Journal of Geriatric Oncology 12 (2021) 410–415

Contents lists available at ScienceDirect

Journal of Geriatric Oncology

Efficacy and safety of Nivolumab in older patients with pretreated

lung cancer: A subgroup analysis of the Galician lung cancer group
David Arias Ron a,⁎, Maria Carmen Areses Manrique a, Joaquín Mosquera Martínez b, Jorge García González c,
Francisco Javier Afonso Afonso d, Martín Lázaro Quintela e, Natalia Fernández Núñez f,
Cristina Azpitarte Raposeiras g, Margarita Amenedo Gancedo h, Lucía Santomé Couto i,
María Rosario García Campelo b, Jose Muñoz Iglesias a, Juan Ruiz Bañobre c, Rocío Vilchez Simo d,
Joaquín Casal Rubio e, Begoña Campos Balea f, Iria Carou Frieiro g, Guillermo Alonso-Jaudenes Curbera b,
Urbano Anido Herranz c, Jesús García Mata a, Jose Luis Fírvida Pérez a
a
Medical Oncology Department, University Hospital Complex of Ourense, Ourense, Spain
b
Medical Oncology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
c
Medical Oncology Department, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela 15706, Spain
d
Medical Oncology Department, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain
e
Medical Oncology Department, Hospital Alvaro Cunqueiro, Vigo, Spain
f
Medical Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain
g
Medical Oncology Department, Complejo Hospitalario de Pontevedra, Pontevedra, Spain
h
Centro Oncológico Coruña, A Coruña, Spain
i
Medical Oncology Department, Hospital POVISA, Pontevedra, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Background: Nivolumab is an anti PD1 immunotherapy drug approved for advanced Non-Small Cell Lung Cancer
Received 24 July 2020 (NSCLC) patients who previously received at least one prior line of treatment. Older patients are often not repre-
Received in revised form 14 October 2020 sented in clinical trials and drugs with acceptable safety profiles are necessary. We aim to report the efficacy and
Accepted 30 November 2020 safety profile of Nivolumab in the real-world older subgroup of the Galician lung cancer group study.
Available online 21 December 2020
Patients and Methods: We retrospectively reviewed 188 advanced NSCLC patients treated with at least one prior
therapy. We collected data from patients who were ≥70 years old treated with Nivolumab in second or subse-
Keywords:
Nivolumab
quent lines. Patient characteristics, treatment efficacy (overall survival, progression-free survival, and response
Lung cancer rate), and safety profile were reported.
Real world data Results: Thirty-eight patients aged ≥70 years were included in the subgroup analysis. The median age was
Older patients 74.5 years, a high percentage of patients were males (95%), most had a Performance Status of 1 (79%) and
Pretreated only 13% were non-smokers. The predominant histology was adenocarcinoma (53%), and 18% of patients re-
ceived 2 or more lines. The median Progression-Free Survival was 7.53 months (CI 4.3–17.3, p = 0.15) and the
median Overall Survival was 14.85 months (CI 10.5–20.7, p = 0.44). The objective response rate was 42%. No
new adverse events were reported in comparison to a global population.
Conclusions: The efficacy and safety profile of Nivolumab in advanced NSCLC patients treated with at least one
prior therapy and age ≥70 years old can be overlapped to a global population. Further prospective trials are
needed to define and confirm these results.
© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Abbreviatures: AE, Adverse Events; CI, Confidence Interval; CR, Complete Response;
CT, Computed Tomography; HR, Hazard Ratio; NSCLC, Non-small cell lung cancer; OS,
Overall Survival; PD, Progression Disease; PR, Partial Response; PFS, Progression free sur-
vival; PS, Performance Status; QoL, Quality of life; RWD, Real World Data; SD, Stable
Disease; SIOG, International Society of Geriatric Oncology; TPS, Tumor Proportion Score.
⁎ Corresponding author at: Complexo Hospitalario Universitario de Ourense, Calle
Ramon Puga Noguerol, 54, Ourense 32005, Spain.
E-mail address: david.arias.ron@gmail.com (D. Arias Ron).
Non-small cell lung cancer (NSCLC) accounts for more than 85% of
lung malignancies. It is the leading cause of cancer-related mortality
worldwide and has less than 5% survival rates at five years in the major-
ity of trials [1,2]. High mortality is mostly related to late diagnoses; half
of all patients with lung cancer have metastatic disease at presentation.
Until recently, platinum-based chemotherapy was considered the
gold-standard first-line treatment, but resulted in poor median Overall

