Table 1.
Characteristics of ICI-treated cancer patients with and without neurological irAEs.
| Characteristic | ICI-treated cancer patients without irAEs (controls) (n = 44) |
Patients with irAE-n, all (n = 29) |
Patients with irAE-n, brain-reactive ab+ (n = 13) |
Patients with irAE-n, brain- reactive ab- (n = 16) |
Patients with irAE-n, Neuromuscular ab+ (n = 15) | Patients with irAE-n, Neuromuscular ab- (n = 9) |
|---|---|---|---|---|---|---|
| Female | 15/44 (34) | 8/29 (28) | 4/13 (31) | 4/16 (25) | 3/15 (20) | 3/9 (33) |
| Age at onset, y | 68 (60-76) | 65 (61-74) | 61 (61-68) | 69 (61-77) | 63 (60-76) | 65 (61-68) |
| Neoplasm | ||||||
| Melanoma | 24/44 (55) | 16/29 (55) | 7/13 (54) | 9/16 (56) | 9/15 (60) | 4/9 (44) |
| NSCLC/SCLC | 5/44 (11) | 4/29 (14) | 1/13 (8) | 3/16 (19) | 3/15 (20) | 1/9 (11) |
| Hepatocellular carcinoma | 11/44 (25) | 2/29 (7) | 2/13 (15) | 0/16) (0) | 2/15/13) | 0/9 (0) |
| Gastric cancer/OGJ | 0/44 (0) | 2/29 (7) | 1/13 (8) | 1/16 (6) | 0/15 (0) | 2/9 (22) |
| Other | 4/44 (9)a | 5/29 (17)b | 2/13 (15) | 3/16 (19) | 1/15 (7) | 2/9 (22) |
| Brain metastases | 5/44 (11) | 3/29 (10) | 1/13 (8) | 2/16 (13) | 0/15) (0) | 3/9 (33) |
| Neurological comorbidity | 9/44/20)c | 3/29 (10)d | 0/13 (0) | 3/16 (19) | 2/15 (13) | 1/9 (11) |
| Non-neurological irAEs | 9/44 (20)e | 18/29 (62) | 8/13 (62) | 10/16 (63) | 11/15 (73) | 5/9 (56) |
| ICI therapy | ||||||
| PD-1 | 26/42 (62) | 17/28 (61) | 7/13 (54) | 10/15 (67) | 10/15 (67) | 4/9 (44) |
| PD-L1 | 14/42 (33) | 5/28 (18) | 4/13 (31) | 1/15 (7) | 3/15 (20) | 2/9 (22) |
| ICI combination (PD-1 + CTLA-4) |
2/42 (5) | 6/28 (21) | 2/13 (15) | 4/15 (27) | 2/15 (13) | 3/9 (33) |
| IrAE-n | ||||||
| Encephalitis | n/a | 7/29 (24) | 3/13 (23) | 4/16 (25) | 3/15 (20) | 4/9 (44) |
| Hypophysitis | n/a | 5/29 (17) | 2/13 (15) | 3/16 (19) | 2/15 (13) | 1/9 (11) |
| Neuropathy (incl. GBS) |
n/a | 13/29 (41) | 7/13 (54) | 6/16 (38) | 7/15 (47) | 3/9 (33) |
| Myositis/ Myopathy/ Myocarditis |
n/a | 11/29 (38) 1/29 (3) isolated myocarditis |
4/13 (31) | 7/16 (44) 1/16 (6) isolated myocarditis |
8/15 (53) 1/15 (7) isolated myocarditis |
3/9 (33) |
| Myasthenia gravis | n/a | 4/29 (14) | 2/13 (15) | 2/16 (13) | 4/15 (27) | 0/9 (0) |
| ≥ 2 irAE-ng | n/a | 10/29 (34) | 5/13 (38) | 5/16 (31) | 6/15 (40) | 3/9 (33) |
| Brain-reactive autoantibodies | before ICI: 9/44 (20) after ICI: 15/44 (34) |
13/29 (45) | 13/13 (100) | 0/16 (0) | 6/15 (40) | 6/9 (67) |
| Neuromuscular autoantibodies | before ICI: 7/41 (17) after ICI: 3/41(7) |
15/24 (63) | 6/12 (50) | 9/14 (64) | 15/15 (100) | 0/9 (0) |
| Onset after first ICI cycle, weeks | n/a | 12 (7-24) | 15 (9-24) | 12 (5-21) | 9 (5-30) | 15 (10-24) |
| Highest CTCAE grade of irAE-n | n/a | 3 (3-4) | 3 (2-3) | 3 (3-4) | 3 (3-4) | 3 (3-4) |
| Treatment | ||||||
| Corticosteroids | n/a | 27/29 (93) | 12/13 (92) | 15/16 (94) | 15/15 (100) | 8/9 (89) |
| IVIG | n/a | 7/29 (24) | 3/13 (23) | 4/16 (25) | 5/15 (33) | 1/9 (11) |
| Plasma exchange | n/a | 2/29 (7) | 0/13 (0) | 2/16 (13) | 1/15 (7) | 1/9 (11) |
| Unfavorable outcome (CTCAE ≥ 3 at 3m) | n/a | 13/29 (45)h | 4/13 (31) | 9/16 (56) | 8/15 (53) | 4/9 (44) |
| Corticosteroids at 3m | n/a | 22/24 (92) | 10/11 (91) | 12/13 (92) | 13/13 (100) | 6/7 (86) |
| Lethal outcome of irAE-n | n/a | 3/29 (10) | 1/13 (8) | 2/16 (13) | 2/11 (18) | 1/9 (11) |
Values are median (interquartile range, IQR) or n (%). ab, autoantibody; CTCAE, Common Terminology Criteria for Adverse Events; CSF, cerebrospinal fluid; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GBS, Guillain-Barré syndrome; ICI, immune checkpoint inhibitor; ICU, intensive care unit; irAEs, immune related adverse events; IVIG, intravenous immunoglobulin therapy; n/a, not applicable; NSCLC, non-small cell lung cancer; OGJ, oesophagogastric junctional adenocarcinoma; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SCLC, small cell lung cancer; y, years; 3m, three months. a = basal-cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma. b = cholangiocarcinoma, Hodgkin lymphoma, Merkel cell carcinoma, prostate cancer, urothelial carcinoma. c = five cases of previous stroke, one case of previous stroke and epilepsy, one case of previous stroke and meningioma, one case of chemotherapy-induced polyneuropathy, one case of previous vestibular neuritis. d = one case of previous stroke, one case of Korsakoff syndrome, one case of preexisting myasthenia gravis with anti-AchR and anti-titin autoantibodies. e = patients with high-grade irAE (CTCAE grade ≥ 3) were excluded. f = two patients in the control cohort and one patient in the irAE-n group were blinded for ICI-type (nivolumab +/- ipilimumab). g = one patient had three irAE-n: myositis, neuropathy, encephalitis h = in two patients CTCAE grade was scored at one month, as patients were lost to follow-up afterwards. In one patient, last CTCAE grade was evaluated, as the patient died of sepsis one week after onset of irAE-n.