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Adebrelimab combined with concurrent chemoradiotherapy as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma: A prospective, single-arm clinical trial.
e16139 Background: The prognosis for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) remains poor. While immune checkpoint inhibitors have shown efficacy in advanced disease, their synergistic potential with concurrent chemoradiotherapy (CRT) in the neoadjuvant setting for LA-ESCC requires prospective validation. This study aimed to prospectively evaluate the efficacy and safety of the PD-L1 inhibitor adebrelimab combined with concurrent CRT as a novel neoadjuvant strategy for resectable LA-ESCC. Methods: This was a prospective, single-arm trial. Eligible patients had resectable thoracic ESCC, clinically staged as cT2N+ or cT3-4a any N M0. The regimen comprised adebrelimab (1200 mg intravenously every 3 weeks for 2 cycles) plus concurrent CRT (weekly paclitaxel/carboplatin and radiotherapy totaling 41.4 Gy in 23 fractions). Radical esophagectomy was scheduled 4-8 weeks after neoadjuvant therapy completion. The primary endpoint was the pathological complete response (pCR; ypT0N0) rate. Key secondary endpoints included the major pathological response (MPR; ≤10% residual viable tumor) rate, R0 resection rate, and safety. Results: Between June 2024 and October 2025, 32 patients were enrolled (median age 64.6 years; 75.0% male; 75.0% stage III). Of these, 24 patients proceeded to surgery, achieving a 100% (24/24) R0 resection rate. The primary endpoint was met, with a pCR rate of 58.3% (14/24). The MPR rate was 91.7% (22/24). Pathological downstaging was profound: 87.5% (21/24) of patients achieved primary tumor (T-stage) downstaging (ypT < cT), and 66.7% (16/24) achieved nodal clearance (ypN0). Regarding safety, grade ≥3 leukopenia occurred in 43.8% (14/32) of patients, all of whom had concomitant grade ≥3 lymphopenia. Common non-hematological toxicities included nausea (58.1%), constipation (54.8%), decreased appetite (48.4%), and vomiting (41.9%), which were all grade 1-2 and manageable with supportive care. Conclusions: Neoadjuvant adebrelimab plus concurrent CRT demonstrated remarkable efficacy in LA-ESCC, yielding high rates of pCR (58.3%) and MPR (91.7%), alongside significant pathological downstaging. While hematologic toxicity requires vigilant management, the profound tumor regression achieved offers a promising new strategy for improving outcomes in this population. These compelling results warrant further validation in a phase III randomized controlled trial. Future studies should explore optimization of the chemotherapy component to potentially enhance tolerability. Clinical trial information: ChiCTR2400084445.
Comparative safety and efficacy of trastuzumab deruxtecan (T-DXd) in HER2-positive and HER2-low gastrointestinal malignancies: A systematic review and meta-analysis.
e16337 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate approved for HER2-positive gastrointestinal (GI) cancers, with emerging evidence in HER2-low tumors. This systematic review and meta-analysis evaluated and compared T-DXd safety and efficacy in HER2-positive versus HER2-low GI malignancies. Methods: Following PRISMA guidelines, we searched Medline, Embase, Cochrane Central, and ClinicalTrials.gov. Of 7,060 studies, three met inclusion criteria (160 patients). HER2-positive was defined as IHC 3+ or IHC 2+/ISH-positive; HER2-low as IHC 1+ or IHC 2+/ISH-negative. NIH quality assessment was performed. Pooled analyses used the 'meta' package (R programming). Results: Median age was 58.5 years (range: 27–79); 68% male. Median follow-up: 4.2 months (range: 0.5–26.8). In HER2-positive patients, pooled ORR was 27.5% (95% CI: 19.6–36.1; I² = 0%), lower than pivotal trials (42-51%), likely reflecting more heavily pretreated populations. Median PFS and OS were 6.0 months (95% CI: 4.1–8.7) and 11.5 months (95% CI: 8.8–20.8), respectively, versus 5.6-6.9 and 12.5-14.7 months in DESTINY-Gastric trials. Median DoR was 7.0 months (95% CI: 5.8–9.5). In HER2-low patients, pooled ORR was 3.5% (95% CI: 0.0–24.5; I² = 91%), substantially lower than exploratory cohorts (9.5-26.3%). High heterogeneity (I² = 91-92%) limits interpretation. Despite low ORR, disease control rate was 76.3% (95% CI: 43.3–97.7), suggesting benefit through disease stabilization. Median PFS and OS were 3.25 months (95% CI: 1.4–7.1) and 7.55 months (95% CI: 3.0–NE). Median DoR was 7.6 months. Adverse events included myelosuppression, gastrointestinal toxicity, and interstitial lung disease (ILD)/pneumonitis. ILD/pneumonitis occurs in 10-14% of patients (predominantly grade 1-2), with grade ≥3 in 1.5-2.8% and rare fatalities (0.7-1.2%). No significant differences in adverse event incidence were observed between HER2 groups. Conclusions: T-DXd demonstrates efficacy in HER2-positive GI malignancies and is established as standard second-line therapy based on DESTINY-Gastric04. Although HER2-low response rates are limited, high disease control rates warrant further investigation. HER2-low remains investigational and not approved for T-DXd. High heterogeneity in HER2-low results and lack of standardized definitions in GI cancers are significant limitations. Larger prospective trials with standardized HER2-low definitions are needed. Rebiopsy to confirm HER2 status after prior anti-HER2 therapy is recommended.
Single center retrospective analysis of neoadjuvant therapy in resectable pancreatic adenocarcinoma.
e16467 Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers and is expected to become the second leading cause of cancer-related death in the United States by 2030. Only 10-15% of patients are resectable at diagnosis. For those who undergo surgery, five-year survival is close to 20%. Current guidelines recommend surgery followed by adjuvant systemic therapy. Neoadjuvant therapy (NAT) to improve patient outcomes is controversial owing to conflicting evidence. 1 The NorPACT-1 trial, which evaluated resectable PDAC, showed improved median overall survival (mOS) in upfront surgery (US) cohort while subgroup analysis of resectable PDAC cohort in the PREOPANC trial found similar mOS between NAT and US. These findings are contradictory to the Roesel et al 2023 meta-analysis that reported improvements in OS and R0 resections in patient who received NAT. 2,3 Against this backdrop, we conducted a retrospective single-center study to evaluate outcomes from NAT vs. US in resectable PDAC patients. Methods: Data was collected on patients diagnosed with resectable PDAC over a 10-year period (1/1/2015-1/1/2025). Patient characteristics evaluated included age, sex, ECOG performance status, stage at diagnosis, tumor location (e.g., head, body, tail), and mismatch repair (MMR) gene status. Patients who received NAT were evaluated by regimen, number of cycles, delayed or missed cycles, grade ≥3 toxicities, and radiographic response based on RECIST criteria. Those who underwent surgery (i.e., following NAT vs. US) were evaluated for resection status (e.g., R0 vs. R1), adjuvant therapy received, and evidence of progression. Our primary end point was median OS. Secondary endpoints included progression-free survival (PFS) and R0 resection rates. All analysis were performed using SAS software version 9.4. Results: 119 patients met inclusion criteria; 84 received NAT followed by surgery and 35 completed US. Patient demographics between these cohorts were comparable. Median OS (3.38 vs. 3.36 years; HR = 0.86, 95% CI [0.52-1.43]; p = 0.33) and median PFS (1.77 vs. 1.29 years; HR = 0.80, 95% CI [0.50-1.27]; p = 0.35) were similar. R0 resection rates favored US over NAT (89 vs. 85.7%; p = 0.756). Conclusions: Our cohort included resectable PDAC who completed NAT followed by surgery or upfront surgery. We observed no significant difference in mOS or PFS between NAT and US. These results are more closely aligned with the findings of the PREOPANC trial’s subgroup analysis of resectable PDAC rather than the results of the NorPACT-1 trial. Although not statistically significant, R0 resection rates were numerically higher in the upfront surgery cohort, a finding that contrasts with PREOPANC. 2,3 The optimal treatment strategy for patients with resectable PDAC remains an area of active investigation with ongoing trials such as PREOPANC-3 and Alliance A021806 expected to further clarify the role of NAT.
