Dear Editor,
Nivolumab, an inhibitor of programmed cell death 1 (PD-1), is an immune checkpoint
inhibitor (ICI) that enhances T cell functions by preventing negative regulation of
cancer immunity, and it has shown clinically significant efficacy and tolerability
in various types of cancer. Based on the results of randomized phase III trials comparing
nivolumab with docetaxel [1, 2], nivolumab is now used in clinical practice for patients
with previously treated advanced non-small cell lung cancer (NSCLC). Furthermore,
the most recent Japan Lung Cancer Society guidelines include nivolumab monotherapy
in the systemic treatment strategy for previously treated, locally advanced or metastatic
NSCLC [3]. However, ICIs induce characteristic immune-related adverse events (irAEs),
which are not seen with conventional cytotoxic agents or molecular targeted agents.
IrAEs can occur in any organ system, most typically the skin, lung, and gastrointestinal,
hepatic, and endocrine systems. Based on the results of two randomized phase III trials,
grade 3–4 adverse events (AEs) developed in 7% [1] and 10% [2] of patients in the
nivolumab groups, respectively, but no grade 5 events were seen. In the nivolumab
group, 3% and 5% of patients discontinued nivolumab due to AEs, and the rate of drug
discontinuation was lower than that in the docetaxel group [1, 2]. We reported a case
of advanced lung squamous cell carcinoma that showed long-lasting tumor shrinkage
after discontinuation of nivolumab treatment under no further cancer treatments [4].
For that patient, we had no choice but to discontinue nivolumab treatment due to onset
of interstitial lung disease, despite a good response to the first two nivolumab doses.
Continued tumor shrinkage under no further treatments has not been seen in patients
receiving other antitumor agents and may be a unique feature of nivolumab treatment,
and potentially other ICIs. To expand on these observations, we examined the clinical
characteristics of patients with advanced NSCLC who received nivolumab treatment but
discontinued it for a reason other than tumor progression.
This retrospective observational study was performed to obtain real-world data on
the prognosis of patients who discontinued nivolumab (240 mg, intravenous drip infusion,
every 2 weeks), treatment but showed no progression. All patients with advanced NSCLC
who had received nivolumab monotherapy and discontinued it by 31 March 2016 were initially
selected from each institution. Of these 124 patients, 17 who had discontinued nivolumab
due to reasons other than disease progression were included in the analysis (Table 1).
This study was initially approved by Kanazawa University (approval no. 2423-2) and
subsequently approved by the other five institutions. We collected limited and anonymized
clinical data, and no additional interventions were performed. Therefore, written
informed consent was not required.
Table 1
Characteristics of patients with advanced NSCLC who received nivolumab monotherapy
but discontinued it for a reason other than tumor progression
Patient No.
Sex
Histological type
EGFR mutation
ALK fusion gene
Treatment regimen prior to nivolumab
Nivolumab treatment
Age at initiation (years)
ECOG PS at initiation
Number of doses
Responsea
Reason for discontinuationb
1
F
Adenocarcinoma
wt
wt
PEM + BEV
79
1
1
NE
Bone fraction
2
M
Pleomorphic
wt
wt
CBDCA + PTX + BEV, DTX
60
1
3
PR
irAE (grade 5 encephalitis)
3
M
Adenocarcinoma
wt
wt
CBDCA + PEM
61
1
6
SD
Rejection
4
M
Squamous
wt
wt
CBDCA + PTX, VNR, CBDCA + S-1
