Updated clinical results and associated biomarkers from an ongoing phase 1 study of FX-909, a first-in-class peroxisome proliferator-activated receptor gamma (PPARG) inhibitor, in patients (pts) with advanced urothelial carcinoma (adv UC).

Background Peroxisome proliferator-activated receptor gamma (PPARg) is a ligand activated transcription factor and member the nuclear hormone receptor superfamily. Several lines of evidence indicate that PPARg have protective effects in osteoarthritis (OA). Indeed, PPARg has been shown to down-regulate several inflammatory and catabolic responses in articular cartilage and chondrocytes and to be protective in animal models of OA. Aim We have previously shown that IL-1 down-regulated PPARg expression in OA chondrocytes. In the present study we will investigate the mechanisms underlying this effect of IL-1. Methods Chondrocytes were stimulated with IL-1, and the level of PPARg and Egr-1 protein and mRNA were evaluated using Western blotting and real-time reverse-transcription polymerase chain reaction, respectively. The PPARg promoter activity was analyzed in transient transfection experiments. Egr-1 recruitment to the PPARg promoter was evaluated using chromatin immunoprecipitation (ChIP) assays. Small interfering RNA (siRNA) approaches were used to silence Egr-1 expression. Results We demonstrated that the suppressive effect of IL-1 on PPARg expression requires de novo protein synthesis and was concomitant with the induction of the transcription factor Egr-1. ChIP analyses revealed that IL-1 induced Egr-1 recruitment at the PPARg promoter. IL-1 inhibited the activity of PPARg promoter and overexpression of Egr-1 potentiated the inhibitory effect of IL-1, suggesting that Egr-1 may mediate the suppressive effect of IL-1. Finally, Egr-1 silencing with small interfering RNA blocked IL-1-mediated down-regulation of PPARg expression. Conclusion These results indicate that Egr-1 contributes to IL-1mediated down-regulation of PPARg expression in OA chondrocytes and suggest that this pathway could be a potential target for pharmacologic intervention in the treatment of OA and possibly other arthritic diseases.

TPS709 Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .

Endothelin-1(ET-1) is increased in obesity and plays a significant role in the development of multiple obesity related conditions including insulin resistance; however, the mechanisms are poorly understood. Our lab recently reported that targeted deletion of the ET B receptor, specifically in adipocytes, improved insulin sensitivity and mitigated dyslipidemia in obese mice fed a high-fat diet for 10 weeks. These improvements were associated with increased adiponectin levels and enhanced expression of peroxisome proliferator-activated receptor gamma (PPARg), suggesting that ET-1 inhibits PPARg via ET B receptors. Given that PPARg is essential to adipocyte differentiation and adipogenesis, we hypothesized that ET-1 inhibits adipogenesis by blocking differentiation of preadipocytes into mature adipocytes. To test this hypothesis, primary preadipocytes were isolated from visceral adipose of 4-week old floxed control and adipocyte specific ET B receptor knockout (adET B KO) mice. Preadipocytes were cultured and differentiated by exposure to a well-described cocktail of adipogenic hormones. After exposure to differentiation cocktail for two days, cells were allowed to mature to full adipocytes, then treated with vehicle or ET-1 (100nM) for 24 hours. Consistent with published data, treatment of mature adipocytes with ET-1 reduced PPARg mRNA levels (408±83.23 vs. 241.3± 53.53 copies/50 ng RNA) in matured preadipocytes from floxed control mice. Interestingly, baseline mRNA expression of PPARg and adiponectin levels in differentiated preadipocytes from adETBKO mice, were significantly higher 3-fold and 6-fold respectively [ (1584 ± 110.2 vs 408 ± 83.23 copies/50 ng RNA), (7.56 ± 1.021 vs1.35 ± 0.16 copies/50 ng RNA), suggesting greater differentiation efficiency, and treatment with ET-1 had no significant effect on PPARg or adiponectin. Quantification of oil red O staining demonstrated a significant increase in lipid laden adipocytes in adET B KO cells with lipid accumulation present in approximately 2.3-fold more cells compared to controls suggestive of enhanced adipogenic differentiation. Our results suggest that ET-1 inhibits differentiation of visceral preadipocytes into mature lipid storing adipocytes and are consistent with previous findings that ET-1/ETB activation reduces adiponectin by inhibiting PPARg. R01DK124327 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

