Safety of Extended Interval Dosing Immune Checkpoint Inhibitors

^aPercentage calculated on the number of patients with metastatic cancer. CD = canonical interval dosing; ECOG-PS = Eastern Operative Oncology Group Performance Score; ED = extended interval dosing; ICI = immune checkpoint inhibitor; irAEs = immune-related adverse events; NSCLC = non-small cell lung cancer.
^bSurgery refers to resection of primitive tumor or metastatic site or both.
^cRadiotherapy concomitant to ICIs refers to primitive tumor, metastatic site, or both.

^aOverall 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; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Score; ED = extended interval dosing; ICIs = immune checkpoint inhibitors; irAEs = immune-related adverse events; NSCLC = non-small cell lung cancer.

^aLandmark method was used to correct for immortal time bias (all patients who died before 3 months were excluded from the analysis). CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Score; ED = extended interval dosing; ICIs = immune checkpoint inhibitors; irAEs = immune-related adverse events; NSCLC = non-small cell lung cancer.

Authors and Disclosures

Luca Cantini, MD^1–3,‡, Francesco Paoloni, MD^1,‡, Federica Pecci, MD^1,‡, Francesco Spagnolo, MD, PhD⁴, Carlo Genova, MD^5,6 Enrica Teresa Tanda, MD⁴, Sophie Aerts, BSc², Sara Elena Rebuzzi, MD^6,7, Giuseppe Fornarini, MD⁸, Federica Zoratto, MD⁹ Sara Fancelli, MD^10,11, Alessio Lupi, MD¹, Carminia Maria Della Corte, MD, PhD¹², Alessandro Parisi, MD¹³, Chiara Bennati, MD¹⁴ Cinzia Ortega, MD¹⁵, Francesco Atzori, MD¹⁶, Pier Luigi Piovano, MD¹⁷, Corrado Orciuolo, MD¹⁸, Michele De Tursi, MD¹⁹ Michele Ghidini, MD, PhD²⁰, Andrea Botticelli, MD, PhD²¹, Simone Scagnoli, MD²², Lorenzo Belluomini, MD²³ Rita Leporati, MD²⁴, Antonello Veccia, MD²⁵, Anna Maria Di Giacomo, MD²⁶, Lucia Festino, MD²⁷, Diego Cortinovis, MD²⁸ Mirko Acquati, MD²⁸, Marco Filetti, MD²⁹, Raffaele Giusti, MD³⁰, Marco Tucci, MD³¹, Maria Chiara Sergi, MD³¹ Mattia Garutti, MD³², Fabio Puglisi, MD^32,33, Sara Manglaviti, MD³⁴, Fabrizio Citarella, MD³⁵, Matteo Santoni, MD, PhD³⁶ Erika Rijavec, MD³⁷, Giuseppe Lo Russo, MD, PhD³⁴, Daniele Santini, MD³⁸, Alfredo Addeo, MD³⁹ Lorenzo Antonuzzo, MD, PhD^10,40, Alice Indini, MD³⁷, Marco Bruno Luigi Rocchi, MSc⁴¹, Alessio Cortellini, MD, PhD⁴² Francesco Grossi, MD⁴³, Paolo Antonio Ascierto, MD²⁷, Joachim G. J. V. Aerts, MD, PhD^2,§ and Rossana Berardi, MD^1,*<sup>,§

