TPS3634 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 III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (SignateraTM, 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 vs. serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs. more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs. delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs 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. NCT#: NCT05174169. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .
BACKGROUND AND OBJECTIVE:To better understand the role of hormone therapy (HT) with postoperative radiotherapy (RT) for nonmetastatic prostate cancer, the DADSPORT Collaboration planned a systematic review and meta-analysis of aggregate data from randomised controlled trials (RCTs). METHODS:RCTs evaluating HT with postoperative RT in people with nonmetastatic prostate cancer were identified. Methods were prespecified prior to results of recent trials being known (CRD42022325769). The primary outcome was overall survival (OS); metastasis-free survival (MFS) and prostate cancer-specific survival (PCSS) were the secondary outcomes. Summary results, including those by prespecified participant subgroups, were obtained from investigators and combined across trials using a fixed-effect meta-analysis. Sensitivity and network meta-analyses evaluated the consistency of findings. KEY FINDINGS AND LIMITATIONS:Five RCTs (six trial comparisons, 4411 participants; 96% of all eligible) were included in the primary analysis. There was no clear evidence that OS was improved with HT (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.74-1.00, p = 0.057; absolute effect 2% [0-3.5%] at 8 yr) or that effects varied by HT duration (p = 0.6). Any benefit of HT on OS appears to be confined to people with higher pre-RT prostate specific antigen levels (p = 0.07) and CAPRA-S scores (p = 0.09). HT significantly improved MFS (HR = 0.78, 95% CI = 0.69-0.88, p < 0.001) and PCSS (HR = 0.61, 95% CI = 0.47-0.79, p < 0.001), with 4% absolute improvements for both outcomes at 8 yr. CONCLUSION AND CLINICAL IMPLICATIONS:Short- or long-course HT after postoperative RT improves MFS and PCSS. Observed improvements in OS are small and may be limited to people with higher-risk factors.
LBA509 Background: NRG-BR003 is a phase III, randomized trial evaluating whether the addition of carboplatin (carbo) to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide (AC) followed by paclitaxel (P) will improve invasive disease-free survival (IDFS) compared to AC followed by P when administered to patients (pts) with operable node-positive or high-risk node-negative triple-negative breast cancer (TNBC). Methods: Eligible pts had operable node-positive or high-risk node-negative TNBC and were randomized to receive dose-dense (DD) AC every 2 weeks for 4 cycles followed by weekly P (80 mg/m2) for 12 doses or the same regimen with carbo AUC of 5 IV every 3 weeks for 4 cycles. Stratification factors were number of positive nodes (0, 1-3, 4-9, 10+) and BRCA mutation status (positive; negative; or unknown). The study was designed to detect a hazard ratio (HR) in IDFS at 0.67 with the addition of carbo. The stratified log-rank test was used for the primary analysis. Secondary endpoints include DRFI, OS, BCFS, and RFI. Results: 769 pts were randomized to control arm (n=385) and carbo arm (n=384) from June 2015 to May 2022. Patient characteristics include age >50 (66%), primary tumors >2 cm (70%), node-positive (69%), and g BRCA pathogenic variants (9%). Delivery of AC was balanced between arms and P delivery was not compromised by co-administration of carbo with a mean of 11.3 doses (sd=2.1) of P with a relative total dose intensity (RTDI) at 0.97 in the control arm and 11.0 doses (sd=2.3) and a RTDI at 0.95 in the carbo arm. At data cutoff (2/28/25), median follow-up was 79.4 mos. IDFS events were reported in 92 pts (23.9%) in the control group and 76 (19.8%) in the carbo group. The stratified log-rank test p-value was 0.097, not meeting the prespecified significance of 0.049; the HR was 0.77 (95% CI, 0.57-1.05). The 5-year IDFS (95% CI) was 77.8% (73.7%-82.2%) vs 82.9% (79.2%-86.9%), respectively. HR was similar across patient subgroups, including germline BRCA and nodal status. Grade ≥3 treatment-related AE rates were 51.1% in the control group and 72.9% in the carbo group. Grade 5 events were 0.8% vs 0.8%, respectively. Conclusions: The addition of carbo to P following DD AC for adjuvant therapy of node-positive or high-risk node-negative TNBC did not result in a statistically significant improvement in IDFS, DRFI, or OS. However, it increased grade ≥3 treatment-related AE rates. Although not meeting criteria for efficacy across the entire study population, results support planned translational research to identify subsets of pts who may benefit from carbo. Clinical trial information: NCT02488967 . Secondary efficacy results of DRFI and OS. End Points Treatment 5-year Event-free Rate (95% CI) HR (95% CI) DRFI AC → P 84.4% (80.7-88.2) 1 AC → P+Carbo 88.7% (85.5-92.0) 0.74 (0.50-1.10) OS AC → P 84.4% (80.8-88.3) 1 AC → P+Carbo 87.7% (84.4-91.2) 0.81 (0.56-1.16)
