3.1 Prescription-Diagnostics Analysis of ICI in the Japanese Population
The JMDC claims database contains prescription-diagnostics data limited to Japan; it provides more detailed information on drug use. The patient information obtained at the point of treatment for patients treated with ICIs is included in Table 1. Overall patient information was available for 6,231 patients and contained 116,091 ICI-associated prescription-diagnostics data; 75% of the patients were male, and the median age was 71 years. Non-small cell lung cancer was the most common carcinoma, accounting for 60% of cases. Nivolumab and pembrolizumab were used in most patients (44% and 39%, respectively), at almost the same rate. Among the patients, 2310 (37%) developed irAEs as defined using ICD-10 codes, with a total of 3,173 diagnostics. The highest incidence was seen in thyroiditis, followed by nephritis; only 8 patients developed myocarditis, but the mortality rate was the highest at 25%. The flow of the case is shown in Online Resource 3. The median for each AE TTO (time to onset) was 93 for type 1 diabetes (IQR, 39–181), 90 for tuberculosis (IQR, 33–163), 228 for uveitis (IQR, 42–259), 127 for hypophysitis (IQR, 54–205), 75 for pneumonitis (IQR, 32–174), 66 for hepatitis (IQR, 23–177), 64 for thyroiditis (IQR, 28–141), 65 for myositis (IQR, 44–127), 107 for skin related AEs (IQR, 37–197), 81 for neurological AEs (IQR, 35–163), 64 for nephritis (IQR, 25–147), 64 for venous thrombosis (IQR, 18–145), 97 for colitis (IQR, 33–168), 43 for hematological AEs (IQR, 21–195), 119 for adrenal AEs (IQR, 52–197), 32 for myasthenia gravis (IQR, 14–71), 74 for myocarditis (IQR, 47–112), and 125 for pancreatitis (IQR, 38–211) (Figure 1). Online Resource 4 and 5 show the number of patients with each AE by duration in the VigiBase and JMDC claims databases, respectively. Many of the irAEs occurred beyond 30 days, especially those related to type 1 diabetes mellitus, tuberculosis, ocular symptoms, pituitary dysfunction, skin disorders, and pancreatitis, for which there is no concrete onset period.
Table 1: Patient characteristics associated with the administration of cancer immunotherapy.
Patient population
|
Value n (%)
|
Patients
|
6,231
|
Male
|
4,694 (75)
|
Age (years)
|
71 (IQR, 65–76)
|
Type of cancer
|
|
Skin
|
63 (1)
|
Lung
|
3,418 (55)
|
Other malignant neoplasms
|
2,374 (38)
|
Type of ICI therapy
|
|
Nivolumab
|
2,756 (44)
|
Pembrolizumab
|
2,432 (39)
|
Avelumab
|
6 (0·1)
|
Atezolizumab
|
731 (12)
|
Durvalumab
|
306 (5)
|
Time to onset of first irAE after initiation of ICI (days)
|
75 (IQR, 29–160)
|
Type of irAE
|
2,310 (37)
|
Type 1 diabetes
|
65 (1)
|
Tuberculosis
|
28 (0·5)
|
Uveitis
|
11 (0·2)
|
Hypophysitis
|
79 (1)
|
Pneumonitis
|
541 (9)
|
Hepatitis
|
83 (1)
|
Thyroiditis
|
842 (14)
|
Myositis
|
14 (0·2)
|
Skin AE
|
28 (0·5)
|
Neurological AE
|
424 (7)
|
Nephritis
|
455 (7)
|
Venous thrombosis
|
191 (3)
|
Colitis
|
161 (3)
|
Hematological AE
|
19 (0·3)
|
Adrenal AE
|
165 (3)
|
Myasthenia gravis
|
17 (0·3)
|
Myocarditis
|
8 (0·1)
|
Pancreatitis
|
42 (0·7)
|
All-cause death
|
1,899 (30)
|
irAE-related death
|
321 (5)
|
Type 1 diabetes
|
3 (0·05 / 5a)
|
Tuberculosis
|
2 (0·03 / 7 a)
|
Uveitis
|
0
|
Hypophysitis
|
6 (0·1 / 8 a)
|
Pneumonitis
|
98 (2 / 18 a)
|
Hepatitis
|
7 (0·1 / 8 a)
|
Thyroiditis
|
81 (1 / 10 a)
|
Myositis
|
1 (0·02 / 7 a)
|
Skin AE
|
1 (0·02 / 4 a)
|
Neurological AE
|
52 (0·8 / 12 a)
|
Nephritis
|
63 (1 / 14 a)
|
Venous thrombosis
|
36 (0·6 / 19 a)
|
Colitis
|
16 (0·3 / 10 a)
|
Hematological AE
|
1 (0·02 / 5 a)
|
Adrenal AE
|
19 (0·3 / 12 a)
|
Myasthenia gravis
|
1 (0·02 / 6 a)
|
Myocarditis
|
2 (0·03 / 25 a)
|
Pancreatitis
|
8 (0·1 / 19 a)
|
a irAE-dependent mortality rate for each irAE. The mortality rate (%) was calculated as follows: number of deaths from various irAE / number of people with various irAE * 100.
