Metastatic Solid Malignancies Research Articles

An open-label study to assess the safety and efficacy of naporafenib (ERAS-254) administered with trametinib in previously treated patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations (SEACRAFT-1).

TPS3178 Background: The rat sarcoma viral oncogene (RAS)/mitogen-activated protein kinase (MAPK) pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Inappropriate activation of this pathway drives tumorigenesis in a subset of solid tumors. There are 3 isoforms of RAS (KRAS, NRAS, and HRAS) with the most commonly mutated codons being 12, 13, and 61. While these codon mutations map to the active site of RAS, they appear to have differential impacts on pathway activation. Mutations at codon 61 (RAS Q61X) are generally thought to be the most MAPK pathway-activating relative to mutations at codons 12 and 13 and are therefore thought to be the most oncogenic. Naporafenib is a pan-RAF inhibitor that is being evaluated in combination with trametinib, which inhibits MEK, a downstream node of the RAS/MAPK pathway. Clinical proof of concept (PoC) in patients with NRASm melanoma (of which 80 to 90% have Q61X mutations) and preliminary PoC for patients with RAS Q61X NSCLC have been established for the combination. Preclinical data across tumor types suggest that RAS Q61X is a potential predictive biomarker for the combination of naporafenib with trametinib, a hypothesis being tested in this trial. Methods: SEACRAFT-1 (NCT05907304) is a Phase 1b, open-label study evaluating the clinical activity and safety of the combination of naporafenib and trametinib in pts with locally advanced, unresectable, or metastatic solid tumor malignancies that are not responsive to standard therapies or for which there are no standard therapies. Eligible pts must be ≥18 years (or ≥12 and <18 years in an adolescent substudy) with documented RAS Q61X mutation by an analytically validated assay. Pts must also have ≥1 measurable lesion per RECIST (Response Evaluation Criteria in Solid Tumors, v1.1) and Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 (or Karnofsky/Lansky Performance Status ≥70 for adolescent pts). Exclusion criteria include prior therapy with an ERK, MEK, RAF, or RAS inhibitor, QTcF >450 ms at baseline, and left ventricular ejection fraction (LVEF) <50% at baseline. A total of up to 115 pts will be enrolled to receive naporafenib 200 mg BID and trametinib 1 mg QD continuous in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is ORR; secondary endpoints include assessment of PFS, DOR, safety, and tolerability. Clinical trial information: NCT05907304 .

A phase I pilot study of personalized neoantigen peptide-based vaccine in combination with pembrolizumab in advanced solid tumors (PNeoVCA).

TPS2700 Background: Though immunotherapy with anti-PD-1 immune checkpoint inhibitors (ICIs) has led to improvements in clinical outcomes in patients with cancer, when used as monotherapy in the advanced setting, only 18-25% of patients respond to ICI. Notably, ICI frequently lacks anti-tumor activity in immune-cold cancers where T cell priming is missing. Recent breakthroughs in identifying personal neoantigens via a comprehensive analysis of cancer sequencing data have brought increased attention to neoantigen cancer vaccines. Personalized cancer vaccines targeting neoantigens have shown early promise. While neoantigens have recently been investigated in some cancer types, the current neoantigen prediction algorithms have often focused on the MHC class-I subtype, single nucleotide mutations (SNM), small insertions and deletions (INDEL). We recently developed an informatics workflow, REAL-neo, for the identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic SNM, INDEL, aberrant RNA splicing, and gene fusions, generating much more potent neoantigen candidates. Furthermore, we demonstrated robust T-cell response and prolonged survival by combining ICI and cancer vaccines in preclinical models. This single-arm phase I clinical trial is in progress to assess the safety, feasibility, and immunogenicity of personalized neoantigen vaccines in combination with pembrolizumab in patients with advanced solid cancers. Methods: The vaccine consists of up to 20 peptides (15-30 mer) comprising patient-specific neoantigens identified from tumor DNA and mRNA sequencing data using REAL-neo and delivered with GM-CSF as an adjuvant. The first cohort of three patients will be treated at dose level 1 consisting of 4 or 5 peptides at 300 mcg/peptide and GM-CSF 125 mcg per injection site in each of four limbs. After Cohort 1 is deemed safe, the study will expand to cohort 2, when patients will be enrolled at the same dose level for vaccine plus Pembrolizumab 200 mg i.v. Neoantigen vaccine will be given via subcutaneous injection on days 1, 4, 8, 15, and 21 (cohorts 1 and 2) and weeks 5 and 8 (booster dose for cohort 2 only). Cohort 1 has been completed without dose-limiting toxicity (DLT). Enrollment in Cohort 2 began in January 2024. AEs are assessed according to CTCAE v5. and safety findings are reviewed by data safety medical board (DSMB). Key eligibility criteria include 1) histologically confirmed locally advanced or metastatic solid malignancies and 2) cancer progression after at least one line of the standard-of-care (SOC) systemic treatment. For cohort 2, patients must be eligible to receive pembrolizumab per SOC or the treating physician’s judgment. Clinical trial information: NCT05269381 .

