REVIEW ARTICLE

Immuno-oncology—the new
paradigm of lung cancer treatment
D.E. Dawe md msc,* C.H. Harlos md,* and R.A. Juergens md phd†

ABSTRACT
Systemic therapy is an essential part of treatment for all patients with small-cell lung cancer (sclc) and for most
patients with non-small-cell lung cancer (nsclc). Standards of care have evolved dramatically since 2009, especially
in the setting of incurable or advanced nsclc. Part of that evolution has been the incorporation of immuno-oncology
drugs, especially immune checkpoint inhibitors (icis) into multiple therapeutic scenarios.
In the present review, we discuss the role of the immune system in lung cancer and the previous failures of
immunotherapy for patients with lung cancer. We then provide an overview of the existing evidence for the use of
icis in patients with advanced nsclc that is either treatment-naïve or pretreated, for consolidative treatment after
chemoradiotherapy in stage iii nsclc, and for palliative therapy in patients with sclc. Finally, we discuss duration
of treatment, special populations, and the future of immuno-oncology for patients with lung cancer. Overall, we
provide an evidence-based snapshot of immuno-oncology agents in the treatment of lung cancer up to early 2019.

Key Words Immuno-oncology, lung cancer, immunotherapy, PD-1, PD-L1

Curr Oncol. 2020 April:27(S2)78–86 www.current-oncology.com

INTRODUCTION
(tki), than with chemotherapy, but chemotherapy was su-
Lung cancer is the number one cause of cancer-related perior if the mutation was absent. Targeted therapies are
death both in Canada and worldwide. In Canada, 28,600 currently used for metastatic nsclc with mutations in EGFR,
people were diagnosed with lung cancer in 2017, and 21,100 ALK, ROS1, and BRAF 5. For patients with mutation-driven
died. Worldwide, 2,093,876 people were diagnosed, and lung cancers, median survival now approaches 3 years,
1,761,007 died1,2. The number of lung cancers diagnosed in a dramatic improvement compared with the 12 months
North America is driven by smoking rates and demographic historically seen5. Although no evidence yet supports the
shifts (growing populations and an increasing number of use of targeted therapies for patients with sclc or stages i–iii
older adults). nsclc, such therapies have revolutionized the management
Histologically, lung cancer is subdivided into non- of metastatic nsclc. However, in North America, targetable
small-cell lung cancer (nsclc), which accounts for 85% driver mutations are currently found in only approximately
of diagnosed lung cancers, and small-cell lung cancer 25% of patients. The need for improved outcomes for the
(sclc), which accounts for 15% 3. Surgery is the mainstay of other 75% has driven innovation and the emergence of
treatment for stages i and ii nsclc, but 75% of lung cancers immunotherapy (“immuno-oncology”) in the treatment
are diagnosed at stage iii or iv, when resection is no longer of lung cancer5.
possible and the likelihood of mortality is high. Systemic As explored in depth by Esfahani and colleagues6 in
therapy is an essential part of treatment for all patients with their article about the mechanisms of immuno-oncology
sclc and for those with stage iii or iv nsclc. Standards of care in this supplement, immunotherapy attempts to recruit
(socs) have evolved dramatically since 2009, especially in the immune system to attack cancer by simultaneously
the setting of incurable or advanced nsclc 3. overcoming the tumour’s ability to evade the immune
In 2009, publication of the ipass trial established the system and by upregulating the intensity of immune re-
importance of molecular testing in patients with metastatic sponses7. In lung cancer, the rationale for immunotherapy
nsclc 4. Non-small-cell lung cancer carrying an EGFR mu- as a therapeutic option rests on lung cancer’s mechan-
tation was much better controlled with gefitinib, an epider- isms of immune evasion. Lung cancer evades immune
mal growth factor receptor (egfr) tyrosine kinase inhibitor responses by reducing antigen presentation, secreting

Correspondence to: David E. Dawe, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9.
E-mail: [email protected] n DOI: https://doi.org/10.3747/co.27.5183

