See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/344761670

Title: Exploring the immune-checkpoint inhibitors' efficacy/tolerability in

special non-small cell lung cancer (NSCLC) populations: focus on steroids and
autoimmune disease Corresp...

Article  in  Translational Lung Cancer Research · October 2020

DOI: 10.21037/tlcr-20-635

CITATIONS READS

0 60

1 author:

Valerio maria Napoli

Sapienza University of Rome
10 PUBLICATIONS   50 CITATIONS   

SEE PROFILE

All content following this page was uploaded by Valerio maria Napoli on 20 October 2020.

The user has requested enhancement of the downloaded file.

 Author Query Form

Journal: Translational Lung Cancer Research

Manuscript ID: TLCR-20-635
doi: 10.21037/tlcr-20-635
Title: Exploring the immune-checkpoint inhibitors’ efficacy/tolerability in special non-small cell lung cancer (NSCLC) populations:
focus on steroids and autoimmune disease
Corresponding author: Francesco Passiglia

Dear Dr. Passiglia,

The proof of your manuscript is attached on the following pages. Please read through the document carefully to check for accuracy
of the text, tables, and references. Please also be aware that a professional copyeditor may have edited your manuscript to comply
with the TLCR style requirements.

In addition to proofing the article, the following queries have arisen during the preparation of your paper. Please address the queries
listed below by making the appropriate changes in the text.

If you have any other revisions that you would like to make, this will be the last opportunity to do so before the article is published.
In particular, please ensure that the author’s names and affiliations have been identified correctly, and the address of the
corresponding author is correct.

If the changes cannot be easily described through email, please annotate this proof according to the annotation guidelines as detailed
on the following page.

Query reference Query Author’s response

Please note that alterations cannot be made after you have approved
Q1
for publication, irrespective of whether it is Online First.
Author SURNAMES (family names) have been highlighted in red -
Q2
please check that these are correct.
Q3 Please check affiliations, correspondence details.

Q4 Please check acknowledgements section and confirm the conflict.

Please note that the link with the doi number for the manuscript
Q5
should be valid only after the whole issue is officially published.
Q6 Please indicate the citation table 2 in the main text.

Q7 Ref 31: Please supplement the page number.

Q8 Ref 56: Please provide the URL.

Once you have completed your revisions and/or addressed all the queries, or if you are satisfied with the proof in its existing
form, please email: e-proof@amegroups.com.

To ensure the timely publication of your article,

please respond within 48 hours.
 Author Query Form
2

Making corrections

Use Adobe Reader – available for free from http://get.adobe.com/reader/ – to open the attached document.

Adobe Professional 7:
Tools → Commenting → show Commenting Toolbar

Adobe Reader 8:
Tools → Comments & Markup → show Comments and Markup Toolbar

Adobe Reader 10 and above:

Figure 1 Adobe Acrobat X Comment → choose either Sticky Note or Highlight Text

In-text edits Select the appropriate symbol and then click and drag over the text to be modified.
Replace : denotes where the text should be replaced with an alternative option
Strikethrough : crosses out the text
Underline : underlines the text
Add note to text : links selected text with a pop-up note
Sticky notes To make a note: choose the Sticky Note option and then click on a desired location
Changing the name: double-click and choose Options → Sticky Note Properties → General → insert
desired name
To move: click anywhere (apart from the text field) and drag
To resize: click on the right or left hand order and drag
To close: click the box on the upper right corner; this does NOT delete your note
To delete: click and press the Delete keyboard button or right click and select delete from the drop-down
menu
Highlighting This allows you can highlight parts of the text.
To highlight: select Highlight and then click and drag over the text to be highlighted. When finished, click
on Highlight again to turn off the option.
To change the colour: double-click on the highlighted text and choose Options → Properties →
Appearance → Color

Saving your changes:

Click on File → Save before closing the document.

For more detailed instructions on using Adobe Acrobat, please refer to

http://www.adobe.com/support/acrobat/gettingstarted/
 Review Article

Exploring the immune-checkpoint inhibitors’ efficacy/tolerability

in special non-small cell lung cancer (NSCLC) populations: focus
on steroids and autoimmune disease
Francesco Passiglia, Valeria Cetoretta, Marco De Filippis, Valerio Napoli, Silvia Novello

Department of Oncology, S. Luigi Gonzaga Hospital, University of Turin, Orbassano (TO), Italy
Contributions: (I) Conception and design: F Passiglia, S Novello; (II) Administrative support: V Cetoretta, M De Filippis; (III) Provision of study
materials or patients: F Passiglia, V Cetoretta, M De Filippis, V Napoli; (IV) Collection and assembly of data: V Cetoretta, M De Filippis; (V)
Data analysis and interpretation: F Passiglia, V Cetoretta, M De Filippis, S Novello; (VI) Manuscript writing: All authors; (VII) Final approval of
manuscript: All authors.
Correspondence to: Francesco Passiglia, MD. Department of Oncology, S. Luigi Gonzaga Hospital, University of Turin, Regione Gonzole, 10, 10034
Orbassano (TO), Italy. Email: francesco.passiglia@unito.it.

Abstract: The advent of immune-checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/
programmed death ligand-1 (PD-L1) axis, both as monotherapy and in combination strategies, produced
a paradigm change of the treatment algorithm for metastatic, non-oncogene addicted, non-small cell
lung cancer (NSCLC) patients. Although the great efficacy and the optimal tolerability emerging from
clinical studies has been confirmed for the majority of patients treated in the real-word scenario, however
the potential activity and safety profile of these agents in uncommon NSCLC populations remains still
controversial. Particularly, patients with previously diagnosed autoimmune disease or concomitant steroids
treatment at the time of immunotherapy initiation represent two special subgroups of patients not unusual in
the real-word practice, to whom the clinical implication of immune-checkpoint inhibitors administration is
largely unknown. In this review we provided an updated literature overview, summarizing available evidence
and reporting practical suggestions, which may guide physicians in their clinical management of these
NSCLC sub-populations.

Keywords: Immunotherapy; programmed cell death-1/programmed death ligand-1 (PD-1/PD-L1); non-small

cell lung cancer (NSCLC); steroids; autoimmune disease (AID)

Submitted May 06, 2020. Accepted for publication Oct 09, 2020.
doi: 10.21037/tlcr-20-635
View this article at: http://dx.doi.org/10.21037/tlcr-20-635

1 Introduction results, nivolumab and atezolizumab entered in the clinical 13

2 practice for the second/third-line treatment of PD-L1 14
The advent of immunotherapy dramatically changed
3 unselected NSCLC patients, while the KEYNOTE-010 15
4 the therapeutic landscape of non-oncogene addicted
5 metastatic non-small cell lung cancer (NSCLC). In the and 024 studies granted Pembrolizumab approval as new 16

6 last few years, check-point inhibitors (CPIs) targeting standard of care for both pre-treated and untreated NSCLC 17

7 the programmed cell death-1 (PD-1)/programmed death patients with tumor PD-L1 expression of at least 1% and 18

8 ligand-1 (PD-L1) axis, have shown a significant superiority 50%, respectively. The introduction of immunotherapy into 19

9 over chemotherapy, in terms of efficacy and tolerability, clinical practice produced a significant increase of long- 20
10 improving disease control, overall survival (OS) and quality term survival, reaching 16% at 5 years in pre-treated, PD- 21
11 of life (QoL), both in first- and second-line setting (1-7). L1 unselected population, and about 30% when considering 22
12 Based on the Check-Mate 017/057 and OAK clinical trials’ naïve patients with high PD-L1 expression, as compared 23

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 2 Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID

24 to 5.5% in the chemotherapy era (8). More recently, the and the maturation impairment of dendritic cells (DCs) (21). 72
25 combination of Pembrolizumab with first-line platinum- Moreover, some pre-clinical works demonstrated that low 73
26 based chemotherapy resulted in a significant increase dose glucocorticoids administration is sufficient to suppress 74
27 of tumor responses and survival outcomes compared to response to cancer immunotherapy (22). The raising concern 75
28 chemotherapy alone (9-11), regardless of tumor histology on the immunosuppressive effect of glucocorticoids have 76
29 and PD-L1 expression levels, thus emerging as an additional led to a formal exclusion of patients receiving >10 mg/day 77
30 effective option for the treatment of non-oncogene of prednisone or its equivalent, from the majority of CPIs- 78
31 addicted, metastatic NSCLC. Together with the great based randomized clinical trials (23). 79
32 efficacy, CPIs are characterized by an optimal tolerability Different publications have clearly suggested that a short 80
33 profile, thus allowing their administration for prolonged course of glucocorticoids therapy does not significantly 81
34 periods. However, these drugs are not free of side effects, affect T-cells activity (24,25). As a matter of fact, some 82
35 mostly due to the abnormal activation of the immune retrospective studies showed that a transient use of 83
36 system. In fact, it is estimated that about 70% of patients steroids for the clinical management of immune-related 84
37 develop adverse events during the course of CPIs therapy, adverse events (irAEs) do not compromise the efficacy of 85
38 usually not disabling and well manageable with medical immunotherapy (26-31). Similarly, the use of steroids-based 86
39 therapy or drug withdrawal (12). Considering that the premedication in the record trials of recently approved 87
40 majority of available evidence is limited to highly selected chemo-immunotherapy combination regimens did not have 88
41 population which reflects the ones included into clinical any influence on patients’ survival outcomes (9-11). 89
42 trials, few data are available from the real-life setting. Some Conversely, the potential effect of a concomitant 90
43 clinical series have recently confirmed an optimal efficacy administration of steroids at the time of CPIs initiation 91
44 and tolerability of CPIs in special subgroups of patients, in cancer patients remains still controversial. Several 92
45 like elderly (13), poor performance status (14), and brain retrospective studies and case series were carried out with 93
46 metastasis (15), who are quite common in the real-word the intent to clarify the potential clinical implications of 94

47 scenario. Conversely, the potential activity and safety profile concomitant use of steroids in CPIs-treated, advanced 95

48 of CPIs in NSCLC patients who received a concomitant use NSCLC patients (Table 1). 96

49 of steroids or were previously diagnosed with autoimmune Arbour et al. analyzed 640 patients who were treated 97

50 disease (AID) remains still controversial. In this review with anti-PD-1/PD-L1 agents coming from the Memorial 98

51 we provided an updated literature overview, summarizing Sloan Kettering Cancer Centre (MSKCC; 455) and the 99

52 available evidence and reporting practical suggestions, Gustave Roussy Cancer Centre (GRCC; 185). In this study, 100

53 which may guide physicians in their current practice. 90 patients (14%) were treated with a baseline >10 mg-dose 101

54
of prednisone at the time of CPIs beginning, and treatment 102

55
outcomes, including objective response rate (ORR), 103
Concomitant use of steroids progression free survival (PFS), and OS, were analyzed. 104
56 Main factors considered in the multivariate analysis 105
57 Clinical evidences
58
included smoking status, Easter Cooperative Oncology 106
Glucocorticoids are widely used for the clinical management Group performance status (ECOG-PS) and the presence of 107
59
60 of advanced NSCLC patients to treat both cancer-related brain metastases. The pooled analysis showed that ≥10 mg- 108
61 and cancer unrelated symptoms (16-20). The most common prednisone administration at early stages of CPIs’ therapy 109
62 cancer-related palliative indications include dyspnea, fatigue, was significantly associated to poor survival outcomes, 110
63 anorexia, pain and symptomatic brain metastases. Otherwise specifically in terms of PFS (HR 1.31, P<0.03), and OS (HR 111
64 patients could require steroids therapy administration for 1.66, P<0.001). A detrimental effect of steroids on CPIs’ 112
65 the clinical management of a wide range of conditions, like efficacy has been observed in patients receiving ≥10 mg vs. 113
66 AID, chronic obstructive pulmonary disease (COPD) flare, <10-mg prednisone (32). 114
67 prophylaxis of hypersensitivity reactions, and non-cancer In a second retrospective study, Scott et al. analyzed 210 115
68 pain. NSCLC patients treated with nivolumab at the Cleveland 116
69 Steroids exert their dose-dependent immunosuppressive Clinic, with 66 (31%) receiving a concomitant steroids 117
70 effects both on innate and adaptive immunity. Well- therapy. The median OS of patients subjected to steroids 118
71 established effects include the induction of T cell apoptosis treatment within the first 30 days was 4.3 months, compared 119

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 Table 1 Clinical studies reporting efficacy outcomes of CPI-treated advanced NSCLC patients under concomitant steroids therapy
No. of
patients Definition of steroid
Author Study design CPI and line of treatment Reason for steroid use ORR PFS OS
(steroids/no treatment
steroids)

Arbour Retrospective 90/550 Prednisone or Anti-PD-1/anti-PD-L1 Dyspnea/respiratory IGR: 8% vs. IGR: IGR:
et al. (32) Multicentric equivalent >10 mg/day symptoms (33%); 18%, P=0.2 1.7 vs. 1.8 m, 3.3 vs. 9.4 m,
on the day starting CPI fatigue (21%); P <0.001 P<0.001
brain mts (19%)
IGR: I–II line (56% vs. 67%); MSKCC: MSKCC: MSKCC:
>II line (46% vs. 33%) 6% vs. 19%, 1.9 vs. 2.6 m, 5.4 vs. 12.1 m,
P=0.02 P=0.001 P<0.001

MSKCC: I–II line (38% vs. 52%);

Translational Lung Cancer Research, 2020

>II line (62% vs. 47%)

Scott Retrospective 66/144 Prednisone or Anti-PD-1; setting NA COPD/respiratory NA NA 4.3 vs. 11 m,

© Translational Lung Cancer Research. All rights reserved.

et al. (33) single institution equivalent >10 mg/day symptoms (21%); P=0.017
at initiation or within disease-pain and
30 days after CPI constitutional symptoms
(18%); irAEs (17%);
brain mts (27%)

Fucà Retrospective 35/116 Prednisone or PD-1 and CTLA4: 14% NA NA 1.98 vs. 3.94 m,4.86 vs. 15.14 m,
et al. (34) single institution equivalent >10 mg/day P=0.003 P<0.001
PD-1/PD-L1 monotherapy: 96%
for at least 1 day within
28 days after CPI I–II line (57% vs. 56%)

>II line (43% vs. 44%)

Pan Retrospective 11/25 At least 1 dose of Single agent anti-PD-1 Brain mts; radiation NA NA 9.9 vs. 8.1 m,
et al. (35) single institution steroid during anti necrosis; anorexia P value not
PD-(L)1 treatment specified
I–II line (77% vs. 69%) irAEs

>II line (22% vs. 30%)

Martinez Retrospective 146/247 Prednisone or NA irAEs (43%); baseline NA 4.2 vs. 4.6 m, 8.3 vs. 14.7 m,
et al. (36) single institution equivalent >10 mg/day conditions (57%) P value not P value not
at the time of initiation specified specified
or during CPI

Drakaki Retrospective 258/604 Oral or intravenous NA NA NA NA HR: 1.34,

et al. (37) single institution corticosteroids 95% CI:
<14 days prior and up 1.12–1.61
to 30 days after CPI
initiation

Table 1 (continued)

Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635

3
 4
Table 1 (continued)

No. of
patients Definition of steroid
Author Study design CPI and line of treatment Reason for steroid use ORR PFS OS
(steroids/no treatment
steroids)

Patil et al. Retrospective 1,581/11,143 Prednisone or NA NA NA NA HR: 1.16,

(38) single institution equivalent ≥10 mg 95% CI:
within the first 30 days 1.05–1.28
of CPI initiation

Wakuda Retrospective 28/75 NA NA irAEs 46% vs. 7.8 vs. 9.6 m, 14.5 vs. 30.0 m,
et al. (39) single institution 41%, P=0.11 P=0.30
P=0.64

