Advanced Solid Malignancies Research Articles

CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS

Abstract Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.

Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy

BackgroundThe major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI.MethodsSerum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45).ResultsIn the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: pPFS = 0.012, pOS = 0.001; Hamburg ICI: pPFS = 0.040, pOS = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules (“multi-CD27” score) enhanced the predictive ability (HRPFS: 17.21 with p < 0.001, HROS: 6.47 with p = 0.011).ConclusionSoluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy.

Differences in immune-related toxicity between PD-1 and PD-L1 inhibitors: a retrospective cohort study in patients with advanced cancer

Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16–0.88) and OR: 0.63 (95% CI 0.35–0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.

Tolerability Assessment of Tyrosine Kinase Inhibitors in Patients With Solid Tumor Malignancies and Hypoalbuminemia.

Hypoalbuminemia is common in patients with advanced solid tumor malignancies. However, despite the increased use of highly protein-bound tyrosine kinase inhibitors (TKIs) in cancer treatments, the tolerability of these agents in patients with hypoalbuminemia is not fully known. Our aim is to assess whether patients on oral TKIs with hypoalbuminemia are at higher risk for experiencing medication-related adverse events, therefore requiring careful considerations. This is a single-center, retrospective study including patients ≥18 years of age with a solid tumor malignancy who had taken at least one dose of oral TKIs with a protein binding of ≥90% between June 1, 2016, and June 1, 2021. The primary outcome was to compare time to TKI discontinuation due to adverse events between patients with and without hypoalbuminemia. Key secondary outcomes include TKI discontinuation and dose reduction rates, time to TKI dose reduction, and severity of adverse events. Out of 282 included patients, 134 (48%) patients had hypoalbuminemia and 148 (52%) had normal albumin levels. Compared with patients without hypoalbuminemia, patients with hypoalbuminemia had shorter median time on treatment at 2.8 months (95% CI = 2.3-4.5 months) versus 4.3 months (95% CI = 2.8-6.4 months; P = 0.003). In patients who had TKI discontinuation, dose reduction was associated with longer time on treatment in patients in the normal albumin group compared with patients in the hypoalbuminemia group or patients without dose reduction (P < 0.0001). Patients in the hypoalbuminemia group experienced significantly more grade 3/4 adverse events compared with those in the normal albumin group (73% vs 27%, P < 0.0001). Hypoalbuminemia is a risk factor for both shorter time on treatment and more severe adverse events in patients with solid tumor malignancies taking highly protein-bound oral TKIs. This study highlights the need for closer monitoring of this patient population by health care providers.

Phase I/II study of BMS-986156 with ipilimumab or nivolumab with or without stereotactic ablative radiotherapy in patients with advanced solid malignancies

BackgroundBMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and...

2 Oral: Preliminary results from SEACRAFT-1: An open-label study of naporafenib with trametinib in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations

2 Oral: Preliminary results from SEACRAFT-1: An open-label study of naporafenib with trametinib in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations

Genomic Landscape of Advanced Solid Tumors in Middle East and North Africa Using Circulating Tumor DNA in Routine Clinical Practice

Introduction: Next-generation sequencing (NGS) of tumor DNA can detect actionable drivers and help guide therapy for patients with advanced-stage cancers. While tissue-based genotyping is considered a standard of care, blood-based genotyping is emerging as a valid alternative. Tumor genomic profiles may vary by region, and data from the Middle East and North Africa (MENA) are not widely available. This study elucidates the genomic landscape of advanced solid cancers in patients from the MENA region by retrospectively analyzing results from NGS circulating tumor DNA (ctDNA) testing. Methods: In routine clinical practice, 926 plasma samples from 767 patients with advanced cancers from the MENA region were profiled using a comprehensive NGS assay (Guardant360®). We conducted a pan-cancer analysis and sub-analyses focusing on lung, breast, and colorectal cancers. Results: In the pan-cancer group, TP53 (58.5%), EGFR (20.4%), and KRAS (18.9%) were the most frequently mutated genes. EGFR (10.2%), FGFR1 (4.9%), and PIK3CA (4.9%) showed the most amplifications, while fusions were observed in 2.7% of patients, including ALK, FGFR2, and RET. For lung adenocarcinoma, EGFR (30.5%), KRAS (19.3%), and ERBB2 (4.6%) were the most frequently identified alterations among the genes recommended for evaluation by the National Comprehensive Cancer Network (NCCN). In patients with breast cancer, PIK3CA (35.3%), ESR1 (21.7%), and BRCA1/2 (13.3%) had the most prevalent alterations among NCCN-recommended genes. In colorectal cancer, KRAS (39.0%), NRAS (8.0%), and BRAF (V600E, 4.0%) were the most observed mutations among genes recommended by the NCCN. Comparing this cohort to publicly available Western and Eastern datasets also indicated similarities (including PIK3CA in breast cancer) and variances (including EGFR in lung adenocarcinoma) in key genes of interest in the analyzed cancer types. Conclusion: Overall, our findings provide insight into the genomic landscape of individuals with advanced solid organ malignancies from the MENA region and support the role of ctDNA in guiding therapeutic decisions.

