Solid Tumor Patients Research Articles

Identification of intratumoral and peripheral T-cell receptor (TCR) repertoire features associated with acquired (Ar) and primary (Pr) resistance to immune checkpoint inhibitors (ICI).

59 Background: Our understanding of the mechanisms of Pr vs Ar to ICI is limited. T-cells are the main driver of ICI response. Therefore, interrogation of intratumoral and peripheral TCR repertoire could expand our comprehension of T-cell mediated factors underlying Pr and Ar to ICI. Methods: The Immune Resistance Interrogation Study (NCT04243720) is a prospective study to comprehensively characterize cancers with Pr vs Ar to ICI (Genta et. al., ASCO 2021). We conducted TCRβ capture and sequencing (CapTCR-seq) on paired tumors and blood samples collected from solid tumor patients (pts) at the time of progression on ICI. Tumor and peripheral TCR diversities were calculated for each pt. Grouping Lymphocyte Interactions by Paratope Hotspots (GLIPHII) was used to investigate the potential antigen specificities of intratumoral T-cells. Pt-derived TCRs were pooled with TCRs from a public database with known antigen specificities (TCRdb). GLIPHII grouped pt-derived and external TCRs with similar CDR3s (hypervariable TCR domains) in clusters. The clusters were then converted into a network model representing unique TCRs as nodes. The number of connections between each pt-derived TCR and similar TCRs from TCRdb was defined as node degree. Comparisons between groups were done using Mann Whitney U Test. Results: As of February 2023, 75 pts (45 Pr/30 Ar) were enrolled. CapTCR-Seq in blood and tumor samples was completed in 13 pts (7Pr/6Ar) with the following characteristics: median age 57 years (26-77), 8 male (62%), 8 melanoma (62%), 4 HNSCC (31%), and 1 GE-junction (7%). 5 pts received PD-1/PD-L1 inhibitor monotherapy (38%), 8 pts ICl-based combinations (62%). No significant differences in intratumoral (10.3 [1.3-34.2] vs 15.2 [6.6-32.4] p=0.29) and peripheral (145.5 [65.3- 521.9] vs 136.0 [35.1-474.4] p=0.53) Shannon diversities were observed between Pr and Ar. Twelve of 13 (92%) pts had at least 1 intratumoral TCR clustered with TCRdb derived TCRs. A higher median of node degree was observed in non-melanoma tumors (5.5 [2-12] vs 2.0 [1-4] p=0.03). A trend towards a higher median of node degree was reported in Ar vs Pr (5.5 [1-12] vs 2.0 [1-4] p=0 .07 ). Some of the GLIPHll-identified clusters contained TCRs derived from multiple Ar pts. Conclusions: lntratumoral TCRs from non-melanoma and Ar pts had a higher node degree, indicating similarity with a larger number of external TCRs. The difference between Pr and Ar was not significant, potentially due to the small sample size. Similar TCRs belonging to the same GLIPHll-identified clusters were shared among multiple Ar pts. If confirmed in a larger dataset, these findings might suggest the existence of a set of intratumoral exhausted T-cells shared by multiple pts contributing to Ar but not to Pr. Pt accrual, sample collection and analysis are ongoing. Additional data will be presented.

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Advances in the use of ECMO in oncology patient.

Over the past decade, ECMO has provided temporary cardiopulmonary support to an increasing number of patients, but the use of extracorporeal membrane oxygenation (ECMO) to provide temporary respiratory and circulatory support to adult patients with malignancy remains controversial. This paper reviews the specific use of extracorporeal membrane oxygenation (ECMO) in oncology patients. We searched PubMed, CINAHL, Cochrane Library, and Embase databases for studies on the use of ECMO in cancer patients between 1998 and 2022. Twenty-four retrospective, prospective, and case reports were included. The primary outcome was survival during extracorporeal membrane oxygenation. Most studies suggest that ECMO can be used in oncology patients requiring life support during surgery, solid tumor patients with respiratory failure, and hematological tumor patients requiring ECOM as a supportive means of chemotherapy; however, in patients with hematologic oncology undergoing hematopoietic stem cell transplantation, there was no clear benefit after the use of ECMO. Current research suggests that ECMO may be considered as a salvage support in specific cancer patients. Future studies should include larger sample sizes than those already conducted, including studies on efficacy, adverse events, and health.

Comparing end-of-life care of hematologic malignancy versus solid tumor patients in a tertiary care center.

To compare end-of-life (EOL) care for solid tumor and hematologic malignancy (HM) patients. We collected data on the last 100 consecutive deceased HM and 100 consecutive deceased solid tumor patients who died prior to June 1st 2020, treated at a single center. We compared demographic parameters, cause of death as ascertained by review of medical records by two independent investigators, and EOL quality indicators including: place of death, use of chemotherapy or targeted/biologic treatment, emergency department visits as well as hospital, inpatient hospice and Intensive Care Unit admissions and the time spent as inpatient over the last 30 days of life; mechanical ventilation and use of blood products during the last 14 days of life. In comparison with solid tumor patients, HM patients more commonly died from treatment complications (13% vs. 1%) and unrelated causes (16% vs. 2%, p < .001 for all comparisons). HM patients died more frequently than solid tumor patients in the intensive care unit (14% vs. 7%) and the emergency department (9% vs. 0%) and less frequently in hospice (9% vs. 15%, p = .005 for all comparisons). In the 2 weeks prior to death HM patients were more likely than solid tumor patients to undergo mechanical ventilation (14% vs. 4%, p = .013), receive blood (47% vs. 27%, p = .003) and platelet transfusions (32% vs. 7%, p < .001); however, no statistical difference was found in use of either of chemotherapy (18% vs. 13%, p = .28) or targeted treatment (10% vs. 5%, p = .16). HM patients were more likely than solid tumor patients to undergo aggressive measures at EOL. Rarity of HM deaths, frequently caused by complications of treatment and unrelated causes, may affect treatment choices at EOL.

