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Multicenter Study
. 2023 Jul 6;115(7):796-804.
doi: 10.1093/jnci/djad061.

Safety of extended interval dosing immune checkpoint inhibitors: a multicenter cohort study

Luca Cantini  1   2   3 , Francesco Paoloni  1 , Federica Pecci  1 , Francesco Spagnolo  4 , Carlo Genova  5   6 , Enrica Teresa Tanda  4 , Sophie Aerts  2 , Sara Elena Rebuzzi  6   7 , Giuseppe Fornarini  8 , Federica Zoratto  9 , Sara Fancelli  10   11 , Alessio Lupi  1 , Carminia Maria Della Corte  12 , Alessandro Parisi  13 , Chiara Bennati  14 , Cinzia Ortega  15 , Francesco Atzori  16 , Pier Luigi Piovano  17 , Corrado Orciuolo  18 , Michele De Tursi  19 , Michele Ghidini  20 , Andrea Botticelli  21 , Simone Scagnoli  22 , Lorenzo Belluomini  23 , Rita Leporati  24 , Antonello Veccia  25 , Anna Maria Di Giacomo  26 , Lucia Festino  27 , Diego Cortinovis  28 , Mirko Acquati  28 , Marco Filetti  29 , Raffaele Giusti  30 , Marco Tucci  31 , Maria Chiara Sergi  31 , Mattia Garutti  32 , Fabio Puglisi  32   33 , Sara Manglaviti  34 , Fabrizio Citarella  35 , Matteo Santoni  36 , Erika Rijavec  37 , Giuseppe Lo Russo  34 , Daniele Santini  38 , Alfredo Addeo  39 , Lorenzo Antonuzzo  10   40 , Alice Indini  37 , Marco Bruno Luigi Rocchi  41 , Alessio Cortellini  42 , Francesco Grossi  43 , Paolo Antonio Ascierto  27 , Joachim G J V Aerts  2 , Rossana Berardi  1
Affiliations
Multicenter Study

Safety of extended interval dosing immune checkpoint inhibitors: a multicenter cohort study

Luca Cantini et al. J Natl Cancer Inst. .

Abstract

Background: Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown.

Methods: Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described.

Results: A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P = .025 upfront).

Conclusions: Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials.

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Conflict of interest statement

LC reported stock and/or other ownership interests in Labcorp Drug Development. FS reported receiving personal fees from Bristol-Myers Squibb, Novartis, Merck, Sun Pharma, Sanofi, and Pierre-Fabre outside the submitted work and serving on the advisory boards of Merck, Pierre-Fabre, Sun Pharma, and Philogen. CG reported receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Roche, Sanofi, Takeda, and ThermoFisher outside the submitted work. ETT reported receiving personal fees from Merck, and Bristol-Myers Squibb. CB reported serving as advisory board member for Bristol-Myers Squibb, Merck, Boheringer Ingelheim, and AstraZeneca; and receiving personal fees from AstraZeneca, Bristol-Myers Squibb, Novartis outside the submitted work. CO reported receiving personal fees from Merck, Bristol-Myers Squibb, Janssen, Merck, and Astellas outside the submitted work. MG reported serving as advisory board member and receiving personal fees from Merck, Servier, Eli Lilly, Amgen, and Italfarmaco outside the submitted work. AB reported serving as advisory board member and receiving personal fees from Merck, Bristol-Myers Squibb, Incyte, Pierre-Fabre, Novartis, Roche, Eli Lilly, Pfizer, Daichii Sankyo, Seagen, and Gilead outside the submitted work. SS reported serving as advisory board member and receiving personal fees from Novartis, Roche, Pierre-Fabre, Eli Lilly, Pfizer, and Daichii Sankyo outside the submitted work. LB reported receiving personal fees from AstraZeneca, Roche, and Merck outside the submitted work. AMDG reported serving as advisory board member for Merck Sharpe & Dohme, Bristol-Myers Squibb, Incyte, Pierre-Fabre, Sanofi, GlaxoSmithKline, and Novartis; and receiving personal fees from Merck Sharpe & Dohme, Roche, Bristol-Myers Squibb, Sanofi, Pierre-Fabre, GlaxoSmithKline, and Vyvamed outside the submitted work. DC reported receiving personal fees from Merck, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Roche, Novartis, Sanofi, Amgen outside the submitted work. MaG reported serving as advisory board member for Novartis, Eli Lilly, Pierre-Fabre, and Roche; and receiving personal fees from Daichii Sankyo outside the submitted work. FaP reported receiving grants from AstraZeneca, Eisai, and Roche; and receiving personal fees from Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Merck, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris outside the submitted work. SM reported serving on the advisory board of Italfarmaco. GLR reported serving as a consultant/advisory board member for Merck, Bristol-Myers Squibb, Roche, AstraZeneca, Novartis, Italfarmaco, Pfizer, Sanofi. AA reported serving as a consultant/advisory board member for Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Aventis, and Takeda; and receiving personal fees from AstraZeneca, Amgen, Novartis, Eli Lilly outside the submitted work. AC reported receiving grants from Merck, AstraZeneca, IQVIA, and Oncoc4; and receiving personal fees from EISAI and AstraZeneca outside the submitted work. PAA reported serving as consultant/advisory board member for Bristol-Myers Squibb, Roche, Merck, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune; and receiving grants from Bristol-Myers Squibb, Roche, Pfizer, Sanofi outside the submitted work. JGJVA reported receiving grants from Amphera, Eli Lilly, and Roche, holding ownership interest (including patents) in Amphera, and serving as a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Takeda, Bayer, AstraZeneca, and Roche outside of the submitted work. RB reported serving as a consultant/advisory board member for AstraZeneca, BMS, Boehringer Ingelheim, EISAI, Novartis, MSD, Otsuka, Eli Lilly, Pierre Fabre, GSk, Italfarmaco, Incyte, Seagen, and Roche, outside the submitted work. All remaining authors have no disclosures to report.

Figures

Figure 1.
Figure 1.
STROBE diagram of the EDICI study. EDICI = Extended interval Dosing in patients receiving Immune Checkpoint Inhibitors; ICIs = immune checkpoint inhibitors.
Figure 2.
Figure 2.
Spectrum of irAEs for cancer patients before (during upfront CD) and after switch to ED, overall and per organ or system involved. CD = canonical interval dosing; ED = extended interval dosing; irAEs = immune-related adverse events.
Figure 3.
Figure 3.
Overall survival stratified by irAEs onset in patients who switched from CD to ED (A) and in patients treated upfront with ED ICIs (B). Overall survival was calculated since start of ED treatment. Landmark method was used to correct for immortal time bias (all patients who died before 3 months were excluded from the analysis). CD = canonical interval dosing; ED = extended interval dosing; ICI = immune checkpoint inhibitors; irAEs = immune-related adverse events.
See this image and copyright information in PMC

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