S78 Current Oncology, Vol. 27, Supp. 2, April 2020 © 2020 Multimed Inc.
 IO IN LUNG CANCER, Dawe et al.

immune-inhibitory cytokines, upregulating immune adjuvant therapy with a mage-A3–directed immunother-

checkpoints, and stimulating immunosuppressive cell sub- apy did not affect disease-free survival13. The allogeneic
sets8. Antigen presentation is reduced through decreased tumour cell vaccine belagenpumatucel-l did not improve
expression and haplotype loss of human leukocyte antigen. median survival14. In each of those nsclc vaccine trials, a
The cytokine transforming growth factor beta is elevated hint of benefit was observed, with modest improvements
in the serum of lung cancer patients. Transforming growth in outcomes, but without the primary survival metrics ever
factor beta inhibits proliferation of normal bronchial ep- meeting statistical significance.
ithelial cells, drives conversion of cytotoxic T cells to im- Finally, in an attempt to overcome immunosuppres-
munosuppressive T regulatory cells, and possibly enhances sive checkpoints, the ctl a-4–directed ici ipilimumab,
cell death for activated T cells. The latter mechanism also when compared with chemotherapy, failed to improve os
helps to explain the proliferation of T regulatory cells, in patients with advanced nsclc whether given alone or
which prevent effective immune responses to tumour anti- with chemotherapy15,16. Fortunately, recent trials focused
gens. Finally, increased presentation of the co-stimulatory on icis targeting the PD-1/PD-L1 interaction (Table i) have
molecule PD-L1 on lung cancer cells downregulates and demonstrated clinically meaningful benefit for patient sur-
inhibits antitumour immune responses8. Recently adopt- vival and have transformed the treatment of lung cancer.
ed agents (Figure 1) have targeted those co-stimulatory
molecules primarily through blockade of the interaction Biomarkers
between PD-1 and PD-L1 or PD-L27. Building on the success of treatment directed at driver
mutations, multiple biomarkers have been investigated to
predict benefit with PD-1/PD-L1 icis17. (Biomarkers related
REVIEW to icis are discussed in depth elsewhere in this special issue.)
To date, the primary biomarker used for lung cancer has
Historical Failure of Immuno-oncology
been PD-L17,17. Multiple assays to measure PD-L1 in his-
in Lung Cancer tologic samples of lung cancer are available. Although the
Multiple randomized controlled trials (rcts) have inves-
cut-offs for positivity vary with the test, each assay identifies
tigated immunotherapies in lung cancer. Those therapies
negative and positive subgroups that translate into patient
have included cytokines, vaccines, and immune check-
populations that are, respectively, less and more likely to
point inhibitors (icis).
respond to icis. Most trials in the relapsed or refractory
In 1994, a small rct involving 60 patients with ad-
setting identified an os benefit in the full intention-to-treat
vanced nsclc compared interleukin 2 plus melatonin
population. Upon subgroup analysis, though, higher levels
with cisplatin–etoposide 9. Interleukin 2 promotes the
of PD-L1 were associated with superior response and greater
differentiation of immature T cells into effector T cells,
improvements in median os with PD-1 or PD-L1 inhibitors
thus attempting to overcome immunosuppression. The
than with docetaxel. The randomized trials of pembroli-
response rate to immunotherapy was similar to that with
zumab uniquely excluded patients who did not express
chemotherapy, but survival at 1 year was superior. A larger
PD-L1. The PD-L1 companion diagnostic result therefore
trial of chemotherapy with or without interleukin 2 showed
affects the use of pembrolizumab, most importantly in the
no difference in response, median progression-free surviv-
first-line setting, in which pembrolizumab, compared with
al (pfs), or 1-year survival10.
platinum doublet chemotherapy, improves os for patients
Four vaccines have aimed to improve antigen pres-
with nsclc and PD-L1 expression of 50% or greater18.
entation and to drive an immune response. Maintenance
Absence of PD-L1 expression does not conclusively
vaccination with Bec2/bacillus Calmette–Guérin did not
identify patients who will not benefit from immunother-
improve survival in sclc patients11. Similarly, tecemotide,
apy, leading to investigation of many other biomarkers7,17.
directed against the mucin 1 glycoprotein, failed to im-
Tumour mutational burden (tmb) is the second most prom-
prove overall survival (os) in patients with unresectable
inently investigated biomarker in patients with lung cancer.
stage iii nsclc when given after chemoradiotherapy12. In the
High tmb is associated with both a higher response rate and
setting of resected (stages ib –iiia) mage-A3–positive nsclc,
better os for patients treated with nivolumab–ipilimumab19.
PD-L1 and tmb appear to be independently predictive.
Their levels are not highly correlated, and they potentially
provide complementary information for decision-making.
Even basic patient characteristics appear to help predict
who will benefit from immunotherapy. Female sex might
be associated with poorer survival and less benefit 20.
Never-smoker status also appears to be linked to less bene-
fit 21,22. Those trends are possibly driven by the prevalence
of EGFR and ALK mutations in women and never-smokers.
Reports from additional trials will clarify the issue.