Efficacy of immune checkpoint inhibitors (ICIs) in locoregionally advanced nasopharyngeal carcinoma (LA NPC): A meta-analysis of phase II and III randomized controlled trials.
e18068 Background: Locoregionally advanced nasopharyngeal carcinoma (LA NPC) is primarily managed with definitive chemoradiotherapy, with induction chemotherapy improving disease control in higher-risk patients. However, distant metastasis remains an issue, with suboptimal long-term survival outcomes. While immune checkpoint inhibitors (ICIs) have demonstrated clinical activity in recurrent or metastatic NPC, their role in earlier-stage, curative-intent settings remains under active investigation. We conducted a meta-analysis of randomized controlled trials to evaluate the efficacy of ICIs in patients with LA NPC. Methods: We performed a comprehensive literature search using EMBASE and MEDLINE databases, from inception through January 9th, 2026. Eligible studies were randomized controlled trials, phase II and III, involving ICIs in patients with LA NPC. Studies reporting overall survival (OS), progression/event-free survival (PFS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were included in the analysis. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random-effects models for PFS/EFS and OS due to some inter-study heterogeneity. Heterogeneity was assessed using Cochran’s Q test and the I² statistic. Results: A total of four trials, two phase III (CONTINUUM and DIPPER) and two phase II (Liu S et al. 2024 and Li W et al. 2025), were included in the analysis. CONTINUUM examined the addition of sintilimab to induction-concurrent chemotherapy. DIPPER compared adjuvant camrelizumab to observation after induction-concurrent chemotherapy. Liu S et al. 2024 compared neoadjuvant and adjuvant toripalimab to standard of care chemotherapy. Li W et al. 2025 examined the addition of adjuvant tislelizumab after endoscopic surgery. Patients receiving ICIs were associated with a significant improvement in PFS compared to standard therapy (HR 0.48; 95% CI 0.33-0.69; p<0.0001). Overall survival did not differ significantly between ICI and standard therapy arms (HR 0.64; 95% CI 0.33-1.23; p=0.18). Among studies reporting secondary efficacy endpoints, ICIs were associated with significant improvements in DMFS (HR 0.52; 95% CI 0.36–0.75; p=0.0005) and RFS (HR 0.47; 95% CI 0.31–0.71; p=0.0003). Conclusions: This meta-analysis demonstrated that ICI-based regimens were associated with significantly improved PFS, RFS, and DMFS. No statistically significant difference in overall survival was observed, though OS data remain immature. Longer follow-up and additional randomized studies are warranted to clarify the durability of benefit and define the impact of ICIs on long-term survival outcomes in LA NPC.
Updated results from a phase 2 trial of SSGJ-707 (PF-08634404), a PD-1/VEGF bispecific antibody, as monotherapy in patients with advanced non-small cell lung cancer (NSCLC).
8514 Background: SSGJ-707 is a fully human IgG4 bispecific antibody that simultaneously binds PD-1 and VEGF. In the phase 2 study (NCT06361927), SSGJ-707 monotherapy demonstrated promising efficacy and manageable safety in first-line NSCLC with PD-L1 tumor proportion score (TPS) ≥1%. We report updated results from this study with the FDA-aligned pivotal dose of 10 mg/kg Q3W. Methods: Patients (pts) with treatment-naive advanced NSCLC (without actionable genomic alterations and PD-L1 TPS ≥1%) were enrolled to receive SSGJ-707 at 5 mg/kg, 10 mg/kg, 20 mg/kg, or 30 mg/kg Q3W until disease progression or unacceptable toxicity. Primary endpoint is objective response rate (ORR) per RECIST 1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and correlation between circulating tumor DNA (ctDNA) and efficacy. Results: As of Nov 28, 2025, 83 pts received ≥1 dose of SSGJ-707, of which 27.7% remained on treatment. In pts treated with the FDA-aligned dose of 10 mg/kg Q3W (n = 34), 41.2% remained on treatment and median duration of follow-up was 15.2 mos (95% CI, 14.3-16.2). In the 10 mg/kg group, confirmed ORR was 67.6% (95% CI, 49.5-82.6%), median DOR was not reached (NR; 95% CI, 10.9-NR), median PFS was 12.4 mos (95% CI, 8.2-NR), and median OS was NR (95% CI, 14.8-NR). High efficacy was noted for the 10 mg/kg Q3W dose irrespective of histology and TPS (table). Among all treated pts (n = 83), treatment-related adverse events (TRAEs) occurred in 92.8%; grade ≥3 TRAEs occurred in 42.2%. The most common grade ≥3 TRAEs (≥5%) were pneumonia (8.4%), hypertension (7.2%), and hemoptysis (6.0%). VEGF-related AEs occurred in 62.7% (grade ≥3, 18.1%) of pts; immune-mediated AEs occurred in 37.3% (grade ≥3, 8.4%). In the 10 mg/kg group, TRAEs led to permanent discontinuation in 1 pt (2.9%) and none had grade 5 TRAE. In pts with detectable ctDNA at baseline (n = 65), median PFS was NR (95% CI, 12.4-NR) in pts with nondetectable ctDNA at C3D1 (n = 19) compared to 7.6 mos (95% CI, 5.6-9.4) in those with detectable ctDNA at C3D1 (n = 33). Conclusions: With longer follow-up, SSGJ-707 monotherapy continues to show promising efficacy with a manageable safety profile in pts with treatment-naive advanced NSCLC across histology and PD-L1 expression subgroups. These results supported initiation of the phase 3 study (Symbiotic-Lung-01) of SSGJ-707 with platinum-based chemotherapy in 1L squamous (SQ) and nonsquamous (NSQ) NSCLC irrespective of TPS (NCT07222566). Clinical trial information: NCT06361927 . n=34 Confirmed ORR, % (95% CI) DOR, mos, median(95% CI) PFS, mos, median (95% CI) OS, mos, median(95% CI) Histology SQ 12 75.0(42.8-94.5) 6.2 (4.1-NR) 8.9 (2.7-NR) NR(4.9-NR) NSQ 22 63.6(40.7-82.8) NR(10.9-NR) 12.4 (8.2-NR) NR(14.8-NR) TPS 1%-49% 21 61.9(38.4-81.9) NR(4.1-NR) 9.6 (7.6-NR) NR(12.1-NR) ≥50% 13 76.9(46.2-95.0) NR(5.6-NR) 12.4(5.9-NR) NR(NR-NR)
Should CDK4/6 inhibitor plus endocrine therapy be standard of care for ER-low (1–10%) HR+/HER2− metastatic breast cancer? A multicenter registry cohort.