Recent advances in anticancer mechanisms of molecular glue degraders: focus on RBM39-dgrading synthetic sulfonamide such as indisulam, E7820, tasisulam, and chloroquinoxaline sulfonamide.

Synthetic sulfonamide anticancer drugs, including E7820, indisulam, tasisulam, and chloroquinoxaline sulfonamide, exhibit diverse mechanisms of action and therapeutic potential, functioning as molecular glue degraders. E7820 targets RBM39, affecting RNA splicing and angiogenesis by suppressing integrin α2. Phase I studies have demonstrated some stability in advanced solid malignancies; however, further efficacy studies are required. Indisulam causes G1 cell cycle arrest and delays the G1/S transition by modulating splicing through RBM39 degradation via DCAF15. Despite its limited initial efficacy, it shows promise in combination therapies, particularly for hematopoietic malignancies and gliomas. Tasisulam inhibits VEGF signaling, suppresses angiogenesis, and induces apoptosis. Although early trials indicated broad activity, safety concerns have halted its development. Chloroquinoxaline sulfonamide, initially investigated for cell cycle arrest and topoisomerase II inhibition, was discontinued owing to its limited efficacy and toxicity, despite promising initial results. Recent studies revealed the structural interaction of E7820 with DCAF15 and RBM39, although phase II trials on myeloid malignancies have shown limited efficacy. Indisulam is effective against glioblastoma and neuroblastoma, with potential synergy in combination therapies and metabolic disruption. Recent research on tasisulam reveals its potential in cancer therapy by targeting RBM39 degradation through DCAF15-mediated pathways. Understanding these mechanisms could lead to new treatments that affect alternative splicing and improve cancer therapies Overall, although these drugs exhibit promising mechanisms of action, further research is required to optimize their clinical efficacy and safety.

1069TiP A phase I/IIa dose escalation and expansion study of 23ME-01473, an anti-ULBP6/2/5 antibody, for patients with advanced solid malignancies

1069TiP A phase I/IIa dose escalation and expansion study of 23ME-01473, an anti-ULBP6/2/5 antibody, for patients with advanced solid malignancies

1315P BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in human phase I study in patients with advanced solid malignancies

1315P BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in human phase I study in patients with advanced solid malignancies

989O Novel gene therapy in advanced solid malignancies: A phase I/II clinical trial

989O Novel gene therapy in advanced solid malignancies: A phase I/II clinical trial

680TiP A phase I/IIa first-in-human clinical trial evaluating MDX2001, a multi-specific antibody in patients with advanced solid tumor malignancies

680TiP A phase I/IIa first-in-human clinical trial evaluating MDX2001, a multi-specific antibody in patients with advanced solid tumor malignancies

Patient eligibility for trials with imaging response assessment at the time of molecular tumor board presentation

