Keywords immune checkpoint inhibitors - responders - survival outcomes - immune-related adverse
effects - solid tumors
Introduction
Employing immunotherapy for the treatment of cancer is not new; the first approved
cancer immunotherapy was Bacillus-Calmette-Guerin (BCG) for patients with early bladder
cancer in the year 1990.[1 ] Even long before BCG in 1891, “Coley's toxins,” a mixture of live and inactivated
Streptococcus pyogenes and Serratia marcescens achieved responses such as durable complete remission in several malignancies including
sarcoma, lymphoma, and testicular carcinoma.[2 ] Interleukin-2 as a therapeutic measure was approved for metastatic kidney cancer
in 1991 and for metastatic melanoma in 1998.[3 ] The real breakthrough in immuno-oncology came when immune checkpoint inhibitors
(ICI) such as cytotoxic T lymphocyte antigen-4 and programmed cell death 1 (PD1) and
its ligand (PD-L1) inhibitors entered the landscape.[4 ] The characterization of immune checkpoint pathways that can be targeted with immune-modulating
antibodies led to drug development programs focused on inhibiting the effects of immune
checkpoints. Subsequently, ICIs have been approved by the United States Food and Drug
Administration in a variety of solid and hematologic malignancies.
Compared with traditional cancer therapies that are directed to kill the tumor cells,
ICIs engage the immune system to recognize and eradicate tumor cells. Notable features
of ICI therapy include specificity, breadth of response, and memory. These can contribute
to complete tumor regressions, often providing more durable clinical outcomes and
improved quality of life relative to cytotoxic chemotherapy, molecular targeted therapeutics,
and radiation, particularly in metastatic settings. Simultaneously, the unique kinetics
of immunotherapy result in different incidences and types of adverse effects, treatment
length, and durability of response.[4 ] Immune-related adverse effects (irAEs) arise due to perturbation of immunological
tolerance by ICIs, leading to T cell-mediated damage of self-antigens expressed in
the host cells. A meta-analysis of 11,328 patients reported the incidence of irAEs
of any grade with anti-PD1 to be ∼25%.[5 ] Also, some studies have shown that the development of irAEs can corroborate with
the response to ICIs, keeping up with the similar mechanism of action and effect of
irAEs in response to ICIs.[6 ]
[7 ]
[8 ] However, there is very limited data on the association of irAEs with survival in
patients who have shown a response to ICIs. Thus, we conducted a retrospective audit
of patients who received ICIs and responded to the treatment.
Patients and Methods
Study Population
This study is a retrospective audit of a prospectively collected database of patients
who received PD1 inhibitors in any line for metastatic/advanced solid tumors not suitable
for curative intent therapy between August 2015 to November 2018 at Tata Memorial
Hospital, Mumbai, India. Responders were defined as patients who attained the best
response of either complete response (CR) or partial response (PR). Patients received
nivolumab at a dose of 3 mg per kilogram or flat 240mg every 2 weeks intravenously
or pembrolizumab 200mg every 3 weeks. The treatment was continued until disease progression
or unacceptable toxicities. All the patients received single-agent immunotherapy as
combination ICI, and cytotoxic chemotherapy was not yet approved in our country at
the time of this study. Also, PD-L1 testing was not done, as most of the patients
received nivolumab therapy in the second-line or beyond. Steroids were required as
a part of the management of irAEs or palliation of symptoms. The study was approved
by the institutional review board and ethics committee. The study was conducted as
per the Declaration of Helsinki and local guidelines of the Indian Council of Medical
Research, New Delhi, India.
Clinical Outcomes
Response assessment was performed using radiological evaluation according to the response
evaluation criteria in solid tumors version 1.1. Response assessment was done 8 to
12 weeks after the commencement of ICI or at any symptoms/signs of clinical progression,
whichever was earlier. Adverse events during immunotherapy were documented and graded
using the common terminology criteria for adverse events, version 4.02. Progression-free
survival (PFS) was defined as the interval from the date of starting ICI till the
date of progression or death due to any cause if it occurred before disease progression
or the last follow-up date, whichever was earlier. Overall survival (OS) was calculated
from the date of start of ICI to the date of death. Patients who were still alive
were censored at the date of the last contact.
