Advanced Solid Tumor Cancer Research Articles

Depression care quality among patients with solid tumor cancers detected to have depression in Veterans Health Administration primary care clinics.

Patients with cancer, especially advanced cancer, experience depression at high rates. We aimed to evaluate the quality of depression care received by patients with solid tumor cancer and advanced solid tumor cancer in Veterans Affairs (VA) primary care clinics. This is a retrospective cohort study of patients seen in 82 VA primary care clinics who newly screened positive for depression on the Patient Health Questionnaire (PHQ-2). Outcomes included timely follow-up within 84 or 180 days (3+ mental health specialty, 3+ psychotherapy, or 3+ primary care visits with depression diagnosis codes) and minimum treatment within 1 year (60+ days antidepressants prescribed, 4+ mental health specialty visits, or 3+ psychotherapy visits). 608,042 individuals were seen in VA primary care clinics during this period; 49,839 patients (8.2%) had solid tumor cancer and 9,278 (1.5%) had advanced or poor-prognosis solid tumor cancer. For 686 observations of patients with cancer and new depression, rates of appropriate follow-up were 22.3% within 84 days and 38.2% within 180 days. For 73 observations of patients with advanced or poor-prognosis cancer and new depression, rates of appropriate follow-up were 21.9% within 84 days and 34.3% within 180 days. Rates of minimum treatment within 1 year were 68.4% and 64.4% for patients with cancer and patients with advanced or poor-prognosis cancer, respectively. Quality of timely depression management is low in patients with solid tumor cancers. Even in health systems with well-integrated mental health services, care gaps remain for patients with cancer and depression. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Economic costs of family caregiving for persons with advanced stage cancer: a longitudinal cohort study.

To form a multifaceted picture of family caregiver economic costs in advanced cancer. A multi-site cohort study collected prospective longitudinal data from caregivers of patients with advanced solid tumor cancers. Caregiver survey and out-of-pocket (OOP) receipt data were collected biweekly in-person for up to 24weeks. Economic cost measures attributed to caregiving were as follows: amount of OOP costs, debt accrual, perceived economic situation, and working for pay. Descriptive analysis illustrates economic outcomes over time. Generalized linear mixed effects models asses the association of objective burden and economic outcomes, controlling for subjective burden and other factors. Objective burden is number of activities and instrumental activities of daily living (ADL/IADL) tasks, all caregiving tasks, and amount of time spent caregiving over 24h. One hundred ninety-eight caregivers, 41% identifying as Black, were followed for a mean period of 16weeks. Median 2-week out-of-pocket costs were $111. One-third of caregivers incurred debt to care for the patient and 24% reported being in an adverse economic situation. Whereas 49.5% reported working at study visit 1, 28.6% of caregivers at the last study visit reported working. In adjusted analysis, a higher number of caregiving tasks overall and ADL/IADL tasks specifically were associated with lower out-of-pocket expenses, a lower likelihood of working, and a higher likelihood of incurring debt and reporting an adverse economic situation. Most caregivers of cancer patients with advanced stage disease experienced direct and indirect economic costs. Results support the need to find solutions to lessen economic costs for caregivers of persons with advanced cancer.

Transitions of care with a community-based palliative care program: Results from a pilot project for advanced solid tumor oncology patients.

e24113 Background: Hospice underutilization among patients with advanced cancer at the end of life can result in patients not receiving the full benefit of hospice and lead to significant distress to patients, families, staff and caregivers. Through multidisciplinary root cause analyses, we identified a gap in services where hospice care, if pursued at all, did not occur until late in the course. A pilot program for community-based palliative services partnering with Calvary Hospital Advanced Healthcare Coordination was introduced for patients with advanced solid tumor cancer in February 2022. Methods: Solid tumor oncologists, social workers and palliative care physicians identified eligible patients with advanced stage cancer who may or may not be undergoing cancer-directed treatment with palliative intent. Patients received home-based support by palliative trained nurse practitioners, licensed social workers and spiritual counsel including symptom management, advanced care planning, care coordination and hospice transition if indicated. The pilot was launched initially in thoracic oncology in February 2022, with expansion to all solid tumor oncology patients in April 2022. Results: From February 1, 2022 to December 31, 2022, a total of 34 patients were referred for community-based palliative care services. Only 15/34 (44%) referrals were taken under care. Of the patients taken under care 7/15 (46.7%) were eventually transitioned to hospice services, and 4/15 (26.7%) patients expired while receiving community-based palliative care services. Of the remaining patients that were not taken under care (n = 19), 6/19 (31.5%) required a higher level of care and were hospitalized, 4/19 (21.1%) went directly to hospice care. Process measures including pain scores, completion of advanced care planning documents, depression scores, treatments given while in pilot, number of hospitalizations, as well as patient-reported outcomes are ongoing. Conclusions: Our pilot demonstrates that while community-based palliative care services can potentially bridge patients from palliative care services to hospice at the end of life, several patients may still have been referred “too late” in their course. Future plan-do-study-act cycles aim to continue to improve the number and timing of referrals to this pilot program and evaluate its impact in hospice utilization for patients with advanced cancer at end of life.

