Extending venous thromboembolism secondary prevention with apixaban in cancer patients. The EVE trial.

BACKGROUND: Cancer-associated venous thromboembolism (VTE) management guideline recommendations include continued therapeutic anticoagulation while active cancer persists. The Federal Drug Administration label for apixaban for secondary VTE prevention includes a dose reduction to 2.5 mg twice daily after 6 months of treatment. OBJECTIVES: The study's purpose was to determine whether this dose reduction is advisable for cancer-associated VTE. METHODS: A randomized, double-blind trial compared apixaban 2.5 mg with 5 mg twice daily for 12 months among cancer patients with VTE who had completed 6 to 12 months of anticoagulation therapy. The primary outcome was combined major bleeding plus clinically relevant nonmajor bleeding. RESULTS: Of 370 patients recruited, 360 were included in the intention-to-treat analyses. Major plus clinically relevant nonmajor bleeding occurred in 16 of 179 patients (8.9%) in the apixaban 2.5 mg group compared with 22 of 181 patients (12.2%) in the 5 mg group (hazard ratio [HR], 0.72; 95% CI, 0.38-1.37; P = .39). Major bleeding occurred in 2.8% of the apixaban 2.5 mg group and in 2.2% of the 5 mg group (HR, 1.26; 95% CI, 0.34-4.66; P = .73). Recurrent VTE or arterial thrombosis occurred in 9 of 179 patients (5.0%) in the apixaban 2.5 mg group and 9 of 181 patients (5.0%) in the 5 mg group (HR, 1.0; 95% CI, 0.40-2.53; P = 1.00). All-cause mortality rates were similar between groups, 13% vs 12% (HR, 1.14; 95% CI, 0.63-2.04; P = .67). CONCLUSION: For secondary prevention of cancer-associated VTE, apixaban 2.5 mg compared with 5 mg twice daily did not lower combined bleeding events (EVE trial NCT03080883).

Radiation Therapy Quality Assurance Analysis of Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Pancreas.

PURPOSE: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered. METHODS AND MATERIALS: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable deviations. Additionally, we performed a post hoc RT QA analysis in which contours and plans were reviewed by 3 radiation oncologists and assigned a score (1, 2, or 3) based on adequacy. A score of 1 indicated no deviation, 2 indicated minor deviation, and 3 indicated a major deviation that could be clinically significant. Clinical outcomes were compared by treatment modality and by case score. RESULTS: Forty patients were registered to receive RT (1 planned but not treated) at 27 centers (18 academic and 9 community). Twenty-three centers were appropriately credentialed for moving lung/liver targets and 4 for static head and neck only. Thirty-two of 39 patients (82.1%) were treated with SBRT and 7 (17.9%) with hypofractionated RT. Five cases (13%) required revision before treatment. On post hoc review, 23 patients (59.0%) were noted to have suboptimal contours or plan coverage, 12 (30.8%) were scored a 2, and 11 (28.2%) were scored a 3. There were no apparent differences in failure patterns or surgical outcomes based on treatment technique or post hoc case score. Details related to on-treatment imaging were not recorded. CONCLUSIONS: Despite rigorous QA, we encountered variability in simulation, contouring, plan coverage, and dose on trial. Although clinical outcomes did not appear to have been affected, findings from this analysis serve to inform subsequent PDAC SBRT trial designs and QA requirements.

HER2 Gene Expression Levels Are Predictive and Prognostic in Patients With Metastatic Colorectal Cancer Enrolled in CALGB/SWOG 80405.

PURPOSE: The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data. PATIENTS AND METHODS: Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points. RESULTS: High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group (P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group (P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS (Pintx = .017), PFS (Pintx = .048), and objective response rate (Pintx = .001). CONCLUSION: HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.

SerpinB3/4 Expression Is Associated with Poor Prognosis in Patients with Cholangiocarcinoma.

Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; p = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8-Not Estimable, NE) vs. 2.4 (1.8-3.4) years; p = 0.0007; extrahepatic CCA: median 0.8 (0.2-NE) vs. 2.2 (1.5-5.4) years; p = 0.011). Vascular invasion (p = 0.027) and SerpinB3/4 scores (p = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, p = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, p = 0.0026, for SerpinB3/4-IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass.