e16555 Background: Checkpoint inhibitors (CPIs) are approved for treating advanced urothelial carcinoma (UC). However, many patients (pts) present with/develop resistance and new therapies are urgently needed. The release of active transforming growth factor beta-1 (TGF-β1) from the glycoprotein-A repetitions predominant (GARP):TGF-β1 complex on regulatory CD4+ T cells suppresses antitumor response. Inhibiting active TGF-β1 release from the GARP:TGF-β1 complex could address CPI resistance in UC. Livmoniplimab (livmo), an antibody targeting the GARP:TGF-β1 complex, is being investigated as monotherapy and in combination with budigalimab (budi), an anti–PD-1 antibody, in a phase 1 study (NCT03821935). We present expanded results from the livmo + budi dose expansion (EXP) in pts with UC. Methods: This is a global, dose escalation (ESC) and EXP study in pts (≥18 yr) with advanced solid tumors; the UC EXP cohort enrolled pts with UC of the bladder and urinary tract that progressed on platinum-based therapy and a CPI in the metastatic setting. The maximum tolerated dose was not reached in the ESC part, and pts in EXP cohorts received the maximum administered dose of 1500 mg livmo (IV, Q2W) and 500 mg budi (IV, Q4W) until disease progression/intolerable toxicity. The primary efficacy endpoint was ORR per RECIST v1.1. Additional efficacy outcomes included DOR and PFS. Safety and PK were also assessed. Results: As of 30 Mar 2023, 200 pts were enrolled, 57 in ESC and 143 in livmo + budi EXP, including 48 pts in the UC EXP cohort. For the UC cohort, median age was 66 yr (49–85), 77% of pts were male, 40%/60% had ECOG PS 0/1, and median prior lines of therapy was 3 (1–9). Livmo PK was not impacted by budi coadministration and no on-treatment anti-drug -antibodies were detected. TEAEs were observed in 100% of pts; most common were pruritus (44%) and decreased appetite (21%). Grade 3/4 TEAEs occurred in 23 pts (48%), with anemia and malignant neoplasm progression (10% each) being the most common; 11 pts (23%) died but no death was related to livmo or budi. TRAEs were observed in 29 pts (60%)/26 pts (54%) for livmo/budi; pruritus (livmo: 33%; budi: 31%) and rash (17% for both) were most common. Among the 45 response evaluable pts, best response rate was 24% (n=11; 95% CI: 12.9, 39.5); confirmed ORR was 18%. Median restricted mean DOR was 7.9 mo (95% CI: 6.0, not reached); median/75th percentile PFS were 1.8 mo (95% CI: 1.6, 4.2)/8.0 mo (95% CI: 2.7, 14.9). Conclusions: Livmo + budi had manageable safety and promising efficacy in pts with advanced UC that progressed on platinum-based therapy and a CPI. ORR in the UC cohort (pts postprogression with platinum + CPI therapy) are comparable with ORR in CPI-naive pts with pembrolizumab (KEYNOTE-045) and nivolumab (CheckMate 275) monotherapy. A subpopulation of pts in the UC cohort had a durable response to livmo + budi. Clinical trial information: NCT03821935 .

Cardiotrophin (CT-1) is a naturally occurring protein member of the interleukin (IL)-6 cytokine family and signals through the gp130/leukemia inhibitory factor receptor (LIFR) heterodimer. The formation of gp130/LIFR complex triggers the auto/trans-phosphorylation of associated Janus kinases, leading to the activation of Janus kinase/STAT and MAPK (ERK1 and -2) signaling pathways. Since adipocytes express both gp130 and LIFR proteins and are responsive to other IL-6 family cytokines, we examined the effects of CT-1 on 3T3-L1 adipocytes. Our studies have shown that CT-1 administration results in a dose- and time-dependent activation and nuclear translocation of STAT1, -3, -5A, and -5B as well as ERK1 and -2. We also confirmed the ability of CT-1 to induce signaling in fat cells in vivo. Our studies revealed that neither CT-1 nor ciliary neurotrophic factor treatment affected adipocyte differentiation. However, acute CT-1 treatment caused an increase in SOCS-3 mRNA in adipocytes and a transient decrease in peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA that was regulated by the binding of STAT1 to the PPARgamma2 promoter. The effects of CT-1 on SOCS-3 and PPARgamma mRNA were independent of MAPK activation. Chronic administration of CT-1 to 3T3-L1 adipocytes resulted in a decrease of both fatty acid synthase and insulin receptor substrate-1 protein expression yet did not effect the expression of a variety of other adipocyte proteins. Moreover, chronic CT-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin-stimulated glucose uptake. In summary, CT-1 is a potent regulator of signaling in adipocytes in vitro and in vivo, and our current efforts are focused on determining the role of this cardioprotective cytokine on adipocyte physiology.

