Development of a novel immune-related toxicity grading system for predicting outcomes in patients with solid tumours treated with immune checkpoint inhibitors (ICI).
Authors: Kapiris Matthaios , Santaolalla Aida , Bratsos Sosipatros , Ghunam Sundeep , McDonald Louisa , Muhith Moe , Wu Yin , Georgiou Alexandros , Josephs Debra Hannah , Sarker Debashis , Cope Andrew 
Published: June 2023

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Background: Adoption of ICI in clinical practise has led to improved outcomes in many tumour types. Their use is associated with immune related adverse events (irAEs), with unpredictable onset targeting multiple organs and for which conventional CTCAE toxicity grading has significant limitations. In addition, the correlation of irAEs to efficacy of ICI is becoming increasingly recognised. Here we present a novel toxicity assessment tool and describe its relationship with cancer outcomes. Methods: Data were collected from the Pathobiology of Adverse Immune Reactions (PAIR) prospective cohort study at Guy’s Hospital from February 2018 until end of May 2022. Solid tumour patients with advanced disease naïve to ICI who received at least 1 dose were included. Minimum 6 months of follow-up was required. IrAEs were captured based on the OST score which evaluates the number of affected Organs (O), number of Severe CTCAE (³G3) toxicities (S) and sum of all grade Toxicities (T). OST was calculated at death or end of follow-up. Patients were divided in high and low toxicity groups, defined by the median value for each parameter. Descriptive statistics and crude and multivariate survival Cox Proportional Hazards regression analyses were performed accounting for age, tumour type and treatment. Results: A total of 123 patients were included. Median age was 68 years (range 23-87 yrs); 67 (54%) were male; 104 (85%) were White Caucasian. Most common tumour types were melanoma (33%), non-small cell lung (24%) and renal cell carcinoma (22%). Forty-six patients (37%) received Ipilimumab-Nivolumab, 37 (30%) Pembrolizumab and 24 (20%) Nivolumab. Twenty-two (18%) had autoimmune disease at baseline. Hypothyroidism (6%) and psoriasis (2%) were most common. Median number of affected organs was 2 (range 0-7), 32 (26%) had ≥1 G3 toxicity and the median T score was 3 (range 0-15). Survival data were available for 120 patients. After median follow-up of 39 months, 66 deaths (53.7%) occurred. Median OS was 16.9 months (95% C.I 9.9-24.1). High toxicity groups presented reduced risk of death compared to low-toxicity groups when evaluated for individual OST parameters [HR for Organ tox group (95% CI): 0.359 (0.198-0.649), HR for Severity group (95% CI): 0.402 (0.200-0.808), HR for Toxicity score group (95% CI): 0.353 (0.190-0.657)]. Of the three parameters, the number of Organs (O) was most strongly associated with reduced risk of death when analysed as a continuous variable [HR (95% CI): 0.683 (0.577-0.808)]. Conclusions: We have developed a novel immune toxicity grading system which can potentially predict survival outcomes for patients treated with ICI. Further prospective evaluation and correlation to translational secondary endpoints with immunological phenotyping is ongoing. External validation is warranted to support further use of OST in routine clinical practice.