1102 Background: ER-low (1–10%) HR+/HER2− metastatic breast cancer (MBC) is increasingly recognized as a distinct clinical subgroup with limited endocrine sensitivity, yet ER-low–specific evidence to guide optimal first-line treatment is sparse. We assessed real-world effectiveness of CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) in ER-low MBC and benchmarked outcomes against contemporaneous ER-high disease treated with the same approach. Methods: We performed a multicenter cohort study using a prospective institutional registry of women with HR+/HER2− MBC who initiated CDK4/6i (palbociclib/ribociclib/abemaciclib) plus an aromatase inhibitor or fulvestrant between January 2018 and October 2024, with follow-up through December 2024. ER expression by immunohistochemistry was categorized as low (1–10% or Allred 3–4), intermediate (10–66% or Allred 5–6), or high (>66% or Allred 7–8). Primary endpoints were progression-free survival (PFS) and overall survival (OS), analyzed by Kaplan–Meier/log-rank methods and multivariable Cox regression adjusting for age, ECOG performance status, progesterone receptor status, disease extent, CDK4/6i choice, and other clinicopathologic factors. Results: Among the 540 women with advanced HR+ HER2- breast cancer, 75% received CDK4/6i+ET in the first-line setting; ER-low tumors comprised 4.8% (n=26). ER-low disease had poor outcomes on CDK4/6i+ET with median PFS 2.9 months (95% CI 1.2–4.7) and median OS 12.6 months (95% CI 7.24–18.0), versus ER-high median PFS 23.3 months (95% CI 18.8–27.8) and median OS 49.7 months (95% CI 40.6–54.9) (log-rank p<0.001). ER-low status remained independently associated with inferior PFS (HR 10.6, 95% CI 5.02–22.4; p<0.001) and OS (HR 4.66, 95% CI 3.03–7.95; p<0.001) compared with ER-high after adjustment. Within the ER-low patients, the poor outcome was universally observed regardless of ET partner (AI vs fulvestrant), disease extent (visceral vs bone only), ECOG and HER2 status (low vs 0). Conclusions: ER-low HR+/HER2− MBC demonstrated very poor outcomes with CDK4/6i+ET, suggesting CDK4/6i plus AI/ET should not be assumed to be an effective default “standard HR+” approach for this subgroup. Given reported clinicopathologic and molecular similarities between ER-low/HER2− tumors and triple-negative breast cancer, ER-low–dedicated prospective trials and evaluation of TNBC-oriented strategies (including prioritization of chemotherapy-based regimens and TNBC clinical trial enrollment) are urgently needed.
Plasma epigenomic profiling for identification of mechanisms of sensitivity, primary and acquired resistance to tepotinib in METex14 skipping metastatic NSCLC.
8637 Background: MET exon 14 skipping mutations (METex14) are an actionable biomarker in a subset (3-4%) of advanced/metastatic NSCLC patients, with an approved oral and highly selective MET TKI, tepotinib. However, heterogenous clinical responses in patients warrant additional biomarkers of response and resistance. We applied Precede’s epigenomic liquid biopsy platform to explore the feasibility of identifying transcriptional programs associated with sensitivity and resistance to tepotinib in patients with METex14 NSCLC. Methods: A total of 144 baseline, on-treatment (OT), and end-of-treatment (EOT) samples from patients with METex14 NSCLC from the VISION study (NCT02864992) were profiled using Precede’s assay using 1mL of plasma. ctDNA fraction was independently estimated. Genome-wide differential epigenomic activity and pathway analyses compared PFS-stratified responders (top tertile PFS) vs. non-responders at baseline (bottom tertile PFS), and paired baseline vs. EOT samples to identify acquired resistance programs. SCLC/neuroendocrine transformation was assessed in all samples using an independent Precede lineage classifier. Plasma-inferred gene expression models, based on Precede’s proprietary algorithms identified additional therapeutic targets. Results: At baseline, responders showed higher epigenomic activity in pathways underlying addiction to METex14 signaling, including the FAK-integrin axis, ECM remodeling and EMT/invasion. Non-responders displayed increased translational/intrinsic proliferative programs, altered metabolic fitness, and inflammatory/immune signaling, implicating these programs in intrinsic resistance to tepotinib. These METex14 signaling-associated pathway scores stratified clinical outcomes, highlighting their potential in patient selection. Paired analyses revealed EOT samples had increased activity of regulators of lineage plasticity and neuroendocrine differentiation, relative to baseline. Correspondingly, SCLC scores were elevated in OT and EOT samples, with a subset of baseline samples already harboring neuroendocrine features. Epigenomic activity of GD2 synthase ( B4GALNT1 ) significantly increased with treatment, underscoring a potential rationale for combination therapies using anti-GD2 ADCs. Conclusions: Precede’s comprehensive epigenomic liquid biopsy platform resolved METex14 skipping NSCLC biology associated with response and identified programs associated with intrinsic and acquired resistance to tepotinib, including emergence of neuroendocrine differentiation and induction of GD2 synthase. These findings support the use of plasma-based epigenomic profiling to inform therapy selection for patients at baseline and progression and non-invasively monitor resistance mechanisms in METex14 NSCLC.
The impact of MRD and post-remission strategies on outcomes following dose-dense mini-hyper-CVD inotuzumab and blinatumomab in relapsed B-cell acute lymphoblastic leukemia.
