Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FindingsOf 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1•84, 95% CI 1•53-2•21), male sex (1•63, 1•07-2•48), smoking status (former smoker vs never smoked: 1•60, 1•03-2•47), number of comorbidities (two vs none: 4•50, 1•33-15•28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3•89, 2•11-7•18), active cancer (progressing vs remission: 5•20, 2•77-9•77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2•93, 1•79-4•79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0•24, 0•07-0•84) or the US-Midwest (0•50, 0•28-0•90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.
Despite improvements in the multi-modality treatment of colorectal liver metastasis (CRLM), survival after resection remains varied. Determining prognosis after surgical resection has historically been predicated on preoperative clinicopathological factors such as primary tumor stage, carcinoembryonic antigen levels, number of liver metastases, presence of extrahepatic disease, as well as other factors. While scoring systems have been developed by combining certain preoperative factors, these have been inconsistent in accurately determining prognosis. There has been increasing interest in the use of biologic and molecular markers to predict prognosis following CRLM. The role of markers such as KRAS, BRAF, p53, human telomerase reverse transcriptase, thymidylate synthase, Ki-67, and hypoxia inducible factor-1α and their correlation with accurately predicting survival after surgical resection have been supported by several studies. Furthermore, other elements such as pathological response to chemotherapy and the presence of circulating tumor cells have shown promise in accurately determining prognosis after resection for colorectal liver metastasis. We herein review past, present, and possible future markers of prognosis among colorectal cancer patients with liver metastasis undergoing resection with curative intent.© 2013 Baishideng Publishing Group Co., Limited. All rights reserved.Key words: Colorectal; Metastasis; Prognosis; Risk score; Molecular markers; Outcomes Core tip: Historically, prognosis after resection has been largely assessed based on preoperative clinicopathologic features. Data validating the prognostic value of patient and tumor specific factors have been mixed, with many recent studies showing these scoring systems to correlate poorly with survival. Rather, there has been an emerging interest in biological or molecular markers of prognosis to more effectively assess patient prognosis after resection of colorectal liver metastasis. In this review, we discuss past, present, and possible future markers of prognosis among colorectal cancer patients with liver metastasis undergoing resection with curative intent.
Background: BTCs are aggressive cancers with a poor prognosis. In preclinical models, MEK inhibition modulates the tumor immune microenvironment and enhances responses to programmed death-ligand 1 (PD-L1) inhibition. We report a randomized, open-label, multicenter phase 2 trial of atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor) in BTC (NCT03201458). Methods: Eligible patients had advanced BTC [intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC)], with 1-2 lines of prior therapy in the metastatic setting, measurable disease by RECIST v1.1, and ECOG performance status ≤1. Patients randomized to Arm A received atezolizumab 840 mg IV Q2w. Patients randomized to Arm B received oral cobimetinib 60 mg daily (21 days on/7 days off) plus atezolizumab 840 mg IV Q2w. The primary endpoint was progression free survival (PFS) using the Kaplan-Meier method and compared between groups under the assumption of Cox proportional hazards, stratified for primary tumor site. Secondary endpoints included objective response rate (ORR), safety and tolerability, and overall survival (OS). Results: 86 patients were enrolled at 23 centers in the United States; 77 patients were randomized and received at least one dose of study therapy (Arm A: n=37, ICC=21, ECC=7, GBC=11; Arm B: n=38, ICC=22, ECC=8, GBC=8). Median age was 63 (range 44-86), and 48 (62%) were female. The trial met its primary endpoint, with a median PFS of 3.65 months (cobimetinib+atezolizumab) vs 1.87 months (atezolizumab monotherapy) (p=0.027). OS data are not mature at the time of analysis. There was 1 PR (3.2%), 13 SD (41.9%), and 17 PD (54.8%) in the combination arm and 1 PR (2.9%), 10 SD (29.4%), and 23 PD (67.6%) in the atezolizumab monotherapy arm. Two patients in the combination arm remain on therapy 15+ months from enrollment. One patient in each treatment arm had known mismatch repair deficiency (MMRd), of whom 1 had PD as a best response and the other withdrew prior to response evaluation. Grade 3-4 treatment-related adverse events were similar in both arms, and there were no treatment-related deaths. 4 (10%) of patients receiving atezolizumab monotherapy and 8 (22.2%) receiving cobimetinib+atezolizumab discontinued therapy due to adverse events. Changes in tumor CD8, CD4, FoxP3, PDL1, and MHC expression from paired tumor biopsies will be presented at the conference. Conclusions: We report the first randomized trial of immunotherapy in BTC. The combination of atezolizumab plus cobimetinib met its primary endpoint and significantly prolonged PFS as compared to atezolizumab monotherapy in BTC. The combination of atezolizumab and cobimetinib had manageable toxicity and warrants further investigation in BTC. Citation Format: Mark Yarchoan, Leslie Cope, Robert A. Anders, Anne Noonan, Laura W. Goff, Lipika Goyal, Jill Lacy, Daneng Li, Anuj Patel, Aiwu R. He, Ghassan Abou-Alfa, Kristen Spencer, Edward Kim, Stephanie Xavier, Amanda Ruggieri, S. Lindsey Davis, Autumn McRee, Paul Kunk, Qingfeng Zhu, Andrea Wang-Gillam, Andrew Poklepovic, Helen Chen, Elad Sharon, Gregory B. Lesinski, Nilo Azad. A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT043.
Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62–415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.
Background: Tumor associated macrophages have been proposed to suppress the anti-tumor immune responses potentiated by immune checkpoint blockade. CSF1 receptor (CSF-1R) blockade enhances anti-PD1 or PD-L1 anti-tumor efficacy in various tumor models. SNDX-6352 is a high affinity, humanized monoclonal antibody against CSF1R. This Phase 1 study was designed to identify a recommended phase 2 dose for the combination of SNDX-6352 and the anti-PD-L1 antibody, durvalumab. Methods: Study SNDX-6352-0502 was a multi-center Phase 1 study consisting of Phase 1a (monotherapy) and Phase 1b (combination with durvalumab). The primary objective of 1b was to define MTD or RP2D of the combination as evaluated by the incidence of DLTs. The 1b cohorts included 1, 2, and 3 mg/kg administered q2wk in combination with a fixed dose of 1500 mg durvalumab q4wk. The RP2D was determined based on safety, drug exposure, and PD biomarker changes. Results: 12 patients with advanced solid tumors were treated with durvalumab and SNDX-6352 (3 at 1 mg/kg, 3 at 2 mg/kg, and 6 at 3 mg/kg). Median number of prior therapies was 6.5 (range 2-13). Median age at enrollment was 67 years (range 34-74), and 75% of patients had ECOG performance status of 1. Median exposure in terms of cycles was 2 (range 2-4). Nine SAEs occurred in 5/12 (42%) patients. All SAEs were assessed as unrelated to study drug and generally reflected co-morbidity in this population of patients with advanced cancer. Most common treatment-related AEs were edema peripheral (33%), fatigue (25%), periorbital edema (25%), and hypothyroidism (25%). Grade 3 or higher treatment-related AEs were reported in 4 patients (33%). One patient had two events (anemia and pericardial effusion); amylase increased, diarrhea, and rash occurred in 1 patient each. Elevations in circulating enzymes were consistent with the known effect of the class on Kupffer-cell mediated clearance of circulating enzymes. No objective responses have been reported to date. Plasma concentrations of SNDX-6352 increased in a dose-proportional manner with drug accumulation observed at > 1mg/kg. Treatment led to elevations of plasma concentrations of CSF1R ligands, CSF1 and IL-34, which remained above pre-dose levels at doses > 1 mg/kg. CSF1 receptor occupancy was saturated at 4 hours post-dose in all treatment cohorts. Circulating non-classical monocytes (CD14+CD16hi) were depleted at all dose levels after one day. Conclusion: SNDX-6352 is a potent CSF1R antagonist that demonstrates tolerability and robust PD biomarker modulation in combination with durvalumab. The recommended phase 2 dose of 3 mg/kg administered q2wk in combination therapy will be explored in future studies. Citation Format: Anthony W. Tolcher, Drew Rasco, Sunil Sharma, Matthew Taylor, Christine Quaranto, David L. Tamang, Robert Nordness, Michael L. Meyers, Serap Sankoh, Peter Ordentlich, Nilo Azad. SNDX-6352-0502: A phase 1, open-label, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamic activity of SNDX-6352 in combination with durvalumab in patients with unresectable, recurrent, locally-advanced, or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT242.
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