1</sup>Clinical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy
²Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
³Labcorp Drug Development Inc, Princeton, NJ, USA
⁴Medical Oncology Unit 2, Istituto di ricovero e cura a carattere scientific (IRCCS) Ospedale Policlinico San Martino, Genova, Italy
⁵Academic Medical Oncology Unit, Istituto di ricovero e cura a carattere scientific (IRCCS) Ospedale Policlinico San Martino, Genoa, Italy
⁶Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Italy
⁷Medical Oncology Unit, Ospedale San Paolo, Savona, Italy
⁸Medical Oncology Unit 1, Istituto di ricovero e cura a carattere scientific (IRCCS) Ospedale Policlinico San Martino, Genoa, Italy
⁹UOC Oncologia, Ospedale Santa Maria Goretti, Latina, Italy
¹⁰Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
¹¹Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
¹²Department of Precision Medicine, University of Campania, Italy
¹³Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
¹⁴S Maria delle Croci Hospital, AUSL della Romagna, Ravenna, Italy
¹⁵Oncology, Asl Cn2, Ospedale Michele e Pietro Ferrero, Verduno, Italy
¹⁶Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
¹⁷Oncology Unit, Azienda Ospedaliera "SS. Antonio e Biagio e C. Arrigo", Alessandria, Italy
¹⁸Istituto di ricovero e cura a carattere scientific (IRCCS), National Cancer Institute Regina Elena, Rome, Italy
¹⁹Department of Innovative Technologies in Medicine and Dentistry, University G. D'Annunzio, Chieti-Pescara, Italy
²⁰Oncology Unit, Fondazione Istituto di ricovero e cura a carattere scientific (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
²¹Medical Oncology Unit A, Policlinico Umberto I, Radiological, Oncological, Pathological Sciences Department, Sapienza University of Rome, Italy
²²Medical Oncology Unit B, Policlinico Umberto I, Rome, Italy
²³Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
²⁴Medical Oncology, Fondazione Istituto di ricovero e cura a carattere scientific (IRCCS) Istituto Nazionale dei Tumori, Milano, Italy
²⁵Medical Oncology, Santa Chiara Hospital, Largo Medaglie d'Oro 1, Trento, Italy
²⁶Center for Immuno-Oncology, University of Siena, University Hospital of Siena, Siena, Italy
²⁷Melanoma Unit, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori Istituto di ricovero e cura a carattere scientific (IRCCS) Fondazione "G. Pascale", Naples, Italy
²⁸SC Oncologia Medica ASST H S Gerardo, Monza, Italy
²⁹Phase 1 Unit, Fondazione Policlinico Universitario Agostino Gemelli, Istituto di ricovero e cura a carattere scientific (IRCCS), Rome, Italy
³⁰Medical Oncology Unit, Sant'Andrea Hospital of Rome, Italy
³¹Medical Oncology Unit, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Italy
³²CRO Aviano, National Cancer Institute, Istituto di ricovero e cura a carattere scientific (IRCCS), Aviano, Italy
³³Department of Medicine (DAME), University of Udine, Udine, Italy
³⁴Thoracic Unit, Medical Oncology Department 1, Fondazione Istituto di ricovero e cura a carattere scientific (IRCCS) Istituto Nazionale dei Tumori di Milano, Italy
³⁵Department of Medical Oncology, Campus Bio-Medico University, Rome, Italy
³⁶Oncology Unit, Macerata Hospital, Macerata, Italy
³⁷Medical Oncology Unit, Ospedale di Circolo e Fondazione Macchi, asst Settelaghi, Varese, Italy
³⁸UOC Oncologia Medica Territoriale, Sapienza Universit_a, Polo Pontino, Rome, Italy
³⁹Oncology Department, University Hospital Geneva, Geneva, Switzerland
⁴⁰Clinical Oncology Unit, and Medical Oncology Unit, Careggi University Hospital, Florence, Italy
⁴¹Biomolecular Sciences Department, University of Urbino, Urbino, Italy
⁴²Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
⁴³Medical Oncology Unit, Ospedale di Circolo e Fondazione Macchi, asst Settelaghi, University of insubria, Varese, Italy

*Correspondence to
Rossana Berardi, MD, Clinical Oncology, Polytechnic University of Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Via Conca 71, Ancona 60126, Italy (e-mail: r.berardi@staff.univpm.it).

^‡These authors contributed equally to this work.

^§These authors contributed equally to this work.

