Citations

Background Heterogeneous evidence exists on the effect of coronavirus disease 2019 (COVID‐19) on the clinical outcomes of patients with cancer. Methods A systematic review was performed using the Medline, Embase, and CENTRAL databases and the World Health Organization Novel Coronavirus website to identify studies that reported mortality and characteristics of patients with cancer who were diagnosed with COVID‐19. The primary study outcome was mortality, defined as all‐cause mortality or in‐hospital mortality within 30 days of initial COVID‐19 diagnosis. The pooled proportion of mortality was estimated using a random‐effects model, and study‐level moderators of heterogeneity were assessed through subgroup analysis and metaregression. Results Among 2922 patients from 13 primarily inpatient studies of individuals with COVID‐19 and cancer, the pooled 30‐day mortality rate was 30% (95% CI, 25%‐35%). The overall pooled 30‐day mortality rate among 624 patients from 5 studies that included a mixture of inpatient and outpatient populations was 15% (95% CI, 9%‐22%). Among the hospitalized studies, the heterogeneity (I 2 statistic) of the meta‐analysis remained high (I 2 , 82%). Cancer subtype (hematologic vs solid), older age, male sex, and recent active cancer therapy each partially explained the heterogeneity of mortality reporting. In multivariable metaregression, male sex, along with an interaction between the median patient age and recent active cancer therapy, explained most of the between‐study heterogeneity (R 2 , 96%). Conclusions Pooled mortality estimates for hospitalized patients with cancer and COVID‐19 remain high at 30%, with significant heterogeneity across studies. Dedicated community‐based studies are needed in the future to help assess overall COVID‐19 mortality among the broader population of patients with cancer.

Background: Knee osteoarthritis is a painful and sometimes debilitating disease that often affects patients for years. Current treatments include short-lasting and often repetitive nonsurgical options, followed by surgical intervention for appropriate candidates. Cooled radiofrequency ablation (CRFA) is a minimally invasive procedure for the treatment of pain related to knee osteoarthritis. This trial compared the efficacy and safety of CRFA with those of a single hyaluronic acid (HA) injection. Methods: Two hundred and sixty subjects with knee osteoarthritis pain that was inadequately responsive to prior nonoperative modalities were screened for enrollment in this multicenter, randomized trial. One hundred and eighty-two subjects who met the inclusion criteria underwent diagnostic block injections and those with a minimum of 50% pain relief were randomized to receive either CRFA on 4 genicular nerves or a single HA injection. One hundred and seventy-five subjects were treated (88 with CRFA and 87 with HA). Evaluations for pain (Numeric Rating Scale [NRS]), function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), quality of life (Global Perceived Effect [GPE] score and EuroQol-5 Dimensions-5 Level [EQ-5D-5L] questionnaire), and safety were performed at 1, 3, and 6 months after treatment. Results: Demographic characteristics did not differ significantly between the 2 study groups. A total of 158 subjects (76 in the CRFA group and 82 in the HA group) completed the 6-month post-treatment follow-up. In the CRFA group, 71% of the subjects had ≥50% reduction in the NRS pain score (primary end point) compared with 38% in the HA group (p < 0.0001). At 6 months, the mean NRS score reduction was 4.1 ± 2.2 for the CRFA group compared with 2.5 ± 2.5 for the HA group (p < 0.0001). The mean WOMAC score improvement at 6 months from baseline was 48.2% in the CRFA group and 22.6% in the HA group (p < 0.0001). At 6 months, 72% of the subjects in the CRFA group reported improvement in the GPE score compared with 40% in the HA group (p < 0.0001). Conclusions: CRFA-treated subjects demonstrated a significant improvement in pain relief and overall function compared with subjects treated with a single injection of HA. No serious adverse events related to either procedure were noted, and the overall adverse-event profiles were similar. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. Significance: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access. This article is highlighted in the In This Issue feature, p. 1426