Tumor-Informed Circulating Tumor DNA for Minimal Residual Disease Detection in the Management of Colorectal Cancer.

PURPOSE: Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA). Here, we examined the pattern of use of a tumor-informed ctDNA assay in CRC MRD monitoring in routine clinical practice at Mayo Clinic, Rochester. METHODS: We conducted a retrospective analysis of health records of patients with CRC who had at least one tumor-informed ctDNA assay from May 2019 through July 1, 2022. Recurrence was defined as radiographic evidence of disease. Descriptive characteristics of the cohort, ctDNA results, and subsequent interventions were recorded. RESULTS: Of the 120 patients included, the median age at diagnosis was 67 years, 46% were female, and 94% were White. At diagnosis, 10 patients had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. Of 476 ctDNA assays performed, 70% were performed in patients who had recurrent disease most commonly to monitor the effectiveness of therapeutic interventions and 16% resulted in a change in clinical decision making. There were 110 recurrences identified in 62 patients, as some patients experienced more than one recurrence over time. Compared with serum carcinoembryonic antigen levels, ctDNA results correlated better with radiologic imaging. CONCLUSION: Routine ctDNA monitoring for MRD detection has been adopted in clinical practice; however, 84% of ctDNA assays performed did not result in a change in clinical management. This suggests the need for further clinical research data to guide routine clinical use of ctDNA MRD testing in CRC.

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study.

BACKGROUND: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear. METHODS: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan-Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0. RESULTS: We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2-6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7-19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis. DISCUSSION: Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial.

Physical activity in recurrent colon cancer: Cancer and Leukemia Group B/SWOG 80702 (Alliance).

BACKGROUND: One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence. METHODS: A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET-h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two-sided hypothesis tests. RESULTS: Compared with patients expending <3.0 MET-h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET-h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42-0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%-69.2%) with <3.0 MET-h/week of physical activity and 72.2% (95% CI, 63.1%-79.6%) with ≥18 MET-h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2-20.8 percentage points). CONCLUSIONS: Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.

Impact of perioperative chemotherapy on survival in patients with cholangiocarcinoma undergoing curative resection.

BACKGROUND: Most patients with localized cholangiocarcinoma (CCA) endure cancer relapse after curative resection underscoring the importance of systemic therapy. The current study attempts to determine the impact of perioperative chemotherapy (PC) on survival in patients with CCA undergoing resection. METHODS: Patients diagnosed with CCA undergoing curative-intent resection between January 1, 2000, and December 31, 2019, in a tertiary care center were included. Cox proportional hazard modeling was used to determine the impact of PC on disease-free survival (DFS) and overall survival (OS). In addition, a nomogram was constructed to estimate 3-year DFS. RESULTS: Among the 182 patients included in the analysis, 102 underwent surgery alone, and 80 received surgery plus PC. Forty-two patients received neoadjuvant therapy, and 38 patients received adjuvant therapy. On multivariate analysis, PC was significantly associated with an improved DFS (HR, 95% CI: 0.63, 0.41-0.98; p = 0.04) and OS (HR, 95% CI: 0.46, 0.27-0.78; p < 0.01). In the interaction analysis, the survival benefit was especially seen in patients with positive resection margins and tumor size > 5 cm. CONCLUSION: In patients with CCA undergoing curative resection, receipt of PC was associated with improved DFS and OS. The nomogram constructed from this database provides an estimate of 3-year DFS after surgical resection. Randomized trials are needed to define the optimal regimen and sequence.

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance).

PURPOSE: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. EXPERIMENTAL DESIGN: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). RESULTS: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. CONCLUSIONS: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

Association between physical activity and the time course of cancer recurrence in stage III colon cancer.

