a random-effect model to evaluate if post-treatment changes in CRP are associated with ORR, PFS, or OS. Subgroup analysis for primary cancer type was performed. Heterogeneity was assessed using the I-squared statistic. Results: We screened 691 eligible studies; 19 met inclusion criteria and 2,101 patients were included. Patients experiencing post-ICB declines in CRP had improved ORR HR=4.67 [95% CI] [2.81-7.78] (p<0.0001, I 2 =42%), PFS HR=2.47 [1.98-3.09] (p<0.0001, I 2 =18%), and OS HR=2.28 [1.68-3.08] (p<0.0001, I 2 =56%). Heterogeneity among subgroups was low in ORR (I 2 =14.6%) and PFS analysis ( I 2 =0%), and moderate in OS analysis (I 2 =64.2%). Conclusions: In patients receiving ICB therapy, post-treatment declines in CRP were associated with improved ORR, PFS, and OS across multiple histologies. These findings support the integration of on-treatment CRP decline as a clinically relevant response biomarker for novel therapies directed at modulating tumor-promoting inflammation. A meta-regression analysis will help determine optimal post-treatment CRP cutpoints. Pooled OR of ORR [95%CI] and HR [95%CI] of PFS and OS with subgroup analysis results and heterogeneity assessment. [Table: see text]
IntroductionPatients with lung cancer (LC) are susceptible to severe outcomes from COVID-19. This study evaluated disruption to care of patients with LC during the COVID-19 pandemic.MethodsThe COVID-19 and Cancer Outcomes Study (CCOS) is a prospective cohort study comprised of patients with a current or past history of hematological or solid malignancies with outpatient visits between March 2 and March 6, 2020, at two academic cancer centers in the Northeastern United States (US). Data was collected for the three months prior to the index week (baseline period) and the following three months (pandemic period).Results313 of 2365 patients had LC, 1578 had other solid tumors, and 474 had hematological malignancies. Patients with LC were not at increased risk of COVID-19 diagnosis compared to patients with other solid or hematological malignancies. When comparing data from the pandemic period to the baseline period, patients with LC were more likely to have a decrease in in-person visits compared to patients with other solid tumors (aOR 1.94; 95% CI, 1.46–2.58), but without an increase in telehealth visits (aOR 1.13; 95% CI 0.85–1.50). Patients with LC were more likely to experience pandemic-related treatment delays than patients with other solid tumors (aOR 1.80; 95% CI 1.13–2.80) and were more likely to experience imaging/diagnostic procedure delays than patients with other solid tumors (aOR 2.59; 95% CI, 1.46–4.47) and hematological malignancies (aOR 2.01; 95% CI, 1.02–3.93). Among patients on systemic therapy, patients with LC were also at increased risk for decreased in-person visits and increased treatment delays compared to those with other solid tumors.DiscussionPatients with LC experienced increased cancer care disruption compared to patients with other malignancies during the early phase of the COVID-19 pandemic. Focused efforts to ensure continuity of care for this patient population are warranted.
