Citations

TPS309 Background: Patients with oligometastatic colorectal cancer (CRC) often experience long-term progression-free survival and overall survival (OS) following aggressive local treatment of isolated metastases, especially in the liver. However, the effectiveness of local ablative therapies, such as microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), in patients with inoperable limited metastatic CRC or those with additional metastases outside the liver or lungs, remains uncertain. Despite the historical use of local therapy for oligometastatic CRC, often influenced by provider bias rather than strong evidence, questions persist about the potential benefits of applying this approach to patients with more extensive disease. This trial aims to address this clinical challenge by evaluating the safety and efficacy of adding total ablative therapy (TAT) of all disease sites to standard systemic treatment in patients with limited metastatic CRC. Methods: A022101/NRG-GI009 is a randomized phase III study within the National Clinical Trials Network, set to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable). Patients with liver-only metastatic disease are excluded. Pre-registration during first-line systemic therapy induction is encouraged. Eligible lesions must be treatable with surgical resection, MWA, and/or SBRT. Patients without significant radiographic progression after 12-39 weeks of first-line systemic therapy, with 4 or fewer disease sites post-induction chemotherapy, will be randomized 1:1. Randomization will be stratified by the number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and the presence of metastatic disease outside the liver/lungs in at least one site. Patients in Arm 1 will receive TAT, targeting all metastatic sites with a combination of surgical resection, MWA, and/or SBRT, followed by standard systemic therapy. Patients in Arm 2 will continue with standard systemic therapy alone. The choice of systemic therapy is at the discretion of the medical oncologist and may include continued therapy, maintenance chemotherapy, or observation. The primary endpoint is OS, with secondary endpoints including event-free survival, treatment-related toxicities, and local recurrence. Exploratory biomarker analyses will also be conducted. The study requires 346 evaluable patients across the two arms to demonstrate an OS improvement with a hazard ratio of 0.7, providing 80% power with a one-sided alpha of 5%. The trial employs a group sequential design with two interim analyses (at 25% and 50% of events) to assess futility. The trial began in January 2023, and patient recruitment is ongoing. Clinical trial information: NCT05673148 .

Abstract Background The National Clinical Trials Network (NCTN) is the largest government-sponsored organization in the United States; it is tasked with funding randomized controlled trials in oncology. It is unknown whether there are differences in study design by treatment modality. We evaluated differences in methodology between trials testing radiation therapy (RT) vs systemic therapy. Methods The Clinical Trials Support Unit website was used to identify active randomized controlled trials of systemic therapy or RT across NCTN cooperative groups through December 31, 2023. Studies in disease sites with more than 5 RT trials were included. Each trial’s protocol was reviewed to obtain key design information that was descriptively compared: primary endpoint, hypothesis testing type (superiority vs noninferiority), noninferiority margin, hypothesized effect size, power, and statistical significance level. Results A total of 186 randomized controlled trials (142 systemic therapy, 44 RT) were examined. Comparing primary endpoints, 59.1% vs 26.8% of RT vs systemic therapy trials, respectively, had a primary endpoint of overall survival. Nearly one-third (31.2%) of RT trials were noninferiority vs 6.3% of systemic therapy trials. Among breast cancer trials, 75% of RT studies were noninferiority vs 11.1% systemic therapy. Target effect size, power, and statistical significance level were similar by treatment modality within tumor types and disease settings. Conclusion Among NCTN cooperative group randomized controlled trials, there were marked differences in study design between RT vs systemic therapy trials. A higher benchmark for defining success for RT interventions was observed, with greater emphasis on overall survival as the primary endpoint. This finding may reflect differences in therapeutic mechanism by modality and types of study questions posed.