Opioid use, gabapentinoid use, and pain-related emergency department visits for patients living with advanced cancer.

12119 Background: Regulatory efforts in response to the United States opioid epidemic have resulted in a decrease in opioid prescribing among oncologists and non-oncologists. Understanding how decreased opioid prescribing affects cancer-related pain can provide key insights into the downstream effects of these efforts. In this study, we explored temporal trends in opioid use, gabapentinoid use, and pain-related emergency department (ED) visits in older adult patients with advanced cancer and those without cancer. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 1/1/2012 to 12/31/2017 to identify patients aged 66 years or older diagnosed with advanced solid tumor cancer (defined as stage IV and/or metastatic disease). A cohort of patients without a cancer diagnosis was identified using the Medicare 5% random sample. The three dependent outcomes assessed were opioid use, gabapentinoid use, and pain-related ED visits. Multivariable logistic regression was used to identify predictors of these outcomes and to calculate the predicted probability of each outcome for patients with and without cancer. We determined the absolute change in the predicted probability of each outcome from 2012 to 2017. Results: A total of 294,113 patients were included in the cohort; 45,899 (15.6%) with cancer and 248,214 (84.4%) without cancer. Between 2012 and 2017, the absolute change in predicted probability of opioid use declined less in the cancer [-6.1%; 68.6% to 62.5%] compared to the non-cancer cohort [-8.2%; 35.8% to 27.6%] (p<.001 for difference). Gabapentinoid use increased more in the cancer [3.9%; 10.8% to 14.7%] than non-cancer [1.8%; 10.5% to 12.3%] cohort (p<.001 for difference). There was no statistically significant change in pain-related ED visits in patients with cancer [0.6%; 12.4% to 13.0%] and a decrease in patients without cancer [-0.5%; 2.6% to 2.1%] (p=0.005 for difference). Conclusions: Our findings showed that opioid use decreased to a lesser degree among older patients with advanced cancer compared to patients without cancer, whereas gabapentinoid use increased to a greater degree among patients with cancer. There was no corresponding rise in pain-related ED visits, suggesting that these shifts in medication use may not have adversely affected this important outcome. [Table: see text]

P62 Parametric Survival Extrapolations of Larotrectinib and Entrectinib for NTRK Fusion Cancers

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm Phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of these agents. The objective was to extrapolate clinical trial results to compare estimated progression-free and overall life-years (LYs) and quality-adjusted LYs (QALYs) for larotrectinib and entrectinib in patients with colorectal cancer (CRC), soft tissue sarcoma (STS), and brain metastases (BM) at baseline.

Abstract B044: Bromodomain and Extra-Terminal Protein inhibition decreases pancreatic cancer proliferation via MYC-independent pathways

Abstract Introduction: The bromodomain and extra-terminal (BET) protein family contains proteins which have evolutionarily conserved bromodomains (BRDs) that specifically recognize acetylated lysine residues on the histone tails of chromatin and regulate gene transcription. Deregulation of these BRD-containing proteins has been seen in carcinogenesis as they are also known to play role in the regulation of the cell-cycle and MYC oncogenes. BMS-986158 is an oral BET inhibitor which has been used in the clinical trials for both hematologic and advanced solid tumor cancers. We hypothesized that BET inhibition (BETi) decreases pancreatic ductal adenocarcinoma (PDA) proliferation. Methods: Pancreatic cancer cell lines and patient-derived cell-lines (PDCLs) were treated with 2.5 to 100nM BMS-986158 for 72 hours to study dose-response effect with Incucyte. We performed RNA-seq, qPCR, protein analysis, and flow cytometry to evaluate comprehensive changes and underlying mechanisms/pathways including epithelial to mesenchymal transition (EMT) and the cancer stem cell (CSC) phenotype. Various doses of BMS-986158 were used in PDCL and PDA patient-derived organoids (PDO) in combination with chemotherapy drug to evaluate combinational effects. Results: We found that BETi induced dose-dependent decrease in growth of PDA and PDCLs and induced cancer cell death. BETi demonstrated PDO growth inhibition which was enhanced when combined with gemcitabine and paclitaxel chemotherapy. Next, we found that BETi did not affect MYC expression but decreased expression of the SNAI1 (a mesenchymal marker) protein and increased E-cadherin protein expression in PDA cell line and PDO consistent with decreased activation of an EMT program. BETi also decreased expression of CD133, a marker of CSCs in PDO. BETi also induced G1/S Phase cell cycle arrest in PDA PDCLs. Furthermore, RNA-seq studies revealed that BETi treatment inhibits KRAS pathway and upregulates pathways involved in metabolism of lipids and lysosomal degradation. RNA-seq and qPCR demonstrated that GPX3 (glutathione peroxidase 3, a key protein in reactive oxygen species response) gene expression is upregulated in BETi treated samples. Conclusions: Thus, our data demonstrate that BETi through BMS-986158 is an additional therapy for inhibiting PDA growth through mechanisms that are independent of MYC pathway, inhibition of abnormal lipid metabolism and scavenging of reactive oxygen species. Citation Format: Manjul Rana, Rita G. Kansal, Jie Fang, Benjamin T. Allen, Jun Yang, Evan S. Glazer. Bromodomain and Extra-Terminal Protein inhibition decreases pancreatic cancer proliferation via MYC-independent pathways [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B044.

