Association of Rare Immune-Related Adverse Events to Survival in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors: A Real-World Single-Center Cohort Study

Abstract

Immune checkpoint inhibitors (ICIs) are associated with immune-related (ir) adverse events (AEs) resembling autoimmune diseases. In this retrospective cohort study of patients (pts) treated with ICIs at Oulu University Hospital from 2014–2020, we analysed the spectrum of severe irAEs and their prognostic nature, focusing on rare irAEs. Pts (n = 173) with lung cancer (n = 76, 43.9%), melanoma (n = 56, 32.4%), renal and bladder cancers (n = 34, 19.7%), head and neck cancers (n = 4, 2.3%), SCC (n = 2, 1.2%), and CRC (n = 1, 0.6%) receiving single anti-PD-(L)1 (n = 160) or combination (ICI-ICI n = 9, ICI-chemotherapy n = 4) therapy were included. The survival analysis focused on single anti-PD-(L)1-treated patients with melanoma, lung cancer, and renal and bladder cancers (n = 142). Grade ≥ 3 irAEs of multiple aetiology occurred in 29 patients treated with single-PD-L1 therapy (20.4%), which was associated with improved progression-free survival (PFS) (HR 0.50, CI 0.31–0.78) but not overall survival (OS) (HR 0.88, CI 0.52–1.50). Rare grade ≥ 3 events occurred in 10 (7.0%) pts with no association with PFS (HR 0.90, CI 0.42–1.94). Hence, the presence of rare grade ≥ 3 irAEs was associated with a tendency for inferior OS (HR 1.44, CI 0.66–3.11). Pts with rare grade ≥ 3 irAEs had inferior OS, possibly reflecting the delay in diagnostic workflow and the treatment of irAEs. One explanation for the high incidence of irAEs could be the Finnish population-based genetic variation affecting the immune system.

The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare Immune Checkpoint Related Adverse Effects

“…While in case of high grade rare irAEs; grade 3 or more rare irAEs were associated with inferior overall survival and no impact on PFS [32].…”

“…Thus, they represent a more specific activation of adaptive immunity [33]. Cutaneous, autoimmune diseases occur more frequently with anti-PD-1/programmed cell death ligand 1 (PD-L1) than with anti-CTLA-4 therapy [32].…”

“…For patients with psoriasis, episodes of exacerbation have been reported in patients receiving pembrolizumab, nivolumab or durvalumab [38]. In a single centre experience rare dermatological irAEs were reported as single cases of pemphigoid and bullous dermatitis respectively [32]. Other reported cutaneous irAEs that occurred rarely were vasculitis, neutrophilic dermatosis, erythema nodosum [39][40][41].…”

“…Central adrenal insufficiency and autoimmune diabetes mellitus are extremely rare adverse events related to ICI. Central adrenal insufficiency can be life threatening when it is severe as it is associated with severe electrolyte disturbance, dehydration, and hypoglycemia [7,32,34,47,48]. Another well-known endocrine irAE is hypophysitis.…”

Unexpected Adverse Events of Immune Checkpoint Inhibitors

“…Reiter’s syndrome, an autoimmune disorder, is characterized by a triad of symptoms, which include conjunctivitis, genitourinary symptoms and arthritis. The most common underlying causes associated with Reiter’s syndrome are intestinal or genital infections [ 26 ].…”