Ricciuti Retrospective 93/557 Prednisone or PD-1 and CTLA-4 5% Cancer related: n=66 10.8% vs. 2.0 vs. 3.4 m, 4.9 vs. 11.2 m
et al. (40) single institution equivalent >10 mg/day (70%); cancer unrelated 19.7%, P=0.1
PD-1/PD-L1 monotherapy 95% P<0.001

© Translational Lung Cancer Research. All rights reserved.

within 24 hours after n=27 (30%) P=0.4
CPI initiation I line 29%

≥II line 71%

De Giglio Retrospective 49/424 Prednisone or equiva- NA Cancer-related: n=39 NA 1.3 vs. 2.6 m, 2.3 vs. 13.8 m,
et al. (41) single institution lent >10 mg/day within (80%); cancer unrelated: P<0.0001 P<0.0001
the first 8 weeks of CPI n=10 (20%)
initiation
Outcomes (ORR, PFS, OS) comparison have been reported as “steroids- versus non-steroids-users”. COPD, chronic obstructive pulmonary disease; ECOG-PS, Eastern
Cooperative Oncology Group performance status; CPIs, immune checkpoint inhibitors; IGR, Institute Gustave Roussy; irAE, immune-related adverse event; ORR, objective
response rate; PFS, progression-free survival; OS, overall survival; m, months; HR, hazard ratio; CI, confidence interval; NA, not available; PD-L1, programmed death-ligand 1;
PD-1, programmed cell death 1; MSKCC, Memorial Sloan Kewttering Camcer Centre.

Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635

Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID
 Translational Lung Cancer Research, 2020 5

120 to 11-month OS of other patients (HR 2.30, 95% CI: or lower dose of steroids (PFS: 1.4 vs. 4.6 vs. 3.4 months, 168
121 1.27–4.16, P=0.006). Among them, 31 individuals receiving P=0.001; OS: 2.2 vs. 10.7 vs. 11.2 months, P=0.001). 169
122 steroids for the clinical management of irAEs did not show Conversely no survival differences were observed between 170
123 significant differences in terms of OS as compared to those patients receiving ≥10 mg prednisone for non-cancer 171
124 without irAEs (OS: 16.1 vs. 10.5 months; 95% CI: 8.6–12.2, related indications and those on lower dose of steroids, 172
125 P=0.50) (33). both in terms of PFS (4.6 vs. 3.4 months; HR 0.77; 95% CI: 173
126 Fucà et al. conducted another retrospective analysis on 0.50–1.19; P=0.24) and OS (10.7 vs. 11.2 months; HR 0.93; 174
127 a total of 151 patients diagnosed with metastatic NSCLC 95% CI: 0.59–1.48; P=0.77) (40). 175
128 undergoing CPIs treatment. In this study, steroid exposure Similarly, De Giglio et al. performed a retrospective 176
129 was defined as the ≥10 mg-prednisone administration in analysis on a total of 49 NSCLC patients who received early 177
130 at least one of the 28 days preceding the CPIs’ treatment steroids therapy at Gustave Roussy Cancer Institute, whose 178
131 initiation. The 35 steroid-exposed patients (23% of the 39 patients for cancer-related symptoms, including dyspnea 179
132 overall population) showed significantly worse PFS (HR (50%), brain metastases (15.8%), pain (7.9%), superior vena 180
133 1.80, P=0.003) and OS (HR 2.60, P<0.001) than the non- cava syndrome (7.9%), fatigue (5.3%), others (13.1%), and 181
134 exposed cohort (34). the remaining 10 patients for other causes, like the clinical 182
135 Numerous subsequent reports, which were published as management of irAEs (54.6%). Patients receiving steroids 183
136 abstracts in several congresses, appear to be aligned with the for cancer-related symptoms had significantly poorer 184
137 above-mentioned evidence, overall showing a detrimental outcomes with early steroids introduction reported to be an 185
138 effect of a concomitant use of steroids at baseline on CPIs’ independent prognostic factor for both poor PFS (HR 3.04; 186
139 efficacy and patients’ survival (Table 1) (35-38). 95% CI: 1.38–6.66; P=0.006) and OS (HR 1.21; 95% CI: 187
140 Of note the only report considering corticosteroids 0.53–2.8; P<0.0001). No differences were observed between 188
141 administration during CPIs’ therapy exclusively devoted the group of patients subjected to steroids therapy for other 189
142 to the clinical management of irAEs showed no significant indications [PFS 2.7 months (1.21–NR); OS 13.4 months 190
143 difference in terms of OS (14.5 vs. 30.0 months, P=0.30; (4.30–NR)] and the group of steroids-naïve patients [PFS 191
144 HR 0.69), PFS (7.8 vs. 9.6 months, P=0.11; HR 0.65) and 2.6 months (2.20–3.94); OS 13.8 months (11.4–18)] (41). 192
145 ORR (46% vs. 41%; P=0.64) between steroids and non- 193
146 steroids group, respectively (39). 194
Critical discussion
147 Interestingly, two most recent studies, analyzed the
195
148 effects of corticosteroids on CPIs’ treatment efficacy Corticosteroids are immunomodulatory agents regulating 196
149 considering the reason of their administration by splitting gene expressions and signaling pathways through both 197
150 cancer-related palliative indications (brain metastases, genomic and non-genomic mechanisms (21,42), thus 198
151 dyspnea, bone metastases, anorexia) from cancer-unrelated exerting their dose-dependent immunosuppressive 199
152 indications (irAEs, COPD exacerbation, AID, pain, action on T cells, which constitute the effector arm of 200
153 chemotherapy or iodinate contrast prophylaxis etc.). immunotherapy. 201
154 In the retrospective study by Ricciuti et al., the poorest In the antitumor response, PD-1 exerts its inhibitory effects 202
155 survival outcome likely applies to the subgroup of patients mainly at local level, in the tumor microenvironment (43) 203
156 who received 10 mg-prednisone for palliative purposes. thus PD-1/PD-L1 CPIs aim to reverse the exhaustion 204
157 They identified a total of 650 CPI-treated, advanced of pre-existing tumor-residing T-cells, by restoring their 205
158 NSCLC patients, of whom 93 received prednisone ≥10 mg effector functions, in order to produce tumor regression 206
159 or its equivalent within 24 hours of CPI initiation. Among (44-46). 207
160 them, 66 patients were on steroids treatment for cancer- Nonetheless, it has not been clarified yet whether 208
161 related palliative symptoms, including symptomatic brain steroids administration block the differentiation of 209
162 metastases (57.6%), dyspnea (18.2%), bone metastases stimulated T cells or deplete already differentiated tumor- 210
163 (16.7%), and anorexia (7.6%), whilst 27 patients for cancer reactive lymphocytes. Therefore, it remains unclear how 211
164 unrelated conditions. Patients who received ≥10 mg of steroids alter the adaptive anti-tumor immunity and 212
165 prednisone for palliative indications showed significantly whether steroids effects on immune response may vary 213
166 worse survival outcomes compared to those receiving according to their dosage, administration time-point/ 214
167 ≥10 mg of prednisone for cancer unrelated indications duration, as well as on the basis of primary tumor location. 215

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 6
Table 2 Clinical studies reporting efficacy/safety outcomes in CPI-treated advanced NSCLC patients with preexisting autoimmune diseases
Author Type of study Patients, n Tumor type CPI type Line of treatment Preexisting AIDs AIDs flare irAEs ORR

Danlos Prospective 397 (AID 45; Melanoma (80%); PD-1/PD-L1 Median of 1 Vitiligo 32%; 24.4% AID 44.4%; AID 38%; no AID
et al. (59) no AID 352) NSCLC (13%); previous line of Ps/PsA 22%; no AID 28%
others (7%) treatment TD 13%; pSS 7.5%; 23.8%
RA 3.8%; MS 3.8

Cortellini Multicenter 751 (AID 85; NSCLC (65.5%); PD-1 1st line 83.3%; Thyroid disorders (60%); 47.1% AID 65.9%; Active AID (50%);
et al. (60) retrospective no AID 666) melanoma (21.2%); 2nd line 51.4%; dermatologic (16.4%); no AID inactive AID (38.1%);
observational renal cell (12.5%); 3rd line 18%; rheumatologic (11.8%); 39.9% no AID (35.3%)
others (0.8%) >3rd line 7.3% others (7.1%);
multiple site (4.7%)

Leonardi Retrospective 56 AID NSCLC PD-1/PD-L1 NA Ps/PsA (25%); IBD (20%); 23% 38% 22%
et al. (61) RA (19.5%); TD (16%)

PMR (9%); SS (3.8%);

© Translational Lung Cancer Research. All rights reserved.