BASECAMP-1: Leveraging human leukocyte antigen (HLA) loss of heterozygosity (LOH) in solid tumors by next-generation sequencing (NGS) to identify patients with relapsed solid tumor for future logic-gated Tmod CAR T-cell therapy.

TPS2676 Background: Solid tumors comprise > 90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively) (ACS. 2021). Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies (Neelapu S. et al. N Engl J Med. 2017). Translating engineered T-cell therapies to solid tumors has proven to be challenging due to a lack of tumor-specific targets that can discriminate cancer cells from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and mesothelin (MSLN) CARs resulted in dose-limiting on-target, off-tumor toxicities (Parkhurst M, et al. Mol Ther. 2011; Tanyi J. Cellicon Valley '21). To create a therapeutic safety window, Tmod CAR T-cell therapy utilizes dual-signaling receptors to create a robust NOT logic gate capable of killing tumor cells, while leaving healthy cells intact (Hamburger A, et al. Mol Immunol. 2020). The 2 receptors in Tmod CAR T-cell therapy comprise an activator that recognizes an antigen on the surface of tumor cells that may also be present on normal cells, such as CEA and MSLN, and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. The frequency of HLA LOH among advanced GI solid tumor cancers in the Tempus real-world dataset is 16.3% with a range of 15.6%-20.8% between colorectal, pancreatic, and gastroesophageal tumors (Hecht R. et al. ASCO-GI 2022. Abstract #190). As such, HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy. Different activator/blocker combinations can be engineered with the Tmod platform technology and may be applied to T cells and natural killer cells in autologous and allogeneic settings. BASECAMP-1 is a currently enrolling observational study with key objectives of 1) To identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) To obtain leukapheresis and feasibility for the future EVEREST Tmod CAR T-cell trial. Methods: BASECAMP-1 (NCT04981119) patient eligibility has 2 parts: 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central NGS. If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed for somatic mutations by xT-Onco NGS testing. 2) If the tumor demonstrates HLA-A*02 LOH and the patient is eligible after screening, the patient will undergo leukapheresis. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study to reduce waiting time at relapse. Clinical trial information: NCT04981119.

Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity.

190 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal (GE) cancers are the leading causes of GI cancer–related mortality (5-yr survival rate, 14%, 3% and ̃5-6%, respectively). T-cell immunotherapy targeting GI-associated tumor antigens has been attempted, but efficacy has been constrained by on-target off-tumor toxicity, limiting the therapeutic window. The Tmod (TM) platform is an AND-NOT logic-gated CAR T modular system, versions of which have a CEA- or MSLN-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor to protect normal cells. Tmod CAR T exploits HLA LOH, common in GI malignancies (10-33% in primary solid tumors [TCGA]) and can kill tumor cells without harming healthy cells in vitro and in vivo. However, the prevalence of HLA LOH across GI tumors is unknown in the real-world setting. We utilized the Tempus xT oncology NGS database of patients with multiple GI tumors. From a standard-of-care NGS assay, GI cancer patients can be readily identified for HLA LOH and future treatment with Tmod CAR T therapy. Methods: The occurrence of HLA LOH in GI tumors of 1439 patients was assessed using paired germline and somatic DNA sequencing using a research assay [6]. CRC, PANC and GE patients with ≥ stage 3 were then extracted, and rates of HLA LOH were identified (ie, whether loss occurred across high-frequency HLA-A alleles). In addition, mutations in KRAS and BRAF, as well as MSI status were stratified to determine any association with HLA-A LOH. Results: HLA-A LOH was detected in 830 (17.3%) of all solid tumor records, and a similar proportion when all GI cancer records were analyzed (17.0%). For GI subtypes, these values ranged from 13.5% to 23.1% (Table). No high-frequency HLA-A allele (A*01, A*02, A*03, A*11) was more likely to be lost. Clinical biomarkers ( KRAS, BRAF and MSI status) were not associated with HLA-LOH. Conclusions: The frequency of HLA LOH among advanced solid tumor cancers in this dataset is 17.3%, with a range of 13.5-23% between CRC, PANC and GE. The HLA LOH frequency observed in these GI tumors is consistent with that in primary tumors from TCGA, which also used germline-matched and tumor samples. Clinical biomarkers were not associated with HLA LOH. Tempus NGS was able to identify HLA LOH, which can be used for Tmod CAR T therapy to an enhanced therapeutic window. Identification of these patients in BASECAMP-1 (NCT04981119) will enable novel Tmod CAR T therapy. [Table: see text]

