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. 2024 Dec;42(6):664-674.
doi: 10.1007/s10637-024-01481-9. Epub 2024 Nov 4.

Modernizing the assessment and reporting of adverse events in oncology clinical trials using complementary statistical approaches: a case study of the MOTIVATE trial

Mathilde Morisseau  1 , Carlos Gomez-Roca  2 , Marie Viala  3 , Audrey Rabeau  4 , Delphine Loirat  5   6 , Nadia Munsch  7 , Kristell Thomas  2 , Cécile Pages  8 , Iphigenie Korakis  2 , Vincent Sibaud  8 , Jean-Pierre Delord  2 , Thomas Filleron #  9   10 , Bastien Cabarrou #  1
Affiliations

Modernizing the assessment and reporting of adverse events in oncology clinical trials using complementary statistical approaches: a case study of the MOTIVATE trial

Mathilde Morisseau et al. Invest New Drugs. 2024 Dec.

Abstract

The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes.

Keywords: Adverse events analysis; Immune checkpoint inhibitor; MOTIVATE trial; Oncology clinical trials; Prevalence.

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Conflict of interest statement

Declarations. Ethics approval: The protocol was approved by a French Ethical Research Committee (CPP) and registered in Clinical-Trials.gov (NCT03447483). The study was conducted in accordance with the Declaration of Helsinki and ICH guidelines for Good Clinical Practice. Written informed consent was obtained from all patients prior to inclusion. Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: CGR reported receiving personal fees from BMS, Macomics, Pharmamar, Pierre Fabre, Roche / Genentech outside the submitted work; institutional fees from Amunix, BMS, Hookipa, IDEAYA, Kazia Therapeutics outside the submitted work; research grant from Roche / Genentech outside the submitted work. MV reported receiving personal fees from Lilly, BMS outside the submitted work. DL reported receiving personal fees from Roche, AstraZeneca, Pfizer, Novartis, MSD, Daiichi Sankyo, Lilly, Amgen, EISAI, Exact Sciences, Gilead, Daiichi outside the submitted work; support for attending meetings and/or travel from Roche, AstraZeneca, Pfizer, Novartis, MSD, Gilead outside the submitted work. VS reported receiving personal fees from BMS, MSD, Sanofi, Janssen, Astellas, Incyte, Bayer, Pierre Fabre outside the submitted work. JPD reported receiving institutional fees from BMS, Merck Serono, MSD, Pierre Fabre, Roche ouside the submitted work; research grant from Amgen, AstraZeneca, BMS, Genentech, MSD, Transgene outside the submitted work. TF reported receiving personal fees from Jansen outside the submitted work; institutional fees from Roche, Lilly outside the submitted work. All other authors declare no competing interests.

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