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Characterisation of Toxicity Profiles of Immune and Molecularly Targeted Agents in Phase I and II Studies

Overall, more adverse events were reported with targeted therapies than with immunotherapy.
01 Mar 2021
Anticancer agents & Biologic therapy;  Cancer Immunology and Immunotherapy

Findings from a large longitudinal analysis reported at the ESMO Targeted Anticancer Therapies (TAT) Virtual Congress 2021 held on 1-2 March showed that grade 3/4 adverse events (AEs) occurred in fewer patients treated with an immunotherapy as monotherapy or in combination than those receiving a targeted therapy either as monotherapy or in combination, and that less than 10% of them occurred at cycle 1.

According to Louaï Missri of the Drug Development Department, Institut Gustave Roussy in Villejuif, France, AEs related to immunotherapy have been primarily described for immune checkpoint blockers (ICB) when used as a monotherapy but the safety profile of immunotherapy in combination or for other than ICB has not been fully characterised.

Together with colleagues, Dr. Missri analysed the safety profile of immunotherapy as a monotherapy or in combination therapy with other anti-cancer agents in phase I and phase II studies. Furthermore, they compared this profile to an anticancer agent assessed in the same patient population.

Their longitudinal study included all consecutive patients participating in a phase I or II studies at the Gustave Roussy Drug Development Department from January 2008 to August 2020. Patient and study characteristics, AEs of any grade and any type occurring at any study cycle, the dose administered, and all treatment modifications were categorised according to treatment regimen: Immunotherapy as monotherapy (IT-M), immunotherapy in combination (IT-C), IT in combination with molecularly targeted agents only (MTA+IT), Molecularly targeted agents as a monotherapy (MTA-M), MTA in combination excepted IT (MTA-C), and combinations of two non-IT or non-MTA agents (nIT+nMTA).

Overall, 1980 record inclusions represented 1924 patients with a median age of 56 years; of these, 10% of patients had haematological malignancies. 43 % were women. The most frequent tumour types were gastrointestinal (21%), thoracic (18%), skin / mucosa (10%), haematological (10%), gynaecological (9%), and breast (8%) malignancies. A total of 11582 treatment cycles were administered in 197 phase I and II studies. Of the 499 patients (518 inclusions) in studies assessing immunotherapy, 146 patients (150 inclusions) received immunotherapy as monotherapy and 353 (368 inclusions) received an immunotherapy combination. Trials assessing an immunotherapy in combination with a molecularly targeted agents comprised 211 patients (214 inclusions). Studies assessing molecularly targeted agents comprised 1046 patients (1077 inclusions), of which 541 patients (559 inclusions) received a targeted therapy agent as monotherapy and 505 (518) received an agent in combination. Studies that did neither assess an immunotherapy nor a molecularly targeted agents concerned 168 patients (171 inclusions).

The most frequently evaluated MTA were an EGFR inhibitor (cetuximab in 9 studies), a HDAC inhibitor (abexinostat in 6 studies), a VEGF inhibitor (bevacizumab in 5 studies), and an mTOR inhibitor (everolimus in 5 studies). The most evaluated IT were PD-1 inhibitors (nivolumab in 18, and pembrolizumab in 12 studies), PDL-1 inhibitors (atezolizumab in 16 and durvalumab in 6 studies), and a CTLA-4 inhibitor (ipilimumab in 6 studies).

Nine toxic deaths occurred, and 8881 AEs were reported in 1493 included patients. Among them, 682 (8% of AEs; 11% of inclusions) occurred at cycle 1 and 1842 (21 %) were severe grade (G) 3-4 toxicities. The latter occurred in 23 (15%), 57 (16%), 44 (21%), 237 (43%), 306 (59%) and 77 (45%) inclusions performed in studies evaluating IT-M, IT-C, IT+MTA, MTA-M, MTA-C and nIT+nMTA, respectively; G3-4 AEs occurred in 146 (7.4 %) inclusions at cycle 1, corresponding to 3 (2%), 11 (3%), 9 (4%), 41 (7%), 61 (12%) and 21 (12%) AEs in studies evaluating IT-M, IT-C, IT+MTA, MTA-M, MTA-C and nIT+nMTA, respectively.

The most frequent G3-4 AE type was haematological events (neutropenia, febrile neutropenia, anaemia, and or thrombocytopenia; 748 events, 41% of G3-4 AEs), representing 28 (55%), 20 (20%), 22 (30%), 193 (34%),  386 (44%) and 99 (55 %) G3-4 AEs in studies evaluating IT-M, IT-C, IT+MTA, MTA-M, MTA-C and nIT+nMTA, respectively. At cycle, 1, the most frequent G3-4 AE type was gastrointestinal events (80 events; 29 % of all G3-4 AEs at cycle 1), which represented 5 (33%), 18 (22%), 50 (42%), 7 (23%) AEs in the same respective study groups.

G1-2 AEs (7030 events, 79% of AEs) occurred in 55 (37%), 141 (38%), 103 (48%), 225 (40%), 166 (32%) and 59 (35 %) inclusions of the same study groups, respectively.


Inclusions with adverse events at any cycle (upper part) and Cycle1 / after cycle 1 (bottom part).

© Louaï Missri.

Fifty-one percent of AEs resolved, and 33% required dedicated co-medications, which allowed the resolution of 5% of them.


Data from Missri et al. suggest that severe adverse events occur more frequently in studies evaluating molecularly targeted agents as a monotherapy or in combination than in studies evaluating immunotherapies as a monotherapy or in combination. Among these, less than 10% occur at cycle 1, highlighting the need for careful follow-up of patient’s safety beyond the DLT period, in order to ensure the long-term drug tolerability.

This study did not receive external funding.


22P – Missri L, Martin-Romano P, Helissey C, et al. Toxicity profile of immune and non-immune therapies in phase I/II trials: A comprehensive longitudinal analysis. ESMO Targeted Anticancer Therapies (TAT) Virtual Congress (1-2 March 2021).

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