Research Spotlight

Pal, S. K., B. McGregor, C. Suárez, C. K. Tsao, W. Kelly, U. Vaishampayan, L. Pagliaro, B. L. Maughan, Y. Loriot, D. Castellano, S. Srinivas, R. R. McKay, R. Dreicer, T. Hutson, S. Dubey, S. Werneke, A. Panneerselvam, D. Curran, C. Scheffold, T. K. Choueiri and N. Agarwal (2021). “Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study.” J Clin Oncol: Jco2100939.

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COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non–clear cell (ncc) renal cell carcinoma (RCC). This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety. A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs. The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes. [Abstract from article].

Brewer, A., S. Joseph, K. Hammonds and M. P. Hofkamp (2021). “Incidence and Effect of Intrathecal Fentanyl Use in Spinal Anesthesia for Cesarean Deliveries in the Community Setting: A Single-Center Observational Retrospective Study.” Ochsner J 21(3): 267-271.

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Background: The addition of intrathecal fentanyl to spinal anesthesia for cesarean delivery has been shown to be beneficial, but its rate of utilization in the community setting is unknown. The primary aim of our study was to determine the rate of intrathecal fentanyl use for cesarean deliveries with spinal anesthesia in a community hospital, and our secondary aim was to determine its effect on anesthetic outcomes. Methods: Patients who underwent cesarean delivery from June 1, 2017 to November 30, 2019 with spinal anesthesia as the initial anesthetic technique were included. Results: Seven hundred sixty-one cesarean deliveries met inclusion criteria, and 161 (21.2%) patients received intrathecal fentanyl in their spinal anesthetic for cesarean delivery. A multivariate model that controlled for patient weight and time from spinal placement to procedure end showed that patients who received intrathecal fentanyl were less likely to have conversion to general anesthesia or administration of systemic anesthetic adjuncts compared to patients who did not receive intrathecal fentanyl (odds ratio 2.889, 95% CI 1.552-5.903; P=0.0017). Conclusion: Only 1 in 5 patients received intrathecal fentanyl for cesarean deliveries performed under spinal anesthesia in a community hospital despite known benefits. Patients who did not receive intrathecal fentanyl had increased odds of conversion to general anesthesia or administration of systemic anesthetic adjunct administration, a finding consistent with previous studies. The addition of intrathecal fentanyl to spinal anesthesia for cesarean delivery should be strongly considered in the community setting.

van Zyl, J. S., T. Sam, D. M. Clark, J. Felius, A. K. Doss, K. R. Kerlee, Z. O. Cheung, K. Martits-Chalangari, A. K. Jamil, S. A. Carey, R. L. Gottlieb, C. Y. Guerrero-Miranda, P. Kale and S. A. Hall (2021). “De novo tacrolimus extended-release tablets (LCPT) versus twice-daily tacrolimus in adult heart transplantation: Results of a single-center non-inferiority matched control trial.” Clin Transplant: e14487.

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Extended-release tacrolimus for prophylaxis of allograft rejection in orthotopic heart transplant (OHT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release tacrolimus (IR-tacrolimus). We compared the efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. Twenty-five prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 1 year was compared using non-inferiority analysis. LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 20% (90% CI: -40%, -.5%; non-inferiority P = .001). Tacrolimus trough levels peaked at 2-3 months and were higher in LCPT (median 14.5 vs. 12.7 ng/ml; P = .03) with similar dose levels (LCPT vs. IR-tacrolimus: .08 vs. .09 mg/kg/day; P = .33). Cardiovascular-related readmissions were reduced by 62% (P = .046) in LCPT patients. The complication rate per transplant admission and all-cause readmission rate did not differ significantly. These results suggest that LCPT is non-inferior in efficacy to IR-tacrolimus with a similar safety profile and improved bioavailability in OHT.

Rosas, I. O., G. Diaz, R. L. Gottlieb, S. M. Lobo, P. Robinson, B. D. Hunter, A. W. Cavalcante, J. S. Overcash, N. A. Hanania, A. Skarbnik, J. Garcia-Diaz, I. Gordeev, J. Carratalà, O. Gordon, E. Graham, N. Lewin-Koh, L. Tsai, K. Tuckwell, H. Cao, D. Brainard and J. K. Olsson (2021). “Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial.” Intensive Care Med: 1-13.

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PURPOSE: Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or “ready for discharge” (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days. RESULTS: Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or “ready for discharge” was 14 (95% CI 12-15) days with tocilizumab plus remdesivir and 14 (95% CI 11-16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78-1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28. CONCLUSIONS: Tocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.

Mozaffari, E., A. Chandak, Z. Zhang, S. Liang, M. Thrun, R. L. Gottlieb, D. R. Kuritzkes, P. E. Sax, D. A. Wohl, R. Casciano, P. Hodgkins and R. Haubrich (2021). “Remdesivir treatment in hospitalized patients with COVID-19: a comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort.” Clin Infect Dis. [Epub ahead of print].

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BACKGROUND: Remdesivir (RDV) improved clinical outcomes among hospitalized COVID-19 patients in randomized trials, but data from clinical practice are limited. METHODS: We examined survival outcomes for US patients hospitalized with COVID-19 between Aug-Nov 2020 and treated with RDV within two-days of hospitalization vs. those not receiving RDV during their hospitalization using the Premier Healthcare Database. Preferential within-hospital propensity score matching with replacement was used. Additionally, patients were also matched on baseline oxygenation level (no supplemental oxygen charges (NSO), low-flow oxygen (LFO), high-flow oxygen/non-invasive ventilation (HFO/NIV) and invasive mechanical ventilation/ECMO (IMV/ECMO) and two-month admission window and excluded if discharged within 3-days of admission (to exclude anticipated discharges/transfers within 72-hrs consistent with ACTT-1 study). Cox Proportional Hazards models were used to assess time to 14-/28-day mortality overall and for patients on NSO, LFO, HFO/NIV and IMV/ECMO. RESULTS: 28,855 RDV patients were matched to 16,687 unique non-RDV patients. Overall, 10.6% and 15.4% RDV patients died within 14- and 28-days, respectively compared with 15.4% and 19.1% non-RDV patients. Overall, RDV was associated with a reduction in mortality at 14-days (HR[95% CI]: 0.76[0.70-0.83]) and 28-days (0.89[0.82-0.96]). This mortality benefit was also seen for NSO, LFO and IMV/ECMO at 14-days (NSO:0.69[0.57-0.83], LFO:0.68[0.80-0.77], IMV/ECMO:0.70[0.58-0.84]) and 28-days (NSO:0.80[0.68-0.94], LFO:0.77[0.68-0.86], IMV/ECMO:0.81[0.69-0.94]). Additionally, HFO/NIV RDV group had a lower risk of mortality at 14-days (0.81[0.70-0.93]) but no statistical significance at 28-days. CONCLUSIONS: RDV initiated upon hospital admission was associated with improved survival among COVID-19 patients. Our findings complement ACTT-1 and support RDV as a foundational treatment for hospitalized COVID-19 patients.