OBJECTIVE: We determined if postoperative physical activity prevents or delays cancer recurrence in patients with stage III colon cancer. METHODS: This cohort study nested within a randomised trial enrolled 1696 patients with surgically resected stage III colon cancer. Physical activity was calculated based on self-reporting during and after chemotherapy. Patients were classified as physically active (≥9 MET-h/wk, comparable with the energy expenditure of 150 min/wk of brisk walking, consistent with the current physical activity guidelines for cancer survivors) or physically inactive (<9 MET-h/wk). The confounder-adjusted hazard rate (risk of recurrence or death) and HR by physical activity category were estimated with continuous time to allow non-proportionality of hazards. RESULTS: During a median 5.9 years follow-up, 457 patients experienced disease recurrence or death. For physically active and physically inactive patients, the risk of disease recurrence peaked between 1 and 2 years postoperatively and declined gradually to year 5. The risk of recurrence in physically active patients never exceeded that of physically inactive patients during follow-up, suggesting that physical activity prevents-as opposed to delays-cancer recurrence in some patients. A statistically significant disease-free survival benefit associated with physical activity was observed during the first postoperative year (HR 0.68, 95% CI 0.51 to 0.92). A statistically significant overall survival benefit associated with physical activity was observed during the first three postoperative years (HR 0.32, 95% CI 0.19 to 0.51). CONCLUSIONS: In this observational study of patients with stage III colon cancer, postoperative physical activity is associated with improved disease-free survival by lowering the recurrence rate within the first year of treatment, which translates into an overall survival benefit.

Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

PURPOSE: To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. METHODS: We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. RESULTS: During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). CONCLUSION: Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.

Cabozantinib Following Immunotherapy in Patients with Advanced Hepatocellular Carcinoma.

(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan-Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3-3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3-14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.

Outcomes following FGFR Inhibitor Therapy in Patients with Cholangiocarcinoma.

BACKGROUND: Sequencing efforts in patients with cholangiocarcinoma (CCA) have provided insights into molecular mechanisms including fibroblast growth factor receptor (FGFR) alterations. There is a lack of data on outcomes of patients following cessation of FGFR inhibitor (FGFRi) therapy. OBJECTIVE: We describe the clinical outcomes following initial FGFRi treatment in CCA harboring FGFR alterations. PATIENTS AND METHODS: We conducted a multicentric, retrospective analysis of patients with FGFR-altered CCA diagnosed between 2010 and 2021. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. RESULTS: We identified 88 advanced or metastatic CCA patients, 28 males (31.8%) and 60 females (68.2%), harboring FGFR alterations who received FGFRi. Median PFS on initial FGFRi was 6.6 months (95% confidence interval (CI): 5.5-8.3). Following cessation of first FGFRi therapy, 55% patients received systemic therapy as next line: 67% received chemotherapy or targeted treatment and 33% received another FGFRi. Median PFS for patients who received chemotherapy or targeted agent was 2.1 months (95% CI 1.6-5.7) and for patients who received a second FGFRi was 3.7 months (95% CI 1.5-not evaluable). OS was 2.0 months for patients who did not receive any therapy compared to 8.7 months with chemotherapy and 8.6 months with another FGFRi. In addition, one patient treated with pemigatinib developed FGFR2 M540_I541insMM alteration at time of resistance, which has not been functionally characterized and its effect on protein function remains unknown. CONCLUSIONS: Understanding the mechanisms of resistance with FGFRi is essential to understand sequencing of treatments. In this study, patients received standard chemotherapy in the first line and were fit enough to be considered for subsequent therapy with an FGFRi. Almost half of the patients become ineligible to receive further systemic therapy following progression on FGFRi. As more agents are being introduced, detailed understanding of outcomes following treatment with an FGFRi, including subsequent FGFRi, is essential.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

PURPOSE: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAFV600E, and mismatch repair status. RESULTS: Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High (P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION: Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.

Evaluating the Significance of Pancreatobiliary Fluorescence In Situ Hybridization Polysomy on Prognosis in De Novo Cholangiocarcinoma.