https://doi.org/10.1016/j.jgo.2020.11.010
1879-4068/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
D. Arias Ron, M.C. Areses Manrique, J. Mosquera Martínez et al.
Survival (OS) [3] and high toxicity rates. Later, the detection of oncogenic
driver mutations and the use of tyrosine kinase inhibitors as targeted
therapies consistently improved the Progression-Free-Survival (PFS)
and OS [4,5].
More recently, immune checkpoint inhibitors have demonstrated
that blocking the programmed cell death protein 1 (PD-1) and its ligand
PD-L1 pathways, resulted in the activation of T-cells against tumoral
cells. The anti-PD-1 drugs nivolumab [6,7] and pembrolizumab [8],
and the anti PD-L1 drug atezolizumab [9] were tested in pretreated
NSCLC patients in comparison with Docetaxel and they became the
gold-standard treatment in the second line because they improve the
OS and safety profile. Progressively, they have taken a role in treatment
naïve patients, either alone or in combination with chemotherapy.
Immunotherapy has completely changed the therapeutic landscape
of lung cancer,which has led us to analyze these results in real-world
patients[10–12]. It seems obvious that if treatment with nivolumab is
less toxic, it would be a good option in older adult patients. Moreover,
more than a half of lung cancers are diagnosed in patients older than
65 years of age, and one of three patients are aged over 70 years, making
it necessary to study outcomes in this subgroup of patients [1]. None-
theless, there is an underrepresentation of patients aged over 70 years
in clinical trials, probably due to a decreased Performance status (PS),
presence of comorbidities, and physical and cognitive problems. The
lack of inclusion of older adults in trials has led to an absence of prospec-
tive data in older patients receiving Nivolumab. In 2018, Areses et al.
[13] conducted an observational study of 188 previously treated
NSCLC patients who received Nivolumab, showing consistent results
in terms of PFS (4.83, CI 3.6–5.9), OS (12.85, CI 9.07–16.62), and safety
profile. Performance Status 2 was associated with poor prognosis, but
no significant differences were observed by age, and this is an important
result because most of the patients in Galician healthcare area are older.
This paper aims to analyze the older subgroup of NSCLC patients
treated with Nivolumab in the Galician lung cancer cohort, and report
the treatment efficacy results and safety profile in this population. We
also performed a review of the literature to summarize outcomes in
this setting.
2. Methods
2.1. Patients
A full methodology for the Galician Lung Cancer database has been
published already [13]. In this retrospective, multicenter, observational
review, 188 NSCLC patients of the Galician Lung Cancer database were
included. Patients with the diagnosis of advanced NSCLC including clin-
ical stage IIIB and IV, and PS ≤2, were eligible; they must have received
Nivolumab between August 2015 and January 2017 after at least one
prior therapy. There is no universally accepted cut-off age to define
“older adult patients”. However, for the International Society of Geriat-
ric Oncology (SIOG), 70 years is currently the most commonly used cut-
off for defining patients as older within the field of geriatric oncology.
Chronic treatments with immunosuppressive drugs as corticosteroids
or diagnoses of autoimmune disease were not allowed. Due to the retro-
spective analysis performed and the heterogeneity of geriatric assess-
ment between centers, these data were not collected.
2.2. Study Design
Patients were ≥70 years of age and treated with Nivolumab 3 mg/kg
endovenously (ev) every two weeks after progression on one or more
prior lines of chemotherapy. They were treated until Progression of