MS (3.8%); others (5.4%)

Tison et al. Retrospective 112 Melanoma (59%); PD-1/PD-L1 (84%); 1st line 44%; Psoriasis/PsA (28%); 42% 38% Melanoma 48%;
(64) cohort study NSCLC (35%); CTLA-4 (13%); 2nd line 32%; RA (18%); IBD (13%); NSCLC 54%
other (6%) combination (3%) >2nd line 23% SpA (4.5%); lupus (6.3%);
PMR/GCA (6.3%);
others (25%)

Abu-Sbeih Multicenter 102 Melanoma (44%); PD-1/PD-L1 (83%); NA Crohn’s disease (48%); NA 41% 48%
et al. (65) retrospective lung (23%); GI CTLA-4 (7%); ulcerative colitis (48%);
(17%); GU (7%); combination (10%) unclassified (4%)
others (10%)
AID, autoimmune disease; GCA, giant cell arteritis; GI, gastrointestinal; GU, genitourinary; IBD, inflammatory bowel diseases; ICI, immune checkpoint inhibitor; irAEs,
immunotherapy-related adverse events; MS, multiple sclerosis; NA, not available; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS,
progression-free survival; PMR, polymyalgia rheumatica; pSS, primary Sjögren syndrome; Ps, psoriasis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SpA, spondylosis
arthropathy; SS, scleroderma; TD, thyroiditis.

Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635

Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID
 Translational Lung Cancer Research, 2020 7

216 Although initial real-world clinical data (32) suggested prognostic clinical features, such as ECOG-PS ≥2, baseline 264
217 a significant association between the dose of steroids brain metastases, and higher number of metastatic sites 265
218 administration and the therapeutic effects of CPIs, recent (32-34), thus confirming the predominant prognostic role 266
219 evidence (34,40) revealed that the immunosuppressive effect of steroids at CPIs’ therapy initiation. 267
220 of corticosteroids is more timely- than dose-dependent. On the other hand, once anti-tumor immunity has 268
221 Several preclinical studies explored whether the been initiated, the negative impact of corticosteroids on 269
222 dexamethasone administration timing may significantly immune function is markedly reduced (47). In line with 270
223 affect immunotherapeutic treatment efficacy (47,48). this hypothesis, neither steroid administration for irAEs 271
224 The results of these studies revealed that early steroid treatment nor the short-course of steroid use within 272
225 administration only, through the reduction of the T premedication protocol for chemo-immunotherapy 273
226 lymphocyte peripheral pool, might compromise the early combinations (9-11) significantly influenced the survival 274
227 adaptive immune response enhanced by anti-PD-1 therapy, outcomes of NSCLC patients (28,29,31). 275
228 thus impairing the clinical efficacy of these agents. Finally, preclinical studies suggested that blocking 276
229 Most of the studies exploring the implications of steroids C T L A - 4 , b u t n o t P D - 1 , p a r t i a l l y r e s c u e d T- c e l l 277
230 administration in NSCLC patients under CPIs’ treatment, proliferation in the presence of dexamethasone in vitro (49). 278
231 which are being considered in this instance, appear to This type of evidence is likely related to the different 279
232 support this item. Particularly, Fucà et al. provides a effect of CTLA-4 blockade, usually acting on less 280
233 potential biological explanation to the early corticosteroid differentiated and more dexamethasone-sensitive T-cells 281
234 use negative effects on the antitumor immune response subsets, suggesting a different effect of steroids on anti- 282
235 elicited by CPI therapy (34), showing as white blood CTLA-4 and anti-PD-1/PD-L1 agents activity. Different 283
236 count (WBC), absolute neutrophil count (ANC) and studies have previously found that corticosteroids did not 284
237 derived neutrophil to lymphocyte ratio (dNLR), were negatively impact OS of cancer patients on immunotherapy 285
238 significantly higher in steroids-treated patients than the involving CTLA-4 blockade (28,50–54). Although none of 286
239 non-exposed cohort, both at baseline and at 4/6 weeks after 287
these studies was specifically powered to address the impact
240 CPI initiation. Interestingly a high percentage of steroids- 288
of steroids on CPIs’ efficacy, these evidences could partially
241 treated patients showed a NLR ≥5 (OR 5.40, 95% CI: 1.95– 289
reflect the anti-CTLA-4 specific capability of counteracting
242 16.70, P<0.001) and a dNLR ≥3 (OR 10.32, 95% CI: 3.43– 290
steroids effects. Conversely other clinical experiences
243 39.43, P<0.001) as compared to the control cohort, thus 291
suggested a potential detrimental effect of early steroids
244 suggesting as the dynamic modulation of peripheral blood 292
administration on the ipilimumab anti-tumor activity,
245 immune cells during the treatment course might mediate 293
requiring further investigation in dedicated studies. (55).
246 immunotherapy resistance induced by corticosteroid 294
Moving from bench to bedside, it will be interesting
247 administration. 295
to see whether and how steroids use could affect the anti-
248 Nonetheless, the relevance of the negative prognostic 296
CTLA-4 plus anti-PD-1 blockade efficacy, since this kind
249 effect of steroids should be cautiously considered when they 297
of combination has been recently entered as additional first
250 are used in NSCLC patients with metastatic disease. Indeed, 298
line treatment option for patients with metastatic, non-
251 when steroids administration was stratified and analyzed 299
oncogene addicted NSCLC, at least in the United States.
252 separately according to the specific clinical indication, 300
253 the concomitant use of corticosteroids for non-palliative 301
254 purposes did not appear to significantly affect CPIs-treated AIDs
302
255 patients’ survival anymore, regardless of their dose of 303
Clinical evidences
256 administration (40,41). Although limited by a retrospective 304
257 design, low number and heterogeneity of included Among patients diagnosed with lung cancer, a percentage 305
306
258 patients, the results of most recent studies suggested that ranging from 14% to 25% is likely to have a concomitant 307
259 the negative impact of steroids on CPIs’ efficacy may AID (56). Female patients, elderly and early stage have 308
260 be mainly ascribed to the worse prognosis of patients higher chances of being part of this overlapping group 309
261 candidate to early palliative cure for their symptomatic (P<0.001). Moreover, it has been shown that some 310
262 disease. Moreover, subgroup analysis suggested that steroid- autoimmune disorders such as rheumatoid arthritis (RA), 311
263 treated patients were commonly characterized by negative contribute to the onset of neoplasms. Indeed, subjects

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 8 Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID

312 affected by RA present a double risk of developing lung with previous AIDs was 65.9% (95% CI: 49.7–85.5%), 360
313 cancer as compared to the healthy population, with cigarette compared to 39.9% (95% CI: 35.2–45.0%) in patients 361
314 smoking and lung chronic inflammation underlying this without AIDs. However, not significant differences in 362
315 clinical association (57). the incidence of grade 3–4 irAEs [9.4% (95% CI: 4.1– 363
316 The concerns about exacerbations of pre-existing 18.5%) vs. 8.8% (95% CI: 6.7–11.4%)], ORR (38.1% 364
317 AID as well as the major susceptibility to severe irAEs inactive/50% active AID vs. 35.3% no AID), median PFS 365
318 as consequence of the reactivation of immune response (14.4 inactive/6.8 months active AIDs vs. 8 months no AID) 366
319 induced by the checkpoint blockade led to the exclusion of and median OS (15.7 inactive/9.8 months active AID vs. 367
320 patients with autoimmune disorders from the randomized 16.5 months no AID) were reported. Focusing on specific 368
321 phase III clinical trials leading to the approval of CPIs’ subgroups, patients with active AIDs seemed to have higher 369
322 therapy in lung cancer patients. ORR (50%) compared with patients with inactive AIDs 370
323 A study published in 2018, including 172,285 patients (38.1%) and those without (35.3%) AIDs. Conversely, a 371
324 with a lung cancer diagnosis performed between 1992 and not significant trend toward a worse median PFS has been 372
325 2009, showed that, in absence of CPIs’ administration, observed in patients with active (6.8 months) vs. inactive 373
326 the presence of a concomitant AIDs did not influence the (14.4 months) AIDs (59). Similarly, worse median OS has 374
327 treatment pattern and was not associated with an increased been reported in patients with active (9.8 months) compared 375
328 mortality (58). to inactive (15.7 months) or no (16.5 months) AIDs, likely 376
329 In a prospective study based on REISAMIC (Registry of due to the impact of the disease on life expectancy, being 377
330 Severe Adverse events of Immunomodulating monoclonal aware that the transient interruptions of immunotherapy 378
331 antibodies in oncology), the association between pre- due to toxicity should not affect OS (26,60). 379
332 existing AIDs and irAEs free survival, OS and best ORR Interestingly, patients with ECOG-PS >2 seemed to have 380
333 was investigated, with 45 out of 397 enrolled cancer a lower incidence of irAEs, likely due to their poor general 381
334 patients harboring a concomitant AIDs diagnosis. The conditions, which may have impaired the reactivity of their 382
335 most frequent AIDs were vitiligo (n=17), psoriasis (n=12), immune system (60). 383
336 autoimmune thyroiditis (n=7), Sjögren's syndrome (n=4) Another study published in 2018 in JCO, analyzed a 384
337 and RA (N=2). The incidence of irAEs in patients with total of 56 patients diagnosed with NSCLC and AIDs 385
338 autoimmune pathologies was 44.4% compared to 23.8% undergoing immunotherapy. About 55% of patients 386
339 of the remaining population. IrAEs median free survival developed irAEs (38%) and/or AIDs’ exacerbation (23%). 387
340 was seen to be lower in patients with previous AIDs (5.4 The irAEs were mostly of mild grade (74%) but in 26% of 388
341 months) compared to the control cohort (13 months). cases, a severe irAE has been reported. Half of them did not 389
342 However, no OS and ORR differences were observed require immunosuppressive therapy for symptom control 390
343 between the two groups (59). The study did not consider and, the majority of the remaining patients were treated 391
344 grade 1 immune-mediated toxicities in order to avoid with only corticosteroids. As regards AIDs’ exacerbations, 392
345 detection bias, since the diagnose of mild immune-mediated they were G1–G2 in 87% of cases, and G3 in the remaining 393
346 toxicities is easier in patients with previous autoimmune 13% of cases, while no G4 events occurred. Importantly 394
347 disorders. On the other hand, this may have led to an exacerbations were more frequent in patients with 395
348 underestimation of the incidence of irAEs. Furthermore, symptomatic versus non-symptomatic AIDs (50% vs. 18%) 396
349 the authors didn’t differentiate between clinically active and at the time of immunotherapy initiation. Furthermore, no 397
350 inactive AID at the time of anti PD-1 blockade initiation. difference in flares incidence was found between patients 398
351 In another multicenter retrospective study published assuming an immunosuppressive drug at baseline and those 399
352 in 2019, among 751 stage IV cancer patients, the most who did not, while in the 5% of cases a concomitance of 400
353 represented tumor was NSCLC (65.5%) followed by AIDs and irAEs flares has been described. 401
354 melanoma and kidney cancer. Seventy out of 751 had a In this study, the overall percentage of G3–G4 irAEs 402
355 pre-existing inactive AID, i.e., not being treated at the was found to be 11%, in line with that (7–15%) emerging 403
356 time of immunotherapy initiation, and 15 presented from the CPIs registration studies, which did not include 404
357 an active disease that required the administration of AIDs affected patients. However, the rate of treatment 405
358 immunosuppressive drugs (corticosteroids in 73.3% of discontinuation due to immune related toxicity was 406
359 cases). The incidence of any grade irAEs in the population significantly higher (14% vs. 3–8%) (61). 407

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 Translational Lung Cancer Research, 2020 9

408 A poster presented at ASCO 2019 by Sean Khozin during the follow-up period. Patients who had active IBD 456
409 showed the results of a retrospective observational cohort in the three months prior to immunotherapy initiation 457
410 study including 2,425 patients with stage III–IV NSCLC, experienced higher grade diarrhea than patients with 458
411 who received at least one dose of CPI therapy. A diagnosis inactive IBD. No difference in severity of GI adverse effects 459
412 of AID was reported in 22% of patients (n=538), whose was observed between patients who were being treated for 460
413 median survival was similar to that observed in the IBD at the beginning of immunotherapy and those who 461
414 remaining population not affected by AIDs. Unlike the were not. The tumor response to CPIs’ therapy was similar 462
415 previous evidence, the results of this study did not show between patients affected by IBD and those who did not, 463
416 increased risk of developing irAEs in the AIDs-affected suggesting the effectiveness of immunotherapy treatment 464
417 subgroup (62). even in this particular population (65). 465
418 Similarly, a recent retrospective study including 29 CPIs’ 466
419 treated patients with advanced lung cancer (adenocarcinoma 467
Critical discussion
420 59%, squamous cell carcinoma 34%, small cell cancer 7%,
468
421 undifferentiated 3%), showed a not-increased incidence The major concerns about the use of immunotherapy in 469
422 of irAEs in patients with AIDs compared to the control NSCLC patients with pre-existing AIDs was related to an 470
423 population. Furthermore, no significant survival differences increased risk of developing serious irAEs and a flare-up of 471
424 have been observed according to both irAE occurrence their baseline pathological conditions, as compared to the 472
425 and baseline immunomodulatory therapy (63). However, general cancer population (4-6). 473
426 another retrospective study including 112 cancer patients The occurrence of irAEs has been reported to be 474
427 with AIDs treated with immunotherapy (anti-PD-1/PD- higher in patients with pre-existing AIDs compared to 475
428 L1 83%, anti-CTLA-4 13%, combination 3%), showed a the control population, however the majority of irAEs 476
429 reduced PFS in patients who developed immunotoxicity are mild and well-controlled by corticosteroids use, with 477
430 (irAEs or AID flares), as compared to the control cohort (HR a limited number of patients requiring non-steroidal 478
431 1.97, P=0.032) (64). immunosuppressive drugs for high grade toxicities (61,64). 479
432 An international multicenter retrospective study A transient discontinuation of CPIs’ therapy (60,63,64) 480
433 analyzed 102 cancer patients with a concomitant diagnosis due to irAEs occurrence may be required, but, according 481
434 of inflammatory bowel disease (IBD) who were treated to available evidence, no significant increased risk of high- 482
435 with immunotherapeutic drugs. Among these, 49 patients grade irAEs leading to permanent suspension of CPIs’ 483
436 suffered from Crohn’s disease, 49 from ulcerative colitis and treatment has been reported. Particularly the percentage 484
437 4 from unclassified inflammatory disease, while the control of NSCLC patients experiencing high-grade irAEs and 485
438 group consisted of 11,377 cancer patients with no IBD CPIs’ treatment discontinuation were 11% and 14%, 486
439 receiving immunotherapy. The most represented tumor respectively, thus very similar to those reported in clinical 487
440 was melanoma (44%) followed by NSCLC (23%) and trials not including AIDs population. Conversely the 488
441 gastrointestinal (GI) tumors (17%), with 83% of patients risk of developing AID flare seems to be related to the 489
442 receiving an anti PD-1/PD-L1 agent. Among the 102 presence of AID symptoms at the time of CPIs initiation 490
443 analyzed patients, 42 (41%) presented a GI side effect, with with a mild prevalence among patients diagnosed with 491
444 a median incidence of 62 days from the treatment initiation, rheumatologic AID (61). Therefore, particular attention 492
445 and 23 of them discontinued immunotherapy. Forty-one should be paid to the clinical management of patients with 493
446 patients developed diarrhea, of grade 3–4 in about half active and symptomatic preexisting AIDs who are candidate 494
447 of cases, and 29% required the administration of non- to receiving CPIs’ therapy. As regards the immunotherapy 495
448 steroidal immunosuppressive drugs, such as Infliximab and effectiveness in this special population, the available 496
449 Vedolizumab. Due to the side effects, 32 patients underwent evidence suggested a similar activity of CPIs’ therapy in 497
450 endoscopic investigation leading to the detection of mucosal NSCLC patients with or without AIDs, with worse OS 498
451 ulceration in 38% and of non-ulcerative inflammation limited to symptomatic AIDs cases. 499
452 in 44% of cases. A total of 4 patients underwent a colic In the majority of the aforementioned studies CPIs have 500
453 perforation. In the control group, the incidence of GI side been administered in pre-treated patients, thus leading to 501
454 effects was significantly lower (11%). Of the 42 patients a potential underestimation of the real incidence of irAEs 502
455 who developed toxicities, 15 presented a second episode in this special population considering that the long lasting 503