Infections occurring following IL6 blockade for the management of cytokine release syndrome in onco-hematology patients.

Cytokine release syndrome (CRS) is a common adverse event of CAR T cell or bispecific antibody (bsAb) therapy. Anti-IL6/IL6R drugs are used in the management of auto-immune diseases. Some reports showed increased risk of bacterial infection in this context. In onco-hematology, there are few data about the occurrence of infection after administration of an anti-IL6/IL6R for CRS. We retrospectively reviewed all consecutive patients treated in Gustave Roussy Cancer Campus between 2018 and 2021, who received anti-IL6/IL6R for CRS due to bsAb in phase I clinical trials or adoptive cellular therapy (ACT). We constituted a control group including all the patients treated in the same clinical trials or standard of care ACT, naïve of anti-IL6/IL6R. Fifty-two patients have been included. In the anti-IL6/IL6R group (n = 26), five patients developed a grade 2 to 5 infection within a month after anti-IL6/IL6R treatment, including two grade 5 infections. In the control group (n = 26), only one patient had a grade 3 infection. The two patients who had grade 5 infections were treated for diffuse large B cell lymphoma (DLBCL), one with bsAb and the other with CAR T cell. Fifty percent (3/6) of DLBCL patients who received an anti-IL6/IL6R presented an infection, one of which was a grade 5. In solid tumor patients treated with bsAb and anti-IL6/IL6R, only one patient (/9, 11%) developed a grade 2 viral infection. It seems that the use of anti-IL6/IL6R in CRS secondary to bsAb administration in solid tumors patients does not significantly increase the risk of infection, as opposed to DLBCL patients where secondary infection might be a concern.

Circulating tumor DNA sequencing of pediatric solid and brain tumor patients: An institutional feasibility study

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time “liquid biopsy” for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.

Bloodstream infection burden among cancer clinic patients with PICC Lines: A prospective, observational study

Background: Oncology patients are at high risk for bloodstream infection (BSI) due to immunosuppression and frequent use of central venous catheters. Surveillance in this population is largely relegated to inpatient settings and limited data are available describing community burden. We evaluated rates of BSI, clinic or emergency department (ED) visits, and hospitalizations in a large cohort of oncology outpatients with peripherally inserted central catheters (PICCs). Methods: In this prospective, observational study, we followed a convenience sample of adults (age&gt;18) with PICCs at a large academic outpatient oncology clinic for 35 months between July 2015 and November 2018. We assessed demographics, malignancy type, PICC insertion and removal dates, history of prior PICC, and line duration. Outcomes included BSI events (defined as &gt;1 positive blood cultures or &gt;2 positive blood cultures if coagulase-negative Staphylococcus), ED visits (without hospitalization), and unplanned hospitalizations (excluding scheduled chemotherapy hospitalizations). We used χ2 analyses to compare the frequency of categorical outcomes, and we used unpaired t tests to assess differences in means of continuous variable in hematologic versus solid-tumor malignancy patients. We used generalized linear mixed-effects models to assess differences in BSI (clustered by patient) separately for gram-positive and gram-negative BSI outcomes. Results: Among 478 patients with 658 unique PICC lines and 64,190 line days, 271 patients (413 lines) had hematologic malignancy and 207 patients (232 lines) had solid-tumor malignancy. Cohort characteristics and outcomes stratified by malignancy type are shown in Table 1. Compared to those with hematologic malignancy, solid-tumor patients were older, had 47% fewer clinic visits, and had 32% lower frequency of prior PICC lines. Overall, there were 75 BSI events (12%; 1.2 per 1,000 catheter days). We detected no significant difference in BSI rates when comparing solid-tumor versus hematologic malignancies (P = 0.20); BSIs with gram-positive pathogen were 69% higher in patients with solid tumors. Gram-negative BSIs were 41% higher in patients with hematologic malignancy. Solid-tumor malignancy was associated with 4.5-fold higher odds of developing BSI with gram-positive pathogen (OR, 4.48; 95% CI, 1.60–12.60; P = .005) compared to those with hematologic malignancy, after adjusting for age, sex, history of prior PICC, and line duration. Differences in gram-negative BSI were not significant on multivariate analysis. Conclusions: The burden of all-cause BSIs in cancer clinic adults with PICC lines was 12% or 1.2 per 1,000 catheter days, as high as nationally reported inpatient BSI rates. Higher risk of gram-positive BSIs in solid-tumor patients suggests the need for targeted infection prevention activities in this population, such as improvements in central-line monitoring, outpatient care, and maintenance of lines and/or dressings, as well as chlorhexidine bathing to reduce skin bioburden.Disclosures: None

Association of presenting symptoms with COVID-19 disease severity and outcomes among hospitalized patients with cancer and COVID-19.