Comparative effectiveness of larotrectinib and entrectinib for TRK fusion cancer.

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors that are indicated for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of larotrectinib and entrectinib vs established standard-of-care treatments in cancers with NTRK gene fusions. Furthermore, no studies have directly compared the 2 agents. This article reviews what is known about the comparative effectiveness of larotrectinib and entrectinib vs standard therapies in TRK fusion cancer and examines the comparative effectiveness of the 2 TRK inhibitors. Historical and intrapatient comparisons suggest that TRK inhibitors improve disease response compared with preexisting treatments across most tumor histologies; indirect and limited comparisons of phase 1/2 data and preliminary simulation modeling suggest a potential advantage for larotrectinib over entrectinib in terms of clinical response and survival. Although limited, these data provide some insight into the position of these treatments in established treatment paradigms for TRK fusion cancer, a setting where real-world evidence will be slow to accrue due to the rare nature of these tumors but may be the only way in the future to answer the outstanding questions regarding these 2agents. Meanwhile, we need to try to obtain the maximum benefit that can be achieved for our patients using the currently available knowledge.

A Review on Pharmacognosy and Pharmacological Activity of Carica papaya Leaf

Carica papaya has been used for centuries in many non-Western medical practices (e.g., Ayurveda, Traditional Chinese and Vietnamese, Unani) for its homeostatic and health-promoting properties. Anecdotal reports have recently surfaced indicating the daily consumption of tea extract made from C. papaya has been related to cancer remission, including remission from certain advanced solid tumor cancers. As a result, we set out to investigate C. papaya leaf extract's in vitro effects on human cancer cells as well as its in vivo effects in cancer patients using scientific methodologies.The phytochemical composition of C. papaya leaf extract was determined using liquid chromatography-mass spectroscopy (LC-MS), immune-modulatory and anti-cancer properties were analyzed in peripheral blood mononuclear cells and various solid tumor cell lines, and clinical laboratory measurements were examined in 116 cancer patients who obtained capsules of C. papaya leaf extract.Our findings suggest that C. papaya has a lot of promise as an adjuvant therapy for certain cancers, and further research is required. In cultured cancer cells, papaya extract tends to be toxic, meaning that it may be used as a drug. For the first time, scientists discovered that papaya leaf extract increases the development of Th1-type cytokines, which are important signaling molecules. In addition to papaya's direct anti-tumor effect on a variety of cancers, this immune system control indicates potential cancer-fighting therapeutic strategies. Th1-type cytokines are important signaling molecules that are increased by papaya leaf extract. Researchers subjected 10 different types of cancer cell cultures to four strengths of papaya leaf extract and assessed the effect after 24 hours, preventing a typical and destructive outcome of many cancer therapy regimens. In every society, papaya inhibited tumor growth.

Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies.

Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are collectively known as gelatinases whereas MMP-2 is gelatinase-A and MMP-9 is termed as gelatinase-B. Gelatinases and other matrix metalloproteinases (MMPs) have long been associated with solid tumor invasion, metastasis and angiogenesis. However, there is paucity of data available regarding the role of gelatinases in hematological malignancies. Recent studies have shown that gelatinases activities or functions are correlated with hematological malignancies. Strategies for designing more specific gelatinase inhibitors like catalytic (CAT) domain inhibitors and hemopexin (PEX) domain inhibitors as well as signaling pathway based or gelatinase expression inhibitors had been reported against hematologic malignant cells. Several substrate based non-selective to non-substrate based relatively selective synthetic matrix metalloproteinase inhibitors (MMPIs) had been developed. Few MMPIs had reached in clinical trials during the period of 1990s-2000s. Unfortunately the anti-tumor and anti-metastatic efficacies of these MMPIs were not justified with patients having several advanced stage solid tumor cancers in any substantial number of clinical trials. Till date not a single MMPI passed phase III clinical trials designed for advanced metastatic cancers due to adverse events as well as lack of ability to show uniformity in disease prolongation. With the best of our knowledge no clinical trial study has been reported with small molecule synthetic inhibitors against hematological malignancies. This review looks at the outcome of clinical trials of MMPIs for advanced stage solid tumors. This can therefore, act as a learning experience for future development of successful gelatinase inhibitors for the management of hematological malignancies.