This study investigated the effect of Dendrobium officinale polysaccharide (DOP) on the adipogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs). DOP was extracted fresh Dendrobium officinale. Rat BMSCs were prepared, and then were treated with 0 (control), 50, 100, 200, 400, 800 μg/mL DOP, respectively. The cell viability was determined by MTT assay. The adipogenic differentiation was quantitatively analyzed by oil red O staining assay. The mRNA expressions of adipogenic differentiation related gene peroxisome proliferator-activated receptor gamma (PPARG), lipoprotein lipase (LPL) and fatty acid binding protein 4 (FABP4) were detected by RT-PCR. Results showed that, DOP with 0-800 μg/mL concentration had no significant toxicity to BMSCs. 200-800 μg/mL DOP could obviously inhibit the adipogenic differentiation of BMSCs. Compared with control group, the expression levels of PPARG, LPL and FABP4 mRNA 200, 400 and 800 μg/mL DOP groups were significantly decreased (P < 0.05 or P < 0.01). DOP can inhibit the adipogenic differentiation of BMSCs, which may be related with its down-regulation of PPARG, LPL and FABP4 expressions in BMSCs.

432 Background: Pembro monotherapy is a standard of care for advanced urothelial carcinoma (UC) and showed antitumor activity and acceptable safety when combined with lenva in the phase 1b/2 KEYNOTE-146 study. We present results of LEAP-011 (NCT03898180), a randomized, double-blind, multicenter, global, phase 3 study of first-line pembro + lenva vs pembro + placebo in pts with locally advanced or metastatic UC who are cisplatin-ineligible with PD-L1–positive tumors or are ineligible to receive platinum-based chemotherapy. Methods: Adults with histologically confirmed, locally advanced/unresectable or metastatic UC who were cisplatin-ineligible with tumors expressing PD-L1 (combined positive score ≥10) or were ineligible to receive platinum-based chemotherapy regardless of PD-L1 status were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 cycles (̃2 y) + either lenva 20 mg orally once daily or placebo. Primary end points were PFS per RECIST v1.1 and OS. The key secondary end point was ORR per RECIST v1.1. An independent data monitoring committee (DMC) regularly reviewed safety data every 3 months; for the 6th review, a nonbinding futility analysis to evaluate ORR (−1%) and PFS (HR ≥1.1) was performed. There was no futility bound for OS. Results: Of 441 randomly assigned pts, 218 were assigned to receive pembro + lenva (median age, 74 y [range, 43-93]; ECOG PS 2, 83.5%) and 223 (median age, 73 y [range, 47-92]; ECOG PS 2, 83.0%) were assigned to receive pembro + placebo. Median duration of treatment was 3.8 mo (range, 0.0-20.7) for pembro + lenva and 3.4 mo (range, 0.0-22.0) for pembro + placebo. Median PFS was 4.2 mo (95% CI, 3.8-5.9) in the pembro + lenva group and 4.0 mo (95% CI, 2.7-5.4) in the pembro + placebo group (HR, 0.91 [95% CI, 0.71-1.16]). Median OS was 11.2 mo (95% CI, 7.4-14.9) with pembro + lenva vs 13.8 mo (95% CI, 9.8-18.8) with pembro + placebo (HR, 1.25 [95% CI, 0.94-1.67]; 6-mo OS rate, 63.6% vs 70.7%). ORR was 31.2% with pembro + lenva vs 26.5% with pembro + placebo. In 436 treated pts, treatment-related AEs (TRAEs) occurred in 186 of 214 pts (86.9%) in the pembro + lenva group and in 149 of 222 pts (67.1%) in the pembro + placebo group. Grade 3-5 TRAEs occurred in 107 pts (50.0%) in the pembro + lenva group and in 62 pts (27.9%) in the pembro + placebo group. Death from a TRAE occurred in 6 pts (2.8%) in the pembro + lenva group and in 1 pt (0.5%) in the pembro + placebo group. Conclusions: The safety profile of pembro + lenva was consistent with that of previous studies; no new safety signals were observed. The benefit/risk ratio for pembro + lenva was not considered positive vs pembro + placebo in platinum-ineligible pts with advanced UC. Antitumor activity of pembro + placebo was similar to what has been reported in previous studies, and pembro monotherapy remains standard of care as first-line therapy in platinum-ineligible pts with advanced UC. Clinical trial information: NCT03898180.