Statistical Analysis
Among responders, baseline characteristics were compared as a function of presence
or absence of irAEs using Fisher's exact test or chi-squared test. Time-to-event analysis
was done using the Kaplan–Meier estimator, and hazard ratio (HR) was calculated by
using Cox proportional model. Swimmer's plot was constructed by using Microsoft Excel
2010. Point-biserial correlation was used to find out the potential influence of irAEs
(presence or absence) on the OS. All p -values were based on a two-sided hypothesis with confidence interval (CI) at the
95% level, and p < 0.05 was considered statistically significant. All statistical calculations were
performed using SPSS statistical software for windows version 20.0 (IBM Corp, Armonk,
New York, United States).
Results
A total of 155 patients who received PD1 inhibitors during the specified period were
evaluated for this study. The response rate was 19.4% (2 CR and 28 PR). The baseline
characteristics of patients who responded to ICI are shown in [Table 1 ]. The median age of responders was 57 years, with 80% of patients being males and
73% had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1.
Among lung cancer, adenocarcinoma formed 80% of the responding patients without irAEs
group, while it was 77.8% in responders with irAEs. All patients with head and neck
cancer had squamous cell carcinoma histology. [Fig. 1 ] shows the consort diagram of this study. All the responders had received nivolumab,
and 60% had received ICI in the first or second line. With 37 patients having stable
disease as the best response, the disease control rate was 43.2%. The median PFS for
responders was 9.5 months (95% CI: 5.6–13.3), while it was 1.7 months (95% CI: 1.4–1.9)
for nonresponders (HR: 5.1, 95% CI: 2.8–9.0, p < 0.001). One-year PFS for responders was 42.5 (SD: 10.7) and 6.1% (SD: 2.7%) for
nonresponders. The corresponding median OS was not reached versus 3.3 months (95%
CI: 1.8–4.8) with HR: 5.7, 95% CI: 2.6–12.0, p < 0.001 ([Supplementary Fig. S1 ], available online only). One-year OS for responders was 75.6% (SD: 8.8) versus 26.1%
(SD: 5.1). The median follow-up duration of the study patients was 12.9 months (95%
CI: 12.1–13.7). [Supplementary Table S1 ] (available online only) shows the median and 12-month OS of responders.
Fig. 1 Consort diagram of the study. Immune-related adverse effects included grade 4 pneumonitis
in one patient, grade 3 hepatitis and colitis each in one patient, grade 2 skin rash
and nephritis each in two patients, while grade 2 fatigue in four patients. CR, complete
response; PR, partial response.
Table 1
Baseline characteristics of the patients included in the study and classified as responders
versus nonresponders
Factor
Subfactors
Overall responders, n = 30 (%)
Responders with irAEs, n = 12 (%)
Responders without irAEs, n = 18 (%)
p -Value
Age (y)
Median (range)
57 (39–70)
58 (39–68)
57 (42–70)
–
<60 y
19 (63.3)
07 (58.3)
12 (66.7)
0.712
≥60 y
11 (36.7)
05 (41.7)
06 (33.3)
Gender
Female
06 (20.0)
01 (8.3)
05 (27.8)
0.358
Male
24 (80.0)
11 (91.7)
13 (72.2)
ECOG PS
0–1
22 (73.3)
9 (75.0)
13 (72.2)
1.000
2–4
08 (26.7)
3 (25.0)
05 (27.8)
Line of therapy
1–2
18 (60.0)
7 (58.3)
11 (61.1)
1.000
3 or more
12 (40.0)
5 (41.7)
07 (38.9)
BMI (kg/m2 )
<25
19 (63.3)
8 (66.7)
17 (94.4)
1.000
≥25
10 (33.3)
4 (33.3)
01 (5.6)
Comorbidities
Present
22 (73.3)
5 (41.7)
17 (94.4)
0.896
Absent
08 (26.7)
2 (25.0)
6 (75.0)
Steroids use
No
22 (73.3)
5 (41.7)
17 (94.4)
0.003
Yes
08 (26.7)
7 (58.3)
01 (5.6)
Antibiotics use
No
16 (53.3)
5 (41.7)
11 (61.1)
0.296
Yes
14 (46.7)
7 (58.3)
07 (38.9)
Site of primary
Lung
14 (46.7)
5 (41.7)
9 (50.0)
0.778
Head and neck
09 (30.0)
5 (41.7)
4 (22.2)
Others
07 (23.3)
2 (16.7)
5 (27.8)
Smoking
No
25 (83.3)
9 (75.0)
16 (88.9)
0.364
Yes
5 (16.7)
3 (25.0)
02 (11.1)
Abbreviations: BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance
status; irAEs, immune- related adverse effects.