Relationship between cognitive and emotional domains of prognostic awareness with quality of life and psychological distress in patients with advanced cancer.

11106 Background: Prognostic awareness, a measure of patients’ cognitive and emotional perception of their illness and prognosis, allows individuals to align their medical decision-making with their goals and values. Prior studies have shown mixed findings regarding the relationship between prognostic awareness with better quality of life (QOL) and less psychological distress in patients with advanced cancer. However, studies have not investigated whether it is the cognitive or the emotional aspects of patients’ awareness of their prognosis that are associated with QOL and psychological distress in patients with advanced cancer. Methods: We conducted a cross-sectional study of patients with metastatic solid malignancies not being treated for curative intent at a single academic center from 11/2019-6/2022. We used the Prognostic Awareness Questionnaire (PAIS) to measure the cognitive (i.e., the capacity to understand one’s prognosis characterized by the accurate perception that a cancer is curable or not) and emotional coping with prognosis (i.e., the capacity to emotionally process prognostic uncertainty and terminal prognosis). We used the Functional Assessment of Cancer Therapy-General (FACT-G), Hospital Anxiety and Depression scale (HADS), and the Peace, Equanimity and Acceptance in the Cancer Experience (PEACE) scale to measure, QOL, psychological distress, and acceptance of illness, respectively. We used multivariate regression models controlling for age, gender, and cancer type to assess the relationship between the cognitive and emotional prognostic awareness domains and patient-reported outcomes. Results: Overall, 632 participants (age 65 years (SD=11.3), 51% female, 76% married or living with a partner) were enrolled in the study. In multivariate models, higher cognitive understanding of prognosis was not associated with QOL (b=-2.134; p=0.069), psychological distress (i.e., anxiety: b=0.331; p=0.232 and depression; b=0.233; p=0.368), or peaceful acceptance of terminal illness (b=-0.045; p=0.838). However, emotional coping of prognosis was associated with better QOL (b=1.981; p<0.001), less anxiety (b=-0.516; p<0.001) and depression (b=-0.370; p<0.001) symptoms, and more peaceful acceptance of terminal illness (b=0.438; p<0.001). Conclusions: Patients’ emotional coping with their prognosis, rather than their cognitive understanding of their terminal prognosis, was associated with their QOL, psychological distress, and acceptance of their illness. These findings underscore the importance of examining prognostic awareness and its association with patient-reported outcomes by domains. We also highlight the need to develop supportive care interventions to promote effective coping strategies for patients after prognostic disclosure.

Abstract CT077: An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress)

Abstract Background Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (Bordry 2021; Chakrabarti 2022; Merle 2022). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (Baudat 2023; Baudat 2024). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. Citation Format: Funda Meric-Bernstam, Cesar A. Perez, Nehal Lakhani, Meredith Pelster, Justin Call, Suzanne McGoldrick, Tianhua Wang, Brigitte Demers, Amita Patnaik. An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT077.

Patients with advanced cancer and their spouses parenting minor children: The role of the relationship context in parenting concerns.

