The number of early clinical trials evaluating immunotherapies (IT) has increased exponentially over the last decade. These agents expose to adverse events (AE), which have been largely described with immune checkpoint blockers (ICB) as a monotherapy. However, the safety profile of IT other than ICB or in combination, have been poorly characterized. Here, we comprehensively analyze the safety profile of IT in phase I/II (P1/2) trials when used as a monotherapy (M) or in combination (C) with other anti-cancer agents, and compare it to the one of other anticancer agents assessed in the same patient (pt) population.
All consecutive pts treated in a P1/2 trial at the Gustave Roussy Drug Development Department between Jan 2008 and Aug 2020 were included. Pt and trial characteristics, AEs of any grade (G) and any type occurring at any cycle on trial, dose administered and treatment modifications were described in the following subgroups: IT as a M (IT-M), targeted therapy (TT) as a M (TT-M), IT in C (IT-C), TT in C (TT-C), other.
1922 inclusions (1815 pts; median age of 56 years; 10% of hematological malignancies; 11300 treatment cycles) were performed in 195 P1/2 trials; 731 pts were enrolled in trials assessing IT (144 IT-M, 587 IT-C) and 1229 pts in trials of TT (523 TT-M, 706 TT-C). Nine toxic death occurred. Pts presented 8835 AE (7,3 % at cycle 1 and 92,7 % beyond cycle 1) including 1694 G3-4 AEs (3% of pts; 11,1 %, 31,5 %, 54,4 % of pts in trials evaluating IT-M, IT-C, TT-M and TT-C, respectively); 5 (10%), 39 (21%), 83 (16%), 135 (15%) G3-4 AEs occurred at cycle 1 in trials of IT-M, IT-C, TT-M and TT-C, respectively. G1-2 AEs occurred in 85.5 %, 88.3%, 76% and 79.8% of pts in these subgroups; 47,8 % of AEs resolved, of which 1/3 required co-medications. Median AE duration was 12.4, 18.1, 9.3 and 9.7 days in trials of IT-M, IT-C, TT-M and TT-C, respectively. The most common G3-4 AE type was neutropenia / anemia in trials evaluating IT-M and TT-C / TT-M and IT-C, respectively.
Severe AEs do not occur more frequently in P1/2 trials evaluating IT in combination. Only 10 – 21% of severe AEs, potentially scoring for dose-limiting toxicities, occur at cycle 1 in trials of IT or TT in this patient series.
PDF file of trials name attached.
Drug Development Department, Institut Gustave Roussy.
Has not received any funding.
P. Martin-Romano, C. Baldini, A. Varga, A. Hollebecque, J-M. Michot, A. Gazzah, R. Bahleda, S. Champiat, A. Italiano, V. Ribrag, E. Angevin, J-P. Armand, A. Marabelle, C. Massard, S. Postel-Vinay: Non-remunerated activity/ies, As part of the Drug Development Department (DITEP)= Principal/sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicine. C. Helissey: Non-remunerated activity/ies, As part of the Drug Development Department (DITEP)= Principal/sub-Investigator of Clinical Trials: Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare A. E. Deutsch: Non-remunerated activity/ies, AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Therapeutics, Gamamabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut de Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octime: AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicine. J-C. Soria: Leadership role, Research grant/Funding (self), Full/Part-time employment, Senior Vice President (Sept 17 to Dec 19): AstraZeneca; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Blend Therapeutics; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Cytomix; Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Genmab; Research grant/Funding (institution): Inivata; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Netcancer; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Tarveda. All other authors have declared no conflicts of interest.