Citations

TPS4191 Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors (NETs) that arise from chromaffin cells. Few antitumor therapies have been developed for patients (pts) with advanced PHEO/PGLs (APP). Potent poly (ADP-ribose) polymerase (PARP) is activated after DNA damage and regulates base excision repair, homologous recombination and non-homologous end joining. Inhibition of PARP enzymatic activity blocks PARP-mediated DNA repair, therefore PARP inhibitors can be directly cytotoxic to tumor cells which then permits synergy with agents that increase prevalence of single-strand breaks in tumor models. Temozolomide (TMZ) is an alkylating agent that induces single-strand DNA breaks and therefore is an optimal therapeutic pair with a PARP inhibitor. We are conducting a phase II multi-institutional study to evaluate the antitumor activity of TMZ and olaparib [OLA (a PARP inhibitor)] in patients with APP. Methods: Patients with APP with radiographic evidence of disease progression by RECIST v1.1 in the 12 months prior to registration can be enrolled in this phase II randomized study. Patients will be randomized in a 2:1 allocation with more patients to Arm 1. Arm 1 will receive TMZ 75 mg/m2 daily and OLA 200 mg twice daily on days 1-7 of a 21-day cycle. Arm 2 will receive TMZ 200 mg/m2 daily on days 1-5 of a 28-day cycle. Treatment on Arm 1 will continue for 13 cycles, followed by OLA maintenance until disease progression. Treatment on Arm 2 will continue for 13 cycles or until disease progression. The primary objective is to compare the progression-free survival between the two arms with a planned interim analysis for futility. Secondary endpoints include safety, response rate, and overall survival. Correlative endpoints include biochemical response and biomolecular markers (germline succinyl dehydrogenase mutations and tumor status of the repair enzyme methylguanine-DNA methyltransferase). We anticipate a null PFS median of approximately 5.4 months. We plan to accrue a total of 76 patients (randomized at a rate of 2:1 with more patients enrolled to the TMZ+OLA arm) in 38 months with a minimum follow-up of 2.5 months to achieve 56 PFS events. This design includes one interim analysis for futility using Rho Family spending functions (Rho = 2.5) and will yield 89% power to detect a hazard ratio (HR) of 0.5 (median PFS of 5.4 vs. 10.8 months) assuming exponential survival and using a one-sided log-rank test with type I error rate of 0.11. Clinical trial information: NCT04394858 .

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .

TPS3641 Background: Patients with mismatch repair proficient (pMMR) BRAF V600E mutant high-risk stage II (T4) or stage III colon cancer have a substantial risk of recurrence despite standard adjuvant therapy. In patients with metastatic BRAF V600E mutant colorectal cancer, the combination of the RAF inhibitor encorafenib and the EGFR inhibitor cetuximab has been shown to improve overall and progression-free survival compared to standard therapy after at least one prior line of therapy. This study will evaluate if this combination improves disease-free survival (DFS) in patients with resected BRAF V600E mutant pMMR/microsatellite stable (MSS) high-risk stage II (T4) or stage III colon cancer after standard adjuvant therapy. Methods: The study has a seamless phase II/III design, enrolling a maximum of 394 patients. BRAF mutation status can be determined locally or submitted for central testing in trial pre-screening. Eligible patients will be randomized 1:1 to usual surveillance versus 6 months of treatment with encorafenib (300mg oral daily) plus cetuximab (500mg/m2 intravenous every 14 days). Stratification factors are adjuvant chemotherapy regimen (FOLFOX versus CAPOX), duration of adjuvant therapy (3 months versus > 3 months), tumor stage (T4N0 versus T1-3N1 versus T4N1/TanyN2), and ctDNA marker status (detectable versus undetectable) at randomization. Adjuvant therapy must be completed at most 8 weeks prior to registration. For the phase II component, in the ctDNA detectable cohort, the primary endpoint will be ctDNA clearance rate at 6 months, and, in the ctDNA undetectable cohort, the primary endpoint will be 6-month ctDNA recurrence-free survival, where events consist of death, recurrence, or ctDNA positivity. The primary endpoint of the phase III component is DFS, and secondary endpoints are overall survival, adverse events, and alternative DFS calculated from the date of primary resection, rather than date of study randomization. Patient reported symptoms (PRO-CTCAE) will be collected and analyzed as an exploratory endpoint, and serial blood banking will support future correlative studies. The trial will proceed to the phase III portion if either of the two endpoints in the phase II cohorts is statistically superior in patients receiving encorafenib plus cetuximab. The phase III study sample size will provide 80% power at a one-sided α of 0.05 to detect an approximately 10% improvement in the three-year DFS rate, assuming 68% in the control arm. Two interim analyses will be performed for DFS endpoint. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Pfizer, Eli Lilly; Clinicaltrials.gov ID: NCT05710406. Clinical trial information: NCT05710406 .

TPS3640 Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients (pts) with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated it as a primary endpoint. Collaborating with a multidisciplinary oncology team and pt groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation and improve quality of life for pts. Methods: In this Alliance for Clinical Trials in Oncology randomized phase II trial (1:1), up to 312 pts with microsatellite stable LARC, clinical stage T4N0, 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). Pts will be randomized to receive neoadjuvant long course CRT (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks (w) + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Pts will undergo assessment 8-12 w post-TNT completion for the primary endpoint of cCR per previously validated criteria and recommended WW and surveillance if cCR is achieved or TME if an incomplete response is noted. Secondary objectives include time-to event outcomes (disease-free and overall survival, organ preservation time and time to distant metastasis) and adverse effects. Statistical power, based on cCR, incorporates a one-sided alpha = 0.048 and power = 90% yielding 312 patients (156 per arm). Biospecimens including archival tumor tissue, matched / normal blood samples and serial rectal MRI will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and is actively recruiting. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov ID: NCT05610163 Clinical trial information: NCT05610163 .