e13581 Background: COVID-19 has led to several waves of outbreaks over the last 2 years. Cancer patients are among the most vulnerable and have high morbidity and mortality rates. We aimed to determine the association between presenting symptoms and symptom burden and COVID hospitalization outcomes among cancer patients. Methods: We conducted a retrospective cohort study on all adult hospitalized cancer patients during their first admission at our cancer center from March 2020 to May 2021. We reviewed medical charts to identify reported symptoms. We used the Foundry data platform to compile and analyze data, including patient and hospitalization characteristics and outcomes. We used the chi-square test to test differences in categorical variables. Results: Our cohort included 595 patients, 272 with hematologic malignancies (45.7%) and 323 with solid tumor malignancies (54.3%). 52.1% were male, with an age range of 18 to 91 years (median age: 62). 64.2% self-identified as Caucasian, 16.1% as other, 14.3% as African American, and 3.5% as Asian. After univariate analysis, we found that female patients had higher rates of abdominal pain (21.4% vs. 14.5%, p=0.03), GI symptoms (36% vs. 27.4%, p=0.03), and sore throat (14.4% vs. 8.4%, p=0.02) than male patients. Smoking status or Charlson comorbidity score were not associated with any presenting symptoms. Solid tumor patients had higher rates of abdominal pain (26.6% vs. 7.4%, p &lt;0.01) than patients with hematologic malignancies. Patients with hematologic malignancies had higher rates of fever (59.2% vs. 42.7%, p&lt;0.01), cough (66.2% vs. 50.8%, p&lt;0.01), and shortness of breath (53% vs. 41.8%, p&lt;0.01) than solid tumor patients. Solid tumor patients more frequently reported more than 3 symptoms (52% vs. 39.2%, p&lt;0.01) than patients with hematologic malignancies. In terms of COVID outcomes, patients with cough (34.4% vs. 12%, p&lt;0.01), shortness of breath (38.5% vs. 12.9%, p &lt;0.01), and fever (29.1% vs. 20.6%, p=0.02) were more likely to have severe COVID-19. Patients with more than 3 symptoms were more likely to have severe COVID-19 (31.7% vs. 21.3% vs. 7.8%, p&lt; 0.01) than those with 1-3 symptoms or no symptoms. Patients with cough (15.1% vs. 6.4%, p&lt;0.01) and shortness of breath (15.5% vs. 7.9%, p&lt; 0.01) had higher inpatient mortality. Patients with chills (5.8% vs. 12.9%, p&lt; value 0.03) and headache (4.4% vs. 12.7%, p=0.02) had lower inpatient mortality. Conclusions: Our study showed that certain presenting COVID-19 symptoms are associated with patient and clinical characteristics, severity of disease, and inpatient mortality among adult hospitalized cancer patients.

Palbociclib in solid tumor patients with genomic alterations in the cyclin D-CDK4/6-INK4a-Rb pathway: Results from NCI-COG pediatric MATCH trial Arm I (APEC1621I).

10006 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm I evaluated palbociclib, a reversible, selective oral small molecule inhibitor of CDK 4 and 6 in tumors harboring specified genomic alterations in the cyclinD-cdk4/6-INK4a-Rb pathway: amplification of CDK4, CDK6, CCND1, CCND2, or CCND3. Positive Rb expression by IHC was required. Methods: Palbociclib was administered on days 1-21 at 75 mg/m2 once daily in 28-day cycles for up to 2 years, until disease progression, or intolerable toxicity. Response assessment occurred every 2-3 cycles. The primary endpoint was objective response (OR) rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty-three patients (median age 15 yrs; range 9-21) were enrolled between August 2018 and May 2022. Twenty patients received protocol therapy and were evaluable for response. Of treated patients, osteosarcoma was the most common diagnosis (9/20, 45%), with amplification of CCND3 detected in 6/9 patients, CDK4 in 2, and CDK6 in 1. Rhabdomyosarcoma was next most frequent (6/20, 30%), with all tumors harboring CDK4 amplifications. Other diagnoses were high grade glioma (n = 2), soft tissue sarcoma (n = 2), and neuroblastoma (NB) (n = 1). Additional genomic alterations were detected in 9/20 tumors, most frequently TP53 mutations (n = 4, including 2 patients with Li-Fraumeni syndrome). Palbociclib was generally well tolerated with hematologic toxicities being the most common treatment related events and no related grade 5 events. Neutropenia was the most common grade 3-4 adverse event (n = 10, 50%) followed by thrombocytopenia (n = 8, 40%), leukopenia (n = 7, 35%), and anemia (n = 5, 25%). Four patients came off study for toxicity (3 for prolonged thrombocytopenia (cycle 1 (x2) and cycle 2) and 1 for prolonged grade 4 neutropenia (cycle 3)). Non-hematologic toxicities were mild (grade 1-2). No ORs were seen. Two patients with tumors harboring CDK4 amplifications had stable disease (SD): one with NB had SD for 5 cycles and one with sarcoma had SD for 3 cycles but came off therapy for toxicity. Six-month PFS was 10% (95% CI: 1.7%-27.2%) and six-month overall survival was 65% (95% CI: 40.3%, 81.5%). Conclusions: The CDK4/6 inhibitor palbociclib at 75mg/m2 PO daily was well tolerated in this heavily-pretreated cohort. No objective responses were observed in these biomarker-selected patients with treatment-refractory solid tumors. Further evaluation of this agent in combination with chemotherapy in the pediatric population is ongoing. Clinical trial information: NCT03526250 .

Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases.