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 10 Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID

504 and widespread use of immunotherapy in first-line may be the efficacy and safety profile of immunotherapy in NSCLC 552
505 associated to higher risk of developing irAEs, especially diagnosed with AIDs (NCT03656627, NCT03816345). 553
506 in those patients with pre-existing AIDs. Similarly, the 554
507 survival outcomes reported in these studies should be 555
Conclusions
508 carefully interpreted as they reflect the health status of
556
509 cancer patients who had previously received other cancer The real impact of both concomitant steroids therapy and 557
510 treatments, whose influence on immune reactivity is not AIDs on immunotherapy efficacy/tolerability in NSCLC 558
511 known and established yet. patients remains an actual and controversial topic requiring 559
512 Comforting data about the use of immunotherapy prospective investigation, in order to develop standardized 560
513 also comes from studies conducted on patients with IBD, selection criteria and shared recommendations for their 561
514 to whom the treatment benefits seem to outweigh the clinical management. In the current scenario, characterized 562
515 risks. However, patients with active IBD at the time of by limited knowledge and lack of dedicated guidelines, 563
516 immunotherapy initiation, seem to have higher risk of an international panel of experts from the International 564
517 developing severe immune mediated GI adverse events Association for the Study of Lung Cancer (IASLC) have 565
518 and, therefore require to be early identified and adequately recently provided practical suggestions which may guide 566
519 managed and treated, if necessary. In this regard, the early physicians in their current practice (69). Therefore, 567
520 introduction of immunosuppressive drugs such as Infliximab according to the IASLC panel: “patients with metastatic 568
521 and Vedolizumab has been indeed associated to better NSCLC receiving concomitant steroids treatment should not be 569
522 survival outcomes, especially in those patients with a severe excluded from CPIs therapy and discontinuation of steroids is not 570
523 endoscopic presentation (65). always required at the time of CPIs initiation”. Similarly, “CPIs’ 571
524 According to Haanen et al., patients with autoimmune therapy may be offered to NSCLC patients affected by non- 572
525 disorders and cancer requiring immunotherapy could life-threatening and asymptomatic AIDs”. Finally, a clinical 573
526 benefit from a 2-step approach with personalized therapy decision on each individual patient is currently suggested 574
527 depending on the autoimmune pathology itself. The and a close clinical monitoring highly recommended. 575
528 suggested algorithm foresees a first phase lasting 1 month, 576
529 whose objective is to control the autoimmune pathology 577
Acknowledgments
530 with specific immunosuppressive drugs, limiting the use
578
531 and dose of corticosteroids, and a second phase in which the Funding: None. 579
532 immunotherapeutic drug may be introduced. The periodic 580
533 follow-up aims to evaluate any chemical alterations in the 581
Footnote
534 laboratory and clinic to detect any exacerbations at an early
582
535 stage and intervene with specific targeted therapies (66). Provenance and Peer Review: This article was commissioned 583
536 Finally, a 2019 Japanese study investigated the possible by the Guest Editors (Jordi Remon and Benjamin Besse) for 584
537 influence of antinuclear antibody (ANA) positivity on the series “Immunotherapy in other thoracic malignancies 585
538 the incidence of irAEs. The authors demonstrated that and uncommon populations” published in Translational 586
539 ANA+ patients did not present a higher risk of developing Lung Cancer Research. The article has undergone external 587
540 irAEs compared with negative patients but showed shorter peer review. 588
541 PFS and OS. This is likely due to the underlying chronic 589
542 inflammatory status, which is a known factor influencing Conflicts of Interest: All authors have completed the ICMJE 590
543 carcinogenesis (67,68). Furthermore, 10 out of 18 baseline uniform disclosure form (available at http://dx.doi. 591
544 ANA+ patients recruited in the study were monitored for org/10.21037/tlcr-20-635). The series “Immunotherapy in 592
545 ANA titer during CPIs’ treatment, with 3 of them showing other thoracic malignancies and uncommon populations” 593
546 an increase of this value and a subsequent development of was commissioned by the editorial office without any 594
547 irAEs. Although very preliminary, these data suggested that funding or sponsorship. FP reports personal fees from 595
548 a dynamic monitoring of ANA value could play a potential MSD, personal fees from Boehringer Ingelheim, personal 596
549 role in the measurement of patient immunoreactivity, as fees from Astra Zeneca, outside the submitted work. SN 597
550 predictive factor for the development of irAEs (67). reports personal fees from Eli Lilly, personal fees from 598
551 Ongoing prospective studies are currently investigating MSD, personal fees from Roche, personal fees from BMS, 599

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 Translational Lung Cancer Research, 2020 11