TPS3629 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 survival 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 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 one lesion. Patients receive first-line systemic therapy for 4-6 months 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 and lungs in at least one site. Patients in Arm 1 will receive TAT which consists 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 .

ImportanceThe association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited.ObjectiveTo assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer.Design, Setting, and ParticipantsThis cohort study was derived from a National Cancer Institute–sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022.ExposuresPlasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization.Main Outcomes and MeasuresThe primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression.ResultsOf 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103pg/mL (IQR, 2.3-3.6 × 103pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14];P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55];P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34];P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival.Conclusions and RelevanceThis cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes.Trial RegistrationClinicalTrials.gov Identifier:NCT01150045

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56–82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1–24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11–33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.

Abstract Chronic inflammation is a well-established carcinogenic pathway for colorectal cancer (CRC), but the role of inflammation in CRC prognosis is not well understood. Since cytokines are central in extensive biological networks to regulate inflammation, it is of great importance to investigate inflammatory cytokines and CRC survival. Among an NCI-sponsored adjuvant chemotherapy trial for patients with stage III colon cancer conducted between 2010 and 2015 (CALGB/SWOG 80702), we collected serum samples from 1,498 participants at a median of 1.6 months (interquartile [IQR]: 1.3-1.9 months) after surgery. IL-6, TNFR2, and hsCRP were assayed as biomarkers of chronic inflammation and were categorized into quintiles. The primary outcome was disease-free survival, defined as time from randomization to recurrence or death from any cause. Secondary outcomes included overall survival and time to recurrence. We estimated the associations of inflammatory biomarkers with survival using multivariable Cox proportional hazards regression. Of 1,498 participants (median follow-up: 5.9 years), mean age was 61.3 years, 82.2% were White, 55.5% were male, and 387 experienced recurrence or death. Medians (IQRs) of biomarkers were 2.6mg/L (1.2-5.6mg/L) for IL-6, 2.9×103pg/mL (2.3-3.6×103pg/mL) for TNFR2, and 2.6mg/L (1.2-5.6mg/L) for hsCRP. Compared to the lowest quintile (Q1), the highest quintile (Q5) in inflammatory biomarkers was significantly associated with worse disease-free survival (hazard ratios were 1.52 [95% CI, 1.08-2.15] for IL-6, 1.76 [95% CI, 1.22-2.54] for TNFR2, and 1.66 [95% CI, 1.17-2.35] for hsCRP). Similar patterns were observed for overall survival and time to recurrence. Our findings suggest that higher levels of inflammation after diagnosis were significantly associated with worse survival among those with stage III colon cancer, and reducing inflammation may be considered as a potential intervention to improve CRC survival. ‬‬ Associations of Inflammatory Biomarkers with Survival after Adjustment for Clinicopathologic Factors Q1 Q2 Q3 Q4 Q5 P for Trend Disease-free survival IL-6 1.00 1.14 (0.80-1.62) 1.37 (0.97-1.94) 1.44 (1.02-2.03) 1.52 (1.08-2.15) 0.02 TNFR2 1.00 1.21 (0.84-1.74) 1.43 (0.99-2.05) 1.56 (1.09-2.25) 1.76 (1.22-2.54) 0.002 hsCRP 1.00 1.34 (0.95-1.90) 1.62 (1.15-2.29) 1.26 (0.88-1.80) 1.66 (1.17-2.35) 0.04 Overall survival IL-6 1.00 1.44 (0.91-2.29) 1.56 (0.98-2.48) 1.48 (0.93-2.34) 1.68 (1.07-2.65) 0.09 TNFR2 1.00 1.57 (0.94-2.63) 1.88 (1.13-3.13) 1.92 (1.15-3.20) 2.31 (1.39-3.84) 0.003 hsCRP 1.00 1.27 (0.81-2.00) 1.72 (1.11-2.65) 1.22 (0.77-1.92) 1.73 (1.12-2.69) 0.06 Time to recurrence IL-6 1.00 1.34 (0.92-1.95) 1.48 (1.01-2.16) 1.55 (1.06-2.27) 1.54 (1.05-2.26) 0.07 TNFR2 1.00 1.14 (0.78-1.67) 1.28 (0.87-1.87) 1.48 (1.01-2.16) 1.54 (1.04-2.27) 0.02 hsCRP 1.00 1.27 (0.87-1.83) 1.64 (1.14-2.36) 1.21 (0.82-1.77) 1.55 (1.07-2.26) 0.12 Citation Format: En Cheng, Shi Qian, Anthony F. Shields, Elizabeth M. Cespedes Feliciano, Andrew B. Nixon, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Dequincy Lewis, Benjamin Tan, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Bette J. Caan, Jeffrey A. Meyerhardt. Associations of inflammatory biomarkers with survival among patients with stage III colon cancer (CALGB/SWOG 80702 [Alliance]) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 682.

TPS8598 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude patients with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in patients with newly diagnosed peritoneal mesothelioma. Methods: A092001 is a prospective, randomized phase 2 clinical trial. All patients with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed, and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Patients who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible patients per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 patients are enrolled. As stratification factors we have included eligibility for cytoreductive surgery at diagnosis, and histologic subtype. Secondary endpoints include assessment of progression-free survival, overall survival, and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Support: U10CA180821, U10CA180882. Clinical trial information: NCT05001880.