Overall 50 patients (32.2%) developed irAEs with grade ¾ toxicities in 23 (14.8%)
patients. Among responders, 12 (40%) developed at least grade 1 irAE, while among
nonresponders, 38 (30.4%) developed irAE (p = 0.312). The cause of death was disease progression in all the patients. No patient
expired due to irAEs. Among responders, the median PFS for patients who developed
irAE was 8.7 months (95% CI: 5.1–12.4), while it was not reached for patients without
irAE (p = 0.609). The median OS for patients who developed irAE was 12.3 months (95% CI:
8.9–15.6), while it was not reached for patients without irAE (HR: 10.5, 95% CI: 1.2–NR,
p = 0.007, [Fig. 2 ]). One-year OS for the corresponding group of patients was 53.6% (SD: 15.6) versus
92.9% (SD: 6.9), respectively. [Table 2 ] shows the comparison of individual irAEs in responders versus nonresponders. Out
of total responders (n = 30), 14 (46.7%) had lung cancer, while out of all nonresponders (n = 125), 62 (49.6%) had lung cancer. The data for patients with lung cancer were analyzed
separately, and the median PFS for responding lung cancer patients was 9.5 months
(95% CI: 6.9–12.1), while it was 1.6 months (95% CI: 1.3–1.8) for nonresponders. Grade
3/4 irAEs were seen in two (14.3%) responders and seven (11.3%) nonresponder patients
of lung cancer.
Fig. 2 Kaplan–Meier curve showing overall survival in patients who responded to immune checkpoint
inhibitors; blue line shows survival of non-irAEs group versus green line for irAEs
group. CI, confidence interval; irAEs, immune-related adverse events; OS, overall
survival.
Table 2
Immune-related adverse effects (irAEs) in responders versus nonresponders to immunotherapy
irAEs
Responders (n = 30)
Nonresponders (n = 125)
Grade 1/2
Grade 3/4
Grade 1/2
Grade 3/4
Rash
2 (6.7)
0
2 (1.6)
0
Fatigue
3 (10.0)
0
13 (10.4)
3 (2.4)
Hepatitis
1 (3.3)
1 (3.3)
4 (3.2)
3 (2.4)
Pneumonitis
0
1 (3.3)
0
6 (4.8)
Colitis
1 (3.3)
1 (3.3)
2 (1.6)
1 (0.8)
Nephritis
1 (3.3)
0
4 (3.2)
0
Adrenal insufficiency
1 (3.3)
0
2 (1.6)
0
Thyroiditis
1 (3.3)
0
5 (4.0)
0
Anorexia
3 (10.0)
0
6 (4.8)
0
Hyponatremia
1 (3.3)
3 (10.0)
1 (0.8)
5 (4.0)
Encephalitis
0
0
1 (0.8)
0
Hypophysitis
0
0
1 (0.8)
0
A point-biserial correlation was run between the OS of responders and the presence
or absence of irAEs in the corresponding patients. There were outliers in the data,
as assessed by inspection of a boxplot, and these were retained for the analysis.
There was homogeneity of variances for the OS and irAEs, as assessed by Levene's test
for equality of variances (p = 0.802). The OS for the presence or absence of irAEs was normally distributed as
assessed by Shapiro–Wilk test (p > 0.05). The mean OS was higher in the presence of irAEs 6.0 months, 95% CI: 3.1–8.9
as against 5.4 months, 95% CI: 4.4–6.4. However, the coefficient value was 0.141,
and it did not reach statistical significance (p = 0.456). The presence or absence of irAEs accounted for only 1.9% of the variability
in the OS. [Supplementary Fig. S2 ] (available online only) shows the swimmers' plot of responders with and without
irAEs.
Univariate analysis with other factors (ECOG PS, steroids, and antibiotics use) did
not identify any significant factor in responders. Univariate analysis for gender
was not possible as all six female responders in the study had no event for OS in
the study duration. The median time of onset of irAEs in responders was 2.3 months
(range: 0.5–5.5). The clinical course of the responding patients is depicted in the
swimmer's plot in [Supplementary Fig. S2 ] (available online only). The ICI therapy was discontinued in three (10%) responding
patients due to irAEs, including grade 4 pneumonitis in one patient, grade 3 hepatitis
and colitis each in one patient. Other important irAEs included grade 2 skin rash
and nephritis each in two patients, while grade 2 fatigue in four patients. Steroids
were required for management of irAEs in 20% (n = 6) of the responding patients, while 6.7% (n = 2) needed steroids for palliation of symptoms (one each for dyspnea and brain edema
related to metastasis).
