Sarah Cannon

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

Amivantamab is an EGFR-MET bispecific antibody approved as an intravenous formulation for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Intravenous delivery is frequently associated with infusion-related reaction (IRRs), which require adopting slow infusion rates and splitting the first dose over 2 days. The PALOMA study assessed the safety and feasibility of subcutaneous amivantamab administration and identified the formulation and recommended phase II doses (RP2Ds) for multiple dosing schedules. PALOMA is a phase Ib dose-escalation study in 158 participants with advanced solid malignancies. Primary objectives included pharmacokinetics, safety, and determining RP2Ds for every-2-week (Q2W), every-3-week (Q3W), and every-4-week (Q4W) administration. The safety profile of subcutaneous amivantamab was largely consistent with intravenous monotherapy; most common toxicities reflected on-target EGFR/MET inhibition. Subcutaneous amivantamab resulted in meaningfully shorter administration time (≤ 10 minutes vs. 2.3 hours for intravenous beyond cycle 3) and lower incidence and severity of IRRs versus historical intravenous data, which eliminates the need for split-dose administration. Pharmacokinetic analyses and population pharmacokinetic modeling/simulation were used to estimate subcutaneous amivantamab RP2Ds of 1600 mg (2240 mg, ≥ 80 kg), 2400 mg (3360 mg, ≥ 80 kg), and 3520 mg (4640 mg, ≥ 80 kg) for Q2W, Q3W, and Q4W schedules, respectively. The observed efficacy was consistent with intravenous amivantamab monotherapy. Subcutaneous amivantamab administration substantially reduced IRRs, obviating the need for prolonged infusions and 2-day split-dosing at first administration. The identified RP2Ds for subcutaneous amivantamab are implemented in ongoing studies evaluating amivantamab regimens in NSCLC, colorectal cancer, and head and neck squamous cell carcinoma.

LBA639 Background: PPARG is a master regulator of luminal lineage in UC with two-thirds of adv tumors classified as luminal. FX-909 is a first-in-class oral small molecule that potently and selectively inhibits both ligand-mediated and basal PPARG activity, offering a novel approach to targeting key cancer cell-intrinsic biology. Preliminary phase 1A data have demonstrated objective responses with FX-909 monotherapy (Gao, AACR Targets 2025). Here we report updated safety, tolerability, antitumor activity and predictive biomarker discovery to identify pts most likely to benefit from FX-909. Methods: 56 pts enrolled in a phase 1A open-label dose escalation study (30-100 mg PO QD, 28-day cycles), including additional 10 adv UC patients in 30 mg PO and 50 mg PO QD backfill cohorts. Baseline archival tissue (<30 months old) or a fresh biopsy collected for PPARG IHC (SP500 clone) and NGS correlative biomarker analysis. A provisional PPARG TPS cutoff was determined using linear regression modeling leveraging molecular real-world data (RWD) (N=2609 adv UC pts, Tempus xT). Serial blood samples collected for ctDNA analysis. Results: As of Nov 10, 2025, 46 pts with adv UC have been treated across four dose levels; 30 mg (17); 50 mg (16); 70 mg (11); and 100 mg (2). Median age was 71 (range 44-86), 71.7% ECOG PS 1, and 100% had mUC. Median lines of prior therapy was 3 (range, 1-8), including prior EV and anti-PD(L)1 treatment in 69.6%. Concordance between PPARG mRNA and TPS (r = 0.88, p<0.001) supported linear regression modeling, which inferred a provisional TPS cutoff of ≥60% (PPARG high ). Among 40 efficacy-evaluable adv UC pts, 35 had PPARG IHC results. 18/26 PPARG high pts showed tumor regressions, including 5 confirmed and 1 unconfirmed partial response. Decreases in ctDNA VAF occurred in 7/8 PPARG high pts with available results at cycle 2 (3 PR, 3 SD). Additional data demonstrating the relationship between PPARG high status, luminal subtype, and specific genomic alterations (PPARG(CN≥3), RXRA S427F and FGFR3) will be presented. At 30mg and 50mg doses, the most common ≥Gr3 TRAEs were anemia (18.9%), thrombocytopenia (16.2%) and fatigue (10.8%). Other common TEAEs were diarrhea (32.4%), hypertriglyceridemia (27%) and hyperglycemia (24.3%). The 30 mg dose was associated with fewer Gr3 TRAEs (35.3%), longer time to TRAE onset (52 days, range 44, 85), and fewer dose interruptions (29.4%) and dose reductions (11.8%). Conclusions: FX-909, a first-in-mechanism orally bioavailable PPARG inhibitor, demonstrates clinical proof-of-concept for targeting the master regulator of luminal lineage in heavily pretreated adv UC pts and may offer a novel therapeutic strategy for PPARG high adv UC. A randomized phase 1B expansion study is ongoing (NCT05929235). A combination study of FX-909/anti-PD1 is planned for early 2026. Clinical trial information: NCT05929235 .