PurposeTo assess the eligibility of patients with advanced or recurrent solid malignancies presented to a molecular tumor board (MTB) at a large precision oncology center for inclusion in trials with the endpoints objective response rate (ORR) or duration of response (DOR) based on Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).MethodsProspective patients with available imaging at the time of presentation in the MTB were included. Imaging data was reviewed for objectifiable measurable disease (MD) according to RECIST v1.1. Additionally, we evaluated the patients with MD for representativeness of the identified measurable lesion(s) in relation to the overall tumor burden.Results262 patients with different solid malignancies were included. 177 patients (68%) had MD and 85 (32%) had non-measurable disease (NMD) at the time point of MTB presentation in accordance with RECIST v1.1. MD was not representative of the overall tumor burden in eleven patients (6%). The main reasons for NMD were lesions with longest diameter shorter than 10 mm (22%) and non-measurable peritoneal carcinomatosis (18%). Colorectal cancer and malignant melanoma displayed the highest rates of MD (> 75%). In contrast, gastric cancer, head and neck malignancies, and ovarian carcinoma had the lowest rates of MD (< 55%). In case of MD, the measurable lesions were representative of the overall tumor burden in the vast majority of cases (94%).ConclusionApproximately one third of cancer patients with advanced solid malignancies are not eligible for treatment response assessment in trials with endpoints ORR or DOR at the time of MTB presentation. The rate of patients eligible for trials with imaging endpoints differs significantly based on the underlying malignancy and should be taken under consideration during the planning of new precision oncology trials.

BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in-human phase I study in patients with advanced solid malignancies.

e15008 Background: Cadherin-3 (CDH3), a calcium-dependent cell-cell adhesion glycoprotein, is overexpressed on lung, breast, ovarian, colorectal, pancreatic, head and neck and other malignancies, but with negligible expression on nonmalignant tissues, and associated with cancer aggressiveness, invasiveness, and poor prognosis. BC3195 is known as the only antibody drug conjugate (ADC) in clinical stage, targeting CDH3 with payload of monomethyl auristatin E (MMAE). Methods: A phase I, open-label, first in human study to evaluate the safety, tolerability, PK, and preliminary antitumor activity of BC3195 is being performed in subjects with advanced solid malignancies. Disease assessments are performed every 6 weeks using RECIST v1.1. BC3195 is administered as 1 hour (h) IV infusion every 3 weeks. An evaluation of seven dose levels is planned: 0.3, 0.6, 1.2, 2.4, 3.0 and 3.6 mg/kg with a BOIN design guiding dose escalation. Results: Up to January 1st, 2024, nine patients (median age, 59; male, 56%) have been enrolled and treated with BC3195, with 3 patients each in the 0.3, 0.6 and 1.2 mg/kg dose cohorts. No DLT was observed across all the 3 dose cohorts. Treatment emergent adverse events (TEAEs) occurring in ≥3 patients included: aspartate aminotransferase increased (5/9, 55.6%), conjugated bilirubin increased (5/9, 55.6%), triglycerides increased (4/9, 44%), uric acid increased (3/9, 33.3%), heart rate increased (3/9, 33%), and hypoalbuminemia (5/9, 55.6%), cough (4/9, 44.4%), hyponatraemia (4/9, 44.4%), anemia (4/9, 44.4%), asthenia (3/9, 33.3%), rash (3/9, 33.3%), vomiting (3/9, 33.3%) and back pain (3/9, 33.3%). Two subjects experienced ≥ Grade 3 TEAEs unrelated to study drug. Six subjects were evaluable for tumor assessment, and 3 subjects (3/6, 50%) show stable disease (SD) as the best response (2 subjects with target lesion reduction). PK results demonstrated that exposure for the ADC and total antibody (TA) increased with dose, the relationship between AUC0-last and dose was greater than dose-proportional, while Cmax was linear. Free MMAE was highest at the 1.2 mg/kg dose level. Median Tmax values for ADC and TA were 1 h (end of infusion), and median Tmax for free MMAE was 25-169 h. In addition, elimination t1/2 values averaged 27-48 h, 31-68 h and 63-76 h for the ADC, TA, and MMAE, respectively. Conclusions: BC3195 exhibited favorable safety profile and PK characteristics up to 1.2mg/kg. Given BC31095’s safety and PK behavior, as well as preliminary activity at the 0.6 mg/kg dose level, patient enrollment at higher dose levels is ongoing. Clinical trial information: NCT05957471 .

