Spira, A

3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .

3109 Background: Poly(ADP-ribose) glycohydrolase (PARG) is an enzyme that catalyzes the removal of poly-ADP-ribose (PAR) chains from proteins during DNA damage repair. PARG inhibition leads to selective cell death in tumors with underlying replication fork defects, including BRCAm tumors, through a mechanism distinct from PARP inhibition. ETX-19477 is an oral, potent, and selective PARG inhibitor that shows robust preclinical activity in mouse models of ovarian, breast, and gastric cancers. Methods: ERADIC8 is an open-label, multicenter, Phase 1/2 study, consisting of two parts, dose escalation and dose expansion. A Bayesian Optimal Interval Design was used to enroll patients (pts) into dose escalation cohorts, with enrichment for pts with BRCAm high grade serous ovarian (HGSOC) and breast cancers. The primary objective is to assess safety/tolerability of ETX-19477 and define the maximum tolerated dose (MTD) and recommended Phase 2 dose(s). Secondary and exploratory objectives include pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity per RECIST v1.1. ETX-19477 is given orally once or twice daily in 21-day cycles. Results: As of Jan 6 2026, 45 pts were enrolled into the study across 11 dose levels (range: 80-750 mg QD, 190-350 mg BID). Tumor types included ovarian (n=24, BRCAm: 18), breast (n=8, BRCAm: 7), endometrial (n=6, BRCAm: 0), colorectal (CRC, n=3, BRCAm: 1), and other (n=4, BRCAm: 0) cancers. Treatment-related AEs (TRAEs; any grade) occurring in >20% of pts were nausea (53%), vomiting (38%), and fatigue (24%). The only Gr3 TRAE occurring in >5% of pts was neutropenia (16%). There was one Gr4 TRAE of neutropenia in 1 pt (2%) and no Gr5 TRAEs. ETX-19477 exposure is dose proportional, and the BID regimen achieves >85% PARG inhibition throughout the dosing interval in a blood-based PAR accumulation pharmacodynamic assay. As of the data cutoff, dose escalation is ongoing at 350 mg BID (MTD has not been defined) and dose expansion is ongoing at 200-300 mg BID. Among BRCAm, HGSOC pts enrolled at BID dose levels, there were 7 evaluable pts with a median of 4 prior lines of therapy (range 2–11): 2 pts achieved a partial response (PR, 29%) and 3 pts achieved stable disease (SD, 43%). Both pts with PRs were platinum-resistant and received prior PARP inhibitor treatment. 1 pt with BRCAm CRC remains on active therapy (250 mg BID) with SD for 7 months. Conclusions: ETX-19477 was well tolerated and showed anti-tumor activity in heavily pretreated pts with BRCAm, platinum-resistant HGSOC during dose escalation. These findings provide the first clinical proof-of-concept of PARG inhibition in HGSOC. ETX-19477 is being further evaluated in the dose expansion phase of the study. Clinical trial information: NCT06395519 .

3014 Background: Macrocyclic next-generation tyrosine kinase inhibitors (TKIs) have transformed outcomes in ALK- and ROS1-positive NSCLC; such creatively designed medicines are similarly needed to improve outcomes in EGFR-mutant NSCLC. Using a novel, mutant-selective macrocyclic structure, BH-30643 was designed for super-potency against driver EGFRm, largely sparing wildtype (WT) EGFR, and with unique invulnerability to resistance from C797S with or without T790M. Here we report emerging first-in-human dose-escalation data from the SOLARA trial (NCT06706076). Methods: Phase 1 dose escalation used a BOIN design with backfill at potentially efficacious doses. Expansion cohorts targeted populations of interest. Patients (pts) had advanced NSCLC with EGFR and/or HER2 mutations detected on local testing (tissue or plasma). Measurable disease was required; asymptomatic untreated brain metastases (BM) were permitted. Objectives included safety, PK, and RECIST response rate (ORR). Plasma NGS was performed at baseline and on treatment. Results: As of 01/05/2026, 72 pts enrolled into dose escalation and backfill across 7 dose levels at a total daily dose of 20mg -160mg, median age 62, 44% Asian, 65% with history of BM, median of 3 prior lines of treatment (range 1-12). EGFR mutations included classical (38 pts), exon20ins (14 pts) and other/atypical (18 pts) or HER2 mutations (2 pts). Plasma exposures at doses of 40mg BID and above achieved > 10x coverage over target EC90 and exceeded exposure levels of most contemporary EGFR TKIs. Common TRAE ( > 10%) were WT EGFR-associated, including diarrhea (38%), rash (28%), fatigue (15%), stomatitis (13%), and were predominantly grade 1. Bilirubin elevation was seen in 26 pts (36%) related to off-target UGT1A1 inhibition (Gilbert’s-like). Grade 3 TRAE were seen in 15 pts (18%), most commonly bilirubin (8/15); DLTs included bilirubin increase and mucositis, occurring at doses ≥ 60mg BID. No pneumonitis was observed. Responses were observed across diverse EGFRm subsets, including in CNS. Including expansion pts, 28 pts enrolled with C797S on their most recent informative molecular testing (6 with concurrent MET+ or KRAS+), with 23 still on therapy. Of 17 with on-treatment scans, partial responses (confirmed or ongoing) were seen in 10 (59%); ORR was comparable with (50%) or without (66%) T790M. Of 9 pts with baseline C797S detected in ctDNA (3 with T790M), 7 had > 99% reduction of C797S VAF on treatment. Conclusions: Leveraging a novel macrocyclic scaffold, BH-30643 is the first TKI monotherapy to demonstrate clinical responses against C797S both with or without T790M. High plasma exposures combined with super-potency, CNS activity, and favorable safety offers potential for deep and durable EGFR inhibition. Enrollment into backfill and expansion cohorts is ongoing to better characterize activity in both TKI-naïve and resistant pts. Clinical trial information: NCT06706076 .