Background/Objectives: Ciltacabtagene autoleucel (cilta-cel) for relapsed/refractory multiple myeloma is typically administered inpatient (IP) to monitor for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Because cilta-cel toxicities are typically delayed, outpatient (OP) administration (infusion and early monitoring) is being explored. We synthesized available evidence on OP and IP administration. Methods: MEDLINE, Embase, and Cochrane Library were searched from inception to 5 August 2025, supplemented by conference and gray literature searches. Eligible studies of adults with multiple myeloma receiving cilta-cel reported efficacy, safety, resource use, costs, and/or quality-of-life outcomes; findings were synthesized descriptively due to heterogeneity. Results: Seventy-four records (56 studies) were included; 90 patients received OP cilta-cel. OP clinical evidence (primarily three real-world studies) showed high response rates (ORR: 95%; median follow-up 4.6 months) and reported 1-year PFS and OS of 86% and 96%. In IP studies, median ORR was 91%, with median 1-year PFS 76% and median 1-year OS 85%. Any-grade CRS and ICANS occurred in 79-84% and 17-22% of OP patients (largely low grade); IP cohorts reported a median ICANS incidence of 17% (range 5-23%). Most OP patients were later hospitalized (86-93%), but stays were shorter (median 4-6.5 days) than in an IP cohort (median 19 days). Comparisons were unadjusted and may reflect selection differences. One modeling-based economic analysis estimated savings of ~$19,000 per OP-treated patient. Conclusions: OP cilta-cel appears feasible for selected patients and may reduce costs without compromising outcomes. Findings are descriptive and hypothesis-generating and prospective multicenter studies are needed to define long-term safety, durability, quality of life, and cost-effectiveness.

Abstract Background: HER3-targeted antibody-drug conjugates (ADCs) have shown benefits in breast cancer (BC). DB-1310 is a novel ADC comprised of a humanized anti-HER3 IgG1 monoclonal antibody with a highly internalizing unique Domain I epitope, a cleavable peptide linker, and a potent DNA topoisomerase I inhibitor P1021. Initial clinical data demonstrated a manageable safety profile and encouraging anti-tumor activity, particularly in patients with EGFR-mutant NSCLC (Lisberg ASCO 2025). Here, we present the efficacy and safety results of DB-1310 in pretreated hormone receptor-positive (HR+), HER2-negative (HER2-) BC patients. Methods: In the Phase 1 part of this trial (NCT05785741), patients with advanced solid tumors, including HR+/HER2- BC, received DB-1310 monotherapy intravenously every three weeks (Q3W). Safety was the primary endpoint, with efficacy endpoints including objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) as secondary endpoints. Results: As of July 04, 2025, a total of 207 patients with solid tumors were enrolled and treated with DB-1310 monotherapy (1.5-6.5 mg/kg, Q3W) in Phase 1 (ECOG PS 1, 84.1%; White, 26.1%; Asian, 69.1%). Among these, 16 HR+/HER2- BC patients were enrolled (3.0-5.5 mg/kg, Q3W), with 15 of them being efficacy-evaluable, and a median prior line of systemic therapy was 2 (range, 1-7). Efficacy Results (N=15 HR+/HER2- BC patients from Phase 1): nine achieved a partial response (one pending confirmation), and four achieved stable disease, resulting in a confirmed ORR of 53.3% (95%CI: 26.59, 78.73) and a DCR of 86.7% (95%CI: 59.54, 98.34). Notably, all partial responses occurred in patients treated with 5-5.5 mg/kg (N=13), yielding an unconfirmed ORR of 69.2%, a confirmed ORR of 61.5%, and a DCR of 92.3% for this dose range. The median DoR is not reached. Median PFS is 14.78 months (95% CI: 11.60, not evaluable) and median OS is 14.69 months (95% CI: 11.89, not evaluable). Safety Results (N=207, all enrolled patients from Phase 1): The safety profile was assessed in the entire Phase 1 part. Treatment-related adverse events (TRAEs) of Grade (G) ≥ 3 occurred in 89 (43.0%) patients, and 25 patients (12.1%) had treatment-related serious adverse events. TRAEs led to dose reduction in 38 (18.4%) and discontinuation in 9 (4.3%) patients. No TRAE-related deaths were reported. Most common TRAEs (any grade/≥G3; >20% overall) were neutrophile count decreased (49.3%/ 26.1%), anemia (47.8%/ 6.8%), platelet count decreased (45.4%/ 15.9%), white blood cell count decreased (43.5%/ 11.1%), nausea (40.6%/ 1.0%), decreased appetite (29.5%/ 0.5%), aspartate aminotransferase increased (26.6%/ 0), alopecia (26.1%/ 0), vomiting (24.6%/ 0), and hypoalbuminemia (21.7%/ 0). Interstitial lung disease/pneumonitis occurred in 10 pts (4.8%; one Grade 2, all others G1). The safety profile in the 16 HR+/HER- BC patients was consistent with the overall Phase 1 part. Conclusion: DB-1310 showed promising anti-tumor activity in heavily pretreated HR+/HER2- BC patients. The manageable safety profile observed in the larger Phase 1 part, involving 207 patients, is consistent with that of the BC subpopulation, supporting its further development. Citation Format: Y. Yin, A. Spira, H. Lan, M. Zhao, Y. Mao, W. Yao, Y. Sun, J. Wu, X. Sun, S. Liu, H. Mu, K. Wang, Y. Qiu, E. Hamilton. First clinical data of DB-1310 (HER3-targeted antibody-drug-conjugate), in patients with pretreated hormone receptor-positive/HER2-negative breast cancer: efficacy and safety data from a phase 1/2a trial [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 PS4-06-17.