Abstract LB027: Tracking and decoding the antigen specificity of peripherally derived T cells that infiltrate into solid tumors in patients treated with an autologous T cell therapy, PRIME IL-15 (RPTR-147)

Abstract PRIME IL-15 (RPTR-147) is a novel non-genetically modified, autologous, multi-clonal T cell product loaded with an IL-15Fc nanogel. The product is derived from peripheral T cells that are primed and expanded against five tumor associated antigens (TAAs) known to be overexpressed in multiple different tumor types: PRAME, NY-ESO, SSX-2, WT-1 and Survivin. 17 patients with advanced or metastatic solid-tumor cancers were dosed in a Phase I dose escalation study. Where samples were available, we characterized the reactivity and specificity of the cellular product, and tracked its persistence and localization post administration in patients. We report cellular composition of the product, along with phenotype and TAA-specificity of the T cells. Antigen specificity of patient-derived product samples was determined by Repertoire Immune Medicines' proprietary DNA-barcoded pMHC tetramer platform (CIPHERTM), as well as by functional immunological methods including IFNg ELISpot and flow cytometry assessment of activation induced markers (AIM). The CIPHER platform was used to identify TAA-specific CD8 T cell clonotypes, allowing decoding of T cell receptor (TCR) sequences and their cognate epitope/MHC. Distinct peptides binding from all five TAAs were observed across patients, and were presented across multiple HLA alleles. The phenotype of antigen-specific T cells identified via CIPHER was also assessed via single cell gene expression. Consistent with our previous studies on healthy donors, reactivity via IFNg ELISpot and AIM was also observed to all targeted TAAs. TCR CDR3 sequences were used as molecular signatures of antigen-specific cells to track the product post administration. Bulk sequencing of TCRVβ was performed on tumors pre- and post-treatment. Several product-derived, TAA-specific CD8+ T cell clonotypes were observed in the post-, but not pre-treatment biopsies. We identified additional CD4+ and CD8+ clones that were enriched in the post-treatment biopsies, and some of these clonotypes were also enriched in the product. To de-orphan these tumor infiltrating lymphocytes (TIL) of interest, we cloned selected TIL TCRs to assess their reactivity using Repertoire Immune Medicines' proprietary MCR epitope screening platform. In summary, characterization of antigen-specific T cells in the PRIME IL-15 product was performed by a variety of functional and molecular immune-based methods. Antigen specific T cell reactivities and clonotypes were identified in the peripheral repertoire. We confirmed that T cells were successfully expanded against TAAs and that these T cells do infiltrate the tumors as evidenced by bulk TCR sequencing of post-treatment tumor biopsies. Citation Format: John David Pajerowski, William Gordon, Phil Bardwell, Christine McInnis, Ji Young Hwang, Tabasum Huseni, Parul Agnihotri, Josh Francis, Christina Tarr, Florian Renoux, Sebastian Heer, Nastassja Cerreghetti-Terraneo, Marisa Loi, Erika Hamilton, Sarah Nikiforow, George Blumenschein, Mihaela Christea, Keren Osman, Anthony Shields, Harriet Kluger, Franz-Josef Obermair, Daniel Pregibon, Jan Kisielow, Anthony Coyle, Mojca Skoberne. Tracking and decoding the antigen specificity of peripherally derived T cells that infiltrate into solid tumors in patients treated with an autologous T cell therapy, PRIME IL-15 (RPTR-147) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB027.

Abstract 4421: Development of a clinical-genomic database to study tumor evolution and molecular biomarkers of drug resistance in a real-world setting

