Citations

TPS6138 Background: Patients with early-stage oral cavity cancer (OCC; T1-2N0M0; AJCC 8th edition) have a 20-30% risk of occult nodal metastases despite clinical and radiographic evaluations. Standard-of-care treatment for most patients includes elective neck dissection (END), which requires surgical removal of the regional cervical lymph nodes, even though 70-80% of these necks are disease-free. Sentinel lymph node biopsy (SLN Bx), a less invasive procedure, could assess the first echelon lymph nodes as an alternative to END, potentially reducing morbidity and costs. A pivotal clinical trial comparing SLN Bx to END (NCT#04333537) is underway to inform efforts to establish optimal disease management for early-stage OCC. Methods: To assess the efficacy of SLN Bx in this population, we activated an international, multi-institutional, prospective phase II/III trial in July 2020, randomizing patients to two surgical arms: SLN Bx and END. A node-negative 18 F-FDG PET/CT imaging biomarker study with centralized read was required before randomization. OCC patients with a positive PET/CT remained in a registry to compare imaging findings with final neck pathology. Given the current evidence on morbidity for SLN Bx versus END, the phase II was designed to determine whether the change in patient-reported neck and shoulder function and related quality of life (QOL) from baseline to 6 months after surgery, using the Neck Dissection Impairment Index (NDII), showed a signal of superiority of SLN Bx compared to END (minimum important difference ³ 7.5; one-sided a = 0.10; 90% power). As of December 2024, 261 patients had been randomized and 203 were analyzed for the “Go/No-Go” decision to move forward into phase III. The phase III portion is a non-inferiority (NI) trial with disease-free survival (DFS) as the primary endpoint (NI margin hazard ratio 1.34 based on a 5% absolute difference in 2-year DFS; one-sided a = 0.05; 80% power, and two interim looks). The change in NDII from baseline to 6 months after surgery is a hierarchical co-primary endpoint for phase III. Phase III opened in October 2025 upon receiving a “Go” signal from phase II. Target accrual for phase III is 686 node-negative PET/CT patients, including those randomized in phase II (425 additional patients). In addition to sites requiring radiotherapy and imaging credentialing, quality assurance will include central pathology review of all negative SLN Bx cases and surgeon credentialing through an education course with SLN Bx and END case review by the surgical co-chairs. A surgical quality assurance working group will review all trial SLN Bx and END procedures. As of 01/12/26, 351 patients have been screened, and 273 of the planned 686 have been randomized. Clinical trial information: NCT#04333537 .

TPS6126 Background: Oral cavity cancers (OCC) are a rare subtype of head and neck cancer (HNC) with poor outcomes and limited second-line treatment options in the recurrent or metastatic (R/M) setting. Treatment-related morbidity and repeated local recurrences in OCC result in significant impairment of function and quality of life. Rural OCC patients comprise a sizable portion (50%) of our practice and are usually of lower socioeconomic status with lack of access to specialist care. They also have multiple barriers to treatment access and ancillary services, translating to poorer clinical outcomes. There is a critical need for effective and accessible therapies for R/M OCC in rural patients. Triple oral metronomic chemotherapy (TOMC) with Methotrexate, Erlotinib and Celecoxib (MEC) suppresses angiogenesis and activates antitumor microenvironment in HNC. Studies using TOMC in R/M OCC outside the US show reasonable efficacy (6-month OS 52.9%), better safety and lower cost compared to standard second line options. We hypothesize that a decentralized clinical trial with TOMC in R/M OCC is feasible, safe and effective in addition to being economical and accessible for rural patients. Methods: MC240701 is a single institution, open label, decentralized, single arm pilot study of MEC in patients with R/M OCC. Eligible pts must be ≥18 years old, have pathologically confirmed R/M OCC not amenable to curative-intent therapy, ECOG 0-2 and adequate organ function. At least 1 measurable lesion by RECIST 1.1 OR non-measurable disease (evident mucosal lesions, CNS/bone disease, lesions not meeting RECIST criteria) is permitted. Patients must have received standard first line immunotherapy with or without chemotherapy OR should be unable/unwilling to receive first line treatment. Key exclusion criteria include patients unable to take pills by mouth, serious medical co-morbidity or autoimmune disease, immunocompromised patients and other active malignancy. Primary endpoint is to demonstrate feasibility of decentralized clinical trials, secondary outcomes include overall response rate, progression free and overall survival and toxicity. Additional goals are to evaluate patient impact of decentralized treatment through surveys and interviews After initial screening and evaluation, patients are remotely consented and will receive study drugs by mail. All patients will receive the same treatment of Methotrexate 9mg/m 2 PO weekly, Erlotinib 150 mg PO daily, and Celecoxib 200 mg PO BID, each cycle will be 28 days. Treatment will continue until disease progression or treatment tolerance, study duration is for 2 years. All subsequent clinical and laboratory monitoring and response assessments (every 3 cycles) will be remotely performed or have an option for local testing. Enrollment began July 2025 and 4 out of planned 25 patients have been accrued. FDA IND:174540. Clinical trial information: NCT06997068 .

