A multicenter characterization of hepatitis associated with immune checkpoint inhibitors

Figures & data

Figure 1. PFS of the full

Table 1. Patient, tumor, and treatment characteristics

Characteristic	Number of patients (n = 164)	% of total
Age (median)	63 (range = 72)
Cancer type
Lung	12	7.32%
Melanoma	138	83.54%
Renal Cell	5	3.05%
Squamous Cell	2	1.22%
Other*	7	4.27%
Treatment type
Ipilimumab	7	4.27%
Ipilimumab + nivolumab	97	59.15
Ipilimumab + pembrolizumab	3	1.83%
Nivolumab	19	11.59%
Pembrolizumab	34	20.73
Other anti-PD-1/PD-L1**	4	2.44%
Prior therapies
Targeted	37	22.56%
Chemotherapy	9	5.49%
No prior therapy	116	70.73%
Other***	9	5.49%
Liver specific comorbidities at ICI start
Cysts	1	0.61%
Fatty liver	3	1.83%
Hemangioma	3	1.83%
Hemochromatosis	1	0.61%
Prior hepatitis A	1	0.61%
Hepatitis B	1	0.61%
Hepatitis C	3	1.83%
Hepatocellular carcinoma	1	0.61%
Liver metastases at start	42	25.61%
Stage at ICI start
III	22	13.41%
IV****	141	85.98%
Unknown	1	0.61%
Extrahepatic irAEs
Any Extrahepatic irAE	108	65.85%
Grade 1–2	83	50.61%
Grade 3–4	34	20.73%
Required steroids	61	37.20%
Required steroids and additional immunosuppressants	11	6.71%
Best response to ICI
CR	45	27.44%
PR	56	34.15%
SD	28	17.07%
PD	24	14.63%
Progression on ICI during follow up	58	35.37%
ECOG at last f/u
0	65	39.63%
1	42	25.61%
2–4	8	4.88%
5	31	18.90%
Unknown	3	2.44%
Alive at last f/u	130	79.27%
Death from hepatitis	4	2.44%
Duration of follow-up (median, days)	585
*Other cancers include adrenal (n = 1), breast (n = 1), gastric (n = 1), hepatocellular (n = 1), Merkel cell (n = 1), pancreatic (n = 1), urethral (n = 1) **Other treatments include Atezolizumab (n = 2), Avelumab (n = 1), Cemiplimab (n = 1) ***Other prior therapies include autologous vaccine (n = 2), CAVATAK + pembrolizumab (n = 2), IMCgp100 (n = 1), DLI + IL-2 + IL-15, (n = 1), Pembrolizumab + GITR (n = 1), Dendritic cell vaccine (n = 1), pembrolizumab + SD-101 (n = 1) **** 34 patients with brain metastases at ICI start

Table 2. Hepatitis characteristics

Characteristic	Number of patients (n = 164)	% of total
Time to onset (median days)	61 (range 5–1189 days, IQR for combination therapy = 51 days, IQR for monotherapy = 132 days)
Initial hepatitis grade
1	16	9.76%
2	50	30.49%
3	75	45.73%
4	23	14.02%
Symptoms
Asymptomatic	76	46.34%
Abdominal/back pain	19	11.59%
Abdominal distension	4	2.44%
Arthralgias/myalgias	14	8.54%
Chills	7	4.27%
Dark urine	3	1.83%
Diarrhea	9	5.49%
Fatigue/anorexia	28	17.07%
Fever	23	14.02%
Headache	7	4.27%
Jaundice	6	3.66%
Nausea/Emesis	23	14.02%
Neurologic (AMS, numbness, weakness)	4	2.44%
Pruritis	6	3.66%
Rash	7	4.27%
Other*	7	4.27%
Workup
Biopsy performed	32	19.51%
Imaging performed	73	44.51%
Management
Required steroids as initial treatment**	150	91.46%
Initially required low dose steroids (<50 mg daily or <1 mg/kg)	20	12.20%
Required high dose steroids	129	78.66%
Required oral steroids	102	62.20%
Required IV steroids	48	29.27%
Treated with prednisone or methylprednisolone	147	89.63%
Treated with dexamethasone	1	0.61%
Treated with hydrocortisone	2	1.22%
Additional immunosuppressants required***	37	22.56%
Additional steroids required	45	27.44%
Time from hepatitis onset to any improvement (median days)	8
Time to hepatitis improvement by one grade (median days)	13
Time to complete hepatitis resolution (median days)	52
Side effects to treatment for hepatitis
Adrenal insufficiency	2	1.22%
Bacterial infection (cellulitis and respiratory tract infection)	3	1.83%
Fungal infection	4	2.44%
Gastrointestinal	3	1.83%
Hyperglycemia/diabetes	22	13.41%
Insomnia	7	4.27%
Mood changes	7	4.27%
Muscle weakness/myalgias	3	1.83%
Osteoporosis	2	1.22%
Weight gain	3	1.83%
Other****	6	3.66%
ICI re-challenged after hepatitis
ICI permanently discontinued due to hepatitis	98	59.76%
ICI rechallenged*****	66	40.24%
ICI restarted: no hepatitis	39	62.12%
ICI restarted: hepatitis recurred	17	25.76%
ICI restarted: other toxicity developed	9	13.64%
Required steroids for recurrent hepatitis	14	21.21%
Required steroids and mycophenolate for recurrent hepatitis	2	3.03%
Death from recurrent hepatitis	0
Time between resolution and ICI re-challenge (median days)	14
Time between ICI start and recurrence (median)	32.0
Grade of recurrent hepatitis (% out of those that recurred)
1–2	10	58.82%
3	6	35.29%
4	1	5.88%
*Other symptoms include gastric reflux (n = 2), altered taste (n = 1), dysphagia (n = 1), dyspnea (n = 1), hypotension/tachycardia (n = 1), visual changes (n = 1) ** 2 patients with unknown dose ***Mycophenolate (n = 30), mycophenolate + tacrolimus (n = 3), mycophenolate + abatacept (n = 1) infliximab (n = 1) ****Other side effects include edema (n = 4), fatigue (n = 2), hypertension (n = 1), tremors (n = 1) ***** 1 patient lost to f/u and rechallenge data unknown