Gordon, Michael S.

Abstract Purpose: Prostate-specific membrane antigen (PSMA)–directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule. Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging. Results: 99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc–EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer–like morphology. Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

TPS11580 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. KIT and platelet-derived growth factor receptor α ( PDGFRA ) mutations remain the key oncogenic drivers in the majority of patients with advanced GIST, with acquired secondary drug-resistant mutations contributing to the heterogeneity and complexity of the disease. The diversity of these resistance mutations allows escape from standard-of-care tyrosine kinase inhibitor (TKI) therapy, creating an unmet need for novel therapies that inhibit all clinically relevant GIST-driving mutations. DCC-3009 is an investigational, highly potent, and selective switch-control KIT and PDGFRA inhibitor designed to act against known clinically relevant primary and secondary GIST-driving mutations while limiting off-target effects. Preclinical data showed that DCC-3009 has strong antitumor effects in xenograft models driven by resistant KIT mutations, optimized solubility and oral bioavailability, and low risk of cytochrome P450 inhibition. Here, we describe an ongoing phase 1/2 study evaluating DCC-3009 as a monotherapy in patients with advanced GIST. Methods: This study is a multicohort, open-label, phase 1/2 trial evaluating the safety, tolerability, and efficacy of DCC-3009 in patients with advanced GIST (NCT06630234). This trial uses a modular approach, with each module defined according to the therapy (DCC-3009 alone or in combination with other anticancer agents) and divided into 2 parts (dose escalation and dose expansion). For inclusion in the DCC-3009 monotherapy dose escalation, adult patients (≥18 years) must have histologically or cytologically confirmed advanced GIST with documented KIT or PDGFRA mutation and progression on or intolerance to at least 1 approved TKI regimen in the advanced setting (imatinib if KIT -mutant). Patients must have at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) and an Eastern Cooperative Oncology Group Performance Status of 0 or 1 at screening. Exclusion criteria include receiving systemic anticancer therapy (encompassing investigational agents) within 14 days or less than 5 half-lives, radiotherapy within 14 days prior to first dose of study drug, prior or concurrent malignancy requiring treatment or expected to need treatment for active cancer, known allergy or hypersensitivity to the study drug components or any of its excipients, and impaired oral absorption or malabsorption syndrome. Enrolled patients across monotherapy dose escalation will receive DCC-3009 orally in 28-day cycles. The primary outcome measures for monotherapy dose escalation include safety assessment. Secondary outcome measures include objective response rate, duration of response, and progression-free survival by mRECIST v1.1, as well as overall survival and pharmacokinetics. Clinical trial information: NCT06630234 .

Background Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC. Methods PY159 and PY314 were individually evaluated in patients with PROC. Patients were treated with monotherapy (PY159 3 mg/kg or PY314 10 mg/kg), based on the recommended dose for expansion derived from the phase 1a studies. At the time of first progression, patients could continue study drug and crossover to combination therapy with pembrolizumab (200 mg) every 3 weeks at the discretion of the investigator. Disease assessment by Response Evaluation Criteria in Solid Tumor version 1.1 was performed every 6 weeks. Results 17 patients were enrolled in the PY159 study (median age 67, range 22–77; median prior therapies 6, range 2–18) and 16 patients in PY314 (median age 65.5, range 49–81; median prior therapies 4, range 2–10). 7 patients in PY159 and 8 patients in PY314 crossed over to combination therapy. Safety events included the following: treatment-related adverse events occurred in 15 patients (88.2%) in PY159 and 9 patients (56.3%) in PY314. Infusion-related reactions occurred in 6 patients (35.3%) in PY159 and 3 patients (18.8%) in PY314. Immune-related adverse events occurred in 13 patients (76.5%) in PY159 (arthralgias) and 1 patient (6.3%) in PY314 (diarrhea). Serious adverse events occurred in 6 patients (36.3%) in PY159 (1 related) and 12 patients (75%) in PY314 (all unrelated). The best radiographic response in PY159 was stable disease in 8/16 patients (50%; median 16 weeks, range 9–33), and in PY314, it was stable disease in 8/16 patients (50%; median 12 weeks, range 6–36). Median PFS was 2.76 months and 2.69 months in PY159 and PY314, respectively. There were no responses in the crossover arm. Conclusions Both PY159 and PY314 were well tolerated, with an acceptable safety profile, as both single agents and in combination with pembrolizumab. Both agents warrant further investigation in heavily pretreated PROC.