Abstract Background: Real-world evidence (RWE), specifically the integration of clinical and molecular data, plays an increasingly important role in elucidating the molecular landscape of advanced solid tumors, at diagnosis and at progression, and furthering precision oncology research. However, reliance on tissue genomic testing results within these RWE databases significantly limits our understanding of tumor evolution as tissue profiles are typically limited to a single time point, generally at diagnosis, and biopsies are not routinely completed at progression. Circulating tumor DNA (ctDNA) analysis at diagnosis and progression is an alternative to serial tissue testing. Studying the real-world data derived from ctDNA testing results can provide additional information, specifically around tumor evolution and mechanisms of innate and acquired resistance in response to intervening therapies (targeted and non-targeted). Methods: Anonymized results from patients consecutively tested with Guardant360®, a CLIA-certified, CAP-accredited, NYSDOH-approved ctDNA test indicated for patients with advanced and metastatic solid tumor cancers (Guardant Health, Redwood City, California) were analyzed. Using a secure and HIPAA-compliant methodology, these results were then linked to a de-identified encounters database containing medical and pharmacy claims to provide a longitudinal view of patients' journeys, including diagnosis, treatments, and real-world outcomes. Results: Of 85,874 patients, the disease groups most highly represented were lung, breast, colorectal, prostate, and pancreas cancers. 48,317 patients (56.3%) had a record of treatment with an antineoplastic treatment (i.e. chemo, hormonal, small molecule, or immuno-therapy). Of patients with a record of therapy, 14,608 (30.2%) had a record of therapy following, but none prior to, the Guardant360 test date, 14,493 (30.0%) had a record of therapy prior to, but not following theGuardant360 test date, and 19,216 (39.8%) had a record of therapy both before and after Guardant360 test date. Conclusions: In a cohort of patients who underwent ctDNA testing and for whom treatment information was available, post-therapy molecular results were available in 69.8%. The availability of genomic information following systemic therapy suggest that this dataset is a viable resource to study drug resistance and tumor evolution in the real-world setting. Citation Format: Naveen Kumar, Rajesh Kucharlapati, Aaron Hardin, Victoria M. Raymond, Stephen Fairclough, Kathryn Lang. Development of a clinical-genomic database to study tumor evolution and molecular biomarkers of drug resistance in a real-world setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4421.

Conducting Goals-of-Care Discussions Takes Less Time Than Imagined.

To describe the length of encounter during visits where goals-of-care (GoC) discussions were expected to take place. Oncologists from community, academic, municipal, and rural hospitals were randomly assigned to receive a coaching model of communication skills to facilitate GoC discussions with patients with newly diagnosed advanced solid-tumor cancer with a prognosis of < 2 years. Patients were surveyed after the first restaging visit regarding the quality of the GoC discussion on a scale of 0-10 (0 = worst; 10 = best), with ≥ 8 indicating a high-quality GoC discussion. Visits were audiotaped, and total encounter time was measured. The median face-to-face time oncologists spent during a GoC discussion was 15 minutes (range, 10-20 minutes). Among the different hospital types, there was no significant difference in encounter time. There was no difference in the length of the encounter whether a high-quality GoC discussion took place or not (15 v 14 minutes; P = .9). If there was imaging evidence of cancer progression, the median encounter time was 18 minutes compared with 13 minutes for no progression (P = .03). In a multivariate model, oncologist productivity, patient age, and Medicare coverage affected duration of the encounter. Oncologists can complete high-quality GoC discussions in 15 minutes. These data refute the common misperception that discussing such matters with patients with advanced cancer requires significant time.

Prospective Feasibility Study for Using Cell-Free Circulating Tumor DNA–Guided Therapy in Refractory Metastatic Solid Cancers: An Interim Analysis

PurposeRetrospective studies have demonstrated that cell-free circulating tumor DNA (ctDNA) hotspot testing predicts matched therapy response to first- and second-line therapies in patients with advanced non–small-cell lung cancer (NSCLC). However, no prospective outcomes studies have evaluated ctDNA-guided matched therapy decision making on the basis of comprehensive plasma genomic testing including all four major classes of alterations. Here, we report the clinical utility of this approach in advanced solid tumor cancers.Patients and MethodsWe conducted a multiple parallel cohort, open-label, clinical trial using ctDNA-guided matched therapy when tissue was insufficient or unobtainable for next-generation sequencing. Plasma-based digital sequencing identified point mutations in 70 genes and indels, fusions, and copy number amplifications in selected genes. Patients with prespecified targetable alterations in metastatic NSCLC, gastric cancer (GC), and other cancers were matched to several independent targeted agent trials at a tertiary academic center.ResultsSomatic alterations were detected in 59 patients with GC (78%), and 25 patients (33%) had targetable alterations (ERBB2, n = 11; MET, n = 5; FGFR2, n = 3; PIK3CA, n = 6). In NSCLC, 62 patients (85%) had somatic alterations, and 34 (47%) had targetable alterations (EGFR, n = 29; ALK, n = 2; RET, n = 1; ERBB2, n = 2). After confirmation of ctDNA findings on tissue (to meet trial eligibility criteria), 10 patients with GC and 17 patients with NSCLC received molecularly matched therapy. Response rate and disease control rate were 67% and 100%, respectively, in GC and 87% and 100%, respectively, in NSCLC. Response was independent of targeted alteration variant allele fraction in NSCLC (P = .63).ConclusionTo our knowledge, this is the first prospective feasibility study of comprehensive ctDNA-guided treatment in advanced GC and lung cancers. Response rates in this interim analysis are similar to those in tissue-based targeted therapy studies.

Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers

BackgroundRidaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.MethodsEligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.ResultsThirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.ConclusionsTreatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.Trial registrationClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

The emotional toll of caregiving for older patients with advanced cancer: Baseline data from a multicenter geriatric assessment (GA) intervention study in the University of Rochester NCI Community Oncology Research Program (UR NCORP).

10042 Background: Depression is common in caregivers (cgs) of patients (pts) with cancer. However, little is known about the association of health status of older pts with cancer with cg emotional health. Methods: Baseline data from a GA intervention study conducted at 68 oncology practices in the UR NCORP were analyzed. Pts aged ≥ 70 with an advanced solid tumor cancer or lymphoma with ≥ 1 GA impairment were enrolled; pts could enroll with 1 cg. Relationships between pt GA impairments (using 12 validated measures) and cg (spouses or live-in partners) emotional health including anxiety ( ≥ 5 on Generalized Anxiety Disorder-7 (GAD-7)), depression ( ≥ 2 on Patient Health Questionnaire-2), and distress ( ≥ 4 on distress thermometer) were evaluated in separate multivariate logistic models adjusted for pt (cancer type, treatment status) and cg (age, sex, race, education, income, comorbidity) characteristics. Results: Among 213 pts (mean age 76, 70-89), &gt;50% had ≥ 5 impaired GA measures. Of the 213 cg (mean age 73, 52-91), 23% screened positive for anxiety, 16% for depression, and 40% for distress. In bivariate analyses, number of GA impairments, ≥ 1 fall, pt anxiety ( ≥ 5 on GAD-7) and depression ( ≥ 5 on Geriatric Depression Scale (GDS)) were associated with all 3 cg outcomes; pt activities of daily living (ADL) deficits were associated with cg depression and distress. In multivariate analysis, number of GA impairments was associated with cg distress. In separate models, pt ADL deficit and depression were associated with cg distress, and pt ADL deficit was associated with cg depression. GA variables were not associated with cg anxiety in multivariate analysis. Conclusions: A high proportion of cg of older pts with cancer report distress. GA can help identify cg at risk for poor emotional health. Interventions for cgs should address the health status of older pts with cancer. [Table: see text]

Phase I Trial of Triapine-Cisplatin-Paclitaxel Chemotherapy for Advanced Stage or Metastatic Solid Tumor Cancers.

Ribonucleotide reductase (RNR) is an enzyme involved in the de novo synthesis of deoxyribonucleotides, which are critical for DNA replication and DNA repair. Triapine is a small-molecule RNR inhibitor. A phase I trial studied the safety of triapine in combination with cisplatin–paclitaxel in patients with advanced stage or metastatic solid tumor cancers in an effort to capitalize on disrupted DNA damage repair. A total of 13 patients with various previously treated cancers were given a 96-h continuous intravenous (i.v.) infusion of triapine (40–120 mg/m2) on day 1, and then 3-h i.v. paclitaxel (80 mg/m2) followed by 1-h i.v. cisplatin (50–75 mg/m2) on day 3. This combination regimen was repeated every 21 days. The maximum tolerated dose (MTD) for each agent was identified to be triapine (80 mg/m2), cisplatin (50 mg/m2), and paclitaxel (80 mg/m2). Common grade 3 or 4 toxicities included reversible anemia, leukopenia, thrombocytopenia, or electrolyte abnormalities. The combination regimen of triapine–cisplatin–paclitaxel resulted in no objective responses; however, five (83%) of six patients treated at the MTD had stable disease between 1 and 8 months duration. This phase I study showed that the combination regimen of triapine–cisplatin–paclitaxel was safe and provides a rational basis for a follow-up phase II trial to evaluate efficacy and progression-free survival in women with metastatic or recurrent uterine cervix cancer.

Abstract CT142: A phase I open-label, dose escalation study of a novel peptide (SOR-C13) antagonistic to the TRPV6 ion channel in patients with advanced solid tumor cancers

