Patients’ characteristics
The median age of the enrolled patients was 64 years (interquartile range [IQR] 57-73). In total, 61 (69.3%) patients had IMDC intermediate-risk, and 27 (30.7%) had poor risk. The cohort included both clear-cell and nonclear-cell histologies. Most patients had a performance status (PS) of 1 (75%) at the start of treatment. Half of them had primary metastatic disease (52.3%), with over 80% having undergone nephrectomy. The median time to systemic treatment initiation after nephrectomy was 3.4 months. The most common metastatic sites were the lungs, lymph nodes, and bones. The detailed baseline characteristics and comorbidities are presented in Table 1.
Table 1. Baseline clinical characteristics of the enrolled patients: comparison of those with and without immune-related adverse events.
Demographics
|
|
All patients n=88
|
irAEs
n=50
|
no-irAEs
n=38
|
p-value
|
Age
|
64 (57-73)
|
64.5 (60-73)
|
64 (55.5-72.3)
|
0.4
|
Males, n(%)
|
70 (79.5)
|
42 (84)
|
28 (73.7)
|
0.4
|
Females n(%)
|
18 (20.5)
|
8 (16)
|
10 (26.3)
|
0.42
|
Time of follow-up (months)
|
11.3 (4.2-17.9)
|
9.7 (5-17)
|
13 (3.6-18.3)
|
0.9
|
Comorbidities
|
Hypertension, n(%)
|
47 (53.4)
|
28 (56)
|
19 (50)
|
0.67
|
Ischemic heart disease, n(%)
|
10 (11.4)
|
8 (16)
|
2 (5.3)
|
0.18
|
Heart failure, n(%)
|
5 (5.7)
|
4 (8)
|
1 (2.6)
|
0.38
|
Atrial fibrillation, n(%)
|
5 (5.7)
|
2 (4)
|
3 (7.8)
|
0.64
|
Hypercholesterolemia, n(%)
|
15 (17)
|
11 (22)
|
4 (10.4)
|
0.25
|
Hypothyroidism, n(%)
|
18 (20.7)
|
11 (22)
|
7 (18.4)
|
0.79
|
Diabetes mellitus type 2, n(%)
|
12 (13.6)
|
9 (18)
|
3 (7.9)
|
0.22
|
Venous thromboembolism, n(%)
|
6 (6.8)
|
6 (12)
|
0
|
0.03*
|
Other malignancies, n(%)
|
4 (4.5)
|
1 (2)
|
3 (7.9)
|
0.31
|
Baseline characteristics
|
Performance status, n(%)
|
0
|
9 (10.2)
|
4 (8)
|
5 (13.2)
|
0.36
|
1
|
66 (75)
|
38 (76)
|
28 (73.7)
|
0.53
|
2
|
13 (14.8)
|
8 (16)
|
5 (13.2)
|
0.5
|
Nephrectomy, n(%)
|
Yes
|
71 (80.7)
|
39 (78)
|
32 (84.2)
|
0.17
|
No
|
17 (19.3)
|
11 (22)
|
6 (15.8)
|
0.37
|
Time from nephrectomy to treatment initiation (months)
|
3.4 (1.7-7.7)
|
3.5 (1.7-10.3)
|
3.1 (1.7-5.9)
|
0.5
|
T stage after nephrectomy according to AJCC 8th edition, n(%)
|
T1
|
8 (9.1)
|
6 (12)
|
2 (5.3)
|
0.27
|
T2
|
9 (10.2)
|
5 (10)
|
4 (10.5)
|
0.6
|
T3
|
47 (53.4)
|
26 (52)
|
21 (55.3)
|
0.5
|
T4
|
4 (4.5)
|
3 (6)
|
1 (2.6)
|
0.4
|
No data
|
20 (22.7)
|
10 (20)
|
10 (26.3)
|
0.38
|
Histologic grade, n(%)
|
G1
|
3 (3.4)
|
1 (2)
|
2 (5.3)
|
0.4
|
G2
|
16 (18.2)
|
7 (14)
|
9 (23.7)
|
0.24
|
G3
|
19 (21.6)
|
13 (26)
|
6 (15.8)
|
0.25
|
G4
|
31 (35.2)
|
20 (40)
|
11 (28.9)
|
0.3
|
No data
|
19 (21.6)
|
9 (18)
|
10 (26.3)
|
0.3
|
Histologic subtype, n(%)
|
Clear cell
|
66 (75)
|
34 (68)
|
32 (84.2)
|
0.31
|
Sarcomatous components
|
14 (15.9)
|
9 (18)
|
5 (13.2)
|
0.41
|
No data
|
8 (9.1)
|
7 (14)
|
1 (2.6)
|
0.09
|