1040 Background: HER2+ breast cancer brain metastases (BCBM) is an aggressive malignancy with high prevalence and limited treatment options. ZN-1041 is a best-in-class HER2 inhibitor designed to be delivered across the blood-brain barrier (BBB) with high selectivity and broader safety margin to treat HER2+ BCBM. Methods: Brain penetration of ZN-1041 and other approved HER2 tyrosine kinase inhibitors (TKI) were evaluated. Anti-tumor activity of ZN-1041 alone or in combination were evaluated in xenograft models. ZN-A-1041-101 (NCT04487236) is an on-going phase 1, multicenter, open-label study. The study comprises first-in-human dose escalation of ZN-1041 monotherapy (phase 1a) in HER2+ solid tumor patients (pts) with or without BM, dose escalation (phase 1b) and expansion (phase 1c) of ZN-1041 in combination with capecitabine and trastuzumab in pts with HER2+ BCBM (including active BM). The primary objective was safety and tolerability. The secondary objective includes pharmacokinetics and anti-tumor response including ORR per RECIST 1.1 and intracranial ORR (iORR) per RANO-BM. Results: Unlike currently approved HER2 TKIs which are strong human efflux transporter P-gp and BCRP substrates, ZN-1041 is not a substrate of either and has high BBB permeability, therefore predicted to have good BBB penetration. ZN-1041 alone demonstrated dose-dependent and significant anti-tumor activity when compared to tucatinib in BM model. ZN-1041 could synergize with capecitabine and trastuzumab to demonstrate significantly improved intracranial efficacy in BM models, while maintaining good tolerability. In total, 21 HER2+ mBC pts were enrolled to complete phase 1a and 1b. No dose-limiting toxicities or treatment-related SAE were observed across all dose levels. PK exposure was increased with dose escalation and Kpuu,CSF of ZN-1041 was 4.9. In ZN-1041 monotherapy, the overall ORR and iORR were 50% in TKI naïve, unequivocal HER2+ pts. The longest treatment duration was 15 months. As of data cutoff (Dec 02, 2022), totally 35 TKI naïve, HER2+ BCBM pts with median 2L treatments were enrolled for phase 1c and all pts were well tolerated to date. Adverse reactions of grade 3 or higher (≥5%) were hepatic function impairment (8.7%), headache (8.7%), hyperbilirubinemia (5.7%), ALT increased (5.7%), AST increased (5.7%), GGT increased (5.7%) and WBC decreased (5.7%). Among 19 BCBM pts with at least twice tumor assessment, the overall ORR was 78.9% (95% CI: 54.4–93.9) and iORR was 73.7% (95% CI: 48.8–90.9), DCR was 100%. In addition, 6 pts completed first tumor assessment and 5 achieved PR and 1 had SD per RECISIT 1.1. Conclusions: Encouraging efficacy and tolerability was observed for ZN-1041 monotherapy or combined with capecitabine and trastuzumab in TKI naïve, HER2+ BCBM patients. A Phase 2 pivotal trial for HER2+ BCBM with ZN-1041, capecitabine and trastuzumab combination therapy is planned. Clinical trial information: NCT04487236 .

Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).

2501 Background: Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical role in tumoral immunosuppression. Apart from blocking immune-cell entry into the tumor microenvironment, GDF-15 also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success. Here we report initial results of the phase 2a part of the GDF-15 neutralizing antibody visugromab (CTL-002) in combination with nivolumab. Methods: At cut-off date (06-Feb-2023), a total of 79 pts with advanced/metastatic solid tumors have been enrolled and were treated with visugromab 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W in the phase 2a expansion part of the CTL-002-001 phase 1/2 trial (NCT04725474). The primary endpoint of the phase 2a expansion is the Objective Response Rate (ORR) according to RECIST v1.1. Tumor assessments were performed every 8 weeks and patients had to be relapsed/refractory to a minimum of 12 weeks continuous prior anti-PD1/-PD-L1-containing therapy, with relapse or progression after initial response to have occurred on continued anti-PD1/PDL1 therapy. Phase 2a contained several indication-specific expansion cohorts (e.g. NSCLC, Bladder Cancer, HCC, Melanoma), following a Simon 2-stage design, and two cohorts were already expanded to stage 2 in light of initial responses observed. An additional expansion cohort is a pan-tumor basket cohort with sequential tumor biopsies for biomarker analyses. A key component of this multi-arm trial is an extensive translational research program to identify response-predictive tumor and immunologic marker and pattern. Results: Across several expansion cohorts, durable tumor regressions were observed, including several partial responses (PR) and one complete response (CR) in heavily pretreated patients with a median of 3 prior lines of systemic therapy for advanced/metastatic cancer, including at least one prior line of anti-PD1/-PD-L1 therapy and being relapsed/refractory to it. In NSCLC, so far 13 pts underwent at least one tumor assessment. Of these, two experienced a PR (one confirmed), three additional tumor shrinkage &gt; 5% (TS) and one longer-term SD (LT-SD) were seen. In bladder cancer, 7 patients underwent at least one tumor assessment with 1 confirmed CR, 1 TS and 1 LT-SD. The treatment was overall well tolerated. Conclusions: These initial phase 2a results demonstrate promising clinical activity for the combination of visugromab and nivolumab in heavily pretreated anti-PD1/-PD-L1 refractory/relapsed solid tumor patients across various indications, including induction of confirmed partial and complete responses. Extensive biomarker evaluations are ongoing to further evaluate potential response-predictive markers identified during phase 1 development. Clinical trial information: NCT04725474 .

Development of a novel immune-related toxicity grading system for predicting outcomes in patients with solid tumours treated with immune checkpoint inhibitors (ICI).