Abstract Background: T-DXd is approved for the treatment of adult pts with HER2+ mBC who have received a prior anti-HER2-based regimen. Recent results from the planned interim analysis of the Phase 3 DESTINY-Breast09 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review for T-DXd + pertuzumab versus standard of care (taxane + trastuzumab + pertuzumab) in first-line (1L) HER2+ mBC (median 40.7 vs 26.9 months; hazard ratio 0.56 [95% CI 0.44, 0.71]). The T-DXd monotherapy module remains blinded until final PFS analysis. DESTINY-Breast07 (NCT04538742; initiated prior to DESTINY-Breast09) was a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. Results presented are from the final analysis of the dose-expansion phase assessing T-DXd ± pertuzumab as 1L treatment in HER2+ mBC. Methods: Eligible pts had locally assessed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+ / in situ hybridization-positive) mBC. No prior therapy for mBC was allowed and a disease-free interval of ≥12 months from (neo)adjuvant therapy was required. Pts were stratified by hormone receptor status (positive [estrogen or progesterone receptor ≥1%] vs negative), disease status (recurrent vs de novo), and PD-L1 expression (positive [IHC ≥1%] vs negative). Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with pertuzumab 420 mg IV Q3W, with an 840-mg loading dose. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response, and PFS, per RECIST 1.1 by investigator, as well as time to progression on subsequent therapy (PFS2) by investigator, and overall survival (OS). Results: At final data cutoff (January 31, 2025), 75 pts in the T-DXd module and 50 pts in the T-DXd + pertuzumab module had received study treatment; demographics and disease characteristics were well balanced. Median follow up was 37.1 months with T-DXd and 38.6 months with T-DXd + pertuzumab. Median total treatment duration was 26.8 months in the T-DXd module, and 27.6 months for T-DXd and 26.0 months for pertuzumab in the T-DXd + pertuzumab module. Confirmed ORR (80% CI) was 78.7% (71.4, 84.7) with T-DXd and 84.0% (75.3, 90.5) with T-DXd + pertuzumab. At 36 months, 65.5% and 69.4% of pts remained in response in the T-DXd and T-DXd + pertuzumab modules, respectively. At study completion, median PFS and median OS were not reached for either module. The 80% CI lower limit for median PFS was 40.2 months for T-DXd + pertuzumab; all other CI limits were not evaluable. PFS rate (80% CI) at 24 months was 71.4% (63.5, 77.8) with T-DXd and 67.8% (58.2, 75.7) with T-DXd + pertuzumab. Grade ≥3 adverse events (AEs) occurred in 57.3% (n=43/75) and 62.0% (n=31/50), and serious AEs in 21.3% (n=16/75) and 28.0% (n=14/50), of pts in the T-DXd and T-DXd + pertuzumab modules, respectively. Adjudicated drug-related interstitial lung disease / pneumonitis events occurred in 11 (14.7%; Grade 1, n=3; Grade 2, n=8) pts who received T-DXd and 7 (14.0%; Grade 2, n=6; Grade 3, n=1) who received T-DXd + pertuzumab. Additional data by subgroup, including biomarker analyses, will be presented. Conclusion: In this Phase 1b/2 DESTINY-Breast07 study, safety profiles for T-DXd and pertuzumab were generally consistent with the known profiles of each agent. Encouraging clinical activity was demonstrated in pts who received either T-DXd monotherapy or T-DXd + pertuzumab as a 1L treatment for HER2+ mBC; results from the T-DXd + pertuzumab module are consistent with the interim findings from the Phase 3 DESTINY-Breast09 study. Citation Format: F. André, E. Hamilton, S. Loi, C. Anders, P. Schmid, E. Artamonova, R. Villanueva-Vázquez, J. Pedrini, D. Doval, S. C. Chen, S. Boston, A. Konpa, M. Markowska, G. Fabbri, K. Jhaveri. Trastuzumab deruxtecan (T-DXd) monotherapy and T-DXd + pertuzumab in patients (pts) with previously untreated HER2+ unresectable/metastatic breast cancer (mBC): final results from DESTINY-Breast07 [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 PS5-01-14.