8003 Background: Stereotactic body radiation therapy (SBRT) is the standard of care (SoC) for early stage, medically inoperable non-small cell lung cancer (NSCLC). While rates of in-field control exceed 90%, regional and distant control after SBRT remain suboptimal. A prior phase II randomized trial suggested a benefit to adding immunotherapy (PMID 37478883). SWOG/NRG S1914 (NCT#04214262) is a randomized phase III trial evaluating neoadjuvant, concurrent and adjuvant atezolizumab plus SBRT for early-stage NSCLC vs SoC. Methods: Eligible patients (pts) had T1-3N0M0 NSCLC ≤7cm, were medically inoperable or declined surgery, and had ≥1 risk factor for increased recurrence: tumor diameter ≥2 cm, ≥6.2, moderately/poorly/undifferentiated histology. Randomization was to SoC SBRT (S [3-8 fractions, biologically effective dose ≥100 Gy]) or neoadjuvant, concurrent and adjuvant atezolizumab (AS [1200 mg IV Q3 week, 8 cycles]) with SBRT initiated with cycle 3, stratifying by tumor location (central vs peripheral), size (<4 cm vs ≥4cm) and ECOG performance status (PS, 0-1 vs 2). The primary objective was to compare overall survival (OS) between the arms. Secondary objectives included comparisons of progression free survival (PFS), failure patterns, toxicity and quality of life (QoL). OS and PFS were compared using a 1-sided stratified log-rank test at the 2.5% level, confidence intervals (CI) are 95%. The accrual goal was 432 eligible pts. Results: From 8/13/20 - 9/6/24, 417 pts were randomized, 403 met eligibility [201 to S, 202 to AS]. Accrual closed at the first interim analysis for futility based on OS and PFS per design. Median follow-up for pts still alive was 12 (range: 0.03-49) months. Median age was 73 (41-91) years and 89% had PS 0-1. Median tumor diameter was 2.3 cm. No protocol treatment was received for 6 pts on S and 8 on AS. With 49 deaths, OS was not different between the arms (HR (CI): 1.15(0.65-2.01), p=0.63; 2-year OS: 82% S vs 80% AS). With 88 events, PFS was not better with AS (HR (CI): 1.35(0.89-2.06), p=0.16); 2-year PFS was 71% on S vs 60% on AS. Regional (2% vs 3%) and distant (4% vs 5%) failures were not different; there were more local failures with AS (13% vs 7%). Among former (53%)/never (3%) smokers, AS had worse OS and PFS than S (HR(CI): 2.50 (1.11-5.59), p=0.03); HR(CI): 2.16(1.15-4.04), p=0.01), respectively. Grade (G) ≥3 adverse event (AE) rates were 12% on AS (N=21 G3, 1 G4, 1 G5 respiratory failure) vs 2% on S (N=3 G3, 1 G4). Conclusions: In the first reported phase III trial to assess immunotherapy (IO) added to SBRT in early-stage NSCLC, IO failed to improve survival. More G ≥3 adverse events were reported with AS. Central review of local recurrence events is ongoing. Additional investigation into subgroups, PD-L1 status, QoL and blood/tissue are pending to determine whether there are subsets who can benefit from this combination and shed further insights into these findings. Clinical trial information: NCT04214262 .
3520 Background: Recent analyses highlight nonhierarchical outcomes using the 8 th Edition AJCC staging system for CC. For instance, the 5-year survival rate for stages I and IIIa patients (pts) closely align. Additionally, tumor deposits (TDs) have been established as significant prognostic indicators. The AJCCCCEP commissioned this study to develop an updated pathological staging system for CC focused specifically on pts without distant metastasis (M0), while retaining the existing stage IV classification. Methods: Individual patient data (IPD) from pts diagnosed with cc (2010- 2017) in the NCDB were divided into training (70%) and internal validation (30%) datasets. External validation used IPD from clinical trials. The primary endpoint was overall survival (OS). Risk classification development for M0 pts incorporated ungrouped data on pathologic T categories, the number of involved regional lymph nodes (LN+), and TD counts. Recursive partitioning and regression tree analyses were applied to construct hierarchical staging levels. Pre-specified criteria required survival probabilities to be consecutive and show clear separations using Kaplan-Meier (KM) estimates with pairwise log-rank test P of < 0.005 for the training and < 0.05 for validation analyses. Results: Data from 281,997 pts (median age 67 years, 50% male, 81% white, 55% T3, 19% T4, 44% N+, 26% M+, and 11% with ≥1 TD) were analyzed, with a median follow-up of 7.3 years. The updated staging system (Table) met pre-specified criteria, with all observed pairwise P < 0.0001 in the development and internal validation sets. KM OS curves displayed a hierarchical separation across all sub-levels after the 1 st year of diagnosis. Consistent results were seen in pts treated with adjuvant chemotherapy in 4 trials (all pair-wise P < 0.0001). Conclusions: The proposed pathological staging system for M0 pts fulfills pre-specified criteria for hierarchical risk stratification, validated both internally and externally, and provides an evidence-based update. Pending review process, the AJCCCCEP will recommend that these changes be made to the Version 9 staging protocol for colon cancer to improve prognostication for CC pts. Stage T, # of LN+, # of TD M % of pts 1y OS (CI), % 3y OS (CI), % 5y OS (CI), % I T1, 0, 0 0 5 96 (95-97) 91 (90-92) 84 (83-86) IIa T2, 0, 0 0 10 95 (94-95) 88 (88-89) 80 (79-81) IIb T1, 0, 1+T1, 1+, 0T2, 0, 1+T2, 1-4, 0T3, 0, 0 0 27 93 (92-93) 84 (84-85) 75 (75-76) IIIa T1, 1+, 1+T2, 1-4, 1+T2, 5+, 0T3, 0, 1+T3, 1-4, 0 0 14 92 (91-92) 80 (80-81) 71 (70-72) IIIb T2, 5+, 1+T3, 1-4, 1+T3, 5+, 0T4a, 0-4, 0T4b, 0-2, 0 0 13 86 (86-87) 69 (68-70) 58 (57-59) IIIc T3, 5+, 1+T4a, 0-4, 1+T4a, 5+, anyT4b, 0-2, 1+T4b, 3+, any 0 5 78 (77-80) 53 (51-54) 40 (38-41) IVa Any 1a 19 59 (58-60) 28 (28-29) 17 (16-18) IVb Any 1b 7 43 (42-44) 14 (13-14) 6 (6-7) CI: 95% confidence internal; Peritoneum involvement data were not available before 2018 in NCDB. Thus, IVa/b were based on 7 th Edition.