451PD - Updated results of the PARP1/2 inhibitor pamiparib in combination with low-dose (ld) temozolomide (TMZ) in patients (pts) with locally advanced or metastatic solid tumours

Background: Navitoclax (N; ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates docetaxel (D) activity across a variety of solid tumor types. This ongoing phase I study evaluates the maximum tolerated dose (MTD) and safety and pharmacokinetic (PK) profile of N plus D. Methods: Patients (pts) with advanced solid tumors, adequate organ function and ECOG PS ≤1 were eligible. Pts were treated with (a) N 150 mg or 200 mg PO, QD on days (d) 1–3 or d1–5 q21 plus D 75 mg/m2 IV on d1 q21; or (b) N 150 mg PO, QD on d1–3, d8–10, and d15–17 q28 plus D 30 mg/m2 IV given on d1, 8, and 15 q28. To compare the PK of either agent alone, N was given on d3–5 or d3–7 only in cycle 2 of q21. PK samples were collected for N and D in cycles 1 and 2. Treatment-emergent adverse events (TAEs) were graded by NCI CTCAE V3.0. Results: Of 37 pts (M/F, 24/13) enrolled, data on 31 pts are available for safety, 33 pts for tumor response, and 13 pts for PK analysis. Pts (median age, 59 y; range, 30–83 y) were treated at 3 dose levels of N: 150 mg and 200 mg on d1–5 q21; 200 mg on d1–3 q21; and 150 mg on d1–3, d8–10, and d15–17 q28. Dose-limiting toxicities (DLTs) were grade (gr) 3 febrile neutropenia, and gr 4 thrombocytopenia (TCP) at N 200 mg d1–5 plus D 75 mg/m2 q21; gr 3/4 febrile neutropenia, gr 4 neutropenia, and gr 3 fatigue at N 200 mg d1–3 plus D 75 mg/m2 q21; gr 3 febrile neutropenia, gr 4 TCP, and death at N 150 mg d1–5 plus D 75 mg/m2 q21. The MTD of N with D at 75 mg/m2 q21 was 150 mg on d1–5. Other gr 3/4 TAEs (≥20%) were neutropenia (55%), leukopenia (32%), febrile neutropenia (29%), TCP (29%), and fatigue (13%); frequently occurring TAEs (≥20%) were fatigue (55%), TCP (45%), alopecia (42%), nausea (42%), anemia (36%), constipation (32%), decreased appetite (32%), diarrhea (32%), vomiting (32%), and dyspnoea (26%). Best tumor responses were 3 confirmed partial responses (PR), 2 currently unconfirmed PR, 8 stable disease (SD), 13 progressive disease, and 7 pts had incomplete data. Based on limited data, there was no significant PK interaction between N and D (Table). Conclusions: Navitoclax may be administered safely with D in 2 schedules; 150 mg with D 75 mg/m2 q21 and with D 30 mg/m2 q28. Both combinations were tolerable with no significant PK interactions in the D 75 mg/m2 q21 schedule. Antitumor activity was observed. Exploration of N 200 mg with weekly D is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A92.