An open-label, single-arm, dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of the ATR inhibitor SC0245 in advanced solid malignancies.

e15126 Background: Ataxia telangiectasia and Rad3-related (ATR) is a critical protein that senses DNA damage and is an integral part of the DNA damage repair pathway.SC0245, a novel and orally administered small molecule ATR inhibitor, is being developed for advanced solid malignancies. In vitro, SC0245 is highly potent against the ATR/ATRIP(h) enzyme with IC50 values ranging from 14 to 43 nM and has potent antiproliferative activity against a wide range of human cancers. This is the first report of an ongoing first-in-human study of SC0245 monotherapy in patients (pts) with advanced solid malignancies. Methods: An accelerated titration design was used to increase doses in the first two dose levels (40mg and 80mg once daily (QD) continuous, 21 days/cycle) followed by a standard “3+3” design in the remainder of the study (continuous schedule: 120mg and 160mg QD, 21 days/cycle; or intermittent schedule: 200mg, 240mg, 300mg QD, 160mg, 200mg and 260mg twice daily (BID), 3 days on and 4 days off, repeat every week x 4 weeks, 28 days/cycle). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Results: As of the data cut-off-date of January 10, 2024, 27 pts (median age, 56; male, 48.1%) were enrolled and treated with SC0245 doses of 1, 1, 4, 4, 4, 2, 4, 3 and 4 pts in 40, 80, 120, 160, 200, 240 and 300mg QD, and 160 and 200mg BID cohort, respectively. No DLTs have been observed to date. Most TEAEs have been Grade 1 or 2 in severity. TEAEs experienced in ≥25% pts include: leukopenia and thrombocytopenia (9/27, 33.3%, each), and anemia, increased conjugated bilirubin and constipation (8/27, 29.6%, each). There were no ≥ Grade 3 TEAEs experienced in more than 2 pts. There were neither dose adjustment nor treatment discontinuation due to TRAEs. Eleven of 21 pts who were evaluable for tumor assessment had stable disease as their best response, with seven pts having reductions in target lesions. The PK characteristics of SC0245 indicated fast oral absorption (median Tmax, 0.5~2.0 h), a long half-life (mean t1/2,16.1~36.4 h) and high intersubject variability. The relationship between SC0245 exposure and dose was nonlinear with minimal accumulation after cumulative treatment in some pts. Additionally, SC0245 exposure and relevant PK parameters have reached the range associated with efficacy in preclinical studies. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered intermittently at doses up to 200mg BID in pts with advanced solid cancers. SC0245 appeared to induce less hematological toxicity than other ATR inhibitors at relevant doses. Based on these preliminary data, SC0245 will be developed in combination with other anti-tumor agents that may have synergies with ATR inhibitors such as topoisomerase 1 inhibitors and DNA damaging agents. Clinical trial information: CTR20210769.

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 &lt;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 &gt;450 ms at baseline, and left ventricular ejection fraction (LVEF) &lt;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 .

The real-world impact of next-generation sequencing in advanced stages of solid tumor malignancies.

e23066 Background: Next-generation sequencing (NGS) is a revolutionary technology that allows for DNA and RNA genomic analysis of malignant tumors via tissue or blood sample to aid in diagnosis and treatment while providing predictive and prognostic data about cancer patients. 75.6% of US oncologists use NGS in advanced cancer patients. As there are now site-agnostic approvals of certain targeted therapies, ASCO published a provisional clinical opinion stating that there is a rationale for genomic testing of all solid tumors. This retrospective study evaluates the impact of NGS testing in advanced solid tumor patients in a community based cancer center in Florida. Methods: Patients were diagnosed with stage 3 or 4 solid malignancy between January 1st, 2019 - December 31st, 2022. 496 patients were reviewed of which 269 patients were included in the study as they underwent NGS testing with either tissue (70.6%), blood (25.3%) or both (4.1%). Results: Median age of the study population was 71% with 87% of patients being insured with Medicare. 52.4% of patients were male. Overall, 67.7% of patients had biomarkers identified, 47.2% had FDA approved targeted therapies, and 77.3% had clinical trials identified. NGS testing impacted first line therapy in only 10% of patients where a matched therapy was initiated as first line treatment. Median time from initial diagnosis to NGS result was 53 days while the median time from diagnosis to initiation of first line of therapy was 47.5 days. In the entire study population, 14.1% never received therapy and 40.9% of patients passed. Of the 110 patients who passed, median overall survival in patients who had a biomarker identified through NGS testing was 6 months compared to 7 months in patients without a biomarker. Rates of biomarker identification and availability of FDA approved therapy were similar between deceased patients (67.3% and 45.5%) and those who were alive at time of analysis (63.1% and 48.4%). Conclusions: NGS testing has become part of routine oncologic care in patients with advanced solid malignancies, however in only 10% of cases did it impact first line therapy. Though currently NGS testing has a limited role in the initial management of advanced solid tumors, it is imperative that this technology continues to be used and developed as it leads to hypothesis generating and clinically relevant questions in discovery of oncogenic drivers, targets for novel therapeutics, and mechanisms of resistance to therapies. [Table: see text]