Discussion
irAEs have been shown to predict survival outcomes in patients with nonsmall cell
lung cancer (NSCLC) in patients treated with ICIs.[6 ]
[7 ]
[8 ] However, to our knowledge, no study has addressed this issue in patients with primary
other than NSCLC. Also, previous studies have stratified patients based on the occurrence
of irAEs only without comparing the data of irAEs in responders and nonresponders.
In our study, the primaries included NSCLC and head neck cancer, besides a small proportion
of renal cell cancer and urothelial carcinomas. This may explain the differences in
results observed in our study. The incidence of irAEs was not statistically different
in responders and nonresponders in our study. This is in sharp contrast to a recent
study by Akamatsu et al (n = 106), which demonstrated that the incidence of irAEs was significantly higher in
responders (relative risk 7.85).[9 ] It would be prudent to note that this study exclusively included patients with NSCLC,
and the analysis focused on 23 responders. Besides, our study showed statistically
significant longer OS in responders who did not develop irAEs. This suggests that
irAEs might overshadow the benefits of immunotherapy probably when they develop early
in the course of ICI therapy, like in our study where the medium time to onset of
irAEs was 2.5 months. This result is in contrast with the study by Teraoka et al (n = 43). They reported that the development of early irAEs (between 2 and 6 weeks of
ICI commencement) is associated with better outcomes with nivolumab monotherapy in
NSCLC patients.[8 ] Another study that gave contrasting results was that by Cortellini et al[10 ] that reported a positive correlation between any grade irAEs and response rates
and survival outcomes with anti-PD1 immunotherapy in patients with NSCLC. However,
it should be noted that there was no correlation between grade 3/4 irAEs and survival
outcomes, which points toward only less severe irAEs signifying the immune activation
against tumor cells, while severe irAEs might be counterproductive. The grade 3/4
irAEs in this study was 7.7% as against 14.8% in our study, which might explain the
contrasting results. It is prudent to think that patients who were exposed to ICIs
for a longer duration might have experienced more irAEs. In a study by Grangeon et
al, the authors reported that higher rates of irAEs did not match with higher treatment
exposure, which clarifies the above doubt.[11 ] Also, it was reported in this study that patients who developed early irAEs did
not have better survival outcomes, which matches with our study.
Besides the development of irAEs, this study also tried to identify other factors
that might be associated with improved survival in responders. However, no such factor
could be identified. It should be noted that univariate analysis with gender as a
factor could not be done as none of the six female responders developed an event for
OS during the study duration. Another important perspective that the authors would
like to highlight is that the negative association between ICI therapy and irAEs in
responder patients can indicate induction of reactivation of an antitumor immune response
without exacerbating latent autoimmunity. This supposed reactivation of an antitumor
immune response can influence the OS of the patients receiving ICIs. Our study suggests
that the irAEs are not directly associated with good survival. This indicates that
ICI may trigger an antitumor response independently from irAEs. It is important to
understand that pathways for irAEs and survival benefit from immunotherapy may differ
and are not directly linked to each other. This may be explained by the tumor microenvironment
creating the difference and leading to a dampened response to immunotherapy despite
irAEs occurring as a result of the effect of immunotherapy on normal cells. Targeting
the tumor microenvironment to shift the balance toward the proimmunogenic phase is
the main motto of current immunotherapy strategies.[12 ]
This study has some significant limitations. The most important limitation is small
sample size and retrospective nature and data from a single center. However, the real-world
settings data are important in day-to-day practice to make appropriate clinical decisions.
Another important factor that can create big differences in perceived outcomes is
assessing response and classification of an adverse effect as irAE and its grading.
Besides, in our study, the analysis has been performed on different cancer types and
not a homogeneous cohort of patients. The differences observed in this study can also
be because of different ethnicities. There is no study from South-East Asia, and this
study adds important data in this important aspect of immunotherapy. Also, this study
reinforces the importance of establishing cohorts in centers around the world, which
can help in collaboration and data sharing and can ultimately lead to the accumulation
of more meaningful data.
Conclusions
In our study, we found significant improvement in survival of solid tumor patients
treated with ICIs who developed irAEs on treatment as compared with those who did
not. On specifically analyzing patients who responded to ICIs, there was no difference
in OS who developed irAEs versus those who did not. However, this needs to be studied
in a larger sample to reach a definite conclusion.