Author contributions
Luca Cantini, MD (Conceptualization; Data curation; Formal analysis; Methodology; Supervision; Writing – original draft; Writing – review & Editing); Lucia Festino, MD (Investigation; Writing – original draft; Writing – review & Editing); Diego Cortinovis, MD (Investigation; Writing – original draft; Writing – review & Editing); Mirko Acquati, MD (Investigation; Writing – original draft; Writing – review & Editing); Marco Filetti, MD (Investigation; Writing – original draft; Writing – review & Editing); Raffaele Giusti, MD (Investigation; Writing – original draft; Writing – review & Editing); Marco Tucci, MD, PhD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Maria Chiara Sergi, MD (Investigation; Writing – original draft; Writing – review & Editing); Mattia Garutti, MD (Investigation; Writing – original draft; Writing – review & Editing); Fabio Puglisi, MD, PhD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Sara Manglaviti, MD (Investigation; Writing – original draft; Writing – review & Editing); Anna Maria Di Giacomo, MD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Fabrizio Citarella, MD (Investigation; Writing – original draft; Writing – review & Editing); Erika Rijavec, MD (Investigation; Writing – original draft; Writing – review & Editing); Giuseppe Lo Russo, MD, PhD (Investigation; Writing – original draft; Writing – review & Editing); Daniele Santini, MD, PhD (Investigation; Writing – original draft; Writing – review & Editing); Alfredo Addeo, MD (Investigation; Writing – original draft; Writing – review & Editing); Lorenzo Antonuzzo, MD, PhD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Alice Indini, MD (Investigation; Writing – original draft; Writing – review & Editing); Marco Bruno Luigi Rocchi, MD, Prof (Data curation; Methodology; Supervision; Writing – original draft; Writing – review & Editing); Alessio Cortellini, MD, PhD (Investigation; Methodology; Writing – original draft; Writing – review & Editing); Francesco Grossi, MD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Paolo Antonio Ascierto, MD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Matteo Santoni, MD, PhD (Investigation; Writing – original draft; Writing – review & Editing); Joachim GJV. Aerts, MD, PhD, Prof (Conceptualization; Data curation; Formal analysis; Supervision; Validation; Writing – original draft; Writing – review & Editing); Antonello Veccia, MD (Investigation; Writing – original draft; Writing – review & Editing); Lorenzo Belluomini, MD (Investigation; Writing – original draft; Writing – review & Editing); Francesco Paoloni, MD (Conceptualization; Data curation; Formal analysis; Visualization; Writing – original draft; Writing – review & Editing); Federica Pecci, MD (Conceptualization; Data curation; Formal analysis; Methodology; Visualization; Writing – original draft; Writing – review & Editing); Francesco Spagnolo, MD (Data curation; Validation; Writing – original draft; Writing – review & Editing); Carlo Genova, MD, PhD (Data curation; Writing – original draft; Writing – review & Editing); Enrica Teresa Tanda, MD (Data curation; Investigation; Writing – original draft; Writing – review & Editing); Sophie Aerts, MD (Investigation; Writing – original draft; Writing – review & Editing); Sara Elena Rebuzzi, MD (Investigation; Writing – original draft; Writing – review & Editing); Giuseppe Fornarini, MD (Investigation; Writing – original draft; Writing – review & Editing); Federica Zoratto, MD (Investigation; Writing – original draft; Writing – review & Editing); Sara Fancelli, MD (Investigation; Writing – original draft; Writing – review & Editing); Rita Leporati, MD (Investigation; Writing – original draft; Writing – review & Editing); Alessio Lupi, MD (Investigation; Writing – original draft; Writing – review & Editing); Alessandro Parisi, MD (Investigation; Writing – original draft; Writing – review & Editing); Chiara Bennati, MD (Investigation; Writing – original draft; Writing – review & Editing); Cinzia Ortega, MD (Investigation; Writing – original draft; Writing – review & Editing); Francesco Atzori, MD (Investigation; Writing – original draft; Writing – review & Editing); Pier Luigi Piovano, MD (Investigation; Writing – original draft; Writing – review & Editing); Corrado Orciuolo, MD (Investigation; Writing – original draft; Writing – review & Editing); Michele De Tursi, MD, Prof (Investigation; Writing – original draft; Writing – review & Editing); Michele Ghidini, MD (Investigation; Writing – original draft; Writing – review & Editing); Andrea Botticelli, MD, PhD (Investigation; Writing – original draft; Writing – review & Editing); Simone Scagnoli, MD (Investigation; Writing – original draft; Writing – review & Editing); Carminia Maria Della Corte, MD (Investigation; Writing – original draft; Writing – review & Editing); Rossana Berardi, MD (Conceptualization; Data curation; Formal analysis; Supervision; Validation; Writing – original draft; Writing – review & Editing).

Conflicts of interest
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.