2644 Background: Adoption of ICI in clinical practise has led to improved outcomes in many tumour types. Their use is associated with immune related adverse events (irAEs), with unpredictable onset targeting multiple organs and for which conventional CTCAE toxicity grading has significant limitations. In addition, the correlation of irAEs to efficacy of ICI is becoming increasingly recognised. Here we present a novel toxicity assessment tool and describe its relationship with cancer outcomes. Methods: Data were collected from the Pathobiology of Adverse Immune Reactions (PAIR) prospective cohort study at Guy’s Hospital from February 2018 until end of May 2022. Solid tumour patients with advanced disease naïve to ICI who received at least 1 dose were included. Minimum 6 months of follow-up was required. IrAEs were captured based on the OST score which evaluates the number of affected Organs (O), number of Severe CTCAE (³G3) toxicities (S) and sum of all grade Toxicities (T). OST was calculated at death or end of follow-up. Patients were divided in high and low toxicity groups, defined by the median value for each parameter. Descriptive statistics and crude and multivariate survival Cox Proportional Hazards regression analyses were performed accounting for age, tumour type and treatment. Results: A total of 123 patients were included. Median age was 68 years (range 23-87 yrs); 67 (54%) were male; 104 (85%) were White Caucasian. Most common tumour types were melanoma (33%), non-small cell lung (24%) and renal cell carcinoma (22%). Forty-six patients (37%) received Ipilimumab-Nivolumab, 37 (30%) Pembrolizumab and 24 (20%) Nivolumab. Twenty-two (18%) had autoimmune disease at baseline. Hypothyroidism (6%) and psoriasis (2%) were most common. Median number of affected organs was 2 (range 0-7), 32 (26%) had ≥1 G3 toxicity and the median T score was 3 (range 0-15). Survival data were available for 120 patients. After median follow-up of 39 months, 66 deaths (53.7%) occurred. Median OS was 16.9 months (95% C.I 9.9-24.1). High toxicity groups presented reduced risk of death compared to low-toxicity groups when evaluated for individual OST parameters [HR for Organ tox group (95% CI): 0.359 (0.198-0.649), HR for Severity group (95% CI): 0.402 (0.200-0.808), HR for Toxicity score group (95% CI): 0.353 (0.190-0.657)]. Of the three parameters, the number of Organs (O) was most strongly associated with reduced risk of death when analysed as a continuous variable [HR (95% CI): 0.683 (0.577-0.808)]. Conclusions: We have developed a novel immune toxicity grading system which can potentially predict survival outcomes for patients treated with ICI. Further prospective evaluation and correlation to translational secondary endpoints with immunological phenotyping is ongoing. External validation is warranted to support further use of OST in routine clinical practice.

Quality of cancer family history taking in pediatric solid tumor patients.

10045 Background: Approximately 10% of childhood solid tumors occur in individuals with a cancer genetic predisposition. Identifying cancer predisposition permits interventions for prevention and early detection of future cancers in the child and their affected family members and may have other important medical care implications. The American Society of Clinical Oncology (ASCO) guidelines recommend reviewing family history (FHx) to identify high-risk patients who should be offered genetic testing. To our knowledge, adherence to ASCO guidelines by pediatric oncology providers (POPs) has not been studied. Methods: Retrospective chart review of solid tumor patients &lt;18 years of age referred for genetic counseling 1/1/2017-1/31/2019. POP and genetic counselor (GC) FHx documentation was assessed for adherence with the ASCO minimum quality metrics: 2 generation pedigree, patient ethnicity, cancer genetic testing results in relatives (GTRR), and cancer type, age at diagnosis, and lineage (maternal/paternal) for each relative with cancer (RWC). Comparisons of FHx quality between POPs and GCs were evaluated with 1-sided t-tests. Ethnicity was considered assessed if both maternal and paternal ethnicities were documented. GTRR was considered assessed if the results of all relatives who had undergone genetic testing were noted. Cancer type, age at diagnosis, and lineage were considered assessed if they were checked for all RWCs. Whether or not the child underwent genetic testing and their testing results were also documented. Results: Of 129 eligible patients, 102 underwent germline genetic testing. Twelve (12%) had pathogenic alterations in cancer predisposition genes. The POP failed to document FHx in 20 patients (16%), including 2 with pathogenic germline alterations. The POP missed first/second degree RWCs in 32 of 88 patients with RWCs (36%). GCs achieved &gt;99% on each of the 6 ASCO quality metrics, whereas POPs performed significantly more poorly (Table). In patients with RWCs, GCs achieved all 6 metrics in more cases than POPs (99% vs. 3%, p&lt;0.001). Conclusions: POPs performed significantly worse than GCs in documenting family history compliant with ASCO minimum family history guidelines, raising concern for missed genetic cancer predisposition syndrome diagnoses in those not referred to a GC. Routine referral of pediatric solid tumor patients to a GC for family history review and interventions to improve the quality of family history taking by POPs may improve germline cancer predisposition detection, improving care of both patients and their affected family members. [Table: see text]

Assessing the frequency of anemia evaluations in patients who are transfusion-dependent in an academic hematology and oncology practice.