their Disease (PD), unacceptable toxicity, or death. An analysis of the de-
mographic data in this subgroup was performed following guidelines of
the reference trial, including gender, histology, PS, and previous
treatments.
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Journal of Geriatric Oncology 12 (2021) 410–415
All the patients were informed of the treatment design plan and pro-
vided written informed consent before enrollment. The study protocol
was approved by the Galician Local Research Ethics Committees (GGC-
NIV-2018-01) and complied with Good Clinical Practice guidelines,
the principles of the Declaration of Helsinki, and local laws and ethical
requirements.
2.3. Endpoints and Assessments
This study aims to analyze the efficacy and safety profile of the treat-
ment in the older adult subgroup. A second aim is to discuss the role of
older adult patients in lung cancer trials and compare our results with
those described in the literature.
Exploratory endpoints include PFS and OS. The PFS was calculated
from the first day of Nivolumab until progressive disease. A Computed
Tomography (CT) was performed every twelve weeks. OS was calcu-
lated from the first day of Nivolumab until the last date of follow-up
or death.
Tumor response was assessed using the Response Evaluation Criteria
in Solid Tumors (RECIST) version 1.1. Description of safety and toxicity
were conducted according to the Common Terminology Criteria for Ad-
verse Events (CTCAE) guidelines, version 4.0. Immune-related AEs were
analyzed following the specific protocol guidelines for immunotherapy
toxicity. In each visit to Medical Oncology, a short oral questionnaire of
quality of life (QoL) was carried out.
2.4. Statistical Analysis
An identical model to the Areses et al. trial was performed [13]. We
used descriptive statistical analysis, and both PFS and OS were assessed
by the Kaplan-Meier method with the log-rank test. Two-sided P-values
inferior to 0.05 were considered statistically significant.
All patients reported in this subanalysis were included in the demo-
graphic and efficacy analyses.
3. Results
3.1. Patients Characteristics
From August 2015 to January 2017, 188 NSCLC patients from nine
Galician hospitals were enrolled in the study, including a subgroup of
38 patients who were ≥70 years old according to SIOG definition of
“older adult” patients, which represented 22% of the total population.
The baseline clinical characteristics of our patients are presented in
Table 1. The median age was 74.5 years (range 70–83 years). A notably
high proportion of our patients were males (95%), compared to the gen-
eral population in the global analysis (77% of males) [13]. According to
histologic subtypes, 53% were adenocarcinoma and 47% were squamous
cell carcinoma. Despite the patients being older and having more co-
morbidities, the majority of them were PS 1 (79%). Brain metastases at
diagnosis were present in 10% of the patients and only 13% were non-
smokers.
Following the methodology of the trial, all patients received
Nivolumab after progression on at least one platinum-based chemo-
therapy regimen. Only seven patients (18%) received two or more
prior lines of systemic therapy in comparison with seventy-one patients
(38%) in the global cohort. Four patients had received two previous
lines, one patient received three lines and two patients received four
lines, resulting in a lower percentage of multi-treated patients.
3.2. Efficacy Analysis
All 38 patients included in the subgroup analysis received at least
one cycle of Nivolumab at the standard dose of 3 mg/kg. Treatment
was administered every two weeks in a 60-min infusion time according
D. Arias Ron, M.C. Areses Manrique, J. Mosquera Martínez et al. Journal of Geriatric Oncology 12 (2021) 410–415