Abstract Background A previous phase IB/II study of nab‐paclitaxel + cisplatin + gemcitabine (NABPLAGEM) in 25 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) demonstrated favorable results. This phase II study was conducted to further evaluate the safety, efficacy, and impact on quality of life (QOL) of NABPLAGEM in a multi‐center setting. Methods Participants were ≥18 years; had measurable PDAC; Karnofsky performance status of ≥70%; life expectancy ≥12 weeks; <grade 2 pre‐existing peripheral neuropathy, and adequate hematologic, hepatic, and renal function. Study treatment included nab‐paclitaxel (125 mg/m 2 ), cisplatin (25 mg/m 2 ), and gemcitabine (1000 mg/m 2 ), on Days 1 and 8 of a 21‐day cycle. The primary endpoint was 12‐month overall survival (OS). Results A total of 42 patients were enrolled with a median age of 66.8 years, a majority were male (66.7%) and white (76.2%). Treatment‐related adverse events ≥grade 3 were: thrombocytopenia (64.3%), anemia (47.6%), and neutropenia (26.1%). OS at 12 months was 38.1%, with 12% of patients alive as of last contact (20–40+ months). In 37 evaluable participants responses included: partial response (40.5%), stable disease (43.2%), and progressive disease (16.2%), with overall response rate of 40.5% and DCR of 88.6%. Statistically significant improvement in QOL was reported during the first three cycles. Conclusion The primary objective of achieving a 12‐month survival comparable to the previous phase Ib/II NABPLAGEM PCRT 12‐001 was not achieved in this trial. NABPLAGEM has efficacy in advanced PDAC, demonstrating early disease control noted by improvement in patient symptoms, decrease in tumor volume and tumor markers within the first 9 weeks. The activity and tolerability make this a suitable regimen for further testing in the neoadjuvant setting.

e23508 Background: Activating mutations in KIT are found in most pts with GIST. First-line imatinib provides initial clinical benefit in advanced disease, but prognosis is poor for pts whose tumors progress, despite 3 other approved tyrosine kinase inhibitors (TKIs). Resistance is typically driven by secondary KIT mutations in the ATP-binding pocket (exons 13/14) or activation loop (exons 17/18). No approved drug has potent activity against both classes of resistance mutations, and many pts have polyclonal resistance after multiple lines of therapy. THE-630 is an investigational pan-variant KIT inhibitor. Based on preclinical models, an average plasma concentration (Cav) of 100 nM is predicted to have potent activity against all major classes of KIT-activating and resistance mutations. Here, we report initial data from a first-in-human study in pts with advanced GIST (NCT05160168). Methods: This ph 1/2 study is assessing the safety (including dose-limiting toxicities [DLTs] and recommended ph 2 dose [RP2D]), pharmacokinetics (PK), and antitumor activity of THE-630. Pts enrolled in the ph 1 portion were ≥18 y, had unresectable or metastatic GIST previously treated with imatinib and ≥1 additional TKI, and had ECOG performance status ≤2. Pts received THE-630 (QD; 28-day cycles) in a 3+3 dose-escalation design. PK was assessed on days 1 and 15 in cycle 1, antitumor activity was assessed by modified RECIST 1.1, and circulating tumor DNA (ctDNA) was assessed using Guardant360. Results: As of 13 Jan 2023, 19 pts had been treated in the ph 1 portion at THE-630 daily doses of 3 mg (n = 3), 4 mg (n = 7), 6 mg (n = 3), 9 mg (n = 3), and 12 mg (n = 3). Median age was 57 y (range 39–72); 13 pts had ≥4 prior TKIs. Median treatment duration was 55 days (range 1–252). PK analysis shows approximately dose-proportional increase in systemic exposure across doses tested. Mean steady-state Cav at 12 mg was 47 nM. There was 1 DLT at 4 mg (grade 5 myocardial infarction in a pt with 8 prior TKIs and hyperlipidemia where relationship to THE-630 could not be incontrovertibly ruled out). No other DLTs or related serious adverse events have occurred; 13 pts had treatment-related AEs (TRAEs), 91% of which were grade 1–2. The most common TRAEs were fatigue (n = 4), dry mouth (n = 3), anemia, ALT increase, AST increase, diarrhea, dyspepsia, dyspnea, and hypertension (n = 2 each). Reductions in select KIT-mutant allele fractions in ctDNA were observed, consistent with THE-630 levels achieved thus far. Stable disease (SD) was the best response in 1/7 pts at 4 mg, 1/3 pts at 6 mg, and 3/3 pts at 9 mg. Post data cut, SD was seen in 3/3 pts at 12 mg. Dose escalation continues to determine the RP2D. Conclusions: THE-630 had an acceptable initial safety profile, and escalation continues, as target exposure for pan-variant KIT activity is not yet reached. Reduction in KIT-mutant allele fractions in ctDNA and initial evidence of disease control were observed. Clinical trial information: NCT05160168 .