600 personal fees from Takeda, personal fees from Pfizer, 2017;18:1600-9. 648
601 personal fees from Astra Zeneca, personal fees from 8. Garon EB, Hellmann MD, Rizvi NA, et al. Five-Year 649
602 Boehringer Ingelheim, outside the submitted work. The Overall Survival for Patients With Advanced Non‒Small- 650
603 other authors have no other conflicts of interest to declare. Cell Lung Cancer Treated With Pembrolizumab: Results 651
604 From the Phase I KEYNOTE-001Study. J Clin Oncol 652
605 Ethical Statement: The authors are accountable for all 2019;37:2518-27. 653
606 aspects of the work in ensuring that questions related 9. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus 654
607 to the accuracy or integrity of any part of the work are chemotherapy for squamous non-small-cell lung cancer. N 655
608 appropriately investigated and resolved. Engl J Med 2018;379:2040-51. 656
609 10. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. 657
610 Open Access Statement: This is an Open Access article Pembrolizumab plus chemotherapy in metastatic non- 658
611 distributed in accordance with the Creative Commons small-cell lung cancer. N Engl J Med 2018;378:2078-92. 659
612 Attribution-NonCommercial-NoDerivs 4.0 International 11. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab 660
613 License (CC BY-NC-ND 4.0), which permits the non- for first-line treatment of metastatic nonsquamous 661
614 commercial replication and distribution of the article with NSCLC. N Engl J Med 2018;378:2288-301. 662
615 the strict proviso that no changes or edits are made and the 12. Wang Y, Zhou S, Yang F, et al. Treatment-Related Adverse 663
616 original work is properly cited (including links to both the Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: 664
617 formal publication through the relevant DOI and the license). A Systematic Review and Meta-analysis. JAMA Oncol 665
618 See: https://creativecommons.org/licenses/by-nc-nd/4.0/. 2019;5:1008-19. 666
619 13. Nosaki K, Saka H, Hosomi Y, et al. Safety and efficacy of 667
pembrolizumab monotherapy in elderly patients with PD- 668
620 References
L1-positive advanced non-small-cell lung cancer: Pooled 669
621
622 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. analysis from the KEYNOTE-010, KEYNOTE-024, and 670
623 CA Cancer J Clin 2018;68:7-30. KEYNOTE-042 studies. Lung Cancer 2019;135:188-95. 671
624 2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus 14. Facchinetti F, Mazzaschi G, Barbieri F, et al. First-line 672
625 docetaxel in advanced squamous-cell non-small-cell lung pembrolizumab in advanced non-small cell lung cancer 673
626 cancer. N Engl J Med 2015;373:123-35. patients with poor performance status. Eur J Cancer 674
627 3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus 2020;130:155-67. 675
628 docetaxel in advanced nonsquamous non-small-cell lung 15. Mansfield AS, Herbst RS, Castro G, et al. Outcomes 676
629 cancer. N Engl J Med 2015;373:1627-39. with pembrolizumab (pembro) monotherapy in patients 677
630 4. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab (pts) with PD-L1-positive NSCLC with brain metastases: 678
631 versus docetaxel for previously treated, PD-L1-positive, Pooled analysis of KEYNOTE-001, -010, -024, and -042. 679
632 advanced non-small-cell lung cancer (KEYNOTE-010): A Ann Oncol 2019;30:v604-6. 680
633 randomised controlled trial. Lancet 2016;387:1540-50. 16. Ryken TC, McDermott M, Robinson PD, et al. The 681
634 5. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab role of steroids in the management of brain metastases: 682
635 versus docetaxel in patients with previously treated A systematic review and evidence-based clinical practice 683
636 non-small-cell lung cancer (OAK): a phase 3, open- guideline. J Neurooncol 2010;96:103-14. 684
637 label, multicentre randomised controlled trial. Lancet 17. Paulsen Ø, Klepstad P, Rosland JH, et al. Efficacy 685
638 2017;389:255-65. of methylprednisolone on pain, fatigue, and appetite 686
639 6. Reck M, Rodríguez-Abreu D, Robinson AG, et al. loss in patients with advanced cancer using opioids: A 687
640 Pembrolizumab Versus Chemotherapy for PD-L1- randomized, placebo-controlled, double-blind trial. J Clin 688
641 Positive Non-Small-Cell Lung Cancer. N Engl J Med Oncol 2014;32:3221-8. 689
642 2016;375:1823-33. 18. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. 690
643 7. Brahmer JR, Rodríguez-Abreu D, Robinson AG, et al. Reduction of cancer-related fatigue with dexamethasone: 691
644 Health-related quality-of-life results for pembrolizumab A double-blind, randomized, placebo-controlled 692
645 versus chemotherapy in advanced, PD-L1-positive trial in patients with advanced cancer. J Clin Oncol 693
646 NSCLC (KEYNOTE-024): a multicentre, international, 2013;31:3076-82. 694
647 randomised, open-label phase 3 trial. Lancet Oncol 19. Ben-Aharon I, Gafter-Gvili A, Leibovici L, et al. 695

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 12 Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID

696 Interventions for alleviating cancer-related dyspnea: A (L)1 therapy. J Clin Oncol 2017;35:XXX. 744
697 systematic review and meta-analysis. Acta Oncol (Madr) 32. Arbour KC, Mezquita L, Long N, et al. Impact of baseline 745
698 2012;51:996-1008. steroids on efficacy of programmed cell death-1 and 746
699 20. Lin RJ, Adelman RD, Mehta SS. Dyspnea in palliative programmed death-ligand 1 blockade in patients with non- 747
700 care: Expanding the role of corticosteroids. J Palliat Med small-cell lung cancer. J Clin Oncol 2018;36:2872-8. 748
701 2012;15:834-7. 33. Scott SC, Pennell NA. Early Use of Systemic 749
702 21. Franchimont D. Overview of the actions of glucocorticoids Corticosteroids in Patients with Advanced NSCLC 750
703 on the immune response: A good model to characterize Treated with Nivolumab. J Thorac Oncol 2018;13:1771-5. 751
704 new pathways of immunosuppression for new treatment 34. Fucà G, Galli G, Poggi M, et al. Modulation of 752
705 strategies. Ann N Y Acad Sci 2004;1024:124-37. peripheral blood immune cells by early use of steroids 753
706 22. Flint TR, Janowitz T, Connell CM, et al. Tumor-Induced and its association with clinical outcomes in patients with 754
707 IL-6 Reprograms Host Metabolism to Suppress Anti- metastatic non-small cell lung cancer treated with immune 755
708 tumor Immunity. Cell Metab 2016;24:672-84. checkpoint inhibitors. ESMO Open 2019;4:1-8. 756
709 23. Connell CM, Raby S, Beh I, et al. Cancer immunotherapy 35. Pan EY, Merl MY, Lin K. The impact of corticosteroid 757
710 trial registrations increase exponentially but chronic use during anti-PD1 treatment. J Oncol Pharm Pract 758
711 immunosuppressive glucocorticoid therapy may 2020;26:814-22. 759
712 compromise outcomes. Ann Oncol 2017;28:1678-9. 36. Martinez JM, Riuvadets M, García-Campelo MR, et al. 760
713 24. Hinrichs CS, Palmer DC, Rosenberg SA, et al. Impact of corticosteroids and antibiotics on efficacy of 761
714 Glucocorticoids do not inhibit antitumor activity of immune-checkpoint inhibitors in advanced non-small cell 762
715 activated CD8+ T cells. J Immunother 2005;28:517-24. lung cancer. Ann Oncol 2019;30:v525. 763
716 25. Franchimont D, Kino T, Galon J, et al. Glucocorticoids 37. Drakaki A, Luhn P, Wakelee H, et al. Association of 764
717 and inflammation revisited: the state of the art. NIH systemic corticosteroids with overall survival in patients 765
718 clinical staff conference. Neuroimmunomodulation receiving cancer immunotherapy for advanced melanoma, 766
719 2002;10:247-60. non-small cell lung cancer or urothelial cancer in routine 767
720 26. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and clinical practice. Ann Oncol 2019;30:xi16-xi17. 768
721 Safety Outcomes in Patients With Advanced Melanoma 38. Patil P, Jia X, Hobbs B, et al. MA03.01 The Impact of 769
722 Who Discontinued Treatment With Nivolumab and Early Steroids on Clinical Outcomes in Patients with 770
723 Ipilimumab Because of Adverse Events: A Pooled Analysis Advanced NSCLC Treated with Immune Checkpoint 771
724 of Randomized Phase II and III Trials. J Clin Oncol Inhibitors- A Cancerlinq Cohort. J Thorac Oncol 772
725 2017;35:3807-14. 2019;14:S256. 773
726 27. Postow MA, Sidlow R, Hellmann MD. Immune-Related 39. Wakuda K, Miyawaki T, Miyawaki E, et al. The impact of 774
727 Adverse Events Associated with Immune Checkpoint steroid use on efficacy of immunotherapy among patients 775
728 Blockade. N Engl J Med 2018;378:158-68. with lung cancer who have developed immune-related 776
729 28. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events. J Clin Oncol 2019;37:e20583. 777
730 adverse events, need for systemic immunosuppression, and 40. Ricciuti B, Dahlberg SE, Adeni A, et al. Immune 778
731 effects on survival and time to treatment failure in patients Checkpoint Inhibitor Outcomes for Patients With 779
732 with melanoma treated with ipilimumab at memorial sloan Non-Small-Cell Lung Cancer Receiving Baseline 780
733 kettering cancer center. J Clin Oncol 2015;33:3193-8. Corticosteroids for Palliative Versus Nonpalliative 781
734 29. Leighl N, Gandhi L, Hellmann MD, et al. Pembrolizumab Indications. J Clin Oncol 2019;37:1927-34. 782
735 for NSCLC: Immune-mediated adverse events and 41. De Giglio A, Mezquita L, Auclin E, et al. Impact of early 783
736 corticosteroid use. J Thorac Oncol 2015;10:S233. introduction of steroid on immune-checkpoint inhibitors 784
737 30. Von Pawel J, Syrigos K, Mazieres J, et al. Association (ICI) in patients with advanced non-small cell lung cancer 785
738 between immune-related adverse events (irAEs) and treated. Ann Oncol 2019;30:xi16. 786
739 atezolizumab efficacy in advanced NSCLC: analyses from 42. Flammer JR, Rogatsky I. Minireview: Glucocorticoids in 787
740 the phase III study OAK. Ann Oncol 2017;28:v469. autoimmunity: Unexpected targets and mechanisms. Mol 788
741 31. Santini FC, Rizvi H, Wilkins O, et al. Safety of Endocrinol 2011;25:1075-86. 789
742 retreatment with immunoitherapy after immune-related 43. Taube JM, Anders RA, Young GD, et al. Colocalization 790
743 toxicity in patients with lung cancers treated with anti-PD- of inflammatory response with B7-h1 expression 791