INTRODUCTION: We recently developed a fluorescence in situ hybridization probe set for evaluating suspicious biliary and pancreatic duct strictures (PB-FISH). We aimed to determine whether PB-FISH results in biliary brush cytology specimens are associated with outcomes of patients with cholangiocarcinoma (CCA). METHODS: We performed a retrospective study of patients with CCA tested by PB-FISH from January 2015 to August 2018. CCA was stratified by primary sclerosing cholangitis (PSC) into those with (PSC CCA) or without PSC ( de novo CCA). PB-FISH results were categorized as polysomy (gain of multiple loci), nonpolysomy (single locus gain, single locus gain with 9p21 loss, homozygous 9p21 loss, tetrasomy), and disomy (no abnormalities). Overall survival (OS) was estimated using Kaplan-Meier methods and compared between the PB-FISH results using log-rank tests. Cox models were adjusted for age, sex, CA 19-9, cytology results, source of brushing sample, and treatments. RESULTS: Characteristics of 264 eligible patients (median age 60.4; range 18-92) were comparable for patients with PB-FISH polysomy vs nonpolysomy vs disomy. The median OS was similar between disomy, nonpolysomy, and polysomy in the overall population (22.7 vs 22.7 vs 20.3 months, respectively). For de novo CCA, both polysomy and nonpolysomy were associated with worse OS compared with disomy (polysomy: hazard ratio [HR] = 2.09, 95% confidence interval [CI] = 1.14-3.83; nonpolysomy: HR = 2.4, 95% CI = 0.54-2.46; P = 0.027). For PSC CCA, neither polysomy nor nonpolysomy were significantly associated with worse OS (polysomy: 0.90, 95% CI = 0.47-1.75; nonpolysomy: HR = 1.78, CI = 0.71-4.49; P = 0.27). DISCUSSION: PB-FISH alterations are associated with worse survival in de novo CCA, though statistical significance was lost when adjusting for confounding variables.

Tumor Mutational Burden Is a Potential Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Advanced Biliary Tract Cancer.

PURPOSE: Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS: The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS: The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION: ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.

Alliance A082002 -a randomized phase II/III trial of modern immunotherapy-based systemic therapy with or without SBRT for PD-L1-negative, advanced non-small cell lung cancer.

INTRODUCTION: Treatment of advanced stage non-small cell lung cancer (NSCLC) has changed dramatically due to immunotherapy. However, patients without Programmed Death-Ligand 1 (PD-L1) protein expression often benefit less from immunotherapy. This trial is designed to test if stereotactic body radiation therapy (SBRT) to a single tumor site can significantly enhance the outcome of patients with advanced stage PD-L1(-) NSCLC when added to systemic therapy including immunotherapy. MATERIALS AND METHODS: Alliance A082002 is based on subgroup analysis from the randomized phase II PEMBRO-RT trial., PEMBRO-RT compared pembrolizumab alone or with SBRT and revealed improved progression-free and overall survival (PFS and OS, respectively) in PD-L1(-) patients when adding SBRT (8 Gy x 3 fractions). In A082002, patients without PD-L1 expression will be randomized to SBRT (8 Gy x3) plus systemic therapy vs. systemic therapy alone. The primary endpoint of the phase II portion of the trial is PFS and will require 100 patients. The primary endpoint of the phase III portion of the trial is OS and will require an additional 284 patients. This trial will clarify whether adding SBRT to systemic therapy can improve PFS and OS in a larger multi-institutional cohort. Several systemic treatment options are allowed including either immunotherapy alone or chemo-immunotherapy. CONCLUSIONS: This phase II/III Alliance trial A082002 will test whether the addition of SBRT to a single tumor site will enhance the anti-tumor activity of systemic immunotherapy or chemo-immunotherapy in patients with stage IV PD-L1(-) NSCLC. It is now open in the National Clinical Trials Network (NCTN).

Evaluation of methylated DCR1 as a biomarker for response to adjuvant irinotecan-based therapy in stage III colon cancer: cancer and leukaemia Group B 89803 (Alliance).

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan-Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97-3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.

Cetuximab and Irinotecan With or Without Bevacizumab in Refractory Metastatic Colorectal Cancer: BOND-3, an ACCRU Network Randomized Clinical Trial.

BACKGROUND: Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. PATIENTS AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). CONCLUSION: In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted.Clinical Trial Registration: NCT02292758.