Patients with advanced cancer who parent minor children report parenting concerns and increased psychological distress. This cross-sectional study seeks to understand parenting-related issues in patients and spousal caregivers from a relationship perspective. Patients with a metastatic solid malignancy and their spouses independently completed cross-sectional assessments of psychological distress (Hospital Anxiety and Depression Scale), parenting concerns (Parenting Concern Questionnaire) and efficacy (Cancer-Related Parenting Self-Efficacy Scale), and relationship measures (DAS-7, Couples' Illness Communication Scale, and Family Relationship Index). Of the 51 patients (57% female, 49% NHW, mean age 42years) and spouses (43% female, 43% NHW, mean age of 42years), approximately 50% couples endorsed psychological distress and were at risk for family dysfunction. Spouses reported significantly higher levels of parenting-related concerns (t=-2.0, p<0.05) and anxiety (t=-2.8, p<0.001) than patients. Parenting concerns were significantly associated with illness communication (r=-0.56, p<0.001) and family function (r=-0.38, p<0.001). Although the expected interactions between parenting concerns and relationship variables (i.e., illness communication, dyadic adjustment, and family function) were significant for depressive symptoms at p<0.05, the associations were not in the expected direction. Relationship function buffered against depressive symptoms for those with low rather than high parenting concerns. Not only patients but also spouses report cancer-related parenting concerns. The associations between parenting concerns and distress were stronger for spouses than patients. Dual caregiving appears to be a particularly stressful role. Because relationship function was associated with parenting concerns, we suggest that parent support programs that are couple-based and include both parenting-specific and relationship-specific content may be most effective in reducing distress for this vulnerable population.

A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies

ABSTRACT Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

Abstract B160: A phase 1 open-label, dose-escalation study of central nervous system–penetrant cyclin-dependent kinase (CDK)4/6 inhibitor PRT3645 in patients with select advanced or metastatic solid tumors

Abstract Introduction: CDK4/6 mediate cell cycle progression and are important for cancer initiation, growth, and survival. CDK4/6 inhibitors are approved for patients with advanced HR+/HER2– breast cancer but are ineffective against primary or metastatic brain tumors. PRT3645 is an investigational, highly selective, and potent CDK4/6 inhibitor, designed to achieve high tissue and brain penetration. This phase 1 dose-escalation study (NCT05538572) aims to evaluate safety, preliminary efficacy, and pharmacokinetic/pharmacodynamic profile of PRT3645. Methods: Patient eligibility criteria include: age ≥18 years; Eastern Cooperative Oncology Group/Karnofsky performance status ≤1/≥80; adequate organ function; histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy: breast cancer (HR+/HER2– or HR+/HER2+), glioblastoma (isocitrate dehydrogenase [IDH] wild type), CDKN2A/B homozygous deleted IDH–mutant astrocytoma, non-small cell lung cancer (KRAS mutant), or select solid tumors with CDK pathway alterations; and progression on, ineligibility for, or refusal of standard therapy. Patients with treated and untreated brain metastases (lesion &amp;lt;1.5 cm) could enroll if they had no neurological symptoms and did not require immediate local treatment. PRT3645 was taken orally once daily for 28 days (1 cycle) with dose escalation employing a Bayesian optimal interval design to evaluate the safety, tolerability, incidence of dose-limiting toxicities, and pharmacokinetic/pharmacodynamic profile. Results: At data cutoff (May 18, 2023), 8 patients received 20 and 40 mg once daily (first 2 dose levels of dose escalation). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. Median age was 62 (range, 53-76) years; 50% of patients were male; in these early dose cohorts 75% of patients discontinued therapy (all due to progressive disease; median duration of therapy: 8 [range, 4-16] weeks); 5 patients had glioblastoma, 2 had breast cancer, and 1 had sarcoma. All-cause, any-grade adverse events (AEs) reported in ≥1 patients were anemia and dizziness. One grade 1 AE (fatigue) was considered related to PRT3645. No patients had grade ≥3 AEs, serious AEs, diarrhea, QTcF prolongation, or hepatotoxicity. No patients had dose reductions, interruptions, withdrawals, or deaths due to AEs. Between pre-dose and 2 weeks post first dose, a reduction in phosphorylated Rb (&amp;gt;70% in 3/4 patients) and Ki67 (&amp;gt;60% in 2/4 patients) expression was seen at 40 mg; both markers showed a correlation between histochemical score and drug exposure. Conclusions: Treatment with the next-generation CDK4/6 inhibitor PRT3645 was associated with a substantial decrease in phosphorylated Rb and Ki67 expression, indicating a high level of target engagement at a low dose. PRT3645 exhibited tolerable dose escalation in the initial 2 cohorts of patients with no significant gastrointestinal or hematologic events reported to date, leveraging its enhanced selectivity profile. Dose escalation is ongoing. Citation Format: Amita Patnaik, Mohamad A. Salkeni, Manish R. Patel, Atrayee Basu-Mallick, Dale Shepard, Christine Lihou, William Sun, Jennifer Xavier, Sri Sahasranaman, Neelesh Sharma, Erika Hamilton. A phase 1 open-label, dose-escalation study of central nervous system–penetrant cyclin-dependent kinase (CDK)4/6 inhibitor PRT3645 in patients with select advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B160.