Table 1 presented with diarrhea during Nivolumab treatment, two of them

Patients' characteristics. grade 3–4 (5%) and four patients experienced nausea (11%). One patient
Variable N, total number Percentage % presented with severe renal toxicity, and one patient developed grade
Age
1–2 immune-mediated hepatitis.
Median 74.5 In our older adult cohort, the most common immune-related AE was
Range 70.5–83 diarrhea. Two patients developed severe colitis and required hospital
Sex management for endovenous fluid therapy and high-dose corticoste-
Male 36 95
roids. Unfortunately one of them died because of non-related intestinal
Female 2 5
Histology complications. The rest of the immune-related AE, including
Adenocarcinoma 20 53 endocrinopathies, hepatitis and skin rash or pruritus, could be managed
Squamous cell 18 47 with medical treatment including thyroid or antithyroid drugs, oral or
Performance status topic corticosteroids, and postponing treatment for a short period of
0 6 15
1 30 79
time. The patient who developed severe renal toxicity had to stop treat-
2 2 5 ment, as it was related in the original paper [13]. Notably, no pneumo-
Prior lines of treatment nitis cases were described in the older adult cohort.
1 31 82 During the treatment period, patients were asked about the influ-
2 4 10
ence of immunotherapy in daily living. Twenty-two patients (58%) con-
3 1 3
4 2 5 firmed a subjective improvement in QoL, including less need for
Stage external support and better control of cancer-related symptoms.
IIIB-C 10 26
IV 28 74 4. Discussion
Smoking status
Smoker 7 19
Former 26 68 Nowadays, there is a growing number of older adults with newly di-
Non-smoker 5 13 agnosed cancer, with more than two-thirds of newly diagnosed patients
Brain metastases 4 10 aged 65 or older. Older adults can present with decreased physical
health, more comorbidities, organ dysfunction, and higher levels of
polypharmacy. Moreover, social management, social support, and adap-
tive emotional status seem to play a relevant role when oncologic treat-
to the technical datasheet. The median number of administered cycles
ments are proposed to older adults with cancer [1,14,15].
was six, consistent with the global cohort.
This leads to two different issues. First, the management of older
Of the 38 patients included in the subgroup analysis at the data cut
adults with lung cancer has been understudied for years, due to trials fo-
off, twelve (31%) had died. Within 26 evaluated patients, one patient
cused on younger and healthier patients. Second, there is a need to find
achieved Complete Response (CR), ten patients (38%) had Partial Re-
less aggressive treatments that improve survival and maintain quality of
sponse (PR), eight (31%) Stable Disease (SD) and seven (27%) had Pro-
life [16].
gressive Disease (PD). The Objective Response Rate (ORR) was 42%,
In 2018 Areses et al. [13] published a retrospective analysis of 188
compared to the 25.5% of the global cohort (Table 2). No missing or
NSCLC patients treated with Nivolumab after progression on at least
unevaluable patients were reflected in this subgroup.
one prior chemotherapy-based line. They demonstrated similar results
At the time of data analysis, the median PFS of the older adult sub-
to Checkmate 017 and Checkmate 057 with a PFS of 4.83 months (CI
group patients was 7.53 months (95% CI 4.3–17.3, p = 0.15) and the
3.6–5.9) and an OS of 12.85 (CI 9.07–16.62). Our region has one of the
median OS was 14.85 months (95% CI 10.5–20.7, p = 0.44), compared
oldest populations in Europe, therefore we performed a pre-planned
with a median PFS of 4.83 months and OS of 12.85 months in patients
analysis of the older adult subpopulation aged ≥70 years. Data included
aged ≤70 years from the global cohort (Fig. 1). The median duration of
38 patients, with a high percentage of males, probably due to the histor-
response was 3.9 months (95% CI 2.33–5.54).
ical predominance of males with lung cancer and a lower mean age in
females. Our cohort showed a lower percentage of patients who had re-
3.3. Safety ceived at least two previous lines of therapy after starting nivolumab
than the general population (18% vs 38%). This is probably due to a
Treatment-related adverse events (AEs) of any grade were reported higher index of comorbidities, a worse functional status, and a more dif-
in 22 of the 38 patients included (57%). In most cases AEs were grade ficult time tolerating subsequent lines of treatments after progression in
1–2 (92%), and only three patients (8%) had toxicities grade 3–4, com- older adults.
pared to nine patients in the global cohort (4.8%). No grade 5 AEs The efficacy data observered were excellent, with an ORR of 42%
were observed (Table 3). (only seven patients with PD), compared with a 25.5% ORR in the global
The most frequently reported AEs were fatigue/asthenia (eight pa- population. Moreover, the PFS was superior in the older adult cohort
tients, 22%), skin toxicity including rash and pruritus (six patients, (7.53 months, CI 4.3–17.3) though this did not achieve statistical signif-
16%), and dysthyroidism, including hypo and hyperthyroidism (six pa- icance (p = 0.15). The same was true for OS (14.85 months, CI
tients, 16%), and none of them were grade 3–4. Seven patients 10.5–20.7, p = 0.44). Another meaningful finding was that treatment-
related AEs were not greater than the global population. Most cases
(92%) presented with grade 1–2 toxicity and only 3 patients (8%) had
Table 2 grade 3–4 toxicity. These data suggest that Nivolumab can be effective
Overall response rate and duration of response. in older adult patients, although this should be interpreted with caution
Items N, total number (percentage %) due to the small number of patients included in the analysis. Also, the
safety profile of Nivolumab seems to be similar in older adults. However,
Objective response 11 (42%)
Complete response 1 (4%) it must be taken into account that AEs, even grade 1, could deteriorate
Partial response 10 (38%) the clinical and psychological status of patients and notably influence
Stable disease 8 (31%) the quality of life of older adults. Due to this fact, the results of toxicity
Progression disease 7 (27%) or tolerance may be underestimated. Data from Nivolumab trials in
Missing or unevaluable 0%
older patients are presented in Table 4.