6516 Background: Advances in immunotherapy have improved outcomes for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, the optimal sequence of immunotherapies remains undefined, particularly the role of chimeric antigen receptor (CAR) T-cell therapy in the era of sensitive assessment of measurable residual disease (MRD). Here, we provide an update of the phase II trial the dose dense mini-CVD with inotuzumab ozogamicin (InO) and blinatumomab (blina) regimen in R/R B-ALL. Methods: Adults (>18 years) with R/R Philadelphia (Ph) positive (+) or negative (-) B-ALL were treated with dose-dense mini-hyper-CVD with InO and blina. Cycles 1, 3, 5 consisted of mini-hyper-CVD, InO and blina; cycles 2, 4, 6 consisted of mini-methotrexate and ara-C, InO, and blina with Peg-G-CSF administered after each course. Patients (Pts) received 12 IT chemotherapy administrations and rituximab if CD20 positive. Pts with Ph+ ALL received a concomitant BCR::ABL1 tyrosine kinase inhibitor. MRD was assessed by flow cytometry (FC) and next-generation sequencing (NGS). Results: Between September 2021 and January 2026, 27 pts were enrolled (median age 42 years; range, 19–63). Three pts (11%) had Ph+ ALL, and among Ph- pts, 30% had Ph-like disease. Five pts (19%) had adverse risk cytogenetics and (24%) had a TP53 mutation. Twenty-four pts (89%) were in salvage 1. Three pts (11%) had previously undergone allogeneic stem cell transplant (SCT) and 9 (33%) had received blina. All pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), including 22 (81%) CR. MRD negativity was achieved in 96% of pts by FCM and 95% by NGS; 80% and 44% achieved FCM and NGS MRD negativity, respectively, after the first cycle. With a median follow-up of 32 months, 11 pts (41%) proceeded to CAR T-cell consolidation, 5 (18%) to SCT, and 11 (41%) received no further consolidation. Among CAR T recipients, 70% were NGS MRD-negative prior to lymphodepletion. Post CAR T-cells infusion, 10/11 (91%) pts achieved/maintained NGS MRD negativity, while 1 (9%) pt had MRD below level of detection at last follow-up. The 2-year overall survival (OS) and event-free survival (EFS) rates for the entire cohort were 68% and 79%, respectively. The 2-year EFS rates for pts receiving CAR T-cell, ASCT, or no further consolidation were 81%, 80% and 50%, respectively, while the corresponding 2-year OS rates were 89%, 100%, and 55%. Conclusions: Dose-dense mini hyper-CVD combined with InO and blina induces high rates of deep NGS-MRD negative remission in patients with R/R B-ALL, allowing for consolidative strategies including CAR T-cell therapy, leading to favorable survival outcomes at a follow-up of almost 3 years. Clinical trial information: NCT01371630 .
Clinical translation of PeptiCRAd-1: Interim clinical evaluation of a modular oncolytic adenovirus vaccine platform targeting NY-ESO-1 and MAGE-A3 in advanced solid tumors.
2604 Background: Oncolytic viruses can convert poorly immunogenic tumors into inflamed, immune-responsive lesions, but clinical benefit is often limited by insufficient induction of tumor antigen–specific T cells. PeptiCRAd-1 is a novel peptide-guided oncolytic adenoviral immunotherapy designed to deliver tumor antigens while providing intrinsic immune stimulation. It consists of a conditionally replicating adenovirus expressing CD40L and OX40L and coated with NY-ESO-1 and MAGE-A3 peptides to enhance priming of antigen-specific adaptive immunity. Methods: VALO-001 (NCT05492682) is an ongoing, open-label, non-randomized phase 1 trial enrolling adults with injectable advanced solid tumors expressing NY-ESO-1 and/or MAGE-A3, including melanoma, TNBC, NSCLC, sarcomas, and colorectal cancer. Treatment includes low-dose cyclophosphamide followed by intratumoral PeptiCRAd-1 prime/boost injections combined with pembrolizumab. Primary objectives are safety and tolerability; secondary/exploratory endpoints assess innate and adaptive immune activation: antigen-specific T-cell induction, tumor-infiltrating lymphocyte (TIL) density, viral shedding, and preliminary antitumor activity. Immune monitoring includes cytokine profiling, ELISpot for NY-ESO-1/MAGE-A3 responses, and paired biopsies for multiparametric immunophenotyping. Results: Seven patients have been enrolled and treated in the START Phase 1 evaluation of PeptiCRAd-1: five in the intratumoral (i.t.) cohort and two in the combined intratumoral plus subcutaneous (i.t. + s.c.) cohort. Across both groups, study treatment has been feasible and well tolerated, with no dose-limiting toxicities, treatment-related serious adverse events, or unexpected safety signals reported to date. In the i.t. cohort, innate immune activation occurred in 3/5 patients; NY-ESO-1/MAGE-A3-specific T-cell responses in 3/5; and increased TILs in 4/5. Clinical responses were observed in 2/5, with disease control in 3/5 patients. Early i.t. + s.c. data show markedly stronger peptide-specific T-cell responses than i.t. alone, supporting combined local–systemic immunization. This cohort remains open, with eight additional patients required. Across evaluable patients, biopsies demonstrated increased TIL density, and early antitumor activity—including partial responses and durable stable disease—was observed across multiple tumor types. Conclusions: PeptiCRAd-1 shows a favorable safety profile and induces coordinated systemic and intratumoral immune activation in advanced solid tumors. Robust antigen-specific T-cell responses and enhanced TIL infiltration support its potential to strengthen antitumor immunity and justify continued evaluation, including combination with PD-1 blockade. Clinical trial information: NCT05492682 .
Real-world (RW) characteristics and outcomes in platinum-resistant ovarian cancer (PROC) patients treated with mirvetuximab soravtansine (MIRV) monotherapy or single-agent chemotherapy (CTx).
e17606 Background: The phase 3 MIRASOL trial showed that MIRV significantly improved median PFS (5.62 mo) and OS (16.46 mo) vs CTx (PFS: 3.98 mo; OS: 12.75 mo) in adult patients (pts) with FRα positive PROC after 1-3 prior systemic lines of therapy (LOT). Given potential differences between pts treated in routine clinical practice and those enrolled in trials, this study evaluated patient characteristics and outcomes of MIRV monotherapy and single-agent CTx in a RW setting. Methods: This retrospective cohort study used the US-based electronic health record-derived deidentified Flatiron Health Research Database (2011–2025) to identify PROC patients who received either MIRV monotherapy after Nov. 2022 or single-agent CTx (topotecan, paclitaxel, or doxorubicin) after Jan. 2020 (index therapy). Baseline clinicodemographic and biomarker data were recorded for all pts. RW median PFS (mPFS) and OS (mOS) were evaluated for the index therapy using Kaplan–Meier estimates. Scaled RW adverse event (AE) data were described for MIRV pts. Results: There were 129 pts included in the MIRV and 342 pts in the CTx cohorts. While baseline characteristics were largely comparable between groups (Table 1), our study cohort was more clinically diverse than MIRASOL, including primary platinum-refractory pts and a wider range of prior LOT (1-11 vs 1-3). The RW mPFS (95% CI) for MIRV- and CTx-treated pts was 5.65 (4.30–6.21) mo and 3.38 (3.02–3.94) mo, respectively. RW mOS for CTx-treated pts was 7.59 (6.08–8.56) mo. RW mOS data for MIRV-treated pts were not yet mature. In a subgroup of pts with 1-3 prior LOT and no primary platinum refractory disease, the RW mPFS was 5.33 (4.00–7.31) mo and 3.09 (2.76–3.84) mo for MIRV- (n=76) and CTx-treated (n=194) pts, respectively. Scaled RW AE data remain consistent with the previously established safety profile of MIRV. Conclusions: In the RW setting, MIRV monotherapy in PROC patients showed comparable PFS to MIRASOL. These results support the generalizability of trial findings to routine clinical practice and potentially to a broader patient spectrum, as well as demonstrate a consistent MIRV safety profile in RW patients beyond the MIRASOL trial population. Patient Characteristics MIRV Pts (N=129) CTx Pts (N=342) Age, median, y 68 68 Race, White, % 65.9 67.8 Community setting, % 73.6 72.8 Serous Histology, % 88.4 72.2 Stage III/IV at diagnosis, % 78.3 76.6 1-3 prior LOT, % 66.7 67.8 Primary platinum-refractory a , % 10.1 14.3 Prior bevacizumab, % 82.9 72.5 Prior PARPi, % 61.2 48.0 Abbreviations: CTx, single-agent chemotherapy; LOT, lines of therapy; MIRV, mirvetuximab soravtansine; PARPi, poly (ADP-ribose) polymerase inhibitor. a Defined as disease that progressed during a platinum-based regimen or has progressed within 4 weeks of the last dose of first-line platinum-containing CTx.