Introduction: Advances in AI have enabled the generation of synthetic individual patient data (SynthIPD) that mimics the statistical properties of the real IPD, which can help generate subgroup-specific insights in the absence of subgroup-specific IPD. We apply this technology in evaluating Daratumumab treatment benefit in high-risk cytogenetic multiple myeloma subgroup. The addition of daratumumab to standard multiple myeloma (MM) regimens has been associated with improved response rates and clinical outcomes. A systematic review (meta-analysis) enables further evaluation of the effectiveness of daratumumab for MM patients with high-risk cytogenetic factors. However, concerns have been raised about meta-analyses due to the statistical model assumptions they impose. This study aims to address these limitations by employing SynthIPD to provide a more robust analysis. Methods: This study focuses on newly diagnosed multiple myeloma (NDMM) and relapsed or refractory multiple myeloma (RRMM) patients with high-risk cytogenetic profiles. We included six published studies: ALCYONE, CASSIOPEIA, and MAIA for NDMM, and CANDOR, CASTOR, and POLLUX for RRMM. Large language models were used to extract up-to-date clinical evidence from the literature. SynthIPD including cytogenetic risk profile were generated via digitization and an innovative optimization algorithm. Meta-analyses based on random effects models were then conducted, and the results were compared with those from pooled analyses using synthetic data. Results: SynthIPD for cytogenetic high-risk patients were generated for three studies for NDMM: ALCYONE (treatment vs control: n=53 vs n=45), CASSIOPEIA (n=82 vs n=86), MAIA (n=48 vs n=44); and three studies for RRMM: CANDOR(n=48 vs n=26), CASTOR (n=40 vs n=35), POLLUX (n=35 vs n=35). The generated hazard ratios (HRs) for each study closely aligned with the reported HRs for high-risk patients, with a maximum relative error of less than 2%. By pooling these datasets, we obtained SynthIPD datasets for NDMM and RRMM patients. Stratified Cox regression analyses yielded HRs of 0.764 (95% CI 0.529-1.104) for NDMM and 0.431 (95% CI 0.294-0.613) for RRMM. Random-effects meta-analyses showed HRs of 0.764 (95% CI 0.529-1.104) for NDMM and 0.425 (95% CI 0.287-0.621) for RRMM. Compared with traditional meta-analysis techniques, the synthetic data approach provides additional clinical insights that were not available in the original publications. For instance, the clinical results for the six studies within high-risk group (e.g., KM curves in high-risk subgroup) can be reproduced, which were not reported in the original studies. Conclusion: AI-generated synthetic data enhances the robustness of conventional meta-analysis outcomes. The identification of HRs and corresponding confidence intervals through SynthIPD enhances the credibility of our proposed method, offering a reliable approach to evaluating the efficacy of daratumumab in high-risk patients. Since SynthIPD includes individual covariate information, any statistical results derived from the original IPD can be effectively approximated using SynthIPD. Using the SynthIPD, we show that the addition of daratumumab to standard regimens improves PFS for RRMM patients with high-risk cytogenetic factors, although its benefit for NDMM patients is not statistically significant. This analysis can be extended to other multiple myeloma high risk subgroups.

PURPOSE The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined. PATIENTS AND METHODS One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage. RESULTS In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; P int = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349). CONCLUSION No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.

Abstract Background Inflammation and insufficient physical inactivity contribute to individual-level risk of disease recurrence and death in stage III colon cancer. The extent to which increased inflammatory risk can be offset by sufficient physical activity remains unknown. Methods This cohort study was nested within the Cancer and Leukemia Group B (now part of the Alliance for Clinical Trials in Oncology) and Southwest Oncology Group randomized trial. Inflammatory burden was quantified by high-sensitivity C-reactive protein, interleukin-6, and soluble tumor necrosis factor-α receptor 2 after recovery from tumor resection. Physical activity was measured during and after postoperative chemotherapy. The primary endpoint was disease-free survival. Results The 3-year disease-free survival rate was 88.4% among patients with low inflammation and sufficient physical activity (referent group for all comparisons), 84.9% with low inflammation and insufficient physical activity (absolute risk difference = −3.5 percentage points, 95% confidence interval [CI] = −11.3 to 4.3; P = .38), 78.0% with intermediate inflammation and insufficient physical activity (absolute risk difference = −10.4 percentage points, 95% CI = −17.4 to −3.3; P = .007), and 79.7% with high inflammation and insufficient physical activity (absolute risk difference = −8.7 percentage points, 95% CI = −15.7 to −1.6; P = .022). In contrast, the 3-year disease-free survival rate was 87.3% among patients with intermediate inflammation and sufficient physical activity (absolute risk difference = −1.1 percentage points, 95% CI = −7.5 to 5.3; P = .74) and 84.4% with high inflammation and sufficient physical activity (absolute risk difference = −4.0 percentage points, 95% CI = −12.3 to 4.3; P = .34). Conclusion In this observational study of stage III colon cancer patients, physical activity was associated with improved disease-free survival despite high inflammation. Patients with intermediate or high inflammation who were physically active had disease-free survival rates that were not statistically significantly different from those with low inflammation.