Primary metastatic, n(%)
|
46 (52.3)
|
23 (46)
|
23 (60.5)
|
0.2
|
Number of disease sites, n(%)
|
≤ 2
|
51 (58)
|
31 (62)
|
20 (52.6)
|
0.39
|
>2
|
37 (42)
|
19 (38)
|
18 (47.4)
|
0.36
|
Site of metastasis at the baseline CT scan, n(%)
|
Nonregional Lymph nodes
|
35 (39.8)
|
19 (38)
|
16 (42.1)
|
0.83
|
Suprarenal glands
|
11 (12.5)
|
7 (14)
|
4 (10.5)
|
0.75
|
Liver
|
21 (23.9)
|
12 (24)
|
9 (23.7)
|
1
|
Central nervous system
|
6 (6.8)
|
3 (6)
|
3 (7.9)
|
1
|
Lungs
|
62 (70.5)
|
37 (74)
|
25 (65.8)
|
0.48
|
Bones
|
27 (30.7)
|
15 (30)
|
12 (31.6)
|
1
|
IMDC risk group, n(%)
|
Intermediate
|
61 (69.3)
|
37 (74)
|
24 (63.2)
|
0.38
|
Poor
|
27 (30.7)
|
13 (26)
|
14 (36.8)
|
0.28
|
Number of risk factors, n(%)
|
1
|
33 (37.5)
|
21 (42)
|
12 (31.6)
|
0.7
|
2
|
28 (31.8)
|
16 (32)
|
12 (31.6)
|
0.58
|
3
|
23 (26.1)
|
11 (22)
|
12 (31.6)
|
0.3
|
4
|
4 (4.5)
|
2 (4)
|
2 (5.3)
|
0.59
|
No of patients with risk categories, n(%)
|
Time from the diagnosis to treatment onset <1 year
|
76 (86.3)
|
42 (84)
|
34 (89.5)
|
0.54
|
Karnofsky Score <80%
|
19 (21.6)
|
12 (24)
|
7 (18.4)
|
0.61
|
Hemoglobin level <unl
|
53 (60.2)
|
29 (58)
|
24 (63.2)
|
0.67
|
Corrected calcium >unl
|
7 (8)
|
2 (4)
|
5 (13.2)
|
0.23
|
Neutrophils >unl
|
5 (5.7)
|
2 (4)
|
3 (7.9)
|
0.65
|
Platelets >unl
|
19 (21.6)
|
10 (20)
|
9 (23.7)
|
0.8
|
Categorical variables are presented as numbers (percentages), and continuous variables are presented as medians and interquartile ranges.
Abbreviations: AJCC, American Joint Committee on Cancer, CT, computed tomography, DC, International Metastatic Renal Cell Carcinoma Database Consortium, n, number, T, tumor, unl, upper normal limit
Safety
In total, 50 patients (56.8%) experienced irAEs, with 74 events recorded (Table 2). Patients with and without irAEs were comparable in baseline characteristics, except for the number of venous thromboembolic events, which differed significantly (p=0.03) (Table 1). Grade (G) 1 irAEs occurred in 35 patients (70% of individuals with irAEs), G2 in 25 (50%), G3 in 11 (22%), and G4 in 4 individuals (8%). Overall, in the whole group, 20 patients (22.7%) experienced multiple irAE episodes (2 episodes in n=12, 13.6%, 3 episodes in n=7, 8%, and 4 episodes in n=1, 1%). The most frequent irAEs were endocrine-related (n=20, 27%), followed by hepatotoxicity (n=15, 17%), general disorders (n=12, 13.6%), and cutaneous events (n=11, 12.5%) (Figure 1). The median time to onset of irAEs was 2 months (IQR:1.5-3), with 16% of them (n=12) occurring within the first month. Immunosuppressive treatment, primarily steroids at a median dose of 1 mg/kg (IQR: 0.5-1), was administered to 19 patients (38%). Mycophenolate mofetil was used in 2 patients—one for hepatotoxicity and the other for recurrent fever. Twelve patients (13.6%) discontinued treatment because of irAEs, with hepatotoxicity being the most common cause.