267 Background: Financial toxicity (FT) adversely influences patient quality of life and is a barrier to clinical trial enrollment. Early phase clinical trials (EPTs) primarily recruit patients with advanced malignancies who have received all standard therapy regimens and may thus have high levels of FT. We sought to assess baseline FT and its association with clinicodemographic factors in patients participating in early phase clinical trials. Methods: We conducted a study to assess baseline FT in English-speaking patients (pts) with advanced metastatic solid tumors who were participating in EPTs at the Yale Cancer Center (Yale) and the Tisch Cancer Institute at Mount Sinai (Sinai). Pts were consented after EPT consent and prior to day 1 of study treatment. Pts completed a clinical and demographic questionnaire as well as the 11-item validated Comprehensive Score for Financial Toxicity (COST) FT instrument. Primary endpoints included baseline FT and association with clinicodemographic variables. Statistical analysis was performed using two-sided T-tests and Pearson correlations for numeric data and Fisher’s Exact Test for categorical data. Multivariate analysis was performed using a linear regression model. Results: 138 pts enrolled in this study, of whom 132 completed the COST instrument (Yale, N = 84; Sinai, N = 48). Median age was 62 and 49.2% were male. 71.2% patients self-identified as White and 15.2% as Black; 7.2% identified as Hispanic. 32.6% reported an annual income of < $50,000. Insurance providers included private insurers (50%), Medicare (31.8%), Medicaid (10.6%), and Medicaid with Medicare supplemental (3.8%). 56.8% reported monthly out of pocket medical expenses of $100 or more. Median FT score was 22.5 out of a maximum score of 44 (mean 21.5). FT scores ≥ 22.5 in pts were associated with age < 65 (OR = 2.229, P = 0.04), being the household money manager (OR = 2.98, P = 0.02), and being the primary wage earner (OR = 3.12, P = 0.004). FT scores < 22.5 in pts was associated with retirement (OR = 0.15, P = 3.67e-05). In multivariate analysis, retirement was associated with FT score < 22.5 (OR = 0.18, P = 0.02). There was no statistically significant difference in FT scores between Yale and Sinai pts. However, Sinai pts were more racially diverse (p = 3.05e-05), had lower household income (P = 0.01), out of pocket expenses (P = 0.01), ED visits (P = 0.0075), and dependents (P = 0.004) and were less likely to have private insurance (P = 0.004). Conclusions: Pts with advanced cancers consenting to EPTs report significant baseline FT. Our study encompasses a diverse population from two large urban academic centers. Baseline FT was higher among pts < 65 years of age, primary wage earners, and those who managed household finances independently. Retirement was a protective factor, which may be explained by the life savings often required to retire. Ongoing work will compare baseline and 2 month FT in this patient population.
Abstract Immune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non–small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.
Although colorectal cancer (CRC) is traditionally considered to be immunologically inert, some subsets of colorectal cancer, particularly mismatch repair-deficient (MMRd) tumors, can be highly responsive to immune checkpoint blockade (ICB). Recent studies show -that even mismatch repair-proficient (MMRp) tumors can respond to combined PD-1/CTLA-4 ICB. Tumor-associated macrophages (TAMs) are an influential component of the tumor microenvironment (TME), although the exact role of these immune cells in tumor pathogenesis and progression remains enigmatic. TAMs are highly heterogenous and can be either pro-inflammatory or anti-inflammatory, and thus exhibit anti-tumorigenic or pro-tumorigenic effects respectively. Signal regulatory protein α (SIRPα) is a transmembrane protein expressed on TAMs that binds to CD47 on target cells, eliciting a 'don't-eat-me' signal that inhibits phagocytosis by macrophages. In preclinical studies, anti-SIRPα antibodies have been shown to induce macrophage-dependent anti-tumor activity and skew macrophages towards an anti-tumorigenic phenotype. Since colorectal cancer lesions are often dominated by both T cells and anti-inflammatory TAMs, combination therapy with an anti-SIRPα antibody and an anti-PD-1 antibody may result in synergistic killing of tumor cells by TAMs and T cells.
Methods
This phase I, open-label, parallel-cohort, single-center trial (NCT05446129) was designed to assess the safety, feasibility, clinical efficacy, and biological activity of BI-765063 (an anti-SIRPα antibody) in combination with either ezabenlimab (Cohort A) or pembrolizumab (Cohort B), both anti-PD-1 antibodies, in patients with early-stage, resectable CRC (figure 1). Each cohort will enroll 25 patients. Treatment will be given as a single-dose in the neoadjuvant setting. All patients will then be scheduled to undergo surgical resection 2 to 6 weeks after treatment administration. The primary endpoint is a composite safety and feasibility endpoint, defined as the proportion of patients exhibiting any grade-3 or higher treatment-related adverse event or any treatment-related adverse event delaying surgery more than 6 weeks after treatment administration. The secondary endpoints include pathological response, defined as 50% or greater tumor regression, time from treatment administration to surgery, and radiographic response. Tissue, blood, and stool will be collected prior to treatment administration and at the time of resection. Immune monitoring will be performed using multiplex and single-cell analysis platforms to define the immunodynamic effects of these therapies.