3.2 Overlap per irAE in the Japanese Population
We further investigated the overlap per irAE in JMDC. The percentage of concomitant AEs in relation to the number of main AEs was evaluated (Figure 2). A high percentage was shown in red and a low percentage in green. When hypophysitis was the main symptom, 44 and 48 cases of thyroiditis and adrenal complications were observed, respectively; when thyroiditis or adrenal complications were the main symptoms, there was a high rate of endocrine complications. The same was true for the overlap in the incidence of type 1 diabetes (15 cases), hepatitis (17 cases), and colitis (35 cases) in patients who developed thyroiditis. In addition, myositis, myocarditis, and myasthenia gravis co-occurred.
3.3 Disease severity due to overlapping of irAEs.
Next, we examined whether overlapping irAEs altered the severity of the disease. The mortality rates of these complications are shown in Figure 3. The combination of diabetes and pneumonia caused the highest mortality (38%). The number of cases was small for myositis, myasthenia gravis, and myocarditis; however, when complications were observed, outcomes were poor. In terms of ambulance transport, pneumonia (11%) accounted for a higher proportion than all irAEs (7%; p=0·003), and the proportion was even higher when pneumonia overlapped with type 1 diabetes (50%, p=0·02; Table 2). In the cases of concomitant myocarditis, 6 out of 8 cases developed severe cardiac diseases, while 5 had other concomitant irAEs (Table 3).
Table 2: Detailed information on pneumonia severity in patients.
Transported by ambulancea
|
Value (%)
n = 2,209
|
p-value
|
irAE
|
155/2,209 (7)
|
|
Pneumonitis
|
40/360 (11)
|
0·003b
|
Pneumonitis with type 1 diabetes
|
3/6 (50)
|
0·02c
|
Pneumonitis with hypophysitis
|
1/9 (11)
|
1·00c
|
Pneumonitis with hepatitis
|
1/12 (8)
|
1·00c
|
Pneumonitis with thyroiditis
|
4/68 (6)
|
0·20c
|
Pneumonitis with neurological AE
|
1/37 (3)
|
0·10c
|
Pneumonitis with nephritis
|
4/33 (12)
|
0·77c
|
Pneumonitis with venous thrombosis
|
3/23 (13)
|
0·73c
|
Pneumonitis with myasthenia gravis
|
1/3 (33)
|
0·30c
|
Pneumonitis with adrenal AE
|
1/13 (8)
|
1·00c
|
a Administration at the time of onset in the ambulance, ambulance with the doctor on board, doctor-helicopter or disaster prevention helicopter versus b irAE or c Pneumonitis
Table 3. Prognosis of patients who developed myocarditis
Cardiotoxicity (ICD-10)
|
Value (%)
n = 8
|
Prognosis of myocarditis
|
|
Heart failure (I50)
|
3 (38)
|
Paroxysmal tachycardia (I47)
|
2 (25)
|
Cardiac arrhythmias (I49)
|
1 (13)
|
Exacerbation of myocarditis with/without complication
|
|
With complication
|
5 (100)
|
Without complication
|
1 (33)
|
3.4 Global Pharmacovigilance Analysis
Supplementally, we performed a similar analysis for VigiBase to see if JMDC claims database reflected the same irAE incidence. The flow of 9,160 cases in the VigiBase is shown in Online Resource 3. The TTO analysis of VigiBase indicated that the median for each AE was 114 for type 1 diabetes (IQR, 48, 239), 42 for tuberculosis (IQR, 21, 63), 81 for uveitis (IQR, 37, 167), 120 for hypophysitis (IQR, 63, 196), 54 for pneumonitis (IQR, 19, 141), 46 for hepatitis (IQR, 22, 103), 56 for thyroiditis (IQR, 28, 112), 28 for myositis (IQR, 18, 60), 48 for skin AEs (IQR, 18, 155), 59 for neurological AEs (IQR, 18, 144), 78 for nephritis (IQR, 42, 135), 56 for venous thrombosis (IQR, 21, 135), 62 for colitis (IQR, 24, 139), 88 for hematological AEs (IQR, 30, 177), 113 for adrenal AEs (IQR, 56, 216), 30 for myasthenia gravis (IQR, 22, 56), 30 for myocarditis (IQR, 19, 77), and 97 for pancreatitis (IQR, 30, 244) (Figure 4).
The overlap of each irAE was examined. The percentage of concomitant AEs that occurred in relation to the number of main AEs reports is shown in Figure 5; a high percentage is represented in red and a low percentage in green. Similar to the JMDC claims database analysis, endocrine dysfunctions, such as hypophysitis, thyroiditis, and adrenal complications, had a very high co-occurrence rate. Patient reports of thyroiditis had overlapping incidences of type 1 diabetes (17 cases), hepatitis (64 cases), and colitis (47 cases). In addition, there was a high incidence of myositis, myasthenia gravis, and myocarditis co-occurrence. This suggests that there was no large discrepancy in patient populations between VigiBase and the JMDC claims database, which reflect the global and Japanese populations, respectively. In Figure 6 (VigiBase analysis), the concomitant occurrence of pneumonia and type 1 diabetes was associated with an increased mortality rate, consistent with the JMDC results. Concomitant myocarditis also had a high mortality rate.