Table 2. Summary of recorded immune-related adverse events (n=74 events).
|
Any grades,
(n%)
|
Grade 3-4
n=14
|
Steroid use
n=19
|
Discontinuation
n=12
|
Endocrine
|
Hypo/hyperthyroidism, n(%)
|
16 (18.2)
|
0
|
0
|
0
|
Hypophysitis, n(%)
|
3 (2.3)
|
1
|
2
|
0
|
Adrenal insufficiency, n(%)
|
1 (1.1)
|
0
|
0
|
0
|
Hepatic, n(%)
|
15 (17)
|
5
|
8
|
4
|
Pulmonary, n(%)
|
2 (2.3)
|
0
|
1
|
0
|
General
|
Fatigue, n(%)
|
8 (9.1)
|
1
|
0
|
1
|
Infusional-related reactions, n(%)
|
2 (2.3)
|
0
|
0
|
0
|
Fever, n(%)
|
2 (2.3)
|
0
|
1
|
1
|
Cutaneous, n(%)
|
11 (12.5)
|
2
|
2
|
1
|
Diarrhea/colitis, n(%)
|
5 (5.7)
|
1
|
2
|
2
|
Rheumatoid, n(%)
|
2 (2.3)
|
0
|
1
|
0
|
Hematologic
|
Anemia, n(%)
|
3 (3.4)
|
2
|
1
|
2
|
Neutropenia, n(%)
|
1 (1.1)
|
1
|
0
|
0
|
Thrombocytopenia, n(%)
|
1 (1.1)
|
0
|
0
|
0
|
Pericarditis, n(%)
|
1 (1.1)
|
0
|
1
|
0
|
Pulmonary embolism, n(%)
|
1 (1.1)
|
1
|
0
|
1
|
Abbreviations: n-number
Relationships between irAEs and outcomes
Among patients who experienced irAEs, the median OS was 24.8 months (21.4–28.3), whereas in those who did not, the median OS was NR (log-rank p=0.87). In contrast, PFS was significantly longer in patients with irAEs (15.5 months [10.2–24.9] vs. 7.2 months [5.3–9.2], p=0.015), with a 60% reduction in the risk of disease progression (HR 0.44, 95% CI 0.2–0.87, p=0.018) (Figure 2a). The likelihood of longer survival increased with the number of experienced irAEs (log-rank p=0.042, Figure 2b). Subgroup analysis revealed no difference in OS for patients with endocrine or cutaneous irAEs. However, patients with hepatotoxicity had poorer outcomes (p=0.05), with a 2.6-fold higher risk of death (p=0.05), as indicated in Figure 2c. Patients who discontinued the treatment due to toxicity had a 3-fold greater risk of death (HR 3, 95% CI 1–8.3, p=0.04) (Figure 2d).
Data on the best radiologic responses in patients with irAEs are provided in Figure 3. The DCR was recorded in 45 (90%) of the patients with toxicities vs. 24 (63.2%) without (p=0.004). On the other hand, the ORR was comparable between these two subgroups (n=25, 50% vs. n=14, 36.8%, p=0.28).
Clinical outcomes
At the data cut-off date, the median duration of immunotherapy was 6.48 months (IQR: 2.7–11.9), with a median of 8 cycles (IQR: 4–14). Eleven patients (12.5%) received fewer than 4 doses due to toxicity or PD. The median OS was not reached (NR) in the overall population, whereas the median PFS was 12.8 months (6.3–19.3). In the IMDC intermediate-risk group, the median OS was 24.8 months (NR-NR), and the PFS was 15.9 months (9.7–22.1). For the IMDC poor-risk group, the median OS was NR, and the PFS was 7.7 months (6.2–9.2). These subgroups were not significantly different (log-rank p=0.053 for OS, p=0.07 for PFS). The number of patients with ORR and DCR in the whole treatment group was 39 (44.3%) and 69 (78.4%), respectively. The ORR in the IMDC intermediate vs. poor risk groups was 27 (44.3%) vs. 12 (44.4%), p=1, whereas the DCR was 52 (85.2%) vs. 17 (63%), p=0.026.
Univariate analysis indicated that the occurrence of irAEs was the only factor affecting PFS, precluding multivariate analysis. However, factors such as PS³2, hepatotoxicity, and central nervous system (CSN) metastases influence OS. Multivariate analysis (p=0.04 for the model) of these 3 essential predictors revealed that two independent factors, PS³2 and CSN metastases, were significantly associated with OS (Table 3).