Trial Registration
ClinicalTrials.gov Identifier: NCT05446129
Ethics Approval
On 9/23/2022 an Institutional Review Board of the Mount Sinai School of Medicine, in accordance with Mount Sinai's Federal Wide Assurances (FWA#00005656, FWA#00005651) to the Department of Health and Human Services approved the human subject research (ID 1502–0001; PRMC-22–037; STUDY-22–00928) from 9/23/2022 to 9/19/2023.
Consent
Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
9539 Background: The predictive value of PD-L1 tumor proportion score (TPS) on NSCLC tumor cells as a biomarker for response to PD-(L)1 inhibitors is well established. However, its histology specific value in advanced (a) squamous (Sq) versus nonsquamous (NS) cancers remains unclear. Here, we used real world data to assess the differential value of PD-L1 TPS as a predictive biomarker for overall survival (OS) after first-line pembrolizumab (P) in patients (pts) with Sq versus NS NSCLC. Methods: Inclusion criteria for this analysis of the Flatiron Health EHR-derived de-identified database required that pts were diagnosed with aNSCLC, tested for PD-L1 TPS and received a numerical result, had no alteration in EGFR, ALK, or ROS, and received first-line, single agent P. The primary endpoint was overall survival (OS) from the first dose of P in patients with TPS ≥ 50% (H) compared to patients with TPS < 50% (L). Due to the violation of the proportional hazards assumption, a generalized gamma model of OS was used, adjusting for demographic variables and estimated median OS and their confidence intervals with the bootstrap method. The PD-L1-histology interaction was examined by comparing the differences in median OS (H vs. L) between Sq and NS patients. Results: Of 1560 pts with NSCLC treated from 1/2011 – 5/2019, 1055 had NS and 405 Sq. No meaningful differences in age, gender, or smoking history were seen between PD-L1 H and L pts with either histology. Among NS pts, H had significantly longer OS than L, with unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.53 - 0.94; p = 0.018). Among Sq pts, H was not associated with longer OS than L, with unadjusted HR 0.89 (95% CI: 0.64 - 1.25; p = 0.514). Based on the generalized gamma model, PD-L1 H in Sq patients was associated with a 0.19 year improvement in median OS (95% CI: -0.22-0.49, P = 0.283), whereas PD-L1 H in the NS group was associated with a 0.70 year improvement in OS (95% CI: 0.34-1.05, P < 0.001). The median improvements between the Sq and NS patients were significantly different (P = 0.034), after adjusting for demographic variables. Conclusions: PD-L1 TPS of ≥ 50% predicted longer OS in pts with NS NSCLC treated with first-line P compared to pts whose tumors had a TPS of < 50%. However, no relationship between PD-L1 TPS and OS after first-line P was seen in patients with Sq NSCLC. These data suggest that PD-L1 may not be an appropriate predictive biomarker for checkpoint inhibitor use in NSCLC with squamous histology.
ATRC-101 is an engineered, fully human, monoclonal antibody identified via the Atreca discovery platform that targets a novel tumor-specific ribonucleoprotein complex.
Methods
ATRC-101-A01 is a Phase 1b dose escalation and expansion trial of ATRC-101 administered to participants with select solid tumors as monotherapy every 3 (Q3W-Mono) or 2 (Q2W-Mono) weeks and in combination with pembrolizumab (Q3W-Pembro). Participants in Q3W-Pembro must have had suboptimal response to prior/ongoing anti-PD-1/PD-L1 and deemed to potentially benefit from addition of ATRC-101. Objectives include safety (primary), pharmacokinetics, immunogenicity, recommended dose for expansion, and anti-tumor activity (RECIST v1.1). Biomarker analyses include immunohistochemical staining for target expression and CD8+ T cell infiltration in baseline and on-treatment tumor biopsies. For participants described herein, target expression was analyzed retrospectively.