Supportive Care for Dual Caregivers who Care for Their Partner With Cancer and Their Young Children.

Advanced cancer patients and their spouses who parent minor children report parenting concerns and increased psychological distress. This single-arm trial examined the feasibility and initial evidence for efficacy of a novel parent support program. Patients with a metastatic solid malignancy and their spouses completed self-reported assessments of psychological distress (HADS), parenting concerns (PCQ) and efficacy (CaPSE) at baseline. Both patients and spouses jointly attended the first two sessions addressing illness communication and family routines. Spouses individually attended two additional sessions focusing on caregiver support and death preparedness. All four sessions were delivered via videoconference by a licensed psychological counselor. Dyads completed program evaluations and were reassessed six and 12 weeks postintervention. With a consent rate of 61%, 10 patients (50% female; 90% non-Hispanic White; mean age=42 years) and their spouses (50% female; 70% non-Hispanic White; mean age=42 years) completed the assessments. All patients and 90% of spouses attended all intervention sessions and evaluated the program favorably. Paired t-tests revealed significant improvements in patients' parenting concerns at the six weeks (P=0.003) and parenting efficacy at the six weeks (P=0.03) and 12 weeks (P=0.03) follow-ups. For spouses, we found significant improvements in parenting efficacy (P < 0.001) and depressive symptoms (P=0.04) at six weeks and parenting concerns at both six weeks (P=0.006) and 12 weeks (P=0.001) follow-ups. The initial testing of our parenting intervention yielded promising results regarding feasibility and an initial signal of intervention efficacy. Thus, a randomized controlled trial for further testing is warranted.

Immune Checkpoint Inhibitors in Metastatic Bladder and Other Solid Malignancies: How Long is Enough?

The introduction of T-cell targeted immunomodulators blocking the PD-1 and PD-L1 axis is unquestionably one of the most notable advancements in the treatment of advanced or metastatic solid malignancies, including bladder cancer. Immune checkpoint antibodies are now widely utilized as monotherapies or in combination with other systemic therapies in the first or subsequent lines of treatment in approximately 50 cancer types. Deep and durable responses and long tails of survival curves are hallmarks of patients treated with immune checkpoint inhibitors. However, treatment can have negative impacts, including serious treatment-related side effects as well as a high financial burden to individual patients and the healthcare system. There is increasing data that the benefit of immune checkpoint treatment may persist after treatment is discontinued for reasons other than progressive disease, particularly in patients who have achieved a durable complete response. However, the optimal treatment duration and activity after treatment reinitiation remains undefined and will likely be influenced by disease biology (histology and genomics), treatment (monotherapy or combination therapy), and disease context (depth and duration of response). Well-designed prospective clinical trials and the development and validation of biomarkers that predict outcomes after treatment cessation are needed to move the field forward.

Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden

BackgroundPembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe...

Cancer-directed surgery in patients with metastatic cancer: A systematic review and meta-analysis of randomized evidence.