ImportanceThe prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone.ObjectiveTo assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes.Data SourcesLiterature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023.Study SelectionTwo blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach.Main Outcomes and MeasuresOverall and disease-free survival, postoperative morbidity, and mortality.ResultsThe analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]).Conclusions and RelevanceIn this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

TPS4208 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) carries a 5-year relative survival of 3%. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). Signaling through the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells in mouse PDAC models. Longitudinal survival studies testing combinations of CXCR4i, aPD-1, and gemcitabine in the KPC mouse model of PDAC demonstrated a survival benefit with the combination of all three agents. Results from a multicenter, investigator-initiated, single arm pilot study evaluating the preliminary safety and efficacy ofMotixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDAC were recently presented. Seven patients (64%) achieved a partial response, including 6 confirmed partial responses, and 10 patients (91%) had disease control, compared to historic partial response and disease control rates of 23% and 48%, respectively, with gemcitabine and nab-paclitaxel (GN). Preliminary median progression-free survival (PFS) was 9.6 months compared to historic median PFS of 5.5 months with GN. Analysis of paired pre- and on-treatment biopsy samples from demonstrated an increase in CD8+ T-cell density in tumors from all 11 patients treated with MCGN (p=0.007). Based on these promising results, the protocol was amended from a single arm expansion totaling 40 patients to a randomized phase 2 study. Methods: This is an open-label, multicenter, investigator-initiated phase 2 clinical trial. Patients are randomized 2:1 to receive MCGN or GNalone (N=108). The primary endpoint is progression free survival. The study has 80% power to detect an improvement in PFS from 6 to 9.2 months (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include response rate, disease control rate, duration of clinical benefit and overall survival. Patients will undergo optional paired biopsies which will be analyzed in conjunction with samples collected from the phase I pilot study. Exploratory studies include interrogation of the TME using quantitative multiplex immunofluorescence and single-cell RNA sequencing. The randomized phase 2 trial is open to enrollment and one patient has been randomized as of 1/29/2024. Clinical trial information: NCT04543071 .

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

TPS2700 Background: Though immunotherapy with anti-PD-1 immune checkpoint inhibitors (ICIs) has led to improvements in clinical outcomes in patients with cancer, when used as monotherapy in the advanced setting, only 18-25% of patients respond to ICI. Notably, ICI frequently lacks anti-tumor activity in immune-cold cancers where T cell priming is missing. Recent breakthroughs in identifying personal neoantigens via a comprehensive analysis of cancer sequencing data have brought increased attention to neoantigen cancer vaccines. Personalized cancer vaccines targeting neoantigens have shown early promise. While neoantigens have recently been investigated in some cancer types, the current neoantigen prediction algorithms have often focused on the MHC class-I subtype, single nucleotide mutations (SNM), small insertions and deletions (INDEL). We recently developed an informatics workflow, REAL-neo, for the identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic SNM, INDEL, aberrant RNA splicing, and gene fusions, generating much more potent neoantigen candidates. Furthermore, we demonstrated robust T-cell response and prolonged survival by combining ICI and cancer vaccines in preclinical models. This single-arm phase I clinical trial is in progress to assess the safety, feasibility, and immunogenicity of personalized neoantigen vaccines in combination with pembrolizumab in patients with advanced solid cancers. Methods: The vaccine consists of up to 20 peptides (15-30 mer) comprising patient-specific neoantigens identified from tumor DNA and mRNA sequencing data using REAL-neo and delivered with GM-CSF as an adjuvant. The first cohort of three patients will be treated at dose level 1 consisting of 4 or 5 peptides at 300 mcg/peptide and GM-CSF 125 mcg per injection site in each of four limbs. After Cohort 1 is deemed safe, the study will expand to cohort 2, when patients will be enrolled at the same dose level for vaccine plus Pembrolizumab 200 mg i.v. Neoantigen vaccine will be given via subcutaneous injection on days 1, 4, 8, 15, and 21 (cohorts 1 and 2) and weeks 5 and 8 (booster dose for cohort 2 only). Cohort 1 has been completed without dose-limiting toxicity (DLT). Enrollment in Cohort 2 began in January 2024. AEs are assessed according to CTCAE v5. and safety findings are reviewed by data safety medical board (DSMB). Key eligibility criteria include 1) histologically confirmed locally advanced or metastatic solid malignancies and 2) cancer progression after at least one line of the standard-of-care (SOC) systemic treatment. For cohort 2, patients must be eligible to receive pembrolizumab per SOC or the treating physician’s judgment. Clinical trial information: NCT05269381 .

TPS3633 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101/NRG-GI009 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least 1 lesion. Patients receive first-line systemic therapy for 16-26 weeks and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver/lungs in at least 1 site. Patients in Arm 1 will receive TAT consisting of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov identifier: NCT05673148 Clinical trial information: NCT05673148 .