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 Translational Lung Cancer Research, 2020 13

792 in human melanocytic lesions supports an adaptive patients with melanoma and brain metastases: an open- 840
793 resistance mechanism of immune escape. Sci Transl Med label, phase 2 trial. Lancet Oncol 2012;13:459-65. 841
794 2012;4:127ra37. 56. Oncol JC. Prevalence of Autoimmune Disease 842
795 44. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 Among Patients With Lung Cancer : Implications 843
796 blockade induces responses by inhibiting adaptive immune for Immunotherapy Treatment Options Extent of 844
797 resistance. Nature 2014;515:568-71. Resection and Survival in Glioblastoma Multiforme. 845
798 45. Kansy BA, Concha-Benavente F, Srivastava RM, et al. 2016;2(11):2015-6. 846
799 PD-1 Status in CD8+ T Cells Associates with Survival 57. Simon TA, Thompson A, Gandhi KK, et al. Incidence of 847
800 and Anti-PD-1 Therapeutic Outcomes in Head and Neck malignancy in adult patients with rheumatoid arthritis: a 848
801 Cancer. Cancer Res 2017;77:6353-64. meta-analysis. Arthritis Res Ther 2015;17:212. Erratum in: 849
802 46. Wei SC, Levine JH, Cogdill AP, et al. Distinct Cellular Arthritis Res Ther. 2016 May 4;18(1):100. doi: 10.1186/ 850
803 Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 s13075-016-0990-5. 851
804 Checkpoint Blockade. Cell 2017;170:1120-1133.e17. 58. Khan SA, Pruitt SL, Xuan L, et al. How does autoimmune 852
805 47. Cattermole GN, Leung PYM, Ho GYL, et al. The disease impact treatment and outcomes among patients 853
806 normal ranges of cardiovascular parameters measured with lung cancer? A national SEER-Medicare analysis. 854
807 using the ultrasonic cardiac output monitor. Physiol Rep Lung Cancer 2018;115:97-102. 855
808 2017;5:e13195. 59. Danlos FX, Voisin AL, Dyevre V, et al. Safety and efficacy 856
809 48. Maxwell R, Luksik AS, Garzon-Muvdi T, et al. Contrasting of anti-programmed death 1 antibodies in patients with 857
810 impact of corticosteroids on anti-PD-1 immunotherapy cancer and pre-existing autoimmune or inflammatory 858
811 efficacy for tumor histologies located within or disease. Eur J Cancer 2018;91:21-9. 859
812 outside the central nervous system. Oncoimmunology 60. Cortellini A, Buti S, Santini D, et al. Clinical Outcomes 860
813 2018;7:e1500108. of Patients with Advanced Cancer and Pre-Existing 861
814 49. Giles AJ, Hutchinson MND, Sonnemann HM, et al. Autoimmune Diseases Treated with Anti-Programmed 862
815 Dexamethasone-induced immunosuppression: mechanisms Death-1 Immunotherapy: A Real-World Transverse Study. 863
816 and implications for immunotherapy. J Immunother Oncologist 2019;24:e327-e337. 864
817 Cancer 2018;6:51. 61. Leonardi GC, Gainor JF, Altan M, et al. Safety of 865
818 50. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression Programmed Death-1 Pathway Inhibitors Among Patients 866
819 and autoimmunity induced by cytotoxic T lymphocyte- With Non-Small-Cell Lung Cancer and Preexisting 867
820 associated antigen 4 blockade in patients with metastatic Autoimmune Disorders. J Clin Oncol 2018;36:1905-12. 868
821 melanoma. Proc Natl Acad Sci U S A 2003;100:8372-7. 62. Khozin S, Zhi J, Jun M t al. Real-world characteristics and 869
822 51. Harmankaya K, Erasim C, Koelblinger C, et al. outcomes of patients with advanced non-small cell lung 870
823 Continuous systemic corticosteroids do not affect the cancer (aNSCLC) receiving immune checkpoint inhibitor. 871
824 ongoing regression of metastatic melanoma for more J Clin Oncol 2019;37:9110. 872
825 than two years following ipilimumab therapy. Med Oncol 63. Cytryn S, Efuni E, Velcheti V, et al. P2.04-48 Use of 873
826 2011;28:1140-4. Immune Checkpoint Inhibitors in Patients with Advanced 874
827 52. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in Lung Cancer and Pre-Existing Autoimmune Diseases. J 875
828 patients with cancer after antibody blockade of cytotoxic Thorac Oncol 2019;14:S726-7. 876
829 T-lymphocyte-associated antigen 4. J Clin Oncol 64. Tison A, Quéré G, Misery L, et al. Safety and Efficacy of 877
830 2006;24:2283-9. Immune Checkpoint Inhibitors in Patients With Cancer 878
831 53. Attia P, Phan GQ, Maker A V, et al. Autoimmunity and Preexisting Autoimmune Disease: A Nationwide, 879
832 correlates with tumor regression in patients with metastatic Multicenter Cohort Study. Arthritis Rheumatol 880
833 melanoma treated with anti-cytotoxic T-lymphocyte 2019;71:2100-11. 881
834 antigen-4. J Clin Oncol 2005;23:6043-53. 65. Abu-Sbeih H, Faleck DM, Ricciuti B, et al. Immune 882
835 54. Downey SG, Klapper JA, Smith FO, et al. Prognostic checkpoint inhibitor therapy in patients with preexisting 883
836 factors related to clinical response in patients with inflammatory bowel disease. J Clin Oncol 2020;38:576-83. 884
837 metastatic melanoma treated by CTL-associated antigen-4 66. Haanen J, Ernstoff MS, Wang Y, et al. Autoimmune 885
838 blockade. Clin Cancer Res 2007;13:6681-8. diseases and immune-checkpoint inhibitors for cancer 886
839 55. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in therapy: review of the literature and personalized risk- 887

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635
 14 Passiglia et al. Immunotherapy in NSCLC: the role of steroids and AID

888 based prevention strategy. Ann Oncol 2020. [Epub ahead 68. Murata M. Inflammation and cancer. Environ Health Prev 894
889 of print]. doi:10.1016/j.annonc.2020.03.285. Med 2018;23:50. 895
890 67. Yoneshima Y, Tanaka K, Shiraishi Y, et al. Safety and 69. Remon J, Passiglia F, Ahn MJ, et al. Immune Checkpoint 896
891 efficacy of PD-1 inhibitors in non-small cell lung cancer Inhibitors in Thoracic Malignancies: Review of the 897
892 patients positive for antinuclear antibodies. Lung Cancer Existing Evidence by an IASLC Expert Panel and 898
893 2019;130:5-9. Recommendations. J Thorac Oncol 2020;15:914-47. 899

Cite this article as: Passiglia F, Cetoretta V, De Filippis

M, Napoli V, Novello S. Exploring the immune-checkpoint
inhibitors’ efficacy/tolerability in special non-small cell
lung cancer (NSCLC) populations: focus on steroids and
autoimmune disease. Transl Lung Cancer Res 2020. doi:
10.21037/tlcr-20-635

© Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020 | http://dx.doi.org/10.21037/tlcr-20-635

View publication stats