NRG Oncology

TPS256 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. Current accrual (as of 9-4-2025): 967/1,912. Drs. Lieu and Dasari contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

TPS279 Background: A total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone in those with locally advanced rectal cancer. Recent data indicate that optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to improve complete response rates. The use of FOLFIRINOX has shown to improve response and outcomes compared to CRT and surgery alone. Data have also shown that patients with clinical complete response (cCR) after TNT may be managed with a watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to improve cCR rates has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. We designed this NCI-sponsored study of chemotherapy intensification to address this and to increase cCR rates, provide opportunity for organ preservation, and survival outcomes. Methods: In this multigroup randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX (control arm)) or triplet chemotherapy (FOLFIRINOX (experimental arm)) for 3–4 months. LCRT in both arms involve 4500 cGy in 25 fractions over 5 weeks +900 cGy boost in 5 fractions with a fluoropyrimidine. Patients will undergo assessment 8–12 (±4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include overall survival, organ preservation time, time to distant metastasis, and adverse event rates. This study completed accrual as of July 2025 and is investigating exploratory correlatives (e.g., ctDNA). Support: U10CA180821, U10CA180882, U24 CA196171. https://acknowledgments.alliancefound.org. Clinicaltrials.gov ID: NCT05610163. Clinical trial information: NCT05610163 .

Background T cell engagers (TCEs) are powerful therapeutics which can kill cells expressing low levels of target antigen.To limit on-target off-tumor toxicity, it is critical to identify antigens with limited normal tissue expression or apply strategies for conditional engagement.While few antigens are completely tumor-specific, tumor cells may co-express pairs of antigens which are not co-expressed on normal cells.By selectively targeting such antigen pairs but not the individual antigens, AND-gated TCEs can impart anti-tumor efficacy with reduced toxicity.Here, we aimed to identify and validate a tumor-specific antigen pair for a potential AND-gated TCE.Methods Gene signatures were used to identify tumor cells in publicly available single cell RNA-sequencing (scRNA-seq) datasets for colorectal (CRC), 1 2 non-small cell lung (NSCLC), [3][4][5] and breast cancer (BC). 6 7Next, we compiled genes predicted to encode cell-surface proteins. 8To find coexpressed genes, Weighted Gene Correlation Network Analysis (WGCNA) was applied. 9were then analyzed for normal tissue expression using published scRNA-seq data. [10][11]1][12] For one tumor-specific pair, membrane co-expression was examined via multiplex immunohistochemistry (IHC) on normal and tumor tissue-derived microarrays (TMAs).In addition, five adenocarcinoma CRC tissue blocks with known mesothelin (MSLN) expression and five unbiasedly chosen mucinous CRC tissue blocks were also assessed.Results From 66 co-expressed tumor antigen pairs identified by WGCNA in more than one dataset, only three were tumor-specific.Target validation was pursued for mucin 13 (MUC13) and MSLN, due to expression of the pair in CRC and NSCLC and known toxicities of therapies targeting MSLN. [12][13]3][14][15] On a normal TMA, low levels of dual-positive staining for MUC13xMSLN were observed in 3 non-essential tissues.On tumor-derived TMAs, 37% (11/30) of CRC and 0% (0/30) of NSCLC samples were double-positive, consistent with the bioinformatics data where 18% (10/55) of CRC and 4% (2/50) of NSCLC patients showed co-expression.Doublepositive tissue blocks for adenocarcinoma (4/5) and mucinous CRC (3/5) showed respective fractions of double-positive cells of 1-15% and 1-50%.Conclusions To our knowledge, this is the first report of MUC13xMSLN as a potential tumor-specific antigen-pair in CRC.An AND-gated MUC13xMSLN TCE may reduce toxicities seen with MSLN therapies, although the percentage of patients expressing the target pair and the frequency of dualpositive cancer cells in these patients is relatively low.Overall, this data suggests the described bioinformatics and protein validation approach is suitable for identifying targets for ANDgated therapies in other cancer subtypes.

BackgroundThe benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear.MethodsWe evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, ≤2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant metastasis) who had ypN0 status after neoadjuvant chemotherapy were randomly assigned to receive regional nodal irradiation or no regional nodal irradiation. The primary end point was the interval of freedom from invasive breast cancer recurrence or death from breast cancer (invasive breast cancer recurrence–free interval). Secondary end points included the locoregional recurrence–free interval, the distant recurrence–free interval, disease-free survival, and overall survival. Safety was also assessed.ResultsA total of 1641 patients were enrolled in the trial; 1556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group. After a median follow-up of 59.5 months, 109 primary end-point events (50 in the irradiation group and 59 in the no-irradiation group) had occurred. Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence–free interval (hazard ratio, 0.88; 95% confidence interval, 0.60 to 1.28; P=0.51). Point estimates of survival free from the primary end-point events were 92.7% in the irradiation group and 91.8% in the no-irradiation group. Regional nodal irradiation did not increase the locoregional recurrence–free interval, the distant recurrence–free interval, disease-free survival, or overall survival. No deaths related to the protocol-specified therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group.ConclusionsThe addition of adjuvant regional nodal irradiation did not decrease the risk of invasive breast cancer recurrence or death from breast cancer in patients who had negative axillary nodes after neoadjuvant chemotherapy. (Funded by the National Institutes of Health; NSABP B-51–Radiation Therapy Oncology Group 1304 ClinicalTrials.gov number, NCT01872975.)