To assess the impact of primary-site surgery plus systemic therapy compared to systemic therapy alone on overall survival in common metastatic cancer types. Data sources included Embase, PubMed, and Web of Science (January 1, 1995-March 22, 2023). Randomized controlled trials were included that enrolled patients diagnosed with the 10 most common de novo metastatic cancer types in the Surveillance, Epidemiology, and End Results database and randomized patients to resection of the primary site and systemic therapy versus systemic treatment alone. Random-effects models were used to pool associations by cancer type. Eight studies with 1774 patients evaluating the efficacy of surgery in breast, renal, stomach, and colorectal cancer were included. There was no statistically significant reduction in risk of all-cause mortality associated with surgical intervention for metastatic breast (HR = 0.94, 95% CI 0.63-1.40) or renal cancer (HR = 0.79, 95% CI 0.53-1.20), although results were heterogeneous (I2 = 73.7% and 80.6%, respectively). One study evaluating gastrectomy in metastatic stomach cancer found no benefit (HR = 1.09, 95% CI 0.78-1.52), while a small trial suggested that surgery and hyperthermic intraperitoneal chemotherapy might be beneficial for colorectal cancer with peritoneal metastasis (HR = 0.55, 95% CI 0.32-0.95). Few randomized trials have evaluated cancer-directed surgery among patients with metastatic solid malignancies.

A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours.

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or &lt;1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8 mg cohort and 14 in the 16 mg cohort (50% M and 50% F, mean age of 51.4 y). All patients have been discontinued: 16 due to disease progression; 1 due to AEs, 2 developed contra-indication to denosumab &amp; pembrolizumab, 1 withdrawal of consent. PK parameters of ETC-159 in the first cycle were consistent with prior single agent data. TEAEs were reported in all subjects in the study with most events being grade 1/2, with dysgeusia (65%), β-CTX increase (30%), fatigue (25%), constipation (20%), and nausea (20%) being the most common. DLTs were G3 colitis and G3 immune-related enteritis (16 mg, 2 patients), and pneumonitis and erythema with fever (8 mg, 1 patient). Other drug related SAEs were G2 thyroiditis, hematuria, and thrombocytopenia. No fractures or other drug related skeletal SAEs. Of the 15 evaluable patients, 6 (40%) demonstrated clinical benefit (1 PR, 5 SDs) in combination with pembrolizumab (2 ovarian, 1 lung, 1 pancreatic, 1 urachal, 1 MSS CRC patient with RSPO fusion), at the first assessment, in a predominantly MSS population (65% MSS, 25% unknown, 10% MSI). Pharmacodynamics, (hair follicle Axin2 reduction), was detected at both dose levels and was ≥80% from baseline on D15. Conclusions: ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844 .

Individualized treatment estimates to inform on personalized cancer care decisions for treatment selection and treatment management.

e13571 Background: Clinical trials report average effects of treatments at a population level. However, clinicians must balance treatment benefits against risks to personalize therapy. Here, we present a statistical framework which incorporates real-world data to estimate efficacy and symptom burden for an individual patient. We then assess the potential impact of continuing immunotherapy beyond progression in patients with metastatic solid malignancies on immune-related adverse events, progression, and survival. Methods: We corrected for sampling biases with inverse propensity score weighting (IPTW), and used the IPTW-transformed data to train predictive models of patient outcomes under each option. The models utilize a peer-based similarity based on 222 routinely-collected patient characteristics, such as cancer and treatment specific factors, laboratory tests, demographics, vitals, stage, comorbidities and symptoms, which are extracted from the electronic health record or natural language processing of clinician narratives, and Social Determinants of Health from Census data. We developed our methods on “Dataset A”: 5,919 breast and genitourinary (GU) cancer patients at a tertiary cancer center. We computed individualized treatment effect (ITE) estimates on “Dataset B”: 5,486 breast, GU, and thoracic cancer patients who received immunotherapy. Results: Our approach eliminated biases in Dataset A: the IPTW-transformation reduced the between-group standardized mean difference across identified confounders from an average of 0.225 to an average of 0.022. The similarity model exhibited strong discrimination (ROC-AUC &gt; 0.75), and identified associations between patient characteristics and outcomes that matched clinicians’ expectations. Validations are ongoing to assess the ITE estimates on a held-out subset of Dataset B. These include subgroup analyses for metastatic triple-negative breast cancer and non-small cell lung cancer. Conclusions: We introduce a method to estimate the efficacy and toxicity of interventions, actions, or treatment decisions, which replicates the statistical robustness of a clinical trial while obtaining individualized insights. This framework provides causal estimates of symptom burden and risks of progression and survival to inform clinical decisions, including continuation of immunotherapy beyond progression. After IPTW, confounders in Dataset A were balanced between the treatment groups, with weighted standardized mean differences &lt;0.1. [Table: see text]

Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors or lymphoma.