e24104 Background: There is a high rate of anemia present in cancer patients and anemia is also a common referral to a hematologist. Symptomatic anemia can significantly impair an individual’s functional status so identifying its cause is essential for improving quality of life. Correction of nutritional deficiencies, like iron, B12, and folate deficiency can improve hemoglobin counts, prevent recurrent PRBC transfusions, and can often resolve the anemia. In a busy academic hematology oncology practice, we hypothesize that it is easy to overlook performing a basic nutritional evaluation especially in the setting of other causes for anemia such as chemotherapy, hemolysis, blood loss, chronic kidney disease, and other disorders. We aim to evaluate the frequency of anemia workup in the hematology and oncology division at our academic institution. Methods: We conducted a retrospective study of all hematology oncology patients seen in our clinic who received a blood transfusion in 2021. All patients were 18 years old or order and received at least one-unit PRBC transfusion as an outpatient. One “transfusion event” was defined as any number of PRBC transfusions on a single day and any subsequent transfusions within a 90-day periods. A single patient, therefore, can have multiple distinct transfusion events. We analyzed whether patients received a “basic” anemia evaluation, defined as checking ferritin, iron saturation, B12, and folate levels within 3 months before or after the first transfusion, and whether a discrepancy in practice patterns exists between different hematology oncology subspecialties. Results: At the interim analysis, we identified 368 transfusion events for 275 patients. Those events were ordered by providers (physician, nurse practitioner, or physician assistant) in the following subspecialties: oncology (n = 20), malignant hematology (n = 18), classical hematology (n = 3), and fellow-in-training (n = 5). A basic anemia workup was missing in 58% (84 of 146), 27% (49 of 183), 23% (8 of 35), 40% (2 of 5) in the above groups respectively. For patients with macrocytic anemia defined as mean corpuscular volume (MCV) &gt; 100 fL, 48% (38 of 79) did not have B12 or folate levels checked within 3 months before or after a transfusion event. For patients with MCV &lt; 80 fL, 47% (14 of 30) did not have ferritin or iron saturation checked within 3 months before or after a transfusion event. Conclusions: We observed a high percentage of cancer and non-malignant hematology patients who did not receive a basic anemia evaluation within three months before or three months after a blood transfusion. A higher percentage of patients with solid tumors patients who required PRBC transfusions did not receive a basic anemia evaluation in a timely manner. Our study identified an area of quality improvement and need for intervention that can easily be overlooked in a busy academic hematology oncology practice.

Investigator-initiated phase 1 clinical trial of synthetic TIL: Autologous peripheral T cells engineered with polyclonal TIL-derived TCRs.

e14525 Background: The efficacy of tumor-infiltrating lymphocyte (TIL) therapy is limited by the rarity of anti-tumor TCRs and exhausted status of the product. Its improvement should focus on a high frequency of diverse anti-tumor TCRs with stem-like phenotype, which can be achieved synthetically by identifying multiple anti-tumor TCRs from the patient's intra-tumor TCR repertoire and subsequently engineering them into the patient’s peripheral T cells. Such a ‘synthetic TIL’ is cost-prohibitive using existing technologies. To enable a synthetic TIL product, we developed ultra-high throughput TCR gene synthesis and screening methods to synthesize and screen &gt; 50,000 TCRs from scRNA-Seq data from &gt; 30 patients and identified &gt; 100 tumor/NeoAg-reactive TCRs. The gene expression patterns of the T cells carrying such experimentally validated tumor/NeoAg-reactive TCRs gave rise to an algorithm called Interpreter to predict potentially anti-tumor TCRs from scRNA-Seq data. Methods: To translate synthetic TIL to the clinic, we developed a method to generate up to 100 sequence-verified TCR-encoding plasmids (selected by Interpreter) from fresh tumor biopsy in just 3 weeks. Our GMP-grade production uses a collective knock-in approach, where a mixture of up to 100 plasmids (each encoding a distinct TCR) at equal proportion are packaged into AAV which serve as template to precisely insert the TCR genes into a primarily monoallelic locus and simultaneously inhibit the endogenous TCR. This gene editing is characterized by a modified scRNA-Seq method called EntrySeq. In first-in-human, N-of-1 trials, 109 to 6x109 synthetic TIL cells were administered to solid tumor patients with or without lymphodepletion and IL2. An investigator-initiated Phase 1 trial was then opened to evaluate safety, preliminary efficacy, and cellular activity of synthetic TIL and to determine RP2D and MTD. Subjects with relapsed, unresectable locally advanced solid tumors who received at least 1 standard systemic therapy are allowed to enroll in this study. Those patients with no standard treatment regimens available, or those who are unable to obtain effective treatment due to economic conditions are also permitted. Results: EntrySeq confirmed that &gt; 80% of the T cells express only 1 TCR, avoiding mispairing of different TCRs. The frequencies of different TCRs were largely uniform and were stable through plasmid, AAV and T-cell mixtures. Up to 1.5x1010 synthetic TIL cells were produced from a patient’s leukopak. 40 to 60% of the T cells in the product for infusion express an exogenous TCR. In first-in-human trials, the administered T cells showed favorable persistence and safety profile. The Phase 1 trial is ongoing. Conclusions: We established a fast, affordable, and GMP-compliant process to manufacture synthetic TIL products, enabling a Phase 1 trial.

Relationship between tumor microenvironment (TME)-based histomic TGFβ signature (TGFBs), stromal fibroblast recruitment, and exclusion of immune cells as immunotherapy resistance mechanisms.

