Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9-17.4) compared to 1.9 months (95% CI: 1.8-2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17-0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8-30.4) compared to 3.8 months (95% CI: 2.7-4.9) for those with high opioid use (HR 0.26 95% CI: 0.17-0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.

Phase I Study of Entinostat, Atezolizumab, Carboplatin, and Etoposide in Previously Untreated Extensive-Stage Small Cell Lung Cancer, ETCTN 10399.

BACKGROUND: CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors. METHODS: Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%. RESULTS: Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls. CONCLUSION: Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).

Barriers to Access to Hematopoietic Cell Transplantation among Patients with Acute Myeloid Leukemia in Virginia.

Allogeneic hematopoietic cell transplantation (HCT) is a standard therapy for patients with intermediate to high-risk acute myeloid leukemia (AML) and is associated with improved long-term disease-free survival. Disparity exists in access to HCT among different patient populations and requires further study. In this study, we compared HCT rates for AML among different regions in the state of Virginia and identified geographic and socioeconomic factors associated with the likelihood of receiving HCT. We conducted a retrospective, cohort study of patients 18 to 74 years of age diagnosed with AML in Virginia from 2013 to 2017 as reported to the Virginia Cancer Registry (VCR); the VCR was further linked with the Center for International Blood and Marrow Transplant Research database for identification of patients who had undergone HCT within 2 years of diagnosis. Socioeconomic data were generated from the VCR and the American Community Survey. Univariate and multivariable logistic regression models were used to examine selected socioeconomic factors of interest, including patient-level information such as sex, age, race, marital status, and primary insurance payer, as well as factors associated with geography, including the Social Vulnerability Index (SVI) and percentage of African Americans residing in the region. In Virginia, 818 patients were diagnosed with AML from 2013 to 2017, and, of these, 168 patients (21%) underwent HCT within 2 years of diagnosis. Median age was lower in the HCT cohort (55 years) versus the non-HCT cohort (64 years) (P < .001). There was a higher proportion of married patients in the HCT cohort (67%) versus the non-HCT cohort (53%) (P = .005). The rate of HCT varied by geographic region (P = .004). The multivariable analyses (without including SVI) showed decreased likelihood of HCT with increasing age (odds ratio [OR], .96; 95% confidence interval [CI], .95 to .98). Patients from regions that had a greater than 25% African American population were less likely to undergo HCT (OR, .58; 95% CI, .38 to .89). Patients who were not married were less likely to undergo HCT compared with married patients (OR, .56; 95% CI, .36 to .88). Patients with government-sponsored insurance as the primary payer were less likely to undergo HCT compared with patients with private insurance (OR, .49; 95% CI, .32 to .77). Patients living in Zip Code areas with a greater percentage of population with a bachelor's or graduate degree were more likely to undergo HCT (OR, 1.02; 95% CI, 1.00 to 1.03). In a separate multivariate model with SVI, patients residing in a Zip Code with higher SVI were less likely to undergo HCT (OR, .37; 95% CI, .16 to .82). From 2013 to 2017, we found that the likelihood of a patient undergoing HCT in Virginia for AML within 2 years of diagnosis was negatively associated with increasing age, percent of African Americans residing in the region, not-married relationship status, government-sponsored insurance as primary payer, higher SVI, and decreased percent of population with a bachelor's or graduate degree. Resources should be directed toward at-risk patient populations to remove barriers to improve access to HCT. The SVI can be used to identify communities at risk nationwide.

Risk of Major Bleeding with Ibrutinib.

BACKGROUND: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater. MATERIALS AND METHODS: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications. RESULTS: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01). CONCLUSION: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.