TPS5632 Background: Concurrent chemoradiation therapy (CCRT) is the standard of care for locally advanced cervical cancer (LACC); however, outcomes remain suboptimal in patients with high-risk disease. Recent studies suggest that integration of immunotherapy (IO) with definitive chemoradiation, or induction chemotherapy prior to CCRT improves outcomes. Whether treatment intensification with induction systemic therapy and IO prior to CCRT and IO further improves disease control remains unknown. Induction chemotherapy may reduce tumor burden, eradicate micrometastatic disease, and improve tumor immunogenicity prior to definitive CCRT. Preclinical and clinical data support synergy between systemic therapy or radiotherapy and immune checkpoint blockade, providing the rationale for evaluating an induction strategy incorporating chemotherapy and immunotherapy before standard CCRT with immunotherapy, followed by maintenance immunotherapy. Optional tumor tissue and blood samples will be collected for exploratory correlative analyses, including immune and molecular biomarkers associated with response, resistance, and patterns of failure. Methods: NRG-GY037 is a prospective, multi-institutional phase III randomized trial conducted through NRG Oncology. A total of 336 patients will be enrolled (168 per arm). Patients will be stratified by FIGO stage (III vs. IVA) and presence or absence of para-aortic lymph nodes (N2). The primary endpoint is progression free survival (PFS). The study has 90% power to detect PFS hazard ratio of 0.65 in the experimental arm. Treatment: Patients with previously untreated, high-risk LACC are randomized to receive either induction chemotherapy with pembrolizumab for 6 weeks followed by CCRT with pembrolizumab and pembrolizumab maintenance, or standard CCRT with pembrolizumab followed by pembrolizumab maintenance. Major Eligibility Criteria: Eligible patients have histologically confirmed cervical carcinoma (squamous, adenocarcinoma, or adenosquamous), TNM T3 and T4 disease, N0-2, ECOG performance status 0–1, and no prior definitive therapy for cervical cancer. Current Enrollment Status: The trial is actively accruing patients. No efficacy or safety data are available at the time of submission. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT07061977. Clinical trial information: NCT07061977 .

TPS4642 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a Phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, Phase 2/3 trial. In Part A (Phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In Part B (Phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended Phase 3 dose (determined using Part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in Part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in Part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab (<6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of Part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of Part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (Part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (Part B). In Part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In Part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

TPS3686 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA–) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA– (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Accrual is 1,123/1,912 (as of 1/20/2026). *Drs. Dasari and Lieu contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