2585 Background: TGF-beta activates fibroblasts within the TME and may be associated with poor response to immunotherapy.However, objective and reliable assessment of the TGFBs by gene expression profiling (GEP) is challenging. Using H&amp;E whole-slide images (WSI) from The Cancer Genome Atlas (TCGA), we developed an artificial intelligence (AI) model to predict a normalized TGFBs, applying it to real-world datasets (RWDs) of advanced solid tumor patients treated with immunotherapy. Methods: The TGFBs was defined using the mean GEP values of the 'Hallmark TGF-beta signaling' gene set. H&amp;E WSIs of 23 carcinoma types from TCGA (n=6,945) were used to discover the association of the TGFBs with various cell types, including fibroblasts and tumor-infiltrating lymphocytes (TILs) detected by an AI model, Lunit SCOPE IO (AI-1). Another custom AI model (AI-2) to predict TGFBs was developed by integrating self-supervised and supervised features and other semantic content extracted by AI-1 with multilayered perceptron classifiers. TGFBs prediction scores from the AI-2 were applied to 5 different RWDs containing 1,792 immunotherapy-treated patients (&gt; 16 primary tumor types). The immune-excluded phenotype (IEP) was defined by high stromal TIL and low intratumoral TIL density. Results: In the TCGA dataset, TGFBs and fibroblast density detected by AI-1 were closely correlated (R=0.19, p&lt;0.001) compared to other cell types, with both highest in pancreatic adenocarcinoma (PAC)(median [interquartile range, IQR] 0.73 [0.66-0.80], 1306 [985-1588]/mm2, respectively) and CMS4 colorectal cancer (0.61 [0.54-0.67], 868 [582-1128]/mm2) compared to other cancers (0.57 [0.47-0.66], 577 [295-890]/mm2). The AI-2 predicted TGFBs with area-under-the-curve of 0.781 on cross-validation within the TCGA dataset. The TGFBs of immunotherapy-treated RWDs were inferred from their corresponding H&amp;E WSI, with scores comparable to those from the TCGA (0.42 [0.16-0.60] vs 0.58 [0.48-0.67]), with PAC having the highest TGFBs (0.65 [0.45-0.77]) in the RWD as well. Interestingly, TGFBs inferred scores and fibroblast density were significantly correlated (R=0.7, p&lt;0.001) in the RWD and also significantly correlated with the IEP (0.52 [0.30-0.66]) compared to other immune phenotypes (0.42 [0.16-0.60], p&lt;0.001). In the RWD, patients with inferred TGFBs in the upper 75% quartile had a poor clinical response to immunotherapy (objective response rate: 15.1% vs 20.7%, median progression-free survival 3.0 m vs 4.0 m, hazard ratio 1.21, 95% confidence interval 1.07-1.36, p=0.002). Conclusions: TGFBs is closely correlated with fibroblast density within the TME and may confer resistance to immunotherapy. Unique morphologic features of the TGFBs can be captured by AI, enabling scalable application to various datasets for clinical and translational research.

A pan-cancer statistical study of microsatellite instability and Lynch syndrome–associated mismatch repair genes germline mutations.

10593 Background: Lynch Syndrome (LS), known as hereditary nonpolyposis colorectal cancer (HNPCC1), is caused by germline mutations in the mismatch repair (MMR) genes ( MLH1, MSH2, PMS2, MSH6), or epigenetic silencing of MSH2 which caused by deletion of 3-prime exons of the EPCAM gene and intergenic regions directly upstream of the MSH2 gene. DNA mismatches commonly occur in regions of repetitive nucleotide sequences called microsatellites, and the status of microsatellite instability (MSI) is the key feature in LS-associated cancers. Although there are sporadic reports of MSI and LS in certain cohorts, the real-world status of MSI in large pan-cancer cohort remains to be analyzed. Methods: We retrospectively reviewed all 18189 solid tumor patients from August 1, 2020 to February 5, 2023 from HaploX Genomic Sequencing Center and analyzed their germline mutations in MMR genes ( MLH1,MSH2,PMS2,MSH6 and EPCAM). MSI status was determined using Sanger sequencing or Next-generation sequencing, with tumor MSI status classified as microsatellite instability-high (MSI-H), or microsatellite-stable (MSS). Results: LS-associated germline mutations were detected in 0.313% (n = 57) of patients, and75.4% (n = 43) of patients were identified as MSI-H, and 24.6% (n = 14) of patients were MSS. The patients were grouped into CRC/EC group (colorectal cancer and endometrial cancer) and non-CRC/EC (lung cancer, central nervous system tumor, gastric cancer, esophageal cancer, hepatological cancer, pancreatic adenocarcinoma, small bowel carcinoma, kidney cancer, etc.). Among MSI-H patients, the CRC/EC group accounted for 90.7% (n = 39) and the non-CRC/EC group accounted for 9.3% (n = 4). In MSS patients, the CRC/EC patients accounted for 35.7% (n = 5), and the non-CRC/EC patients accounted for 60% (n = 9). Among patients with MSI-H, the most frequently mutated gene was MSH6 (n = 9): MSH6 (NM_000179) c.3261dup (p.F1088Lfs*5) mutation was detected in 4 patients, of which 2 patients were paternal and both were diagnosed as colorectal cancer; MSH6 c.718C &gt; T (p.R240*) mutation was detected in 2 patients with available MMR IHC results, and one of them was MSH6 negative in IHC staining. Conclusions: Traditionally, a family history of colorectal cancer or endometrial cancers was the primary clinical feature to diagnose Lynch syndrome. Once it was recognized that Lynch-associated CRCs were microsatellite unstable, tumor testing became an additional tool for identification of Lynch syndrome. Some previous studies also reported Lynch syndrome mutations, primarily MSH6 and PMS2, were present in a few MSS patients. Thus, MSI status or family history as diagnostic factor alone may result in Lynch syndrome under-recognized, and additional NGS test on MMR genes should facilitate more accurate diagnosis.

Impact of the COVID-19 pandemic on insurance transitions among commercially insured cancer patients in Washington state.

