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Objectives: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19., Design: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study., Setting: Twelve clinical sites in France (ICU and general hospitals)., Patients: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3., Interventions: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2., Measurements and Main Results: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified., Conclusions: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367)., Competing Interests: Dr. Carvelli received support for article research from Innate Pharma. Drs. Carvelli, Allardet-Servent, Barbar, Desgrouas, Camou, Piperoglou, Viotti, Boyer-Chammard, Lacombe, Le Dault, Schleinitz, and Vivier disclosed the off-label product use of avdoralimab. Dr. Guervilly received funding from Xenios FMC. Dr. Demaria’s institution received funding from BPI. Drs. Demaria, Karakunnel, Fares, Batista, Boyer-Chammard, and Vivier received funding from innate pharma. Drs. Demaria, Karakunnel, Fares, Batista, Rotolo, Viotti, Boyer-Chammard, and Vivier disclosed that they are employees of Innate Pharma. Dr. Karakunnel received funding from Primevax Precision Biologics. Dr. Rotolo received funding from Sanofi. Dr. Viotti disclosed work for hire. Dr. Lacombe received funding from MSD, Gilead, Janssen, and ViiV Healthcare. Dr. Vivier disclosed that he is a cofounder, shareholder, and employee of Innate Pharma and that his spouse is a shareholder of Innate Pharma. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials., (© 2022. The Author(s).)

Background: There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade., Methods: We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples., Results: Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3-4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB., Conclusions: In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts., Trial Registration Number: NCT02731729., Competing Interests: Competing interests: CFF reports personal/consultancy fees from AstraZeneca, as well as participation in steering committees (compensation waived) for Merck and Genentech; these are outside the scope of the submitted work. She also reports institutional research funding from Genentech, Merck, Bristol Myers Squibb, Daiichi, and AstraZeneca. AR reports personal/consultancy fees from Amgen, Chugai, Genentech, Jounce, Merck, Novartis, Nurix, Sanofi, and Vedanta; stock from prior consulting with Advaxis, CytomX, Five Prime, RAPT, IsoPlexis, and Kite-Gilead; being a member of the scientific advisory board and stockholder in 4C Biomed, Apricity, Arcus, Highlight, Compugen, ImaginAb, MapKure, Merus, Rgenix, Lutris, PACT Pharma, and Tango; and receiving research funding to the institution from Agilent and Bristol-Myers Squibb through a Stand Up to Cancer Catalyst grant. KKT reports institutional research funding from Array/Pfizer, Bristol Myers Squibb. Oncosec, Regeneron, and Replimune. HT reports personal/consultancy fees from Genentech, Merck, BMS, Novartis, Iovance, and Eisai and research funding to institution from Genentech, Merck, BMS, Novartis, Celgene, and GSK. TL discloses the following: LISCure Biosciences Scientific Advisory Board, June 2020 up to the present and stock ownership in AstraZeneca; consulting: TRex Bio, Grey Wolf Therapeutics, Exosis, and BiOne Cure; these are outside the scope of the submitted work. MP reports personal/consultancy fees from Array BioPharma, Aduro Biotech, Bristol Myers Squibb, Incyte, Merck, Newlink Genetics, Novartis, and Eisai; honoraria from Bristol Myers Squibb and Merck; research funding from Array BioPharma, AstraZeneca/Medimmune, Bristol Myers Squibb, Infinity Pharmaceuticals, Merck, Novartis, and RgenixA. NS reports personal/consultancy fees from Bristol-Myers Squibb, Immunocore, and Castle Biosciences; research funding to institution from BMS, Immunocore, Xcovery, and Novartis. MC reports institutional research support and employment of a family member by Bristol-Myers Squibb, and consulting, advisory, or speaking compensation for AstraZeneca/MedImmune, Incyte, Moderna, Immunocore and Merck. PC reports consulting/advisory/or speaking compensation from Immunocore, Merck, Cell Medica, Takeda Millenium, and Astra Zeneca; stock ownership in Rgenix; and research funding from Pfizer. DKW is a scientific founder of, holds equity in, and receives consulting fees from Immunai. RI discloses the following: scientific advisory board membership at Harpoon, BitBio, and Arcus; board of directors at Surface Oncology; non-compensated board membership at Lyell; non-compensated scientific advisory board membership at ImaginAb; advisor: IMV and Georgiamune. JK discloses the following: either scientific advisory board membership, stock ownership, or receiving consulting fees from AstraZeneca, Arcus Biosciences, Tizona Therapeutics, Trishula Therapeutics, Primevax, and Elucida Oncology. JW is a consultant for Amgen, Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bayer, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Maverick Therapeutics, Merck, Neon Therapeutics, Psioxus, Recepta, Tizona, Trieza, Truvax, Trishula, Sellas, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. JDW reports receiving grant/research support from Bristol Myers Squibb and Sephora; having equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, Georgiamune, Trieza, Maverick, and Ascentage., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)