442 Background: Niraparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) enzymes. Based on the association of mutations in homologous recombination repair (HRR) genes with platinum sensitivity, aim of this phase II trial was to compare maintenance treatment with niraparib plus BSC vs. BSC alone in pts with advanced UC who obtain objective response (OR) or stable disease (SD) with first-line PBCT. Methods: Meet-URO12 is a randomized phase II multicentre trial enrolling pts with advanced transitional cell UC, without evidence of progression after 4-6 cycles of first-line PBCT (cisplatin or carboplatin). Pts were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). Primary endpoint was progression-free survival (PFS). 77 pts were planned and 65 PFS events were needed to detect Hazard Ratio 0.57, with 80% power and one-tailed alpha 0.1. Accrual was prematurely stopped due to availability of avelumab in the same setting, and protocol was amended to perform analysis with ≥ 40 PFS events. Molecular characteristics, including alteration of HRR genes, were assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay. Results: Between Aug 2019 and Mar 2021, 58 pts were randomized in 14 Italian centers (39 assigned to arm A and 19 to arm B); 1 pt assigned to arm A did never start niraparib. Median age was 69y (44-84); ECOG PS0 65.5%/ PS1 34.5%; best response with PBCT OR 55.2%/ SD 44.8%. As of Aug 2021, after a median follow-up of 8.5 mos, 47 PFS events were recorded. Median PFS was 2.1 mos in arm A and 2.4 mos in arm B (HR 0.92; 95%CI 0.49 – 1.75, p=0.81). 6-months progression-free rate was 28.2% and 26.3%, respectively. Time to treatment failure for pts who started niraparib was 2.4 mos. Out of 47 pts with molecular info, 21 (44.7%) had HRR alterations: 6 (12.8%) known pathogenic mutations and 15 (31.9%) variants of unknown significance. In pts with pathogenic mutations, median PFS was 2.0 mos in arm A and 1.9 mos in arm B. In pts with any HRR mutation, median PFS was 2.0 mos in arm A and 2.0 mos in arm B. Any grade≥3 treatment-emergent adverse event (AE) was reported in 25/38 pts (65.8%) in arm A and in 3/19 pts (15.8%) in arm B. 18/38 pts (47.4%) needed dose reduction of niraparib. Most common AEs with niraparib were anemia (50.0%, G3 10.5%), thrombocytopenia (36.8%, G3-4 15.8%), neutropenia (21.1%, G3 5.3%), fatigue (31.6%, G3 15.8%), constipation (31.6%, G3 2.6%), mucositis (13.2%, G3 2.6%), nausea (13.2%, G3 2.6%). Conclusions: Maintenance niraparib plus BSC did not prolong PFS, as compared with BSC alone, among pts with urothelial cancer without progression after first-line PBCT. Clinicaltrials.gov Identifier. NCT03945084. Clinical trial information: NCT03945084.

TPS708 Background: ADP-A2M4CD8 T-cell receptor (TCR) T-cell therapy consists of autologous CD4+ and CD8+ T-cells genetically modified to target melanoma-associated antigen A4 (MAGE-A4) in patients (pts) with advanced cancers who are human leukocyte antigen A*02 eligible. In the late-line setting, ADP-A2M4CD8 monotherapy has demonstrated an acceptable benefit-to-risk profile and clinical responses across multiple tumor types in the ongoing Phase 1 SURPASS trial (NCT04044859). As of November 23, 2022, there were encouraging signs of antitumor activity in the 7 pts with advanced urothelial carcinoma (UC) treated in SURPASS, with best overall responses of 1 complete response, 3 partial responses, and 3 stable disease, giving an overall response rate of 57.1% and a disease control rate of 100% (Aggen DH. et al., Poster 517, ASCO-GU 2023; San Francisco, CA, USA). Furthermore, inhibiting immunosuppressive pathways may enhance antitumor activity. Thus, a new SURPASS cohort consisting of early-line ADP-A2M4CD8 TCR T-cell therapy combined with pembrolizumab in participants with UC has been opened. Methods: A dedicated UC cohort will enroll ≤15 pts with unresectable locally advanced or metastatic UC who have received first-line cisplatin-based standard-of-care (SOC) chemotherapy and are either currently receiving second-line SOC pembrolizumab or have received avelumab maintenance therapy and no second-line therapy. Key eligibility criteria include &gt;30% of tumor cells expressing MAGE-A4 (≥2+ by immunohistochemistry); positivity for HLA-A*02:01, 02:02, 02:03, or 02:06 alleles; measurable disease per RECIST v1.1 prior to lymphodepletion; and ECOG performance status of 0 or 1. T-cells are collected by leukapheresis, transduced with a lentiviral vector expressing the MAGE-A4-specific TCR and an additional CD8α co-receptor designed to increase functionality of CD4+ T-cells, and expanded ex vivo. Pts receive lymphodepletion chemotherapy consisting of cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days followed by ADP-A2M4CD8 infusion (1x109 to 10x109 transduced T-cells) and subsequent pembrolizumab 400 mg (administered every six weeks for ≤2 years, until unacceptable toxicity or disease progression). Primary and secondary endpoints include evaluation of adverse events (AEs), serious AEs, AEs of special interest, and overall response rate per RECIST v1.1 by investigator review, respectively. Trial registration number: NCT04044859. Editorial acknowledgement:This study is sponsored by Adaptimmune (Philadelphia, PA, USA). Writing and editorial support was from Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Adaptimmune. Clinical trial information: NCT04044859 .