A phase II study of neoadjuvant cemiplimab in hedgehog inhibitor (HHI)–naive basal cell carcinoma of the head and neck.
9515 Background: Surgical resection of locally advanced basal cell carcinoma of the head and neck (BCCHN) often carries significant morbidity. This phase II study seeks to investigate the response to neoadjuvant cemiplimab on surgical morbidity in BCCHN patients. Methods: In this prospective, nonrandomized, multicenter, phase II trial (NCT05929664), anti-PD1 and HHI-naive patients with resectable BCCHN received 2 to 6 cycles of cemiplimab (350mg IV Q21 days), followed by surgical resection or biopsy. Surgical plan at enrollment required functional organ sacrifice (orbit, eyelid, ear, nose, lip, or facial nerve). RECISTv1.1 tumor measurements were performed every 2 cycles to determine primary endpoints of ORR and DCR. Patients with PD (>20% growth) or SD with 5 to 20% growth at any assessment were offered HHI or surgery. Patients with CR at any assessment proceeded to surgery or directed biopsy. Secondary endpoints included: surgical benefit rate (SBR, defined as rate of functional organ preservation, determined by the investigator, comparing surgical resection to surgical plan at time of enrollment), rate of pCR, safety (CTCAEv5.0), and quality of life (FHNSI, FACE-Q and VFQ-25). Correlative studies include examination of the tumor immune microenvironment related to functional changes in immune cell composition. Results: Between August 2023 and September 2025, 33 patients were enrolled: 40-89 yo; 22 M/11 F; sites of disease included eyelid (n=17), orbit (n=4), nose(n=5), lip (n=1), facial nerve (n=1), ear (n=1), and scalp or cheek (n=5). 30 were evaluable: 23 (76.7%) completed 6 cycles. Among the remaining 7 patients, 1 experienced CR after 4 cycles; 1 was taken off therapy for grade 3 myalgia; 1 had SD with 5-20% growth and 2 had PD, and were taken to surgery per protocol; 2 chose surgery due to stagnant response after initial PR. 12 patients (40%) experienced a grade 1-2 treatment-related AE. 1 patient (3.33%) experienced a grade 3 treatment-related AE as above. The ORR was 66.67%. The DCR was 90.0%. Based on RECISTv1.1 criteria, 3.33% (n=1) had CR, 63.33% (n=19) had PR, 23.33% (n=7) had SD, and 10.0% (n=3) had PD as best overall response 8 patients (26.67%) achieved pCR. The SBR was 43.3%, with functional preservation of the eyelid (n=7), nose (n=2), lip (n=1), ear (n=1), or orbit (n=1). Conclusions: Neoadjuvant cemiplimab had an acceptable safety profile and shows promising efficacy in the treatment of advanced, surgically-resectable BCCHN. This novel approach may alleviate the morbidity of subsequent surgical resection. (NCT05929664 supported by Regeneron Pharmaceuticals, Inc.). Clinical trial information: NCT05929664 .
Validation of prostate-specific antigen (PSA) decline among the Latin American subgroup of LIBERTAS: A phase 3 study of apalutamide (APA) plus continuous versus intermittent androgen deprivation therapy (ADT) in metastatic castration-sensitive prostate cancer (mCSPC).
5021 Background: APA in combination with continuous ADT showed rapid and deep PSA decline in participants (pts) with mCSPC in the TITAN study, and this deep PSA decline was associated with improved overall survival. LIBERTAS (NCT05884398), a global phase 3 study, is evaluating APA + intermittent ADT as an ADT de-escalation strategy for pts with mCSPC who achieve an undetectable PSA ( < 0.2 ng/mL) after 6 months on APA + ADT. In the initial treatment phase of LIBERTAS, 6 months of APA + continuous ADT resulted in deep PSA responses in the majority of pts with mCSPC. Methods: Pts with mCSPC were eligible if they had ≤3 months of prior ADT, ECOG PS 0–1 and confirmed metastases by conventional or next-generation imaging. In the initial 6-month treatment phase, all pts received APA 240 mg/day + ADT. In the main treatment phase, pts with < 0.2 ng/mL were randomized 1:1 to APA 240 mg/day + intermittent or continuous ADT. Co-primary endpoints were radiographic progression-free survival (rPFS), measured by the 18-month event-free survival rate, and reduction of hot flash burden, measured by the 18-month severity-adjusted hot flash score. Here, we present an analysis of the Latin American (LATAM) subgroup evaluating PSA response results following the initial treatment phase. Results: From Dec 2023 to July 2024, 118 LATAM pts were enrolled (87 pts from 7 sites in Brazil, and 31 pts from 4 sites in Mexico). Racial distribution in LATAM pts was 60.2% White, 10.2% Black, 9.3% Multiple, and 17.8% other. LATAM pts were younger (median age 67 years [range: 48–86]) and had more advanced disease (89.0% with M1 disease at diagnosis; 39.8% with ECOG PS 1, 66.1% with high volume disease; median baseline PSA 22.95 ng/mL [IQR: 3.18–87.00]) compared with the overall study population. Among 109 pts who completed the 6-month initial treatment phase, 104 (95.4%) achieved a ≥50% PSA decline (PSA50), 90 (82.6%) achieved a ≥90% decline (PSA90), and 66 (60.6%) achieved PSA < 0.2 ng/mL (PSA0.2), of which 62 (56.9%) pts were randomized to the main treatment phase. Median time to response was 1.87 months for PSA50, 1.91 months for PSA90, and 3.14 months for PSA0.2. No new safety signals were observed in the LATAM subgroup. Conclusions: LATAM pts in LIBERTAS were younger on average and had more advanced disease compared with the overall study population. Despite having higher baseline PSA levels, LATAM pts with mCSPC demonstrated rapid and deep PSA responses to APA + ADT, consistent with the results from the global analysis. The safety profile of APA was consistent with previous studies. The LIBERTAS study remains on track for the primary readout. Clinical trial information: NCT05884398 .