68
0
2
PR
irAE (grade 2 pneumonitis)
5
M
NOS
wt
wt
CBDCA + PTX + TRT, PEM + BEV
55
2
1
NE
irAE (grade 2 pneumonitis)
6
M
Squamous
wt
wt
CBDCA + PTX
78
1
1
NE
irAE (grade 2 pneumonitis)
7
M
Adenosquamous
wt
wt
GEM + VNR, PEM, DTX, PEM + BEV
90
1
1
SD
Infection
8
M
Adenocarcinoma
wt
wt
CBDCA + PTX + TRT, CBDCA + PEM, DTX
75
1
31
SD
irAE (grade 2 pneumonitis)
9
M
Squamous
wt
wt
CDDP + S-1, CBDCA + nabPTX
67
1
2
PR
irAE (grade 3 dermatitis)
10
M
Adenosquamous
wt
wt
TRT, DTX
83
1
11
PR
Heart failure
11
F
Adenocarcinoma
wt
wt
PEM, DTX
79
1
8
SD
irAE (grade 3 arthritis)
12
M
Squamous
wt
wt
CBDCA + nabPTX
79
2
3
SD
irAE (grade 1 pneumonitis)
13
M
Adenocarcinoma
wt
wt
CBDCA + PEM
69
2
2
SD
irAE (grade 2 pneumonitis)
14
M
Adenocarcinoma
L858R
wt
CBDCA + PEM, Afatinib, DTX, Erlotinib + BEV, nabPTX, GEM, VNR
64
1
1
NE
irAE (grade 5 pneumonitis)
15
M
Adenocarcinoma
NE
NE
CDDP + PEM
59
1
1
NE
irAE (grade 5 pneumonitis)
16
F
Squamous
wt
wt
CBDCA + S-1
76
0
2
NE
irAE (grade 3 pneumonitis)
17
M
Squamous
NE
NE
TRT, CBDCA + S-1, VNR
68
2
5
SD
Rejection
NSCLC non-small cell lung cancer, EGFR epidermal growth factor receptor, ALK anaplastic
lymphoma kinase, ECOG PS the Eastern Cooperative Oncology Group performance status,
F female, M male, NOS not otherwise specified, wt. wild type, NE not evaluable, PEM
pemetrexed, BEV bevacizumab, CBDCA carboplatin, PTX paclitaxel, DTX docetaxel, VNR
vinorelbine, TRT thoracic radiotherapy, GEM gemcitabine, CDDP cisplatin, nabPTX nab-paclitaxel,
PR partial response, SD stable disease, irAE immune-related adverse event
aThe responses were classified by the Response Evaluation Criteria in Solid Tumors
1.1
bAdverse events were graded according to the Common Terminology Criteria for Adverse
Events (CTCAE) version 5.0
Progression-free survival (PFS) was defined as the duration from the initiation of
nivolumab treatment to disease progression or death. The PFS of the patients ranged
from 13 to 580 days, with a median PFS of 163 days (Fig. 1). Notably, 6 of the 17
patients (patients #3, 4, 9, 11, 13, and 16) had a long PFS (≥ 6 months) with no additional
treatment after nivolumab treatment for NSCLC. For these 6 patients, nivolumab treatment
was discontinued because of irAEs in 5 and refusal to continue treatment in 1 patient.
Of the 6 patients, 4 were male, 3 had adenocarcinoma, and 3 had squamous cell carcinoma;
none had EGFR mutations or anaplastic lymphoma kinase (ALK) fusion genes; the age
at treatment initiation ranged from 61 to 79 years, and the Eastern Cooperative Oncology
Group (ECOG) performance status (PS) was good (Table 1). The response rates were 33.3%
among patients with a long PFS and 18.2% among patients with a short PFS. Two patients
died within 1 month after the initiation of nivolumab treatment: patient #14 died
on day 13 and patient #15 on day 28. In both patients, the cause of death was grade
5 pneumonitis induced by nivolumab. Other antitumor agents were administered in only
2 patients after tumor progression. According to Kaplan–Meier analyses of PFS, patients
with a good PS or irAEs had a longer PFS than their counterparts, although without
significant differences (Additional file 1: Figure S1). However, the sample size was
too small to conclude any overall trends.
Fig. 1
Kaplan–Meier survival analysis of the 17 patients with advanced non-small cell lung
cancer who had received nivolumab and discontinued it due to reasons other than disease
progressions. a The duration of nivolumab treatment and survival after treatment discontinuation.
The blue bars indicate the duration of nivolumab treatment, and orange bars indicate
the survival after the discontinuation of nivolumab treatment. Black diamonds indicate
the time of tumor progression, and arrows indicate the alive patients by the last
follow-up. Patient numbers at the vertical axis heading correspond to those in the
first column of Table 1. b Progression-free survival curve of the 17 patients
Two randomized phase III trials (CheckMate 017 for patients with squamous NSCLC and
CheckMate 057 for patients with non-squamous NSCLC) evaluated the survival benefits
of nivolumab versus docetaxel in previously treated patients with advanced NSCLC [5].
One characteristic of PD-1 inhibitors is that some patients have the expectation of
long-term survival compared with conventional cytotoxic chemotherapy. The 2-year PFS
rates of the patients treated with nivolumab were 16% and 12% (in CheckMate 017 and
057, respectively). By comparison, the 2-year PFS rate of the patients receiving docetaxel
treatment was only 1% in the CheckMate 057, and that in CheckMate 017 was not calculated
because no docetaxel-treated patients were followed up for 2 years. Interestingly,
6 of the patients who received nivolumab treatment (1 in CheckMate 017 and 5 in CheckMate
057) achieved a long-lasting response (> 6 months) under no additional treatment.
The predictors for long-term survival after nivolumab treatment have been analyzed
but remained unclear.
The CheckMate 153 trial compared patients who discontinued nivolumab within 1 year
with those who continued treatment until disease progression or severe AEs, and the
major conclusion was that survival was significantly longer in the continuation group
than in the discontinuation group [6]. However, we focused on the long-term survivors
after nivolumab discontinuation in the present study. The 1-year PFS rate of the patients
in the discontinuation group was approximately 40%.
A key finding of the present study was that some patients had a long survival after
nivolumab discontinuation despite no further anti-cancer treatment. We speculate that
patients who discontinue treatment due to AEs, especially irAEs, will have long-lasting
responses to nivolumab. Haratani et al. [7] evaluated the relationship between irAEs
and nivolumab efficacy in patients with advanced NSCLC treated with nivolumab in the
second-line setting or later. The patients with irAEs had a higher response rate and
longer PFS and overall survival compared with those without irAEs [7]. Meanwhile,
there were two early (< 1 month) deaths related to irAEs. The mechanism explaining
why the patients with irAEs had longer survival compared with those without irAEs
remains unknown. One possibility is that tumor-specific T cells also recognize antigens
expressed on normal cells, thereby inducing irAEs. Many commonly targeted tumor antigens
are also expressed in normal tissues [8]. Hasan Ali et al. [9] showed that the pattern
of lymphocytic skin infiltration in patients with skin toxicity differed according
to the histological subtype of NSCLC and was associated with the response to nivolumab.
Although only one patient discontinued nivolumab due to skin toxicity in the present
study, other irAEs may involve similar lymphocytic infiltrations.
Our results should be confirmed by a larger-scale study. The present study was retrospective,
and the results were influenced by the decisions of physicians, such as the time points
of nivolumab discontinuation and initiation of subsequent treatments. In other words,
we obtained data reflecting actual clinical settings. In a phase III trial that compared
pembrolizumab, a PD-1 inhibitor, with chemotherapy in patients with untreated advanced
NSCLC expressing programmed death-1 ligand-1 (PD-L1) in at least 50% of tumor cells,
pembrolizumab resulted in longer PFS and overall survival than did chemotherapy [10].
Since that trial, immunohistochemical analysis of PD-L1 expression is commonly performed
in clinical settings to decide whether pembrolizumab monotherapy should be used as
the first-line treatment. Unfortunately, PD-L1 expression was not investigated in
the patients of the present study because nivolumab treatment was initiated before
approval of the PD-L1 immunohistochemistry test.
In conclusion, some patients with previously treated, advanced NSCLC who discontinued
nivolumab treatment for reasons other than tumor progression may have potential for
a long-lasting treatment response, and irAE onset and a good ECOG PS at nivolumab
initiation may be predictive markers of a long-lasting treatment response.
Supplementary information
Additional file 1: Figure S1. Kaplan–Meier progression-free survival curves of the
17 patients stratified by irAE and PS. (A) Survival curves of patients with or without
irAE. (B) Survival curves of patients with good or poor PS before nivolumab treatment.