TPS2663 Background: Cancer immunotherapies targeting PD-1 or PD-L1 have been proven effective in causing durable antitumor immune responses with less toxicity in many types of tumors. However, the response rate of anti-PD-1/PD-L1 treatments is far from satisfactory and most patients show primary or acquired resistance to the treatments. Tim-3, one of the next generation of immune checkpoint targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&amp;L Biopharma Co., Ltd. for the patients who are resistant to or refractory from PD-1/PD-L1 treatments. It blocked the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways simultaneously, showed better T/DC cell activity and in vivo anti-tumor efficacy compared to Tim-3 and PD-1 antibody combination in preclinical studies. Methods: This is a FIH, multicenter, non-randomized, open label, phase 1 study of LB1410 in Participants With Advanced Solid Tumor or Lymphoma（Keyplus-001）. The planned sample size is approximately 100 patients in two parts: part 1 dose escalation will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, EC etc. Enrollment criteria include adults with life expectancy of &gt; 3 months, ECOG performance status 0-1，histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies or lymphoma for which standard treatment fails, or no standard treatment is available, or standard treatment is not applicable at this stage. Exclusion criteria include pregnancy, lactation, or breastfeeding, ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB1410. Besides, the pharmacodynamics (PD) biomarkers related to LB1410 treatment, clinical activity will be explored. This clinical trial is in progress; cohorts 1 to 5 in dose escalation part have been completed. Clinical trial information: NCT05357651 .

Use of clinical pathways to identify patients with cancer who may benefit from serious illness conversations.

12027 Background: Treatment pathways are widely used to provide decision support and encourage guideline adherence. Pathways data may be used to identify patients for targeted interventions to improve cancer care. For example, pathways data may enable the identification of patients with poor prognoses for whom serious illness conversations (SICs) should be prioritized to ensure goal-concordant care. Methods: For patients starting new therapies at Dana-Farber, oncologists select a node in clinical pathways to indicate the line of treatment. Subspecialty oncologists identified “poor prognosis” nodes in pathways, defined as therapies for patients with expected survivals of &lt; 12 months and for whom an SIC would be appropriate (e.g., 3rd-line treatment for metastatic colon cancer). Pathway node navigations for patients with metastatic solid tumor malignancies with poor prognosis nodes (n = 21 disease pathways) were combined with electronic medical record data to identify SIC documentation in an advance care planning module within 6 months of pathway navigation and patients’ dates of death if present. For each node, we calculated the median overall survival (OS), the proportion of patients with an SIC, and the proportion of patients who died before reaching the next node. Results: There were 10,132 navigations for 7,031 patients (median age 67 years, 52% female, 86% White) between 8/16/2019 and 1/4/2023. With each treatment line, patients’ median OS decreased and SIC rates increased (examples for 3 diseases in Table). Among patients who reached poor prognosis nodes, the median OS was 4.9 months, mean SIC rate was 43.8%, and 60.2% of patients died without reaching a subsequent node. For nodes immediately prior to poor prognosis nodes, the median OS was 7.1 months, the mean SIC rate was 25.2%, and 31.3% of patients died without reaching the next node. 46.3% of patients died without reaching a poor prognosis node. The proportion of patients having an SIC at death was 40.9% among all decedents, 50.8% for decedents reaching a poor prognosis node, and 29.3% for decedents who do not reach a poor prognosis node. Conclusions: Clinical pathways can be used as a scalable method to identify patients with metastatic solid tumors and poor prognoses. In our study, only half of patients who reached a poor prognosis node had an SIC before death and nearly half of decedents never reached a poor prognosis node, underscoring the importance of identifying this population to improve end-of-life care. A clinical trial using pathways to identify and deliver interventions to increase SICs is ongoing. [Table: see text]

Personalized Palliative and Survivorship Care for Patients With Metastatic Cancer Treated With Radiation Therapy.