Background: Tinengotinib is a novel multiple kinase inhibitor that strongly inhibits Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R. Here we present the preliminary safety, pharmacokinetic and efficacy data of tinengotinib in patients (pts) with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) and triple-negative BC (TNBC) from Phase I TT420X2101 (NCT03654547) and Phase Ib/II TT420X1103 (NCT04742959) trials. Methods: Eligible pts with HR+/HER2- BC or TNBC who have no available standard therapeutic treatment options were enrolled to the TT420X2101 and TT420X1103 trials. Tinengotinib was given as monotherapy at different dose levels (5 mg QD, 10 mg QD and 12 mg QD); different dosing schedule (6 mg BID); and as combination (tinengotinib 8 mg QD and Abraxane 100 mg/m2). Recruitment spanned from January 2019 to March 2023. Results: As of June 2023, 36 pts with metastatic BC were treated: 30 with tinengotinib monotherapy at dose levels of 5 mg QD (n=1), 8 mg QD (n=4), 10 mg QD (n=5), 12 mg QD (n=18), 6 mg BID (n=2) and 6 with tinengotinib 8 mg QD in combination with nab-paclitaxel 100 mg/m2. Median age 51 years (range 24-75), ECOG PS 1 in 83.3% of pts, median lines of prior therapy were 5, and 77.8% of pts had prior taxanes. Of 30 pts receiving tinengotinib monotherapy, treatment related adverse events (TRAEs) were reported in 26 (86.7%) pts. 43.4% were Grade (G) 1-2, 43.3% were G3. No G4 or G5 TRAEs were reported. Common TRAEs (≥20%) of tinengotinib monotherapy were hypertension (60.0%), stomatitis (50.0%), palmar-plantar erythrodysesthesia syndrome (46.7%) and diarrhea (20.0%). All six (100%) pts receiving tinengotinib in combination with nab-paclitaxel experienced TRAEs, 16.7% were G1, 66.7% were G3, no G4 TRAEs, and one pt had G5 (pulmonary hemorrhage). Common TRAEs (≥20%) of tinengotinib in combination with nab-paclitaxel were neutrophil count decreased/neutropenia (50.0%), stomatitis (50.0%), hypertension (33.3%), hyponatremia (33.3%), hypokalemia (33.3%), and nausea (33.3%). Twenty-eight pts receiving tinengotinib monotherapy were efficacy evaluable. 11 pts with HR+/HER2- BC achieved objective response rate (ORR) of 45.5%, clinical benefit rate (CBR, CR+PR+SD ≥ 24 weeks) of 54.5% and median progression-free survival (mPFS) of 5.55 (95% CI 1.97-6.18) months. Partial responses were seen in 3 pts with HER2-zero (n=5) and 2 pts with HER2 low (1+/2+) pts (n=6), respectively. 17 pts with TNBC had ORR of 23.5%, CBR of 29.4% and mPFS of 2.73 (95% CI 1.68-6.41) months. In 6 pts treated with tinengotinib in combination with nab-paclitaxel, one out of 2 pts with HR+/HER2- BC achieved PR for 13 weeks as of data cutoff; two out of 4 pts with TNBC had SD. No significant difference in exposure was observed between tinengotinib monotherapy and tinengotinib in combination with nab-paclitaxel. Conclusions: Tinengotinib for the treatment of HR+HER2- BC or TNBC, whether as monotherapy or in combination with nab-paclitaxel, had manageable side effects. Tinengotinib has shown promising clinical benefit in heavily pre-treated pts with refractory HR+HER2- BC or TNBC. Clinical benefit was similar across the subgroups of pts with HR+ HER2-zero and HR+ HER2 low disease. Citation Format: Piha-Paul Sarina, Binghe Xu, Ying Fan, Yuan Yuan, Sayeh Lavasani, Joanne Mortimer, Sanjay Goel, Apostolia Tsimberidou, Nuhad Ibrahim, Sausan Abouharb, Carlos Barcenas, Adaeze lheme, Daniel Karp, Jordi Rodon Ahnert, Ecaterina Dumbrava, Jean Fan, Peng Peng, Caixia Sun, Hui Wang, Katie Hennessy, Ximei Fu, Ruolan Xu, Shumao Ni, Frank Wu, Funda Meric-Bernstam. The efficacy and safety of tinengotinib in patients with advanced or metastatic HR+/HER2- breast cancer or TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-07.