Phase 1/2 OMAHA-U01 substudy 01A: Oral steroidogenesis inhibitor opevesostat alone or in combination with other therapies in participants with metastatic castration-resistant prostate cancer (mCRPC).
TPS5140 Background: mCRPC remains an incurable disease and therapeutic agents with novel mechanisms of action are needed for this patient population. Opevesostat (MK-5684; ODM-208), an oral steroidogenesis inhibitor, selectively inhibits cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. In the phase 1/2 CYPIDES study, opevesostat showed antitumor activity in participants with heavily pretreated mCRPC. OMAHA-U01 is an adaptive, open-label, rolling-arm, multicenter, phase 1/2 umbrella study designed to evaluate opevesostat-based investigational therapies in participants with prostate cancer. Substudy 01A (NCT06353386) will evaluate the safety and efficacy of opevesostat alone or in combination with other therapies in participants with previously treated mCRPC. Methods: Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening, and on or after 1-2 androgen receptor pathway inhibitors for metastatic or nonmetastatic hormone-sensitive prostate cancer and nonmetastatic or mCRPC. Prior treatment with ≤1 taxane-based chemotherapy regimen for mCRPC is allowed. A safety lead-in phase for all opevesostat-based experimental combinations (~10 participants in each arm) will establish the recommended phase 2 dose (RP2D), followed by an efficacy phase (opevesostat alone, ≤100 participants; opevesostat-based combinations, ~40 participants each). Participants will be randomly assigned 1:1:1:1 to receive opevesostat 5 mg PO BID, opevesostat 5 mg PO BID plus olaparib (RP2D), opevesostat 5 mg PO BID plus docetaxel (RP2D), or opevesostat 5 mg PO BID plus cabazitaxel (RP2D). Randomization for the efficacy phase will be stratified according to AR-LBD mutation (AR-LBDm) status (positive or negative). The primary end point for the safety lead-in phase is safety and tolerability. Primary end points for the efficacy phase are safety and prostate-specific antigen response rate per Prostate Cancer Clinical Trials Working Group (PCWG) criteria. Secondary end points include objective response rate and radiographic progression-free survival per PCWG-modified RECIST v1.1 by blinded independent central review (BICR), overall survival, duration of response by BICR, time to first subsequent anticancer therapy, and time to pain progression. The predefined eligibility cap for pts with AR-LBDm-negative status has been reached, and the study is currently only enrolling pts with AR-LBDm-positive status. Clinical trial information: NCT06353386 .
A HER2-targeted NIR-II fluorescent nanoprobe for precision diagnosis and treatment of HER2-positive breast cancer.
e13026 Background: Breast cancer is the most common malignancy and a leading cause of cancer mortality worldwide. HER2-positive breast cancer, characterized by high aggressiveness and frequent therapy resistance, poses a significant clinical challenge. While antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (DS-8201) have improved treatment, the emergence of resistance limits their efficacy. Thus, developing innovative theranostic strategies to overcome these limitations is imperative. Methods: A stable DS-8201-resistant breast cancer cell line was established. RNA-seq analyzed resistance mechanisms and identified potential therapeutic targets. A novel actively targeted NIR-II fluorescent nanoprobe (DS-8201-ICG) was then constructed by conjugating DS-8201 with indocyanine green (ICG). This probe enables high-contrast deep-tissue imaging and real-time intraoperative navigation. Furthermore, based on immunosuppressive pathways identified via transcriptomics, the combined efficacy of the probe with immune checkpoint inhibitors was evaluated in vivo . Results: We established a DS-8201-resistant cell line with a stable resistant phenotype. Transcriptomics suggested the involvement of immune checkpoint pathways in resistance. The DS-8201-ICG nanoprobe exhibited excellent solubility, stable fluorescence, and high-affinity binding to HER2-positive cells. It showed favorable biocompatibility and safety in vitro and in vivo . In an orthotopic mouse model, the probe (2 mg/kg) provided clear tumor visualization 36 h post-injection via NIR-II imaging. Tumor fluorescence was 5-fold higher than normal tissue (TBR ≈ 5), enhancing margin delineation and micro-lesion detection to guide precise resection and potentially overcome resistance. Conclusions: We developed a novel HER2-targeted NIR-II imaging nanoprobe based on trastuzumab deruxtecan. This theranostic probe enables precise intraoperative visualization and resection of HER2-positive breast cancer, and its combination with mechanism-informed immunotherapy represents a novel strategy to overcome DS-8201 resistance.
Impact of access to effective post-progression therapies on survival outcomes in first-line randomized oncology trials.
1500 Background: Effective anticancer systemic therapies are expected to improve overall survival (OS) or quality of life in randomized controlled trials (RCTs) for patients with cancer. However, access to effective post-progression therapies in control arms is inconsistent and may confound the observed OS benefits, especially for agents with known survival benefit in later lines. Here, we investigated whether control-arm post-progression access to effective therapies is associated with improved OS. Methods: This cross-sectional analysis included 52 phase II–III RCTs published between 2010 - 2025 in selected high impact journals. Eligible trials evaluated first line targeted therapies (TT), immune checkpoint blockers (ICB), or hormone therapy (HT) in the experimental arm for advanced lung, breast, or prostate cancer, where the investigational agent had proven OS benefit in later lines. Post-progression access to effective therapies was quantified as the proportion of patients in the control arm receiving the investigational agent (or similar class) relative to all pts randomized to control arm (Ratio_Effective/Control), and relative to patients receiving any subsequent treatment (Ratio_Effective/Therapy). Correlations between the ratio of post-progression access and OS HRs were assessed, with prespecified subgroup analyses by treatment class and tumor type. Geographic distribution was evaluated in trials reporting enrollment by region. Results: Across all trials, the mean proportion of patients in the control-arm receiving any post-progression therapy was 66% (SD 14%), of which 42% (SD 22%) received an effective therapy (or, 62.5%, considering relative numbers). Post-progression access differed significantly by tumor type (p < 0.001), with the lowest rate in breast cancer, followed by prostate and lung cancer. The median proportion of pts enrolled outside the United States and Europe (US/EU) was 36%. The overall median HR for OS was 0.78. No correlation was observed between rate of post-progression access to effective therapies and the HR for OS across studies. However, in TT trials, higher post-progression access to effective treatments was moderately associated with a less pronounced OS benefit (r = 0.44, p = 0.056, Ratio_Effective/Control and r = 0.46, p = 0.046, Ratio_Effective/Therapy). No association was observed in RCTs evaluating ICB. The difference in the correlation between the TT and ICB trials was statistically significant (p = 0.032). No correlation was observed between ratio of effective therapies and tumor type, and enrollment outside of US/EU. Conclusions: Post-progression access to effective therapies in control arms influenced OS benefits in TT trials but not ICB trials in this study. These results warrant caution interpreting TT survival benefits and underscore the need for RCTs to report and standardize post-progression therapy access.