LBA110 Background: There are limited data on COVID-19 in patients with cancer. We characterize the outcomes of patients with cancer and COVID-19 and identify potential prognostic factors. Methods: The COVID-19 and Cancer Consortium (CCC19) cohort study includes patients with active or prior hematologic or invasive solid malignancies reported across academic and community sites. Results: We included 1,018 cases accrued March-April 2020. Median age was 66 years (range, 18-90). Breast (20%) and prostate (16%) cancers were most prevalent; 43% of patients were on active anti-cancer treatment. At time of data analysis, 106 patients (10.4%) have died and 26% met the composite outcome of death, severe illness requiring hospitalization, and/or mechanical ventilation. In multivariable logistic regression analysis, independent factors associated with increased 30-day mortality were age, male sex, former smoking, ECOG performance status (2 versus 0/1: partially adjusted odds ratio (pAOR) 2.74, 95% CI 1.31-5.7; 3/4 versus 0/1: pAOR 5.34, 95% CI 2.44-11.69), active malignancy (stable/responding, pAOR 1.93, 95% CI 1.06-3.5; progressing, pAOR 3.79, 95% CI 1.78-8.08), and receipt of azithromycin and hydroxychloroquine. Tumor type, race/ethnicity, obesity, number of comorbidities, recent surgery, and type of active cancer therapy were not significant factors for mortality. Conclusions: All-cause 30-day mortality and severe illness in this cohort were significantly higher than previously reported for the general population and were associated with general risk factors as well as those unique to patients with cancer. Cancer type and treatment were not independently associated with increased 30-day mortality. Longer follow-up is needed to better understand the impact of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

TPS3154 Background: Immune-related Adverse Events (irAEs) are rare but serious sequelae of treatment with immuno-oncology (IO) therapeutics. These therapeutics, including monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have had transformative effects on outcomes for patients (pts) with advanced cancers. Although most pts tolerate the therapies well, a few experience irAEs ranging in severity up to life-threatening. These irAEs involve diverse organs including the heart, kidney, liver and lung, and gastrointestinal, musculoskeletal, central and peripheral nervous systems. Because of the relatively low incidence and wide variety of irAEs due to various immunotherapies for multiple tumor types, establishment of an efficient centralized repository for acquisition and organized distribution of well-annotated biospecimens is vital for translational studies that improve understanding of the molecular pathogenesis and treatment of these significant toxicities. Methods: This multi-institutional study is open at sites across the National Clinical Trial Network to pts who received ≥ 1 IO therapeutics (e.g., CTLA-4, PD-1 or PD-L1 inhibitor) and experienced 1) ≥ 1 serious (grade 3–5) adverse events that are likely immune-related, 2) rare infection or 3) tumor hyperprogression. IrAEs of interest include myocarditis, colitis, hepatitis, nephritis, myositis, pneumonitis, meningitis/encephalitis, dermatitis, endocrinopathies and neuropathy. Pts may be on an NCTN or non-NCTN IO trial or be receiving standard-of-care therapy. Registration must occur ≤ 72 hours after confirmation of the irAE event. Clinical data are collected at registration, 1 month after registration and for up to 1 year. Biospecimens (tumor blocks, biopsies of inflammatory tissues used to establish irAE diagnosis, and serial blood samples for isolation of plasma, serum and peripheral blood mononuclear cells) are collected at 1-2 timepoints. Stool samples are collected from pts experiencing colitis. Imaging data are collected for pts with hyperprogression or pneumonitis. Goal accrual is 240 pts. Biospecimens and data will be made available to investigators following future submission and approval of proposals. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180820 (ECOG-ACRIN); U10CA180888 (SWOG); U10CA180868 (NRG); https://acknowledgments.alliancefound.org; Clinical trial information: NCT04242095 .