After a median observation period of 11.3 months (IQR: 4.2–17.9), 39 patients (44.3%) continued combined immunotherapy, whereas 49 (55.7%) experienced treatment withdrawal due to PD (n=27, 30.7%), toxicity (n=12, 13.6%), death (n=9, 10.2%) or loss to follow-up (n=1, 1.1%). Among them, 24 patients (27.3%) were disqualified from further treatment due to death or poor general condition, 5 (5.7%) were under active observation, and 20 (22.7%) started cabozantinib as second-line therapy.
Table 3.Univariate and multivariate analyses of factors potentially influencing treatment outcome.
|
Progression-free survival
|
Overall survival
|
|
Univariate
|
Univariate
|
Multivariate
|
Age ³ 65
|
0.5 (0.3-1), p=0.07
|
2.4 (0.9-6.8), p=0.09
|
|
Performance status ³2 vs. <2
|
1.1 (1.5-2.6), p=0.8
|
3.3 (1.3-8.4), p=0.013*
|
3.8 (1.4-10.4), p=0.01*
|
KPS <80% vs. >80%
|
1.3 (0.6-2.7), p=0.5
|
2.9 (1.2-7.2), p=0.22
|
|
IMDC poor vs. intermediate
|
1.9 (0.9-3.7), p=0.07
|
2.4 (0.9-5.9), p=0.06
|
|
Time from the diagnosis to treatment onset <1 year vs. >1 year
|
1.1 (0.4- 2.8), p=0.8
|
1.7 (0.4- 7.4), p=0.5
|
|
Hemoglobin < unl vs. > unl
|
1.1 (0.5-2), p=0.89
|
1.7 (0.6-4.4), p=0.3
|
|
Neutrophils >unl vs. <unl
|
0.7 (0.1- 4.9), p=0.7
|
1.4 (0.2-10.3), p=0.8
|
|
Platelets >unl vs. <unl
|
1.4 (0.7- 3), p=0.4
|
0.6 (0.2-), p=0.4
|
|
Nephrectomy vs. no
|
1.4 (0.5-3.6), p=0.49
|
0.8 (0.3-2.1), p=0.6
|
|
Number of disease sites ³ 2 vs. <2
|
1.6 (0.8-3.1), p=0.2
|
1.3 (0.5-.2), p=0.6
|
|
Liver metastases vs. no
|
0.9 (0.4-2.1), p=0.8
|
1.1 (0.3-3.3), p=0.9
|
|
Central nervous system metastases vs. no
|
1.4 (0.3-5.9), p=0.6
|
4.2 (1.2-14.6), p=0.03 *
|
6.7 (1.8- 25.5), p=0.005*
|
Lungs metastases vs. no
|
1.1 (0.5-2.1), p=1
|
1.7 (0.5- 5.8), p=0.4
|
|
Bones metastases vs. no
|
1.7 (0.9-3.5), p=0.1
|
1.3 (0.5-3.4), p=0.6
|
|
irAEs vs. no-irAEs
|
0.4 (0.2-0.9), p=0.018 *
|
0.9 (0.4-2.3), p=0.9
|
|
Endocrine irAEs vs. no
|
0.5 (0.2-1.3), p=0.2
|
0.4 (0.1-1.6), p=0.2
|
|
Hepatic irAEs vs. no
|
0.7 (0.3- 1.9), p=0.5
|
2.6 (1.1-7), p=0.046*
|
2.5 (0.9-6.9), p=0.07
|
Cutaneous irAEs vs. no
|
0.9 (0.3-.3), p=0.8
|
0.3 (0.03-1.9), p=0.2
|
|
Number of irAEs ³2 vs. <2
|
1 (0.4- 2), p=0.9
|
1.3 (0.5- 3.5), p=0.6
|
|
Immunosupresive treatment vs. no
|
0.4 (0.1-1.4), p=0.2
|
0.9 (0.3- 3.2), p=0.9
|
|
Radiotherapy during immunotherapy vs. no
|
1 (0.4-2.1), p=1
|
0.9 (0.3- 2.5), p=0.9
|
|
Abbreviations: irAEs- immune-related adverse events, n- number, IMDC- International Metastatic Renal Cell Carcinoma Database Consortium Risk Model, KPS- Karnofsky performance score, unl- upper normal limit