Previously Treated Advanced NSCLC

Two large rcts established checkpoint inhibitor therapy
FIGURE 1 Treatment for advanced non-small-cell lung cancer (NSCLC)
with nivolumab as a soc for the second-line treatment of
without driver mutations and with good performance status.
advanced nsclc. CheckMate 017 randomized 272 patients

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 IO IN LUNG CANCER, Dawe et al.

TABLE I Immune checkpoint inhibitors with reported phase III trial regardless of PD-L1 status27. Patients could have received
results for lung cancer up to 2 previous lines of treatment, with 1 being platinum
doublet chemotherapy. Patients with EGFR or ALK muta-
Agent Target
tions had received prior tki therapy as well as a platinum
Ipilimumab CTLA-4 doublet. The os was 13.8 months for atezolizumab com-
pared with 9.6 months for docetaxel ( hr : 0.73; 95% ci: 0.62
Nivolumab PD-1
to 0.87). Patients with high tumour PD-L1 expression ex-
Pembrolizumab PD-1 perienced the greatest benefit from atezolizumab; however,
os was improved even when PD-L1 expression was lacking.
Atezolizumab PD-L1
Benefit was observed across histologic subtypes.
Durvalumab PD-L1 Not all trials using PD-1 and PD-L1 checkpoint in-
Avelumab PD-L1 hibitors for the second-line treatment of advanced nsclc
have yielded positive results. Avelumab, an anti–PD-L1
CTLA-4 = cytotoxic T lymphocyte–associated protein 4; PD-1 = monoclonal antibody, was compared with docetaxel in the
programmed cell death 1; PD-L1 = programmed cell death ligand 1.
javelin Lung 200 trial 28. The os was not significantly differ-
ent between the avelumab and docetaxel groups, even in
w it h adva nced squa mous-cel l ca rcinoma to eit her the subgroup with positive tumour PD-L1 expression. High
nivolumab or docetaxel after progression on platinum dou- post-study use of icis and the non-blinded design of the
blet chemotherapy23. The os was 9.2 months for nivolumab trial might have affected the results. Table ii summarizes
compared with 6.0 months for docetaxel, representing a the second-line ici trials.
41% decrease in risk of death [hazard ratio ( hr): 0.59; 95% Currently, icis are now well established as a soc for
confidence interval (ci): 0.44 to 0.79]. The response rate and the second-line treatment of advanced nsclc, but there
pfs were both superior in the nivolumab arm, and benefit are no data to suggest that one ici is superior to another in
was seen regardless of PD-L1 level. CheckMate 057 ran- that setting. No head-to-head rcts have been conducted.
domized 582 patients with advanced nonsquamous nsclc Recent network meta-analyses using data from studies of
to either nivolumab or docetaxel 24. As in CheckMate 017, nivolumab, pembrolizumab, and atezolizumab did not
all patients had progressed on first-line platinum doublet demonstrate significant evidence of survival differences
chemotherapy. Patients with EGFR- and ALK-mutated nsclc between those drugs 29,30. Factors that could influence
had to have progressed on appropriate tki therapy as well. ici selection include access, dosing schedule, cost, and
The os was 12.2 months for nivolumab compared with 9.4 PD-L1 expression.
months for docetaxel, representing a 27% decrease in the
risk of death ( hr : 0.73; 96% ci: 0.59 to 0.89). The response First-Line Treatment of Advanced NSCLC
rate was not significantly different between the groups, Several phase iii rcts have explored icis in the first-line