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D. Arias Ron, M.C. Areses Manrique, J. Mosquera Martínez et al. Journal of Geriatric Oncology 12 (2021) 410–415

Fig. 1. Kaplan-Meier curves comparison. (A) Progression free survival; (B) Overall survival.

As we have previously stated, several obstacles hinder the incorpo- a subgroup of 556 patients aged ≥70 years received Nivolumab every
ration of older adults into prospective clinical trials, and therefore data two weeks after progression on a chemotherapy-based treatment. A
in this setting are scarce. In the phase 3B/4 Checkmate 153 study [17], non-significant trend to improved OS in this subgroup was observed,
with 10.3 months (CI 8.3–11.5) versus 9.1 months (CI 8.3–10.4) in the
Table 3 total study population. The primary endpoint was the safety profile
Treatment-related adverse events and quality of life. in older adults, expressed as a percentage of grade 3–5 AE, and it
AEs Grade 1–2, n (%) Grade 3–4, n (%) did not differ between subgroups (6% in patients aged ≥70 versus
6% in all treated patients). Similar results were observed when con-
Fatigue/asthenia 8 (22%)
Decreased appetite 3 (8%) sidering any grade adverse events (38% vs 37%). The authors concluded
Nausea 4 (11%) that Nivolumab was safe and could be considered a useful option in
Diarrhea 5 (13%) 2 (5%) this setting. A recent pooled analysis of older adults treated with
Pruritus/Rash 6 (16%) Pembrolizumab in a first or second line included 264 PD-L1 positive pa-
Hypo/Hyperthyroidism 6 (16%)
Renal toxicity 1 (3%) 1 (3%)
tients aged ≥75 years. Results showed a significant OS increase favoring
Liver enzymes increase 1 (3%) Pembrolizumab versus chemotherapy in patients with PD-L1 Tumor
Positive impact in QoL Yes: 22 (58%) No: 16 (42%) Proportion Score (TPS) ≥50% (HR 0.40, CI 0.25–0.64) and a trend to ben-
Abbreviatures: AEs, Adverse Events; QoL, Quality of Life. efit from immunotherapy in all-treated patients (HR 0.76, CI 0.56–1.02),

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D. Arias Ron, M.C. Areses Manrique, J. Mosquera Martínez et al. Journal of Geriatric Oncology 12 (2021) 410–415

Table 4
Older population across trials regarding immunotherapy.

Trial name Number of Design Median Drug Objective Results

patients age

Spigel et al. [17] 556 Prospective phase 3B/4 75 (70–93) Nivolumab Safety and OS Grade 3–5 AE: 6% vs 6%
OS 10.3 months (CI 8.3–11.5)
Felip et al. [18] 278 Prospective phase 2 74 (70–86) Nivolumab Safety and OS Grade 3–5 AE: 15% vs 13%
OS 10.0 months (CI 8.3–11.4)
Nosaki et al. [19] 264 Prospective pooled phase 3 77(75–90) Pembrolizumab OS and safety HR 0.76 (CI 0.56–1.02)
AE 24.2% vs 61%)
Grossi et al. [20] 175 + 70 Retrospective RWD 70 (65–74) Nivolumab OS and safety OS ≥75y 5.8 months, CI 3.5–8-1
77 (75–91) OS 65-75y 8.0 months, CI 5.6–10-4
Grossi et al. [21] 522 Retrospective RWD 74 (70–89) Nivolumab Efficacy PFS 4.0 months, CI 3.6–4.4
OS 11.5 months, CI 10.0–13.0
Joris et al. [22] 108 Retrospective RWD 74 (70–86) Nivolumab Efficacy PFS 4.0 months, CI 1.0–7-0
OS 9.3 months, CI 5.5–13-1
Yamaguchi et al. [23] 131 Retrospective RWD 77 (75–87) Nivolumab and Efficacy PFS 4.5 months, CI 3.0–5.8
Pembrolizumab OS 16 months, CI 12.1–19.8
Khozin et al. [25] 1344 Multicenter RWD 69 (61–75) Nivolumab and Baseline data 64.3% ≥65 years
Pembrolizumab 27.1% ≥75 years
Youn et al. [26] 1256 Multicenter RWD 75 (67–84) Nivolumab and OS 9.3 months (CI 8.5–10.5)
Pembrolizumab
Marur et al. [27] 1073 + 786 Retrospective Nivolumab, OS 14.2 vs 9 months, HR 0.66, CI 0.57–0.76
Pembrolizumab and
Atezolizumab