TPS3678 Background: Advanced and metastatic colorectal cancer (CRC) remains an area of significant unmet clinical need, particularly for patients with MSS/MSI-L tumors. In recent years, there have been several advancements in the treatment of solid tumors with T cell engagers. Our ATLAS scRNA-seq based discovery platform identified LY6G6D as a highly-specific tumor-associated antigen in advanced and metastatic CRC. CBI-1214, a CD3 bispecific T cell engager targeting LY6G6D with potent in vitro and in vivo activity even at low LY6G6D expression levels of ~300 copies/cell ( Yigit B et al, AACR 2025 ), is being developed for the treatment of patients with advanced or metastatic MSS/MSI-L CRC. Methods: This ongoing, open-label FIH study (CBI-1214-001) is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of CBI-1214 and to determine the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) in participants with advanced or metastatic MSS/MSI-L CRC who have exhausted at least one prior line of systemic treatment and do not qualify for available targeted treatment options for actionable genomic alterations. Additional eligibility criteria include: at least 18 years of age, measurable disease (as defined by RECIST v1.1), available archival tumor tissue sample or a fresh tumor sample, ECOG PS 0 or 1, as well as adequate hematologic and organ functions. Patients whose CRC tumor tissues have been identified as dMMR or MSI-H are excluded. The study is conducted in two parts: Part 1 dose escalation, which starts with Part 1a as accelerated dose escalation, followed by Part 1b escalation, which is based on a modified toxicity probability interval (mTPI-2) design, and Part 2, which is designed as a randomized dose optimization study to select the final recommended phase 2 dose (RP2D). For both parts of the study, the study intervention is administered as monotherapy, given as an intravenous (IV) infusion, in 21-day treatment cycles, with a step-up option. After an up-to-28-day screening period, eligible patients receive study medication and are followed for their entire treatment period plus a follow-up period of approximately 90 days. The study is open for recruitment in the United States (NCT07321106). Clinical trial information: NCT07321106 .

TPS3675 Background: Multi-agent chemotherapy regimens (eg, mFOLFOX6) ± anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor regimens are currently the standard of care for patients (pts) with mCRC without targetable mutations. However, the 5-year survival rate remains low at approximately 16% (SEER, 2025). The addition of biological therapies (eg, bevacizumab [bev], an anti-VEGF monoclonal antibody) to immune checkpoint inhibitors (ICIs) has demonstrated a synergistic antitumor effect in solid tumors. However, ICI monotherapy has limited activity in mismatch repair proficient (pMMR)/microsatellite stable (MSS) mCRC. Simultaneous bispecific targeting of programmed death 1 (PD-1) and VEGF in conjunction with cytotoxic chemotherapy has the potential to enhance antitumor activity. PF-08634404 is a fully human immunoglobulin G4 (IgG4) bispecific antibody targeting PD-1 and VEGF. A phase 2 study of PF-08634404 with XELOX or mFOLFOX6 demonstrated promising antitumor activity with a manageable safety profile in first-line (1L) mCRC (Xu X, ESMO 2025; Abstract 796P). Methods: Symbiotic-GI-03 (NCT07222800) is an ongoing, double-blind, randomized, phase 3 study evaluating the efficacy and safety of 1L PF-08634404 + mFOLFOX6 vs bev + mFOLFOX6. Inclusion criteria are age ≥18 y; mCRC with measurable disease per RECIST 1.1; no prior systemic therapy for metastatic disease; ECOG PS 0 or 1; and adequate hematologic, hepatic, and renal function. Pts with BRAF V600E-mutant or mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) CRC, active central nervous system metastases, or clinically significant risk of hemorrhage/fistula will be excluded. Approximately 800 pts will be randomized 1:1 to receive PF-08634404 + mFOLFOX6 or bev + mFOLFOX6 until disease progression, unacceptable toxicity, withdrawal of consent, or death. Randomization will be stratified by region (North America, Europe, or rest of world), RAS status (mutant or wildtype), and presence of liver metastasis (yes or no). The dual primary endpoints are progression-free survival (PFS) by blinded independent central review and overall survival; for each, a stratified log-rank test will be used to compare arms. Hazard ratios with corresponding 2-sided 95% CIs will be estimated using a stratified Cox proportional hazards model, and medians will be estimated using the Kaplan-Meier method with corresponding 2-sided 95% CIs calculated using the log(-log) method. Secondary endpoints include PFS by investigator, objective response rate, duration of response, PFS after next-line therapy, safety/tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes. Enrollment began in December 2025. Clinical trial information: NCT07222800 .