Background: Saruparib (AZD5305) is a highly selective, potent inhibitor and trapper of PARP1. Camizestrant is an oral next generation SERD and complete ER antagonist. PETRA (NCT04644068) is a Phase 1/2a, modular, open label, multicenter study of saruparib as monotherapy or in combination with anticancer agents in pts with advanced solid malignancies. We present safety and preliminary efficacy of saruparib + camizestrant in pts with advanced/relapsed ER+/HER2- breast cancer. Methods: Pts were aged ≥18 years with histologically/cytologically confirmed breast adenocarcinoma, a locally-documented ER+ and HER2- tumor and an ECOG PS 0/1. Pts were required to have recurrence or progression on ≥1 line of endocrine therapy, and were allowed ≤2 prior lines of chemotherapy in the advanced setting and ≤1 prior PARP inhibitor. Pts could receive prior CDK4/6 inhibitors or fulvestrant, but not oral SERDs. Pts received 60 mg saruparib + 75 mg camizestrant daily orally. The primary objective was assessment of safety and tolerability; secondary objectives included pharmacokinetic (PK) assessments and preliminary antitumor activity. Results: At data cutoff (Mar 31, 2025), 38 pts had received ≥1 dose of the combination. Median age was 56 years; median prior lines of therapy was 3.5 (range, 1-13). BRCA1/BRCA2 mutation (m) and PALB2m were detected in 8 (21.1%) and 2 (5.3%) pts, respectively, based on local testing. Safety is summarized in the Table. Hematological toxicities included anemia and neutropenia; gastrointestinal toxicities included nausea and vomiting. PK data showed no evidence of drug interaction between saruparib and camizestrant. Saruparib exposure was comparable following single-dose saruparib versus saruparib at steady-state in combination with camizestrant, for AUC (42,219 vs 41,703 h*ng/mL) and Cmax (2,834 vs 3,250 ng/mL). Eight of 35 evaluable pts achieved confirmed partial responses (by RECIST v1.1) for an objective response rate (ORR) of 22.9%; median duration of response was 5.5 months. In addition, 12 pts (34.3%) achieved stable disease for a disease control rate of 57.1%. An ORR of 33.3% was reported in 9 pts with measurable disease and BRCA1/BRCA2m or PALB2m. The median progression-free survival was 4.4 months (80% CI, 2.0-5.6) overall and 6.1 months (80% CI, 4.4-7.3) in pts with mutations. Conclusion: Saruparib + camizestrant was well tolerated with no new safety signals versus prior monotherapy studies of each drug. PK of saruparib in combination with camizestrant was consistent with monotherapy data. Preliminary efficacy of the combination was promising and compared favorably with camizestrant monotherapy. This combination is being tested in a randomized Phase 3 trial in pts with ER+/HER2- and BRCA1m/BRCA2m or PALB2m (EvoPAR-Breast01; NCT06380751). Citation Format: T. A. Yap, K. Yonemori, W. Li, S. Kitano, F. Lynce, A. Sharp, A. Falcón, J. Garcia-Corbacho, R. D. Baird, J. Balmaña, S. Nanda, I. Song, K. Sugibayashi, L. Womersley, M. Squatrito, E. Gangl, T. Milenkova, S. J. Luen. Phase 1/2a trial of new generation PARP1-selective inhibitor saruparib + next generation selective ER degrader (SERD) camizestrant in patients (pts) with advanced/relapsed ER+/HER2-negative or low (HER2−) breast cancer (PETRA Module 6) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-28.