Abbreviatures: AE, Adverse Events; CI, Confident Interval; HR, Hazard Ratio; OS, Overall Survival; PFS, Progression Free Survival; RWD, Real World Data.

with a notable safety profile improvement (grade 3–5 AE 24.2% vs 61%).
No differences were observed between the older adults and all-
Pembrolizumab treated patients, rendering Pembrolizumab as an inter-
esting option in older adult patients [19].
The complexity of enrolling older adults in pivotal trials has rein-
forced the role of Real-World Data (RWD) studies in recent years,
which provide real results in subgroups that are often excluded from tri-
als. The Italian expanded access program to Nivolumab presented a re-
view of 371 patients, including 70 aged ≥75 years and 175 aged between
65 and 75 years. They observed worse results in older adults in terms of
OS (5.8 months, CI 3.5–8–1) compared with the subgroup aged between
64 and 75 years (8.0 months, CI 5.6–10–4) and the overall population
(7.9 months, CI 6.2–9.6) [20]. However, ORR was similar between sub-
groups and the overall population (18% and 19%). Interestingly, grade
3–5 AE were lower in older adults (3% versus 6% and 9%), suggesting a
good safety profile in this subset and comparable efficacy in patients
aged >65 years, but not over 75 years. Later analysis of a large Italian co-
hort of NSCLC patients treated with Nivolumab included 522 patients
aged ≥70 years from 1588 in total (232 over 75 years) [21]. Most of
the older adults were male (74%) and 92% presented with PS 0–1,
which was similar to our patient cohort. The authors observed higher
ORR in the older subgroup (21% vs 18%), as well as a PFS of 4.0 months
(CI 3.6–4.4) and an OS of 11.5 months (CI 10.0–13.0). Both of them were
superior to the overall population (3.0 months, CI 2.9–3.1, and
11.3 months, CI 10.2–12.4, respectively). These results were maintained
in patients aged ≥75 years. These results could be due to the fact that pa-
tient selection with optimal PS and low comorbidities correlates with an
increase in OS with no worsening of quality of life.
Joris et al. [22] conducted a Belgian RWD cohort, achieving prom-
ising results with Nivolumab in patients aged ≥70 years. Efficacy data
of the 108 older patients included was favorable, with a non-
significant trend towards improved PFS compared with the younger
subgroup (4.0 months, CI 1.0–7–0 vs 3.7 months, CI 2.6–4.8, p =
0.48). Results were also positive in terms of OS (9.3 months, CI
5.5–13–1 vs 8.4 months, CI 6.3–10.5), with no significant differences
in terms of ORR (23% vs 19%). Notably, 24 of the 108 older patients
(22%) presented with PS 2–3, and this subgroup had much worse out-
comes than patients with PS 0–1 in terms of PFS (2.2 vs 5.6 months,
p = 0.001) and OS (3.4 vs 11.1, p > 0.0001). This finding emphasizes
the importance of appropriate patient selection to achieve optimal re-
sults in older populations, highlighting the risks of administering
any cancer treatment to frail older adults and those with poor PS.
A Japanese retrospective review of 131 pretreated patients aged be-
tween 75 and 87 years was conducted by Yamaguchi et al. [23]. All pa-
tients were treated with Nivolumab or Pembrolizumab. Favorable
results in terms of PFS (4.5 months, CI 3.0–5.8) and OS (16 months,
CI 12.1–19.8) were observed, with an ORR of 27.4% and achieving
good rates of CR (5.3%), partial responses (22.1%) and low toxicity
levels (27% of patients discontinued treatment due to any grade
AE). Recently, a retrospective trial of 297 NSCLC raised an interesting
study design, recording patients as elderly (between 70 and 80 years)
and very elderly (≥80 years) [24]. The very elderly population group
presented with poorer PS (p = 0.047), with a higher burden of co-
morbidities, less social support, and increased mortality. It demon-
strated a clear impact of age in patients over 80 years in lung cancer
management, which are not usually candidates for multimodal treat-
ment or toxic drugs. Nonetheless, radiotherapy and surgery were ad-
ministered equally in both subgroups.
Data from several multicenter analyses support the role of immuno-
therapy in older adults with NSLCL. A multicenter retrospective review
conducted by Khozin et al. [25] analyzed baseline characteristics of
NSCLC patients receiving immunotherapy in the first or second line in
a real-world population. Of 1344 included patients, more than a half
(64.3%) were ≥65 years and 27.1% were older than 75 years, a much
higher percentage than pivotal trials [6–9]. It suggests an underrepre-
sentation of older patients in clinical trials compared to RWD cohorts.
A recent RWD database of 1256 older patients treated with immuno-
therapy achieved an OS of 9.3 months (CI 8.5–10.5) with an OS at
12 months of 43% (CI 40.2–45.7%) [26]. Older adult was defined as
≥65 years (median age was 75.3), with no significant differences
achieved between age groups. Moreover, PS and comorbidities were
found to be the most important factors to take into account before
starting immunotherapy. A retrospective analysis of four randomized
trials testing immunotherapy vs docetaxel after first-line platinum-
based chemotherapy in older adults was conducted by Marur. et al.
[27]. The data showed similar results between age subgroups, achieving
a significant benefit for immunotherapy in patients aged <65 years
(14.5 vs 8.8 months, HR 0.71, CI 0.63–0–80) and also in patients aged
≥65 years (14.2 vs 9 months, HR 0.66, CI 0.57–0.76) in terms of OS,
but only a trend in patients ≥75 years of age (14.1 vs 9.2 months, HR
0.81, CI 0.58–1.13). These results suggest a strong role for immunother-
apy in this population.