507 Background: The 21-gene Recurrence Score (OncotypeDX Breast Cancer Assay) predicts outcome and benefit from chemotherapy (CT) in early stage ER+ BC treated with adjuvant endocrine therapy. We evaluated the association between Recurrence Score (RS), time to progression (TTP), and overall survival (OS) in patients with stage IV BC enrolled in TBCRC 013. Methods: TBCRC 013 is a registry study evaluating surgery of the primary tumor in pts presenting with Stage IV BC. From 7/09 - 4/12, 128 evaluable pts were enrolled in two cohorts (A: metastases (mets) with intact primary tumor (n=112); B: mets within 3 months of primary surgery (n=16)). This study includes 110 pts with pre-treatment primary tumor samples available for analysis. Clinical variables, TTP and OS were correlated with RS using long-rank, Kaplan-Meier and Cox regression. Results: Median pt age was 52yrs (21-79) and median tumor size 3.1cm (0.7-15). 82 (80%) were ER+, 83 (81%) Her2(-) and 51 (46%) had bone-only mets. Cohorts A and B did not differ. At a median follow-up of 26 mos (1-47), median TTP is 19 mos (95%CI16-25) and surgery is not associated with OS. 102 samples qualified for RS. 23 (23%) had low RS<18, 29 (28%) intermediate RS, 18-30; and 50 (49%) high RS≥31. Age, tumor size or site of 1stmets was not associated with RS. Risk groups were prognostic for TTP in ER+ pts and for 2 yr OS in ER+Her2- pts (Table). In Cox models continuous RS was also prognostic for TTP in ER+ pts (HR 3.5; for 50 point difference (PD) 95%CI 1.5-8.1, p=0.003) and for OS in ER+Her2- pts (HR 21.4, for 50 PD 95%CI 2.2-204.4, p=0.008). In MVA, adjusting for clinical variables, RS remained prognostic for TTP in ER+ pts (p=0.01). Further analysis of surgery in this trial is ongoing. Conclusions: The 21-gene RS is independently prognostic for TTP in ER+ Stage IV BC. RS is also prognostic for OS in ER+Her2- BC, suggesting that a high RS may be a surrogate for endocrine resistance and could be used to select pts with ER+ Stage IV BC for CT. A randomized trial to address this hypothesis is warranted. Clinical trial information: NCT00941759. [Table: see text]

