Abstract S05-02: COVIDOSE: Low-dose tocilizumab in the treatment of COVID-19 pneumonitis

Background: Morbidity and mortality due to coronavirus disease 2019 (COVID-19) may in part be due to interleukin-6 (IL-6)-mediated hyperinflammation. The IL-6 receptor-targeted monoclonal antibody tocilizumab (TCZ) has been repurposed to treat COVID-19-related hyperinflammation, but prospective data are lacking. Given TCZ’s risks of secondary infection and potential blunting of the adaptive immune response and its finite supply, study of the efficacy, safety, and dose response of TCZ for the treatment of COVID-19-related hyperinflammation is needed. Methods: We conducted an adaptive phase 2 study of low-dose (LD) TCZ in hospitalized, non-mechanically ventilated adult patients with COVID-19 pneumonitis and evidence of hyperinflammatory syndrome, with C-reactive protein (CRP) ≥ 40 micrograms per milliliter. Dose cohorts were determined by a trial Operations Committee, with the initial doses of 80 or 200 milligrams, depending on the magnitude of CRP elevation and epidemiologic risk factors. Doses were decreased to 40 mg and 120 mg after interim assessment. The primary objective was to assess the relationship of dose to clinical improvement in temperature and oxygen requirement and biochemical response by CRP. Results: 32 patients received LD TCZ. 25 of 32 (78%) patients receiving LD TCZ at any dose achieved fever resolution. In terms of dose-response, fever resolution in 24 hours was observed in 6 of 8 (75%) who received 200 milligrams, 3 of 4 (75%) who received 120 milligrams, 11 of 15 (73%) who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0.80 for response rate difference). Biochemical response consistent with interleukin-6 pathway inhibition, corresponding to a ≥ 25% CRP decline, after a single dose of LD TCZ was observed in 5 of 8 (63%) who received 200 milligrams, 4 of 4 (100%) who received 120 milligrams, 10 of 15 (67%) who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0.34 for response rate difference). 100% of patients achieved CRP response within two doses of LD TCZ. Within the 28-day follow-up period, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 4 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 4 (12.5%) patients. Correlative biologic studies examining anti-SARS-CoV-2 antibody production across a range of TCZ doses are presented separately (abstract A-22514927). Conclusions: LD TCZ, in addition to standard of care, was associated with improvement of clinical hyperinflammation parameters in hospitalized adult patients with COVID-19 pneumonitis. No relationship between TCZ dose and clinical or biochemical response relationship was identified. Results of the COVIDOSE trial provide a rationale for a randomized, controlled trial of LD TCZ versus standard of care in those patients with COVID-19 pneumonitis who have evidence of hyperinflammation. (COVIDOSE, ClinicalTrials.gov number, NCT04331795.) Citation Format: Garth W. Strohbehn, Brian L. Heiss, Sherin J. Rouhani, Jonathan A. Trujillo, Athalia R. Pyzer, Jovian Yu, Alec J. Kacew, Alexandra Weiss, Spring Maleckar, Rachel Wright, Adriana Koziol, Bethany Martell, Keith Danahey, Theodore G. Karrison, Cuoghi Edens, Iazsmin Bauer Ventura, Natasha Pettit, Bakhti Patel, Jennifer Pisano, Mary Strek, Thomas F. Gajewski, Mark J. Ratain, Pankti D. Reid. COVIDOSE: Low-dose tocilizumab in the treatment of COVID-19 pneumonitis [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S05-02.