Survival outcomes associated with EGFR and HER2 alterations in advanced urothelial carcinoma treated with novel therapeutics.
e16571 Background: The efficacy of targeted therapies against EGFR and HER2 (ERBB2) has been investigated across multiple cancers, including advanced urothelial carcinoma (aUC). However, the prognostic significance of these alterations remains unclear, particularly in the context of the recent approval of enfortumab vedotin plus pembrolizumab (EVP) as first-line therapy in December 2023. Methods: Flatiron Health's de-identified EHR database was used to identify aUC patients from US cancer clinics 04/09/2021-05/31/2025. Baseline characteristics, first-line treatment (carboplatin, cisplatin, immunotherapy, EVP, or other), and overall survival (OS) time were abstracted. Patients were categorized by EGFR and ERBB2 alteration status—short variants, copy number variants (CNVs), or rearrangements. Chi-square tests evaluated associations of categorical variables. OS in patients with EGFR and ERBB2 alterations versus wild-type (WT) patients was estimated using Kaplan-Meier curves. Log-rank and Cox regression analyses were used to evaluate if EGFR and ERBB2 status modified the effect of first-line therapy on OS. Results: Of the 905 patients identified, 634 were wild type (WT), 209 (23.1%) had ERBB2 alterations, and 79 (8.7%) had EGFR alterations. Of the 209 with ERBB2 alterations, 12 had rearrangements, 103 CNVs, and 138 short variants. Of the 79 with EGFR alterations, 3 had rearrangements, 24 CNVs, and 57 short variants. Alterations were not associated with a specific first-line therapy, race, or ECOG performance status. Men had a higher frequency of ERBB2 alterations vs women (25.6% vs 17.0%, p = 0.0053) but not EGFR alterations (8.9% vs 8.3%, p = 0.80). Patients with ERBB2 alterations had longer OS than WT patients (median 23.2 months vs 16.1 months; HR = 0.57, p <0.000001). Longer OS was associated with ERBB2 CNVs (p<0.0001) and short alterations (p <0.0001). ERBB2 alteration was associated with longer OS compared to WT among patients treated with immunotherapy (HR = 0.48, 95% CI 0.26–0.86, p = 0.014). This finding held true for both ERBB2 CNVs (p = 0.049) and short alterations (p = 0.0084). No difference in OS was observed for patients with EGFR alterations. OS did not significantly differ between patients treated with EVP vs platinum chemotherapy, regardless of EGFR and ERBB2 alteration status. Conclusions: ERBB2 alterations were associated with longer OS compared to WT, especially among patients treated with immunotherapy. EGFR status was not correlated with survival. EGFR and ERBB alterations in aUC. EGFR alterations (n=79) ERBB2 alterations (n=209) WT (n=634) Sig (p) Baseline Characteristics ECOG PS 0-1 (%) 63.3 65.5 64.2 0.942 2-4 (%) 11.4 11.5 13.1 1L Treatment IO (%) 27.8 35.4 33.7 *0.047 EVP (%) 17.7 12.0 12.9 Carboplatin (%) 17.7 21.5 16.8 Cisplatin (%) 20.3 21.1 20.2 Other (%) 12.7 6.7 16.2 Survival mOS (m) 12.0 23.2* 16.1 *p <0.000001
Outcome comparison of once versus twice daily dosing of zanubrutinib.
7049 Background: Zanubrutinib, a Bruton tyrosine kinase inhibitor (BTKi), approved as frontline treatment in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), can be dosed as 320mg once daily (QD) or 160mg twice daily (BID). In phase I trials 160mg BID and 320mg QD achieved comparable BTK occupancy in peripheral blood. While most clinical trials utilized BID dosing, there is limited data evaluating outcomes between regimens. Thus, we performed a retrospective study comparing outcomes of QD vs BID dosing of zanubrutinib in frontline CLL/SLL patients (pts). Methods: We conducted a single center retrospective study evaluating pts with CLL/SLL treated with zanubrutinib QD vs BID at Weill Cornell Medical Center (May 1, 2020 - Feb 1, 2025). Included CLL/SLL pts were treated with frontline zanubrutinib and separated into 3 groups: 320mg QD (Group 1), 160mg BID (Group 2) and dose switch (Group 3). Pearson’s Chi-squared test and Fisher’s exact test were used to compare baseline characteristics. Progression-free survival (PFS) and overall survival (OS) were evaluated with Kaplan-Meier (KM) method and log-rank test was used to compare KM curves; however, few events limited statistical power and prevented formal survival comparison and are presented as descriptive only. The median follow-up time was estimated by reverse KM method. Results: We identified 23 pts initiated on QD dosing, 43 pts initiated on BID dosing, and 33 pts who switched groups. Thirty pts switched from BID to QD and 3 pts from QD to BID. Median follow up time was 28.4 months. Median overall age was 71 with 60% male. There were no differences in age, sex, immunoglobulin heavy chain gene (IGHV) mutational status or incidence of complex karyotype, del11q, del13q, del17p, trisomy 12 and TP53 mutations. There was 1 death (Group 2) due to a second cancer. OS KM curves visually appeared similar (p=0.62). One pt in Group 2 and 2 pts in Group 3 progressed on zanubrutinib. PFS KM curves were visually similar (p=0.88). Twenty-two (22.2%) pts discontinued therapy due to intolerance. In Group 1, one pt (4.3%) discontinued for hypertension (HTN). In Group 2, 17/43 (39.5%) pts discontinued for rash (29.4%), infection (17.6%), bruising/bleeding (17.6%), HTN (11.7%), atrial fibrillation (11.7%) and diagnosis of second cancer (11.7%). In Group 3, 4/33 (12.1%) pts stopped for rash (50%) and HTN (50%). Zanubrutinib cessation was lower in QD vs BID (p < 0.002). Conclusions: We retrospectively compared QD vs BID dosing of zanubrutinib to evaluate impact on outcomes. While lack of progression and death limited our ability to make definitive statements on PFS or OS, we observed overlap of KM curves with 2 years of follow-up. We observed a lower treatment discontinuation rate with QD dosing. Our results suggest QD dosing in frontline CLL/SLL may improve tolerability while maintaining comparable efficacy. Further research is needed to confirm real-world non-inferiority of these safety and survival outcomes.
GT101 autologous TIL therapy in patients with recurrent and metastatic cervical cancer: A phase 1 study.