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D. Arias Ron, M.C. Areses Manrique, J. Mosquera Martínez et al.
Our paper has several limitations. First of all, this is a pre-planned
subgroup analysis of a retrospective, single-arm design trial, which
can induce potential selection bias. Second, our work also lacks data
about comorbidities, social support, health-related quality of life evalu-
ations, and integral geriatric assessments. These instruments have been
revealed as incorporating prominent variables in deciding appropriate
therapy for older adults. Additionally, a global geriatric evaluation of
physical and functional status, cognition, and nutrition could identify
frail patients before starting treatment. Finally, we should also note
the reduced number of older adults in some of our cited papers, and
the absence of data about PD-L1 expression in our cohort.
In conclusion, our findings corroborate that Nivolumab could be
used as an effective and safe treatment in older adults with NSCLC,
showing comparable survival benefits to an overall younger population.
Comorbidities, PS at diagnosis, and social support have been well stud-
ied in the literature as factors to consider before starting immunother-
apy. Future larger prospective trials are needed to confirm these results.
Ethical Statement
The treatment plan was approved by the Galician Local Research
Ethics Committees (GGC-NIV-2018-01) and was executed in accor-
dance with the Declaration of Helsinki, Good Clinical Practice, and
local ethical and legal requirements. We obtained informed written
consent from all patients included, authorizing the publication, which
is attached to the medical records.
Contributions
Conceptualization and Data Curation: Arias Ron D, Areses Manrique MC;
Methodology and Project administration: Arias Ron D, Areses Manrique
MC, Firvida Perez JL; Resources and Supervision: All authors; Formal
Analysis: Ruiz Bañobre J, Arias Ron D, Areses Manrique MC; Writing -
original draft: All authors; Writing - review & editing: All authors.
Declaration of Competing Interest
The authors have no conflicts of interest to declare.
Acknowledgements
Authors would like to thank all members of the study team, the pa-
tients and their families. Authors would like to thank Fundación
Biomédica Galicia Sur for supporting this manuscript.
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