6552 Background: Insurance transitions following cancer diagnosis can disrupt care and impact outcomes. The COVID-19 pandemic impacted employment for millions of Americans, threatening their ability to maintain insurance. Using a large database linking commercial insurance to cancer registry records, we evaluated insurance transitions among newly diagnosed cancer patients in the pre- and post-COVID periods. Methods: We linked Western Washington SEER cancer registry records and enrollment records from two commercial insurers covering 3 million persons and Medicaid in Washington State. Eligible persons were ages 18-63 and commercially insured in the 12 months prior to their first cancer diagnosis. Post-diagnosis follow-up periods were stratified into pre-COVID (January 2017 – February 2020) and post-COVID (March 2020 - December 2020). We created logistic regression models to look at factors associated with (1) disenrollment for any reason and (2) transition to Medicaid, accounting for age, sex, race, year of diagnosis, cancer site, AJCC stage, comorbidities, and Area Deprivation Index (ADI), and diagnosis during the pandemic. Results: Among 5,458 newly diagnosed solid tumor patients enrolled in commercial plans pre-COVID, 16.9% disenrolled for any reason over 12 months following diagnosis. Among disenrollees, 10.0% transitioned to Medicaid. Patients with Lung, Oral, and Myeloma cancers had the highest disenrollments (21.2%, 21.0%, and 19.3% respectively). Among the 1,224 diagnosed post-COVID, 9.7% disenrolled for any reason. Among those who disenrolled, 21.0% enrolled in Medicaid. Patients with Leukemia, Melanoma, Oral, and Gynecologic cancers had the highest disenrollments (23.3%, 14.5%, 13.6%, and 13.6% respectively). In logistic regression, persons diagnosed after the pandemic were less likely to disenroll compared to the pre-pandemic period (Table). Transitions to Medicaid was not greater post-Pandemic. Advanced stage, comorbidity, and living in high ADI regions were significantly associated with transitioning to Medicaid. Conclusions: Newly diagnosed cancer patients with commercial insurance during the COVID-19 pandemic were substantially less likely to disenroll than those diagnosed before the pandemic. The findings may reflect pandemic-related preferences for job stability during a time of personal and societal crisis. [Table: see text]

C-reactive protein as a response biomarker to immune checkpoint blockade: A meta-analysis.

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&lt;0.0001, I2=42%), PFS HR=2.47 [1.98-3.09] (p&lt;0.0001, I2=18%), and OS HR=2.28 [1.68-3.08] (p&lt;0.0001, I2=56%). Heterogeneity among subgroups was low in ORR (I2=14.6%) and PFS analysis ( I2=0%), and moderate in OS analysis (I2=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]

The analysis of BRAF fusions characteristics in Chinese solid tumor patients.

e15073 Background: BRAF encodes a RAF kinase, which signal downstream of RAS and activate the MAPK pathway, and has emerged as a major oncogenic driver and a potential therapy target. BRAF V600E base substitution is an approved target for the BRAF inhibitors in solid tumors. BRAF gene fusions represent a different mechanism of BRAF activation. BRAF fusions have shown responses to MEK inhibitors and non-specific RAF inhibitors (eg, sorafenib) in Melanoma (NCCN). We sought to analysis of BRAF fusions characteristics in Chinese solid tumor patients to explore the possibility of therapeutic intervention in solid tumors. Methods: We comprehensively characterized BRAF fusions from next-generation sequencing (NGS) data from May 2019 to January 2023 in 80083 various solid tumors. Considering the characteristics of the receptor tyrosine kinase, we focused on the BRAF fusions which contain the kinase domain. Results: A total of 164 unique cases (70.1% (115/164) glioma and 29.9% (49/164) non-glioma with BRAF fusions) were identified. The non-glioma cohort consisted up mainly lung tumors (49%, 24/49), colorectal tumors (18.4%, 9/49), pancreatic tumors (10.2%,5/49), melanoma (9.2%, 4/49) and biliary tumors (4.1%, 2/49). In the glioma cohort, the median age of the 115 patients was 12 with a range of 0–66; 43 (37.4%) of the patients were female and 72 (62.6%) were male. On the other hand, the median age was 64 with a range of 33–82; 23 (46.9%) of the patients were female and 26 (53.10%) were male in the non-glioma cohort. In the glioma cohort, 82.4% of the partners were KIAA1549. However, the most common fusion partners were AGK (14.04%), TRIM24(14.0%), SND1(12.28%), TPK1(8.77%) in the non-glioma cohort. These BRAF fusions comprised 49 unique 5′ fusion partners, of which 51% (25) were known and 49.0% (24) were novel. 14 novel partners were TMEM176B, HMBOX1, SEMA3E, LOC441204, PDE4D, DENND2A, STIM1, TNS3, PRRC2B, BCR, MET, COL4A3BP, TPM4, ZBTB16 and 10 novel partners were intergenic region. 130 patients with BRAF fusions could be evaluated for concurrent mutations. Of interest is that no KRAS and BRAF V600E mutations were identified in the 130 cases. Conclusions: BRAF fusions were detected in 0.2% (164/80083) of Chinese solid tumor patients. 70.1% of BRAF fusion positive cases were diagnosed with glioma and 29.9% were diagnosed with non-glioma. 14 novel BRAF fusion partners were discovered. BRAF fusion is an important driver genomic alteration and occur in a mutually exclusive pattern with other activating mutations in the MAP kinase signaling pathway. BRAF fusion targeted therapies should be further explored in solid tumors.