TPS3184 Background: Replication stress (RS) creates cancer cell vulnerability to which the critical DNA damage response kinase, ATR (Ataxia-Telangiectasia and Rad3-related) responds. ATR senses the stress, halts the cell cycle, and promotes DNA repair to allow proliferation. Alnodesertib is an ATR inhibitor developed to prevent cancer cells from successfully repairing RS and proliferating further. In earlier stages of alnodesertib development, preclinical and translational research demonstrated that tumor cells experience three combined biological insults: irinotecan-induced RS, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and RS rescue prevention by ATR inhibition. Data from the dose escalation and initial dose expansion cohorts of this trial in a tumor agnostic population showed encouraging results in ATM-negative cancers (confirmed Overall Response Rate of 50% in 20 patients with ATM negative cancers and responses across 8 cancer types including complete responses, Ulahannan et al, AACR 2025). Tumor-specific dose expansion cohorts are now enrolling, including colorectal cancer (CRC) and pancreas ductal adenocarcinoma (PDAC). Methods: Two tumor-specific cohorts are now open, each enrolling approximately 50 patients (pts): ATM-negative CRC and ATM-negative PDAC. Pts will receive the recommended dose of alnodesertib 200mg orally on days 1-3 and 8-10 combined with low-dose irinotecan 60mg/m 2 IV on days 1 and 8, of each 21-day cycle. Tumor tissue is prescreened by immunohistochemistry for ATM protein loss (H score 0) for enrollment eligibility. Pts with CRC must have received a maximum of 2 prior chemotherapies excluding prior trifluridine/tipiracil, fruquintinib, or regorafenib, and pts with PDAC must have received a maximum of 1 prior chemotherapy for advanced disease. Prior targeted agents are allowed and do not count as prior lines of therapy. Key objectives include safety, tolerability, and preliminary efficacy. Clinical trial information: NCT04657068 .

TPS3182 Background: MTAP deletion in solid tumors causes intracellular accumulation of methylthioadenosine (MTA) which partially inhibits activity of the key methylating enzyme, protein arginine methyltransferase 5 (PRMT5) and creates synthetic lethal dependencies on PRMT5 and methionine adenosyltransferase 2A (MAT2A), the rate limiting step in the synthesis of PRMT5 substrate, S-adenosyl methionine. PRMT5 and MAT2A are essential to transcription modulation, gene splicing, and DNA damage response. IDE892 is an MTA-cooperative PRMT5 inhibitor designed to exploit this vulnerability in MTAPdel tumors. Preclinical studies report robust antitumor activity with IDE892 monotherapy in MTAPdel xenograft models and an enhanced response when combined with IDE397 (an allosteric MAT2A inhibitor). IDE892-001 is a Phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of IDE892 alone and in combination with IDE397. Methods: IDE892-001 is an ongoing, open-label, multicenter four-part study: IDE892 monotherapy dose escalation (Part 1), monotherapy dose expansion in MTAPdel NSCLC (Part 2), IDE892 + IDE397 dose escalation (Part 3), and combination expansion in MTAPdel NSCLC (Part 4). Adults with advanced or metastatic MTAPdel solid tumors including lung, urothelial, gastrointestinal cancers (including pancreatic and biliary tract cancers) and mesothelioma are eligible following disease progression on standard therapies. Key exclusion criteria include symptomatic brain metastases, cardiac disease, active severe infection, and prior treatment with a PRMT5 or MAT2A inhibitor. Part 1 uses a Bayesian optimal interval design to determine maximum tolerated dose (MTD) and recommended doses for expansion (RDE). Part 3 uses a modified toxicity probability interval design to evaluate escalating combinations of IDE892 and IDE397. Oral treatment is given QD in 21-day cycles until progression or unacceptable toxicity. Serial blood samples are collected for PD analyses. Imaging will be performed every 6 weeks through week 24, then every 9–12 weeks. Efficacy endpoints will be assessed by RECIST v1.1. Primary objectives for dose-escalation cohorts (Parts 1 and 3) are safety and tolerability, including determination of MTD/RDE. In expansion cohorts (Parts 2 and 4), co-primary objectives include safety and preliminary antitumor activity (objective response rate and duration of response). Secondary endpoints for all parts include PK of IDE892 alone and in combination with IDE397. Exploratory assessments include progression free survival, changes in circulating and tumor-based markers of PRMT5 pathway modulation, molecular predictors of response, exposure–response relationships, and metabolite characterization. Clinical trial information: NCT07277413 .

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .