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Radiol Oncol 2021; 55(3): 354-361. doi: 10.2478/raon-2021-0019
354
research article
Adverse events during immunotherapy in 
Slovenian patients with metastatic melanoma 
reveal a positive correlation with better 
treatment outcomes
Tanja Mesti
1
, Vid Ceplak Mencin
1
, Biljana Mileva Boshkoska
3,4
, Janja Ocvirk
1,2
1 
Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
2 
Faculty of Medicine, University of Ljubljana, Ljubljana
3 
Faculty of information studies in Novo mesto, Novo mesto, Slovenia
4 
Department for Knowledge Technologies, Institute Jožef Stefan, Ljubljana Slovenia
Radiol Oncol 2021; 55(3): 354-361.
Received 24 November 2020
Accepted 16 March 2021
Correspondence to: Prof. Janja Ocvirk, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, Ljubljana. E-mail: jocvirk@onko-i.si
Disclosure: No potential conflicts of interest were disclosed.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background. Immunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in 
the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from 
the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-
CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse 
events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes 
defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who 
developed immune-related adverse events during immunotherapy.
Patients and methods. A retrospective analysis of patients with metastatic melanoma treated with immuno-
therapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of 
the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with 
immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE 
group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of 
our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used 
survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse 
events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered 
the cut-off point for a statistically significant difference between the groups.
Results. Among the 120 patients treated with immunotherapy, radiological response evaluation was performed for 
99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts 
were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE co-
hort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability 
from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.
Conclusions. Patients with metastatic melanoma treated with immunotherapy who developed immune-related 
adverse events showed better treatment outcomes with longer times to disease progression and better overall re-
sponse rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a 
significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.
Key words: immune related adverse events;  immunotherapy; melanoma; metastases; response; survival

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 355
Introduction
Ipilimumab, an anti-CTLA-4 antibody, was the 
first immunotherapy approved for the treatment 
of metastatic malignant melanoma and is associ-
ated with a median 5-year overall survival rate of 
20 months.
1
 Significantly longer response times 
were achieved with the checkpoint PD1 inhibi-
tors pembrolizumab and nivolumab, with a 5-year 
overall survival rate of approximately 40 months.
1-3 
Ipilimumab in combination with nivolumab re-
sults in an extension of the overall survival time to 
60 months.
1
Immunotherapy with either anti-CTLA-4 anti-
bodies or PD1 inhibitors alone or in combination 
has a broad spectrum of significant immunologi-
cally related adverse events, such as immunologi-
cally related skin toxicity, pneumonitis, thyroid 
dysfunction and other endocrinopathies, hepatitis, 
and renal dysfunction.
1-3
At the Institute of Oncology Ljubljana, a national 
centre for the treatment of patients with metastatic 
melanoma, we used immunotherapy on a daily 
basis. The PD1 inhibitors pembrolizumab and 
nivolumab are the main inhibitors used, as well 
as anti-CTLA-4 antibodies in combination with 
nivolumab, in accordance with the Slovenian na-
tional guidelines, based on the European Society 
for Medical Oncology (ESMO) and National 
Comprehensive Cancer Network (NCCN) guide-
lines for the treatment of metastatic melanoma.
4-6
 
The past years of work with patients on immuno-
therapy have led us to the unusual observation that 
patients who experience immune-related adverse 
events have a better treatment outcome in terms 
of time to relapse. Several recent studies from dif-
ferent melanoma centres and one meta-analysis 
showed that regardless of the cancer type, irAEs 
exhibited a positive correlation with ORR, PFS and 
OS.
7-9
 The meta-analysis revealed that the ORR 
of irAE patients with melanoma was 37.67% but 
was 23.44% in NirAE patients. PFS and OS were 
significantly longer in the irAE population. In par-
ticular, the PFS for irAE ranged from 17.61 months 
to unreached and for NirAE ranged from 2.23 to 3 
months. The OS for irAEs and NirAEs was 15.24 
months and 8.94 months, respectively.
9
 Hence, the 
aim of this study was to assess the correlation of 
immune-related adverse events and treatment 
outcomes defined as significant differences in the 
overall response rate (ORR) and progression-free 
survival (PFS) of patients who developed immune-
related adverse events during immunotherapy 
treatment.
Patients and methods
A retrospective analysis of patients with metastat-
ic melanoma treated with immunotherapy from 
January to July 2020 was performed at the Institute 
of Oncology Ljubljana. Data were collected from 
the clinical database. The study included only 
metastatic melanoma patients with radiographic 
evaluations of immunotherapy treatment. The 
iRECIST (immune Response Evaluation Criteria in 
Solid Tumours) criteria were used to evaluate the 
tumour response. Patient characteristics, includ-
ing age, sex, Eastern Cooperative Oncology Group 
(ECOG) performance status, systemic treatment 
prior to immunotherapy, stage of melanoma, his-
tology type and location of primary melanoma, 
were recorded. The patients were divided into 
two cohorts: the cohort of patients with immune-
related adverse events (irAE group) and the co-
hort of patients without immune-related adverse 
events (NirAE). The irAEs were evaluated by a 
clinician based on the findings of laboratory tests, 
clinical examinations, and imaging studies. The 
irAEs (with a potential immunologic cause) were 
graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events, 
version 4.0.
The Python programming language was used 
for statistical calculations. The Kruskal-Wallis 
H-test was applied, and a p-value of p <= 0.05 was 
considered the threshold for statistical significance.
For survival analysis, we used the Cox propor-
tional hazards model with the covariates time to 
progression and adverse events. For each patient, 
we considered the length of time from introduction 
of immunotherapy to the time the study analysis 
was performed. We considered whether the patient 
remained alive throughout the study duration and 
the occurrence of an adverse event. The hazard rate 
was assumed to be a Weibull distribution. Posterior 
survival probabilities were obtained by Monte 
Carlo simulation implemented in Python using the 
package pymc3.
The study was approved by the Institutional 
Review Board Committee and was carried out ac-
cording to the Declaration of Helsinki.
Results
From January to July 2020, 120 patients with meta-
static melanoma were treated with immunothera-
py. Seventy-six patients did not develop immune-
related adverse events, and 44 patients developed 

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 356
immune-related adverse events. Radiological eval-
uation (PET CT or CT) of the immunotherapy treat-
ment response was performed for 99 out of 120 
patients who were included in our study. The in-
cluded patients were divided into two cohorts. The 
cohort of immunotherapy-treated patients who 
did not develop immune-related adverse events 
(NirAE cohort) included 61 (61, 62%) patients, and 
26%
47%
11%
0%
16%
Type of irAE
pneumoni s hepa s
other
thyroid skin toxicity
TABLE 1. Baseline characteristics of the cohorts
Characteristics
irAE cohort 
n (%)
NirAE cohort 
n (%)
Number 38 (38)  61 (62)
Age mean 67.4 61.6
Sex Male 18 (47.4) 37 (60.7)
Female 20 (52.6) 24 (39.3)
Treatment Naive 34 (89.5) 51 (83.6)
Previously treated 4 (10.5) 10 (16.4)
Immunotherapy Pembrolizumab 34 (89.5) 52 (85.2)
Nivolumab 2 (5.3) 5 (8.2)
Nivolumab + ipilimumab 2 (5.3) 4 (6.6)
BRAF status BRAF mutated 10 (26.3) 17 (27.9)
BRAF wild type 21 (55.3) 27 (44.3)
Not reported 7 (18.4) 17 (27.9)
M1a/b Cohort a and b 22 (57.9) 35 (57.4)
M1c/d Cohort c and d 16 (42.1) 26 (42.6)
LDH increased 7 (18.4) 15 (24.6)
LDH normal 31 (81.6) 46 (75.4)
irAE cohort = patients with metastatic melanoma who developed immune-related side effects 
during immunotherapy; LDH = lactate dehydrogenase; M1a/b = Distant metastasis to skin, soft 
tissue including muscle and/or nonregional lymph node and lungs; M1c/d = Distant metastasis to 
other visceral sites and to the central nervous system (CNS); NirAE cohort = patients with metastatic 
melanoma who did not develop immune-related side effects during immunotherapy
FIGURE 1. Distribution 
of immune-related 
adverse events by 
type in the irAE cohort.
irAE cohort = patients with 
metastatic melanoma 
who developed immune-
related side effects during 
immunotherapy
FIGURE 2. Distribution of immune-related adverse events by 
grade (1-3) regarding the type of immune-related adverse 
event in the irAE cohort presented as a percentage (%).
irAE cohort = patients with metastatic melanoma who developed 
immune-related side effects during immunotherapy
the cohort of patients who developed immune-
related side effects (irAE cohort) included 38 (38, 
38%) patients. The baseline characteristics of both 
cohorts are presented in Table 1.
Of the 38 patients in the irAE cohort, 10 patients 
had thyroiditis (hyperthyroiditis/hypothyroiditis), 
18 patients had skin toxicity (vitiligo, rash, itchy 
skin, dermatitis), 4 had pneumonitis, none had 
hepatitis, and 6 had other adverse events (arthritis, 
colitis, fatigue). The distribution of the immune-re-
lated adverse events of the immunotherapy in the 
irAE cohort is presented in Figure 1 below.
Most of the immune-related adverse events 
were grade 1 or 2. One patient developed grade 3 
immune-related adverse events in the form of pso-
riasiform dermatitis, and immunotherapy had to 
be discontinued. One patient with colitis presented 
with diarrhoea, and four patients with pulmonary 
toxicity presented with pneumonitis (Figure 2). 
No immune-related adverse events of grade 4 or 5 
were present.
The radiological response evaluation was per-
formed for 99 patients, 61 patients representing 
the NirAE cohort and 38 patients representing the 
irAE cohort. The overall response rates (ORRs) for 
the irAE and NirAE cohorts were 57% and 37%, 
respectively. Complete response was achieved in 
14% of patients in the irAE cohort and in 4% of 
patients in the NirAE cohort. The irAE cohort had 
a higher rate of partial response (44%) than the 
NirAE cohort (34%). One-third (31%) of the NirAE 
cohort had progressive disease, and only 14% of 

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 357
the irAE cohort had progressive disease. The data 
are presented in Figure 3.
irAE cohort = patients with metastatic mela-
noma who developed immune-related adverse 
events during immunotherapy; NirAE cohort = 
patients with metastatic melanoma who did not 
develop immune-related adverse events during 
immunotherapy
Our data show that no patient who developed 
severe immune-related adverse events (grade 3), 
had progressive disease, as presented in Figure 4 
below.
Grade 4 and 5 immune-related adverse events 
were not present. irAE cohort: patients with meta-
static melanoma who developed immune-related 
adverse events during immunotherapy.
FIGURE 4. Correlation between the treatment response and 
the grade (1-3) of the immune-related side effect adverse 
events in the irAE cohort presented as a percentage (%). 
CR = complete response; PD = partial response; PR = progression of 
disease; SD = stable disease
FIGURE 5. CORRELATION between the treatment response and 
the type of immune-related adverse events in the irAE cohort 
presented as percentages (%).
CR = complete response; PD = partial response; PR = progression of 
disease; SD = stable disease
FIGURE 6. Progression-free survival difference in patients with 
metastatic melanoma between the two cohorts, cohort with 
immune-related adverse events (irAEs) and cohort with no 
immune-related adverse events (NirAEs), presented in days. 
The orange line indicates the median, while the patients who 
belong to the fourth quartile are represented with plus signs 
(“+”).
irAE cohort = patients with metastatic melanoma who developed 
immune-related adverse events during immunotherapy; NirAE cohort 
= patients with metastatic melanoma who did not develop immune-
related adverse events during immunotherapy
FIGURE 3. Distribution of the treatment response between the irAE and NirAE. The 
numbers above the bars represent the percentages with respect to its cohort, while 
the bar height is the absolute number of patients and is given on the Y axis. 
irAE cohort = patients with metastatic melanoma who developed immune-related adverse events 
during immunotherapy; NirAE cohort = patients with metastatic melanoma who did not develop 
immune-related adverse events during immunotherapy

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 358
No patient who developed immune-related 
pneumonitis had disease progression, as shown in 
Figure 5.
Grade 4 and 5 immune: related adverse events 
were not present; irAE cohort: patients with meta-
static melanoma who developed immune-related 
adverse events during immunotherapy.
Finally, the time to progression of the disease 
in the cohort (Figure 6) that experienced immune-
related adverse events was significantly longer 
than the time to progression in the cohort that did 
not experience immune-related adverse events (p 
= 0.001). There was no significant difference be-
tween the time of progression and the severity of 
immune-related adverse events.
To investigate the differences in progression-
free survival between the irAE cohort and NirAE 
cohort, we used survival analysis, which showed a 
significant increase in the survival probability from 
less than 60% for the NirAE cohort to almost 80% 
for the irAE cohort (Figure 7). This supports our 
study hypothesis that patients with immune-re-
lated adverse events due to immunotherapy treat-
ment have better treatment outcomes (Figure 7).
A Cox proportional hazards model with co-
variates time to progression and AE was used for 
survival analysis. The hazard rate was assumed to 
be a Weibull distribution. The posterior survival 
probabilities were obtained through Monte Carlo 
simulation implemented in Python with the pymc3 
package.
Furthermore, the irAE cohort with elevated 
LDH had better PFS with a 60% survival probabil-
ity than the 40% survival probability for the NirAE 
cohort with elevated LDH (Figure 8). The same 
trend was present for the subgroup of patients 
with irAE stage M1a/b melanoma with a survival 
probability higher than 80% (Figure 9). For the co-
hort of patients with irAE stage M1c/d melanoma, 
the results were reversed, showing lower survival 
probability in comparison with the subgroup of 
NirAE patients with stage M1c/d melanoma. The 
survival probability for irAE stage M1c/d patients 
and NirAE stage M1c/d patients was 50% and 70%, 
respectively (Figure 10). 
A Cox proportional hazards model with co-
variates time to progression and AE was used for 
survival analysis. The hazard rate was assumed to 
be a Weibull distribution. The posterior survival 
probabilities were obtained through Monte Carlo 
simulation implemented in Python with the pymc3 
package.
Cox proportional hazards model with covari-
ates time to progress and AE were used for sur-
FIGURE 7. Difference in progression-free survival between the irAE and NirAE cohorts, 
with a significant increase in the survival probability from less than 60% for the NirAE 
cohort to almost 80% for the irAE cohort. 
irAE cohort = patients with metastatic melanoma who developed immune-related adverse events 
during immunotherapy; NirAE cohort = patients with metastatic melanoma who did not develop 
immune-related adverse events during immunotherapy
FIGURE 8. Difference in progression-free survival between the irAE and NirAE cohorts 
with increased LDH, with a significant increase in the survival probability from less 
than 40% for the NirAE cohort to more than 60% for the irAE cohort. 
irAE cohor = patients with metastatic melanoma who developed immune-related adverse events 
during immunotherapy; NirAE cohort = patients with metastatic melanoma who did not develop 
immune-related adverse events during immunotherapy

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 359
vival analysis. The hazard rate was assumed to 
be a Weibull distribution. The posterior survival 
probabilities were obtained through Monte Carlo 
simulation implemented in Python with pymc3 
package.
Discussion
The main goal of the oncological treatment for 
metastatic melanoma is progression-free survival 
while obtaining good quality of life with as few 
adverse events as possible. Usually, the treatment 
of adverse events results in treatment delays, de-
creases quality of life and, consequently, results in 
loss of disease control and disease progression.
The introduction of immunotherapy in the 
treatment of metastatic melanoma has improved 
the prognosis of this disease, prolonging the sur-
vival time from less than a year to more than three 
years.
1-3
 Additionally, recent data show evidence 
that immunotherapy is much more tolerable, with 
fewer adverse events than chemotherapy. A meta-
analysis of 3450 patients suffering from non-small 
lung carcinoma and melanoma who were treated 
with the PD1 inhibitors nivolumab and pem-
brolizumab and the PDL1 inhibitor atezolizumab 
showed that compared to chemotherapy, the afore-
mentioned drugs had a significantly lower risk of 
any all- and high-grade adverse events (fatigue, 
sensory neuropathy, diarrhoea, haematologic tox-
icities, anorexia, nausea, and constipation) and 
consequently a lower rate of treatment discontinu-
ation.
10
For more than a decade, it has been known that 
malignant melanoma has a unique immunogenic 
nature, and the presence of vitiligo in melanoma 
patients seems to improve the prognosis of mela-
noma in animals and humans, presenting effective 
strategy for antitumour immunity.
15-17
Among immunotherapy drugs used in meta-
static melanoma treatment, the CTLA4 inhibitor 
ipilimumab and the PD1 inhibitors pembrolizum-
ab and nivolumab have immune-related adverse 
events. Ipilimumab is a fully humanized anti-CT-
LA-4 monoclonal antibody; pembrolizumab and 
nivolumab are humanized monoclonal anti-pro-
grammed cell death-1 (PD-1) antibodies.
11-13
 With 
the use of CTLA4 inhibitors or anti-PD1 antibodies, 
also called checkpoint inhibitors, as monotherapy 
or in combination (nivolumab and ipilimumab), 
the increased risk of immune-related lung, intes-
tinal, liver, kidney, skin, or endocrine adverse 
events persists.
11-14 
Due to the severity of the ad-
FIGURE 9. Difference in progression free survival between the irAE and NirAE cohort 
with M1a and M1b (M1a/b) patients, with a significant increase in the survival 
probability of approximately 50% for NirAE cohort to more than 80% for irAE cohort. 
irAE cohort = patients with metastatic melanoma that developed immune-related adverse events 
during immunotherapy; M1a/b = distant metastasis to skin, soft tissue including muscle and/or 
nonregional lymph node and lungs; NirAE cohort = patients with metastatic melanoma that did 
not develop immune-related adverse events during immunotherapy; 
FIGURE 10. Difference in progression free survival between the irAE and NirAE cohort 
with M1c and M1d (M1c/d) patients, with a significant increase in the survival 
probability of almost 70% for NirAE cohort to less than 50% for irAE cohort. 
irAE cohort = patients with metastatic melanoma that developed immune-related adverse events 
during immunotherapy; M1c/d = distant metastasis to other visceral sites than lungs and to the 
central nervous system (CNS); NirAE cohort = patients with metastatic melanoma that did not 
develop immune-related adverse events during immunotherapy

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 360
verse events caused by immunotherapy treatment, 
in some cases, discontinuation of the treatment is 
required. It has been shown that an early discontin-
uation of immunotherapy due to an adverse event 
does not negatively affect the long-term survival 
among these patients.
1,3
The results of this study show that patients 
treated with immunotherapy who developed im-
mune-related adverse events had better treatment 
outcomes than patients without immune-related 
adverse events. This retrospective study, per-
formed on 99 patients with metastatic melanoma 
who were treated with immunotherapy, showed 
that patients with immune-related adverse events 
had an improved ORR in comparison to the ORR 
of patients without immune-related adverse events 
(75% vs. 37%). The PFS was significantly longer for 
the patients with immune-related adverse events, 
301.6 days, compared to 247.29 days for patients 
without immune-related adverse events. Neither 
the severity nor the type of immune-related ad-
verse events correlated with the ORR or PFS.
The presented data are in line with recent pub-
lications reporting a positive correlation between 
immune-related adverse events and survival.
7-9
 
A Dutch prospective study on 147 patients with 
metastatic melanoma treated with pembrolizumab 
showed that high-grade toxicity at any time during 
treatment was associated with higher objective re-
sponse rate, progression-free survival, and overall 
survival.
7
 A retrospective study on 144 metastatic 
melanoma patients treated with pembrolizumab 
showed similar results, as the development of any 
irAE (HR, 0.24, P < .001) was significantly associ-
ated with longer OS times.
8
The Cox proportional hazards regression analy-
sis in this study shows a difference in progression-
free survival between the irAE and NirAE cohorts, 
with a significantly increased survival probability 
from less than 60% for the NirAE cohort to almost 
80% for the irAE cohort. Furthermore, the sub-
group of patients with irAEs with elevated LDH, 
before the start of immunotherapy, had better 
PFS, with a 60% survival probability compared 
to the 40% survival probability for the subgroup 
of NirAE patients with elevated LDH. The same 
pattern was observed for the subgroup of patients 
with irAEs and stage M1a/b with a survival prob-
ability of greater than 80%. The findings were re-
versed for the subgroup of patients with irAEs 
and stage M1c/d melanoma, where the survival 
probability was lower than that of the subgroups 
of patients with NirAEs and stage M1c/d mela-
noma, with survival probabilities of 50% and 70%, 
respectively. There were only a few patients with 
increased LDH for each M1 stage; hence, we omit-
ted these patients from multivariate analysis.
Elevated LDH is a poor prognostic marker for 
melanoma patients; however, LDH and immune-
related side effects are widely used for the progno-
sis of immunotherapy outcomes.
18 
Immunotherapy 
is effective for melanoma patients with dissemina-
tion locations indicating poor prognosis (M1c/d)
19
; 
however, there is a lack of data regarding the nega-
tive correlation in patients with immune-related 
side effects. As reported, developing immune-
related adverse events correlates with better treat-
ment outcomes.
7-9,18
 Dissemination of melanoma in 
visceral organs other than the lungs and CNS, his-
torically, is related to poor prognosis and outcome. 
The response rate of melanoma patients with brain 
metastases ranges from 26% with PD1 inhibitors to 
55% with a combination of CTLA4 and PD1 inhibi-
tors.
20,21
 The expected time to response is longer, 
and the risk for hyperprogression in this subgroup 
of melanoma patients is higher.
22,23
 Our data, 
though represented by a small group of patients, 
contribute to the possibility of new melanoma enti-
ties with worse immunotherapy outcomes-i.e., the 
subgroup of irAE patients with stage M1c/d dis-
ease. Potentially, the small group of patients may 
lead to bias; hence, a broader retrospective analy-
sis of patients with metastatic melanoma treated 
with immunotherapy at the Institute of Oncology 
Ljubljana is planned in the future.
Conclusions
Our study indicates a positive correlation of the 
higher autoimmunogenicity caused by immuno-
therapy in patients with metastatic melanoma with 
the treatment outcome and thus improves knowl-
edge about immunotherapy. In the present co-
hort, patients with immune-related adverse events 
during immunotherapy had better ORRs, OS and 
PFS than patients with metastatic melanoma with-
out any immune-related adverse events. The Cox 
proportional hazards regression analysis showed 
a difference in PFS between the irAE and NirAE 
cohorts, with a significant increase in the survival 
probability from less than 60% for the NirAE co-
hort to almost 80% for the irAE cohort even in the 
presence of elevated LDH. This pattern was not 
observed for the group of patients with M1c/d dis-
ease, stipulating the need for further research.

Radiol Oncol 2021; 55(3): 354-361.
Mesti T et al. / Adverse events during immunotherapy of melanoma 361
Acknowledgement
We thank Pavle Boškoski for his contribution to 
the survival regression model analysis. TM, V ČM, 
JO acknowledges funding from the Slovenian 
Research Agency via program P3-0321. BMB ac-
knowledges funding from the Slovenian Research 
Agency via program Complex Networks P1-0383.
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