Abstract Background: Uveal melanoma (UM) is a rare tumor of the eye which is biologically distinct from cutaneous melanoma (CM) and carries a poor prognosis once metastatic. We aimed to examine a multi-omics profile of UM as compared to CM. Methods: A total of 277 UM and 1,297 CM metastatic or primary samples were analyzed using next-generation sequencing (NextSeq, 592 genes and WES, NovaSeq, &gt;700 genes) and whole transcriptome sequencing (WTS; NovaSeq) (Caris Life Sciences). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cutoff &gt;10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. T- cell inflamed score was calculated using gene expression data. Pathway gene enrichment analysis using WTS data was performed using GSEA. Biostatistical significance was determined using chi-square/Fisher-Exact or Wilcoxon rank sum test and adjusted for multiple comparisons. Results: For all cases (primary and metastatic), UM compared to CM had a higher rate of GNAQ/11 (93.8% vs. 2.1% p≤0.001), SF3B1 (20.4% vs 3% p≤0.001), and BAP1 (52.9% vs. 1.5% p≤0.001) mutations. UM also had higher levels of MYC (7% vs 0.9% p≤0.001), NCOA2 (3.1% vs 0.1% p≤0.001), and RUNX1T1 genomic amplifications (2.3% vs 0.2% p≤0.001). Assessing only samples of liver metastases, UM was shown to have higher abundance of M2 macrophages (P≤0.0001) and less abundance of M1 macrophages(P≤0.0001), monocytes(P≤0.0001), CD4 T-cells(P≤0.0001), and regulatory T-cells (p = 0.0003) as compared to CM. GSEA comparison between liver metastases of UM and CM samples showed G2M checkpoint (NES score, 1.60 p≤0.0001) and E2F targets (NES score, 1.58 p=0.002) to be higher in metastatic CM. When comparing T-cell inflamed, intermediate, and non-inflamed tumors from any site, CM or UM, the average Z scores for both G2M and E2F were highest for inflamed and lowest for non-inflamed, P≤0.0001. A similar trend of higher Z score was seen for TMB high vs TMB low tumors, p≤0.0001. Conclusions: UM and CM are characterized by significantly different genomic and transcriptomic alterations, and cellular composition of TME. Further understanding of these characteristics may lead to better treatment strategies for metastatic UM. Citation Format: Justin C. Moser, Yusra F. Shao, Joanne Xiu, Yasmine Baca, Takami Sato, Lauren A. Dalvin, Sourat Darabi, Michael Korn, Burton Eisenberg, Geoff Gibney, Evidio Domingo-Musibay, Gino In, Dave Hoon, Michael S. Gordon. Multi-omics and immune cell profiling of metastatic uveal melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 50.

Abstract Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.