Results
As of data cut-off (February 15, 2022), 50 heavily pretreated participants (median prior lines of therapy 5, range 1–11) received ≥1 dose of ATRC-101 (Q3W-Mono, n=37; Q2W-Mono, n=9; Q3W-Pembro, n=4). ATRC-101 was administered at 0.3 mg/kg (n=3), 1 mg/kg (n=6), 3 mg/kg (n=12), 10 mg/kg (n=13), and 30 mg/kg (n=16). Tumor types included colorectal (n=24), breast (n=8), ovarian (n=7), non-small cell lung (NSCLC, n=5), melanoma (n=3), head and neck squamous cell (n=2), and urothelial (n=1). Dose escalation has been completed for Q3W-Mono and is ongoing for other cohorts. To date, no dose-limiting toxicities have been reported and no maximum tolerated dose identified. The dose for ongoing cohorts is 30 mg/kg. Treatment-emergent adverse events (TEAEs) are summarized in Table 1. None resulted in treatment discontinuation or dose reduction. Grade ≥3 TEAEs occurred in 13 (26%) participants. Grade ≥3 TEAEs considered by investigators as related to ATRC-101 occurred in 3 (6%) participants (tumor pain, headache, small intestinal obstruction). There was one partial response (NSCLC) in Q3W-Mono (30 mg/kg) and one complete response (melanoma) in Q3W-Pembro (10 mg/kg). The latter participant had previously progressed during treatment with nivolumab. An additional 5 participants experienced stable disease (SD) as best response, with reductions in target lesions. Target expression, as detected retrospectively by immunohistochemical analysis of screening tumor biopsies, was associated with achievement of SD or better and with reduction in the sum of diameters of target lesions.
Conclusions
ATRC-101, without and with pembrolizumab, has been well tolerated and has demonstrated anti-tumor activity among target expressers. Enrollment in specific expansion cohorts now requires pretreatment tumor biopsies demonstrating ATRC-101 target expression (H-score ≥50) by immunohistochemistry. Updated data will be presented at the meeting.
Trial Registration
NCT04244552
Ethics Approval
This trial was approved by the institutional review board or ethics committee as required for each participating site.
e16502 Background: CRP is an acute phase reactant synthesized by hepatocytes in response to inflammatory cytokines including interleukin-6. Peripheral blood CRP, a routinely measured analyte, may reflect tumor microenvironments skewed towards tumor-promoting inflammation. CRP may therefore represent an attractive biomarker to select patients with bladder cancer (BCa) more likely to benefit from therapies directed at modulating tumor-promoting inflammation. Methods: A systematic review was performed to identify studies reporting outcomes based on pre-treatment CRP values in patients with localized and advanced BCa and urothelial carcinoma (UC). The hazard ratio (HR) of overall survival (OS), cancer-specific survival (CSS), relapse-free survival (RFS), and progression-free survival (PFS) between groups with high and low CRP values as defined in each study was extracted. Meta-analysis using the random-effect model was performed to pool HR. Meta-regression analysis was conducted to assess the relationship between CRP cutoff and HR for OS. Subgroup analyses were performed according to clinical disease state and therapies administered. Heterogeneity was assessed using I 2 statistics. Results: Overall, 938 articles were identified at initial screening; 22 studies comprising 2,899 patients were included in the meta-analysis. For OS, 17 datasets from 16 studies were used. High CRP levels were associated with decreased OS (HR=2.03, 95%CI:1.67-2.47, p<0.01) although high heterogeneity was observed (I 2 =91%). Subgroup analyses according to anticancer interventions showed that high CRP values were related to shorter OS, particularly in patients treated with immune checkpoint blockade (ICB; HR=1.78, 95%CI: 1.47-2.15, p<0.01). In meta-regression analysis, the correlation between CRP cutoff value and OS HR was not observed when all 16 studies were considered (Regression coefficient=0.03, 95%CI: -0.13-0.18, p=0.73). However, CRP cutoff value was significantly associated with the HR for OS (Regression coefficient=-0.21, 95%CI: -0.36 to -0.06, p=0.01) when the analysis was limited to eight studies assessing ICB in advanced BCa/UC. Pooled HR of CSS, RFS, and PFS is shown in Table. Conclusions: High CRP values were associated with poorer clinical outcomes in patients with BCa/UC, particularly among patients with advanced disease treated with ICB. CRP may represent an attractive biomarker to enrich populations more likely to benefit from therapies that modulate tumor-promoting inflammation. [Table: see text]
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