While the benefits of early palliative care for patients with metastatic cancer are well established, cancer survivorship remains inadequately integrated into the care of patients with distant metastases. Moreover, the optimal model of care delivery is poorly defined. A prognostic model previously developed and validated at Good Samaritan University Hospital identified four groups of patients with metastatic solid tumor malignancy having very favorable, favorable, standard or unfavorable prognoses with median survival of 31, 14, 4 and 1 month, respectively. This framework holds promise for the personalized delivery of supportive, palliative and survivorship care services in the context of radiation therapy. We review the published literature providing the rationale for a novel multidisciplinary care model where the radiation oncology Clinical Nurse Specialist identifies and coordinates interventions to address unmet physical and emotional issues faced by survivors with metastatic cancer with the goal of improving quality of life and overall survival.

Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations.

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 ubiquitin ligase proteins. In preclinical studies, ASP3082 selectively degraded the KRAS G12D-mutated protein and showed growth inhibitory activity in KRAS G12D-mutated cancer cells but not in KRAS -wildtype cancer cells. Notable antitumor effects of ASP3082 have been demonstrated when intravenously administered weekly in mice xenografted with KRAS G12D-mutated cancer cells. Methods: This first-in-human, open-label, multicenter, phase 1 study evaluates the safety and tolerability of ASP3082 in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer or other solid tumors. Participants with unresectable, locally advanced, or metastatic solid tumor malignancy with documented KRAS G12D mutation are eligible for enrollment. Part 1 consists of dose-escalation cohorts of 3−12 patients receiving intravenous administration of ASP3082 in a 21-day cycle. Part 2 consists of random assignment of ≤20 patients into 2 cohorts with different ASP3082 dose levels to determine the recommended phase 2 dose. Additional tumor-specific expansion cohorts may enroll ≤20 participants per tumor type. Primary endpoints will evaluate safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and Eastern Cooperative Oncology Group performance status. Secondary endpoints will evaluate objective response rate, duration of response, disease control rate per Response Evaluation Criteria in Solid Tumors version 1.1, pharmacokinetics of single and repeated doses of ASP3082, and changes in KRAS G12D in tumor samples. Exploratory objectives will evaluate potential biomarkers that may correlate with treatment outcomes. Tumor assessment follow-up will continue for ≤45 weeks or until progressive disease. Enrollment in Cohort 1 is complete, and enrollment to Cohort 2 began in September 2022. Clinical trial information: NCT05382559 .

Prophylactic Radiation Therapy vs. Standard-of-Care for Patients with High-Risk, Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Trial

<h3>Purpose/Objective(s)</h3> External beam radiotherapy (RT) is standard-of-care (SOC) for pain relief of symptomatic bone metastases. We aimed to test whether radiation for asymptomatic bone metastases prevents skeletal-related events (SRE). <h3>Materials/Methods</h3> We conducted a multicenter, randomized phase 2 trial (NCT03523351) of prophylactic RT to high-risk, asymptomatic bone metastases vs SOC. Patients were eligible if they were at least 18 years old with a metastatic solid tumor malignancy and more than 5 metastatic lesions, including at least one asymptomatic high-risk bone lesion, defined as: bulky disease (≥2cm in longest diameter), junctional spine or posterior spinal element disease, disease involving hip or sacroiliac joint, or disease in long bone involving 1/3-2/3 cortical thickness. Patients were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to RT to all enrolled high-risk bone metastases or SOC alone. The primary outcome of SRE (defined as fracture, cord compression, or intervention with surgery or radiation) was analyzed from randomization to death or 12 months. A sample size of 66 was deemed necessary to achieve 80% power to detect a difference of 30% (experimental arm) versus 60% (SOC arm) using a two-sample, one-sided proportion test with alpha<0.05. We used the log-rank test for time-to-event analyses and Wilcoxon rank sum test to compare hospitalizations, brief pain inventory and quality of life (using EQ-5D-5L) between arms. <h3>Results</h3> Between May 8, 2018 and August 9, 2021, 78 patients with 122 bone metastases were enrolled and randomized to prophylactic RT (n=39) or SOC (n=39). The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). Seventy-one patients (91%) were evaluable for the primary endpoint. At one year, SRE occurred in 1 of 62 lesions (1.6%) in the RT arm and 14 of 49 lesions (29%) in the SOC arm (p<0.001). There was a significant difference in time-to-SRE by type of high-risk feature (p=0.016), with most events occurring in junctional spine and bulky disease. There were significantly fewer patients hospitalized for SRE in the RT arm compared to the SOC arm (4 vs 0, p=0.045). At a median follow-up of 2.4 years, overall survival was significantly longer in the RT arm (HR 0.50, 95% CI 0.28, 0.91; p=0.02). Median OS among 11 patients with an SRE was 1.1 years compared to 1.5 years among 67 patients without an SRE. Pain was reduced at 3 months in the RT arm (p<0.05) compared to the SOC arm. EQ-5D-5L was similar between the groups at all time points. <h3>Conclusion</h3> Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced skeletal-related events, meeting the primary endpoint of the study. Importantly, we observed an improvement in overall survival, with potential mechanisms of palliation or debulking warranting further investigation in a phase 3 trial.