Phase I study of ProAgio, an αvβ3 integrin cytotoxin, in patients with previously treated advanced pancreatic cancer and other solid tumors.

e16336 Background: The limited clinical benefit of combination chemotherapy in patients with advanced pancreatic cancer is in part attributed to the tumor’s dense, hypoxic stroma that is largely composed of extracellular matrix, cancer-associated fibroblasts (CAFs), and myeloid cells. ProAgio is a pegylated peptide drug that targets and kills cells expressing integrin αvβ3, such as CAFs and endothelial cells. Preclinical activity of ProAgio was demonstrated in murine pancreatic cancer models. Here we describe the dose escalation arm of the first-in-human Phase 1 trial of ProAgio in patients with advanced solid malignancies, including pancreatic cancer. Methods: The dose escalation arm of this single institution study of ProAgio monotherapy enrolled adults with previously treated, histologically confirmed advanced solid tumors for which no curative therapy exists. Participants were required to have evaluable disease. The primary objective was to determine the recommended Phase 2 dose (RP2D) of ProAgio. Secondary objectives assessed the safety (CTCAE v. 4.03), pharmacokinetics, and objective response rate. ProAgio was administered as an intravenous infusion every 1-2 weeks depending on the dose level. Response was determined by serial imaging (CT or MRI) or serum tumor marker assessment. Results: Twenty-eight participants (26 with pancreatic adenocarcinoma and 2 with other gastrointestinal malignancies) were treated as of January 30, 2024, completing enrollment to all 6 planned dose levels. ProAgio has been remarkably well tolerated with only transient grade 1 or 2 treatment-related adverse events observed in most participants. Two participants had grade 2 infusion related reaction but were able to continue treatment with increased dose of diphenhydramine pre-medication. Isolated serious adverse events of hyperglycemia, acute kidney injury, or anemia (all grade 3) considered at least possibly related to ProAgio were observed in 3 separate participants. Five participants with pancreatic cancer receiving weekly dosing of ProAgio had stable disease, 2 of which had interval stabilization in CA 19-9 tumor markers. RP2D determination is pending completion of pharmacokinetic analyses. Conclusions: ProAgio is safe and well-tolerated at all dose levels. A dose expansion phase of 15 participants will begin enrolling once RP2D is determined. Clinical trial information: NCT05085548 .

Effect of DeltaRex-G ± DeltaRex-G Plus (an FDA-approved drug) on advanced chemoresistant pancreatic cancer, sarcoma, and breast cancer.

e15086 Background: Expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor, is being studied for advanced cancers. Methods: 137 archived tumor specimens were analyzed with AI RNA sequencing to identify CCNG1 expression levels, reported as: Low = 17%, Medium-low = 17%-49%, Medium-high = 50%-83%, High = 83%. Nine patients with advanced solid malignancies, whose CCNG1 levels were identified, received DeltaRex-G (2-3 x 10e11 cfu/dose one to three times a week), either without an FDA-approved drug, or with an FDA-approved drug (“DeltaRex-G Plus”). Overall survival, duration of treatment, and responses were evaluated. Results: All analyzed tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited High CCNG1 expression, 48 (35%) showed Medium-High CCNG1 expression, 53 (39%) displayed Medium-Low CCNG1 expression, and six (4%) had Low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. Four patients with advanced pancreatic cancer (n = 1), Stage 1 HR+Her2+ invasive breast cancer (n = 1), Stage 1 triple negative breast cancer (n = 1), and squamous cell carcinoma of skin (n = 1), received DeltaRex-G alone or DeltaRex-G Plus between 2008 and 2021 and are alive 15, 3, 2.5, and 2.5 years since treatment initiation, respectively. Retrospective analysis of their respective tumors showed CCNG1 expression levels of 24%, 23%, 74%, and 40%. Three of the patients are in sustained remission and the patient with squamous cell carcinoma had a partial response. Of the five patients currently being treated with DeltaRex-G Plus: one patient with advanced breast cancer had a partial response (n = 1), one patient with advanced pancreatic cancer (n = 1) and three patients with soft tissue sarcoma (n = 3) had stable disease. Four of five patients had previously progressed with standard doses of chemotherapy. All patients are alive from 11 to 22 weeks since treatment initiation. No serious treatment-related adverse events have been reported. Conclusions: Taken together, the data shows that (1) 100% of 137 tumors tested have enhanced CCNG1 expression, further reinforcing the 2021 FDA-CBER authorization for use of DeltaRex-Plus, and (2) DeltaRex-G Plus is a promising therapy for advanced pancreatic cancer, sarcoma, and breast cancer. Randomized Phase 2/3 studies are warranted to confirm the efficacy and safety of DeltaRex-G Plus. Clinical trial information: NCT04091295 .