5532 Background: Adoptive cell therapy with autologous TILs has shown durable clinical benefit in selected advanced solid tumors after progression on standard therapies. We report results from a phase I, open-label, single-arm, multicenter trial (NCT05430373) evaluating GT101 in patients with recurrent or metastatic cervical cancer. Primary objectives were safety; second objectives included preliminary efficacy and PK. Methods: Eleven patients with recurrent or metastatic cervical cancer received a lymphodepletion regimen followed by GT101 infusion and high-dose IL-2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and adverse events (AEs), graded per CTCAE v5.0. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS), assessed by RECIST v1.1. Flow cytometry of immune cells and T cell receptor (TCR) sequencing were performed on peripheral blood samples collected from patients before and after treatment. Results: As of September, 2025, 11 patients were treated (median age was 48 years; median two prior lines of therapy). Following FC lymphodepletion, patients received GT101 at doses ≥5×10⁹ viable cells (median 4.1×10¹⁰), followed by high-dose IL-2 (600,000 IU/kg, up to 6 doses). Most AEs were Grade 1-2. Grade ≥3 AEs were primarily related to lymphodepletion and IL-2, and included lymphopenia, leukopenia, neutropenia, anemia, pyrexia, and thrombocytopenia; most resolved or improved to Grade ≤2 within 14 days. The ORR was 45.5% (5/11), with DCR of 90.9% (10/11). Median DoR was 6.4 month. Four patients (36.4%) achieved confirmed PR, one patient (9.1%) achieved a CR, and five patients (45.5%) had stable disease (SD). Median PFS was 4.83 months; OS follow-up is ongoing. One patient with stage IIIC2 cervical squamous cell carcinoma achieved a confirmed CR lasting 14.5 months, with tumor burden reduced from a baseline sum of diameters of 71.57 mm to complete resolution by Week 12. Pharmacokinetics and Correlation Analyses: Peripheral blood analyses demonstrated peak circulating T cells 5-7 days post-infusion, followed by contraction to near-baseline by two weeks. Responders exhibited lower proportions of CD39 + PD-1 + T cells. TIL infusion increased T-cell clonal diversity in all patients, with greater expansion observed in non-responders who has lower baseline diversity; persistence of TIL-derived clones did not differ consistently between groups. Conclusions: GT101 demonstrated a manageable safety profile with no treatment-related SAEs or dose-limiting toxicities and showed clinically meaningful and durable antitumor activity in recurrent or metastatic cervical cancer. These findings support further clinical development, and a pivotal phase II study is ongoing. Clinical trial information: NCT05430373 .
Genomic classifier–driven NCCN risk reclassification to track distinct transcriptomic signatures in early prostate cancer.
5013 Background: NCCN clinicopathologic risk stratification in early prostate cancer (EPC) may under- or overestimate biologic risk and contribute to over- or undertreatment. The RNA-based Decipher genomic classifier (DGC), endorsed by NCCN, frequently drives NCCN risk reclassification, yet the transcriptomic biology that tracks with reclassification remains incompletely defined. We investigated whole-transcriptome signatures underlying DGC-based risk stratification and NCCN risk reclassification in a real-world EPC cohort. Methods: We performed a retrospective, real-world analysis, of prostate biopsy Decipher testing of 1,272 men with EPC, using the Decipher genomic classifier clinical database (Veracyte, San Diego, CA) and the GRID RWD registry (NCT02609269). Associations between NCCN risk reclassification and clinicopathologic variables (PSA, clinical T stage, and Gleason Grade Group) were evaluated, along with genomic risk scores, transcriptomic signatures, and a panel of gene expression signatures associated with adverse molecular features, including androgen receptor (AR) signaling, PAM50 subtype (Luminal B), inferred TP53/PTEN activity, and pathways related to proliferation, DNA repair, and immune response. Results: By DGC, 21% of tumors were classified as low risk, 34% as intermediate risk, and 45% as high risk. Decipher testing resulted in NCCN risk up-classification in 38% and down-classification in 19%, while 43% remained in the same NCCN risk category. Whole-transcriptome analysis revealed distinct molecular patterns across reclassification groups. Tumors that were up-classified exhibited a shift toward a more proliferative, less androgen-dependent phenotype, with significant increases (p < 0.05) in proliferation, DNA-repair, and immune-related pathways, increased Luminal B prevalence, reduced androgen receptor (AR) signaling, and decreased TP53 and PTEN activity. In contrast, down-classified tumors demonstrated significant downregulation of proliferation, DNA-repair, and immune-related pathways, with preservation of AR signaling and PTEN activity (p < 0.05). Conclusions: Genomic classifier–driven NCCN risk reclassification tracks coherent transcriptomic patterns that extend beyond clinicopathologic stratification. Higher genomic risk and up-classification align with Luminal B enrichment, reduced AR signaling, and loss of TP53/PTEN activity, supporting the clinical and biological validity of genomic risk refinement beyond conventional NCCN classification.
Real-world outcomes of larotrectinib in solid tumors with tropomyosin receptor kinase fusion (GETNE S2411/SPAINTRK).
e23344 Background: NTRK gene fusions have been described as oncogenic drivers in diverse adult and paediatric cancers, as they promote cell survival and proliferation. Larotrectinib is a first-in-class TRK inhibitor with proven activity in a broad range of solid tumors. This study aimed to describe the effectiveness of larotrectinib in patients with solid tumors harbouring NTRK fusions in Spain. Methods: SPAINTRK is an observational, retrospective study that included adult and paediatric patients with a confirmed diagnosis of solid neoplasms bearing NTRK fusions. All patients were treated with larotrectinib in the context of the compassionate drug use program between EMA approval and commercialisation in Spain (October 2019 – September 2023). Patients treated with larotrectinib in clinical trials were excluded. NTRK fusions were detected using NGS, FISH, and/or IHC, along with confirmatory molecular test. The primary endpoint was to determine the effectiveness of larotrectinib using Duration of Response (DoR). The secondary endpoints were objective response rate (ORR) and safety. Results: Between February and June 2025, 20 patients from ten months to 81 years were included, 15 adults and 5 paediatrics. Eight different solid tumor types with NTRK fusions were represented. NTRK fusions were reported in NTRK1 gene (40%), NTRK2 (25%) and NTRK3 (35%), 65% of patients were diagnosed using NGS. Larotrectinib was administered for a median of 13 months (95% CI: 8-21). 45% of patients received larotrectinib as first-line treatment while 55% had received previous treatments. After a median follow-up of 24.4 months (95% CI: 13.2-35), the median DoR was 24.5 months (95% CI: 11.1- not reached) and ORR was 60% (95% CI: 36.1-80.9). ORR was higher among pediatric patients (80%; 95% CI: 28.4-99.5). The highest ORR were seen among patients with infant fibrosarcoma (100%; 95% CI: 29.2-100) and lung tumors (80%; 95% CI: 28.44-99.5). After 1 year of treatment, 60% of patients remained progression-free and 75% of the patients who showed response maintained it. At data cutoff, 41.7% of the patients with a response were disease-free and/or remained on treatment. Treatment-related AEs were uncommon, with neutropenia and transaminitis being the most frequent, reported in up to 15% of patients each. Conclusions: Larotrectinib evoked long antitumor responses in solid tumours with NTRK fusion in the real world, regardless of the tumor type. No safety concerns were reported, even after long-term administration. Screening techniques such as NGS should be implemented, and although its use is increasing, broader access is required. Clinical trial information: NCT06837090 .