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Abstract Background: Patients on systemic therapy for cancer are at varying risk for venous thromboembolism (VTE) and its consequences. Thromboprophylaxis is recommended in hospitalized medical and surgical cancer patients, but most VTE occurs in ambulatory cancer patients where risk can be estimated with a validated score. However, the benefit of extended outpatient thromboprophylaxis is uncertain with heparins and has not been tested with direct oral anticoagulants. Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2). Enrolled subjects were screened for deep-vein thrombosis (DVT) and if none found randomized 1:1 to rivaroxaban 10 mg once daily or placebo up to day 180. Subjects were screened with lower extremity ultrasounds every 8 weeks on study. Primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death. ISTH-defined major bleeding was the primary safety endpoint. All endpoints were adjudicated by blinded independent committees. Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients) for the up-to-day 180 observation period (primary) and the on-treatment period (supportive). Safety analyses were conducted for on-treatment period only for patients who received at least one dose of study drug. Results: Of 1,080 patients who provided consent, 49 (4.53%) had DVT on baseline screening and another 190 screen-failed due to other reasons. Of 841 randomized patients, 274 (32.6%) had pancreatic cancer; 698 (83%) were white and 428 (50.9%) were male. The primary efficacy endpoint occurred in 25 of 420 patients (5.95%) and 37 of 421 patients (8.79%) (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.101) in the rivaroxaban and placebo groups respectively (number needed to treat, NNT=35) in the up-to-day 180 observation period (Figure 1A). Of all patients with VTE, 38.70% experienced events after discontinuing study drug. In a pre-specified analysis of all randomized patients during the on-treatment period, the primary endpoint occurred in 11 of 420 patients (2.62%) and 27 of 421 (6.41%) in rivaroxaban and placebo groups respectively (HR 0.40, 95% CI 0.20 to 0.80, p=0.007) (NNT=26) (Figure 1B). Major bleeding occurred in 8 of 405 (1.98%) in the rivaroxaban group and in 4 of 404 (0.99%) patients in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49; p=0.265) (number needed to harm, NNH=101). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR, 1.34; 95% CI, 0.54 to 3.32; p=0.53) (NNH=135). Adverse events were comparable between groups. For secondary efficacy endpoints, a pre-specified analysis of the composite of primary endpoint with addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period showed significantly fewer events in rivaroxaban versus placebo group (6.90% versus 10.70% respectively; HR, 0.62; 95% CI: 0.39, 0.99; p=0.04). All-cause mortality occurred in 20.0% of patients in rivaroxaban group and 23.8% in placebo group (HR=0.83, 95% CI 0.62, 1.11; p=0.213). A pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in rivaroxaban group and 29.5% in placebo group (HR 0.75; 95% CI 0.57 to 0.97; p=0.03) (Figure 1C). Conclusions: Rivaroxaban significantly reduced VTE and VTE-related death during the on-treatment period but not during the full study period; over one-third of events occurred post discontinuation of study drug. The incidence of major bleeding was low. The Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.53%) and during study (8.79% with additional 1.66% arterial events in placebo group). These results should inform future recommendations regarding thromboprophylaxis in at-risk ambulatory cancer patients. (Funded by Janssen; ClinicalTrials.gov number, NCT02555878) Figure 1 Figure 1. Disclosures Khorana: Parexel: Other: Personal fees and non-financial support for travel; Sanofi: Consultancy, Other: Personal fees and non-financial support for travel; Pfizer: Consultancy, Other: Personal fees and non-financial support for travel; Janssen: Consultancy, Other: Personal fees, Research Funding; TriSalus: Other: Personal fees; Halozyme: Other: Personal fees and non-financial support for travel; Seattle Genetics: Other: Personal fees and non-financial support for travel; AngioDynamics: Other: Personal fees and non-financial support for travel; LEO Pharma: Other: Personal fees and non-financial support for travel; Medscape/WebMD: Other: Personal fees and non-financial support for travel; Pharmacyclics: Other: Personal fees; PharmaCyte: Other: Personal fees; Bayer: Consultancy, Other: Personal fees and non-financial support for travel. Soff:Janssen: Research Funding; Amgen: Research Funding. Kakkar:Bayer AG: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Daiichi Sankyo Europe: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sanofi S.A.: Consultancy; Verseon: Consultancy. Vadhan-Raj:AMAG Pharmaceuticals, Inc: Other: received funding from Amag to support clinical trial; Janssen: Consultancy, Research Funding. Riess:Janssen Scientific Affairs: Other: Travel reimbursement; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Wun:Eli Lilly, Inc.: Research Funding; Emmaus, Inc.: Membership on an entity's Board of Directors or advisory committees; Glycomimetics, Inc.: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees. Streiff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Other: outcome adjudication committee; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Roche: Research Funding; Portola: Consultancy, Research Funding. Garcia:Shingoi: Consultancy; Portola: Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Retham Technologies LLC: Consultancy; Genzyme Corporation: Consultancy; Alexion: Consultancy. Liebman:Janssen (Johnson & Johnson): Other: steering committee of the CASSINI trial during the conduct of the study. Belani:Janssen: Consultancy. O'Reilly:3DMed, Agios, AlignMed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, BeiGene, Bioline, BMS, Boston Scientific, Bridgebio, CARsgen, Celgene, CASI, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Gilead, Halozyme: Consultancy; Hengrui, Incyte, Inovio, Ipsen, Jazz, Janssen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, NewLink Genetics, Novella, Onxeo, PCI Biotech, Pfizer, PharmaCyte, Pharmacyclics, Pieris, QED, RedHill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax: Consultancy; Janssen: Research Funding; Acta Biologica, Agios, Array, AstraZeneca, Bayer, BeiGene, BMS, CASI, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, Novartis, OncoQuest, Polaris Puma, QED, and Roche: Research Funding; Tekmira, twoXAR, Vicus, Yakult, and Yiviva: Consultancy. Patel:Janssen Pharmaceuticals: Research Funding. Yimer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Epizyme: Equity Ownership; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership. Wildgoose:Janssen Scientific Affairs: Employment; Johnson & Johnson: Equity Ownership. Burton:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Vijapurkar:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Kaul:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Eikelboom:AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, sanofi-aventis, and Eli Lilly: Honoraria, Research Funding; Heart and Stroke Foundation: Other: Personnel award. Bauer:Janssen: Consultancy. Kuderer:Celldex: Consultancy; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Myriad Genetics: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Bayer: Consultancy. Lyman:Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research support.

Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them.