A phase 1 study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD), and to determine the recommended phase 2 dose (RP2D) of subcutaneous (SC) cetrelimab (CET) in patients (pts) with advanced solid malignancies.

e14602 Background: In part (P) 1 and P2 of LUC1001 (NCT02908906), the RP2D of intravenous (IV) CET was established as 240 mg IV once every 2 weeks (Q2W) or 480 mg IV Q4W, and the PK/PD characteristics, safety profile, and clinical activity were consistent with known and approved PD-1 inhibitors (Felip et al. Cancer Chemother Pharmacol 2022). CET administered SC was investigated in P3 and P4 of LUC1001. Methods: In P3 and P4 of LUC1001, safety, PK, PD, and clinical activity of low- (30 mg/mL [CET-LC]) and high- (150 mg/mL [CET-HC]) concentration SC CET formulations, respectively, were evaluated. Key entry criteria were advanced or refractory solid tumors, previous receipt of or ineligibility for standard treatment, and being anti-PD-1/PD-L1/2–naïve. In P3, SC CET-LC injection was administered at a dose level of 600 mg with a 6-week dosing interval between doses 1 and 2, then Q3W dosing after dose 2. In P4, SC CET-HC injection was administered as a single loading dose of 900 mg, followed by 600 mg Q3W. Results: Among 30 enrolled pts (P3: n = 11; P4: n = 19), median age was 54.5 years; 17 (57%) were male; most (29 [97%]) were White and heavily pretreated, with a median of 3 (range, 1-8) prior lines of therapy. Most common tumor types were colorectal cancer (6 [20%]), breast cancer (4 [13%]), cholangiocarcinoma and NSCLC (3 [10%] each). Most commonly reported adverse events (AE) were fatigue (11 [37%]), ALT increased (7 [23%]), abdominal pain, constipation and AST increased (6 [20%] each). Overall, 20 (67%) pts had CET-related AEs, 1 (3%) of which led to CET discontinuation. Eight (27%) pts had ≥1 CET-related ≥Grade 3 AE. Immune-related AEs were reported in 9 (30%) pts. No pts experienced systemic-administration–related reactions, and 2 (6%) pts experienced Grade 1 administration-site reactions. No CET-related serious AEs were reported. Durable responses were observed in 2 (7%) patients (cholangiocarcinoma in P3 and thymoma in P4). Stable disease ≥24 weeks was observed in 4 (13% [P3, 0 (0%); P4, 4 (21%)]) pts. According to PK data, the 900-mg SC CET loading dose followed by 600-mg SC CET Q3W would likely result in comparable exposure as observed at steady state with IV RP2Ds. No differences in PK, including absorption, were observed between CET-LC and CET-HC formulations. Maximum PD-1 receptor occupancy was achieved, consistent with historical IV and SC data. Incidence of anti-CET antibodies (P3, 3/11 [27%]; P4, 0/13 [0%]) was low, and no neutralizing antibodies (0/24 [0%]) were detected. Conclusions: SC CET demonstrated a safety profile similar to IV CET. Based on safety, PK, and PD data, the RP2D of SC CET was established as a loading dose of 900 mg followed by 600 mg Q3W. Studies are planned to further evaluate the safety and efficacy of SC CET in combination with other agents. Clinical trial information: NCT02908906 .