3023 Background: Folate receptor alpha (FRα) is overexpressed in several solid tumors. LY4170156 is an Fc-silent, FRα specific humanized IgG1 ADC linked to exatecan, a topo-I inhibitor, via a novel cleavable polysarcosine linker at a homogenous DAR of 8. LY4170156 demonstrated in vivo preclinical efficacy in tumor models, across all FRα expression levels. Methods: This is a multicenter, open-label, first-in-human phase 1a/b study of LY4170156 in patients (pts) with advanced FRα-expressing ovarian, endometrial, cervical, and other solid tumors. Pts with prior ADCs targeting FRα with payloads other than topo-I (including mirvetuximab soravtansine-gynx [mirv]) were allowed. Dose escalation followed the mTPI-2 method. LY4170156 was administered Q3W IV (dose range of 2-6 mg/kg); dose limiting toxicity (DLT) evaluation period was 21 days. Dose escalation included a randomized dose optimization cohort in PROC. Key endpoints were safety, PK, and antitumor activity per RECIST v1.1. Efficacy evaluable pts were those who had a post baseline response assessment or discontinued treatment prior to the response assessment. Results: As of 27 Nov 2024, 45 pts were treated with LY4170156. Median age was 63 yrs (range, 24-85), 100% had ECOG PS 0-1, and 32 (71%) had high-grade serous ovarian cancer (HGSOC). Among the HGSOC pts (32), median lines of prior therapy was 5 (range, 1-10), 19% had received prior mirv, and 44% had FRα expression &lt; 75% by local or central testing. PK of LY4170156, total antibody, and exatecan were linear and dose-proportional within the tested dose range. Unconjugated payload release from ADC at C max was &lt; 4% at 4 mg/kg; median half-life of LY4170156 was 5.7-7.0 days and exatecan was 7.2-8.6 days. Main toxicities were myelosuppression and GI-related, as expected from an exatecan payload. Across all doses, the most common treatment-emergent adverse events (TEAEs; ≥15%) were nausea (58%, 2% gr 3), fatigue (44%, 0% gr 3-4), anemia (33%, 24% gr 3), vomiting (27%, no gr 3-4), diarrhea (22%, 4% gr 3), and neutropenia (20%, 11% gr 3-4). Febrile neutropenia (FN) was observed in 3 pts (7%). To date, no pulmonary or ocular toxicity were noted. Two DLTs were observed (1 gr 3 FN [6 mg/kg]; 1 gr 3 anemia [2 mg/kg]); no MTD has been established to date. Among 13 efficacy evaluable HGSOC pts (6 FRα ≥75%; 6 &lt; 75%; 1 pending data), 9 showed reduction in target lesions; preliminary ORR was 38% (n = 5) with 1 CR, 4 PR, and 4 SD across all dose levels. Combined ORR for 4 and 6 mg/kg dose levels was 55%. All responses were unconfirmed and ongoing at the time of data cutoff. Three of 5 responders had FRa expression &lt; 75% and two ≥75% including 1 who was mirv refractory. Conclusions: LY4170156 was well-tolerated with encouraging clinical activity among HGSOC pts, including those with FRα expression &lt; 75% and those with prior mirv. Randomized dose optimization is ongoing and updated data will be presented. Clinical trial information: NCT06400472 .

Reduced-energy diet improves survival of obese KKAy mice with viral myocarditis: Induction of cardiac adiponectin expression