Abstract Background: Vepdegestrant is an oral PROTAC ER degrader. The VERITAC-2 study (NCT05654623), the first phase 3 trial of a PROTAC, demonstrated statistically significant and clinically meaningful prolongation of progression-free survival (PFS) with vepdegestrant versus fulvestrant in patients (pts) with ER+/HER2- aBC who were previously treated with endocrine therapy (ET) and a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and had ESR1 mutations (ESR1m). Here, we report the results of prespecified subgroup analyses of PFS among pts with ESR1m. Methods: Eligible pts (aged ≥18 years) with ER+/HER2- aBC had received 1 prior line of CDK4/6i + ET, and ≤1 additional line of ET (the most recent line of ET must have been given for ≥6 months before disease progression); pts with prior chemotherapy in the metastatic setting or prior fulvestrant were excluded. Pts were randomized (1:1) to receive vepdegestrant 200 mg orally once daily or fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles; randomization was stratified by ESR1m status and the presence of visceral disease. The primary endpoint, PFS by blinded independent central review (BICR), was assessed across prespecified clinically relevant subgroups without adjustments for multiplicity. Results: In total, 270 pts with ESR1m were randomized to vepdegestrant (n=136) or fulvestrant (n=134). Across groups, the median age was 60.0 years, 21% of pts were premenopausal or perimenopausal, 80% had received prior CDK4/6i therapy for ≥12 months, 45% had liver metastases, and 42% had a PIK3CA, AKT1, or PTEN mutation at baseline. Consistent with the primary analysis, benefit was observed in PFS by BICR with vepdegestrant versus fulvestrant across all prespecified subgroups ( Table ). Conclusions: Vepdegestrant demonstrated PFS benefit compared with fulvestrant across all prespecified, clinically relevant subgroups of previously treated pts with ESR1m ER+/HER2- aBC. These analyses provide further information in key prognostic patient subgroups that may inform clinical treatment decisions for pts with ESR1m. Citation Format: E. P. Hamilton, M. De Laurentiis, K. Jhaveri, X. Hu, S. Ladoire, A. Patsouris, C. Zamagni, J. Cui, M. Cazzaniga, T. Cil, K. J. Jerzak, C. Fuentes, T. Yoshinami, A. Rodriguez-Lescure, O. Valota, D. R. Lu, M. Martignoni, S. Dychter, M. Lachowicz, X. Zhi, M. Campone. Subgroup analyses of VERITAC-2: A phase 3 trial of vepdegestrant, a PROTAC estrogen receptor (ER) degrader, versus fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) [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 PD10-03.