Differences in the utilization of palliative care support services among patients with metastatic solid tumor cancer in a community oncology setting: A retrospective review.

82 Background: Palliative care has been underutilized in the setting of advanced cancer despite its established benefit in improving the quality of life in cancer patients. Few studies have evaluated socioeconomic disparities in receiving palliative care in the outpatient oncology setting. We aimed to evaluate for disparities in utilization of palliative care among patients with metastatic solid tumor malignancies at Tennessee Oncology, a large outpatient community oncology practice with an established palliative care program. Methods: We completed a retrospective review of medical records of 1513 patients that were seen in Tennessee Oncology clinics from 12/2020 to 12/2021. We compared the baseline characteristics of patients with metastatic solid tumor malignancies who did and did not receive palliative care. Chi-square and two-sample t-tests were used for data analysis with the 5% significance level using R statistical software. Results: Male patients utilized palliative care less often than female patients (17% versus 24% for females, p =.0002; 95% CI,.05-1.0). Of payer types, Medicare had the least palliative care utilization (14%) compared to commercial (25%) and other payers (23%). Utilization also varied by cancer type, with melanoma (9%), lung cancer (15%) and renal cancer (21%) being least likely to receive palliative care (p &lt;.00005; 95% CI,.19-1.0). We did examine racial differences in palliative care utilization, but those did not reach statistical significance. Conclusions: There are multiple disparities in the utilization of on-site palliative care support services among patients with metastatic solid tumor cancer in this outpatient community oncology setting. Further research is needed to gain insight into why this is, including an in-depth analysis of both patient and provider utilization/referral practices.[Table: see text]

Humoral and cellular responses to mRNA-based COVID-19 booster vaccinations in patients with solid neoplasms under active treatment

BackgroundPatients with cancer are at high risk for severe coronavirus disease 2019 (COVID-19) infection. Knowledge regarding the efficacy of the messenger RNA (mRNA) vaccines in actively treated cancer patients is limited as they had been excluded from the pivotal studies of these vaccines. We evaluated humoral and cellular immune responses in cancer patients after double vaccination and a booster dose and identified disease- and treatment-related factors associated with a reduced immune response. We also documented the number and outcome of breakthrough infections.Patients and methodsPatients with metastatic solid malignancies undergoing active treatment were included if they had received two doses of the severe acute respiratory syndrome coronavirus 2 mRNA vaccines BNT162b2 or mRNA-1273 and a booster dose. Other causes of immunosuppression and previous COVID-19 infections (positive anti-nucleocapsid titers) were exclusion criteria. Anti-spike antibodies, neutralizing antibodies (nAbs) and T-cell responses were assessed about 6 months after the two-dose vaccination and 4 weeks after the booster.ResultsFifty-one patients had pre-booster and 46 post-booster measurements. Anti-spike titers after two vaccine doses were highly variable and significantly lower in older patients, during treatment with chemotherapy compared to targeted and endocrine treatments and in patients with low CD4+ or CD19+ cell counts. The booster dose led to a significant increase in anti-spike antibodies and nAbs, achieving almost uniformly high titers, irrespective of baseline and treatment factors. The cellular immune response was also significantly increased by the booster, however generally more stable and not influenced by baseline factors and treatment type. Seventeen patients (33%) experienced breakthrough infections, but none required hospital care or died from COVID-19.ConclusionsAn mRNA vaccine booster dose is able to increase humoral and cellular immune responses and to overcome the immunosuppressive influence of baseline and treatment factors in cancer patients. Breakthrough infections were uniformly mild in this vaccinated high-risk population.