Abstract Background: SOR-C13 is a first-in-man selective peptide inhibitor of Transient Receptor Potential Vanilloid 6 (TRPV6) calcium oncochannel. TRPV6 is highly expressed in carcinomas including prostate, breast, lung and ovary and expression is correlated with poor outcomes. TRPV6-mediated Ca2+ entry is responsible for maintaining a high proliferation rate, increasing cell survival and apoptosis resistance. Since SOR-C13 blocks TRPV6-mediated Ca2+ influx it was evaluated as a single agent in patients with late-stage carcinoma. Methods: This was a phase I, multi-center, open-label, dose escalation study to assess safety and tolerability of SOR-C13 in subjects with advanced carcinomas commonly known to express the TRPV6 channel (NCT01578564). Subjects received two 21-day cycles of treatment consisting of SOR-C13 for 3 d on/4 d off, 3 d on/11 d off (21 d/cycle). Tested doses were 1.375, 2.75, 4.13 and 6.2 mg/kg given as i.v. infusion initially over 20 m moving to 90 m. In the event of clinically meaningful response (tumor response or stable disease), additional cycles were offered to subjects. Subjects were assessed for safety, tolerability and preliminary efficacy. Results: Twenty-three subjects with advanced refractory solid tumors were in the study. No study drug-related serious adverse events occurred during the study. The most frequently reported treatment-emergent adverse events (TEAEs) were fatigue (30%), hypoalbuminemia (30%), anemia (30%), urinary tract infection (30%), blood calcium decreased (22%), decreased appetite (22%), nausea (22%), constipation (17%), aspartate aminotransferase increased (17%), cough (17%), blood alkaline phosphatase increased (13%), diarrhea (13%), hypercalcemia (13%), hyperkalemia (13%), hypocalcemia (13%). Anemia (Grade 1 to 3) was the only TEAE reflecting clinically significant hematological abnormalities. In all but one case, these events were assessed as unrelated or unlikely related to the study drug. The only safety concern identified definitely related to SOR-C13 infusion was reductions of serum calcium that were short-lived (resolved during the post-infusion observation time (4 h or within &amp;lt;24 h) and asymptomatic at all doses. A range of safe dosing was established between 4.13 and 6.2 mg/kg. Anti-tumor activity was observed across a wide variety of tumor types. Twelve of 22 evaluable subjects (54.5%) had stable disease after 2 cycles. The duration of response ranged from 4 to 7.5 cycles with one subject still in stable disease after 16 cycles (11 months). Two patients with advanced pancreatic cancer showed tumor reduction of 7% (4.13 mg/kg) and 27% (6.2 mg/kg) after two cycles with attendant decreases in CA 19-9. Conclusions: SOR-C13 was safe and well tolerated in subjects with advanced solid tumors of epithelial origin and demonstrates potential activity in patients with advanced solid tumor cancer. Citation Format: Siqing Fu, Hal H. Hirte, Stephen Welch, Toney T. Ilenchuk, Dominique Dugourd, Tyler Lutes, Christopher Rice, Jack M. Stewart. A phase I open-label, dose escalation study of a novel peptide (SOR-C13) antagonistic to the TRPV6 ion channel in patients with advanced solid tumor cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT142.

Abstract B86: Impact of multi targeted epigenetic therapy (MTET): a series of 100 consecutive advanced solid tumor cancers

Abstract Background: Tumor heterogeneity is a key underlying factor that leads to resistance to chemo-and matched therapies. Circulating cell-free tumor DNA (ctDNA) may capture more tumor heterogeneity than a tissue biopsy-derived DNA analysis. In addition, markers of vasculogenesis have been shown to be sensitive markers of tumor growth vs. response to treatment. Here we study the impact of a novel multitargeted epigenetic therapy (MTET) on ctDNA, markers of vasculogenesis and radiographic response. Methods: One hundred consecutive patients with advanced solid tumor cancers were treated with multi targeted epigenetic therapy (MTET). More than 60% were stage IV, with 52% male and 48% women, 24 to 81 years of age. Pre-treatment and post-treatment imaging, circulatory tumour cells (CTC), (Biofocus Lab), ctDNA (Guardant Health, Inc.) and plasma VEGF (LabCorp) were obtained. PET scan metabolic activities were determined by a radiologist in a tertiary hospital based metabolic imaging canter. The average patient had undergone two or more lines of therapy previously. Patients underwent 10 or more cycles of a novel multitargeted epigenetic therapy (MTET), consisting the administration of polyphenols intravenously, either independently or in addition to conventional chemotherapies, consisting of standard and palliative chemotherapies. Results: Overall positive imaging response rate(in favor for metabolic response) was observed in 62%. The magnitude of response was independent of type of tumor. Among the patients who had circulating tumor cells (CTC) and/or ctDNA analyzed(number 20 and number 4 respectedly), a positive response (80% for CTC) was seen with improved CTCs and/or the ctDNA alterations for the gene variant at highest mutant allele. Reduction and normalization of plasma VEGF were seen in 92% of patients. Tolerability was good and none of the patients discontinued therapy due to toxicity. Conclusions: There were significant radiographic responses in advanced solid tumor cancer patients receiving MTET therapy. These changes were paralleled by the changes in serological assessment of vasculogenic factors and/or CTC/ctDNA. The high response rate is unusual for patients who have undergone multiple lines of therapy and a prospective randomized therapy of MTET is being planned. Citation Format: M. A. Nezami, Steven Hager, Richard Lanman. Impact of multi targeted epigenetic therapy (MTET): a series of 100 consecutive advanced solid tumor cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B86.