but the pfs favoured nivolumab at 1 year (19% vs. 8%). In treatment of advanced nsclc (Table iii). The keynote-024
a subgroup analysis, os was superior with nivolumab only trial randomized patients with previously untreated ad-
in patients with a PD-L1 expression level of at least 1%. vanced nsclc without EGFR or ALK mutations to either
Durable responses were noted in both trials, with 37% pembrolizumab or platinum doublet chemotherapy18. Only
and 34% of confirmed responders having squamous and patients with a PD-L1 tumour proportion score of 50% or
nonsquamous tumours respectively experiencing ongoing greater were enrolled. The initial analysis demonstrated a
responses at 2 years25. Rates of treatment-related adverse significant improvement in pfs for pembrolizumab com-
events were lower with nivolumab than with docetaxel23,24. pared with chemotherapy (10.3 months vs. 6.0 months).
Pembrolizumab has also demonstrated efficacy in the The estimated os rate at 6 months was 80.2% for pem-
second-line treatment of advanced nsclc. The keynote-010 brolizumab compared with 72.4% for chemotherapy, with
trial randomized 1034 patients to pembrolizumab at two response rates also favouring pembrolizumab. An updated
dose levels (2 mg/kg and 10 mg/kg) or to docetaxel26. Patients analysis confirmed those results, showing a median os of
with squamous and nonsquamous tumours were enrolled; 30.0 months in the pembrolizumab arm compared with
however, PD-L1 expression had to be 1% or greater. All pa- 14.2 months in the chemotherapy arm ( hr : 0.63; 95% ci:
tients had progressed on first-line platinum doublet thera- 0.47 to 0.86) 38. Thus, keynote-024 defined a new soc for
py, and those with driver mutations had also progressed advanced nsclc with a PD-L1 tumour proportion score of
on appropriate tki therapy. The os was 10.4 months for 50% or greater.
pembrolizumab 2 mg/kg, 12.7 months for pembrolizum- CheckMate 026 randomized patients with treatment-
ab 10 mg/kg, and 8.5 months for docetaxel. Survival was naïve advanced nsclc without EGFR or ALK mutations and
significantly better for each pembrolizumab group than with a PD-L1 level of 1% or greater to either nivolumab or
for the docetaxel group ( hr : 0.71 for 2 mg/kg and 0.61 for platinum doublet chemotherapy39. Despite the benefit seen
10 mg/kg), without a significant difference between the with nivolumab in second-line treatment, os was not su-
pembrolizumab dose levels. No significant difference in pfs perior to that with chemotherapy in the first-line setting.
was observed between the treatment arms. Pembrolizum- Treatment with nivolumab resulted in an os of 14.4 months
ab efficacy was greatest in patients with a PD-L1 tumour compared with 13.2 months with chemotherapy. There
proportion score of 50% or greater. was also no significant improvement in pfs or response
The oak trial randomized patients with previously rate. Interestingly, an exploratory analysis of tmb demon-
treated advanced nsclc to either atezolizumab or docetaxel strated an increased response rate and improved pfs for

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TABLE II Randomized trials of immune checkpoint inhibitors in previously treated advanced non-small-cell lung cancer

Reference Enrolment Treatment arms Pts Median OS Grade 3 or greater

(trial name) period (n) treatment-related
(months) HR CI
adverse events (%)
Brahmer et al., 201523 2012–2013 Nivolumab 287 12.2 0.73 96%: 10
(CheckMate 057, 0.59 to 0.89
nonsquamous) Docetaxel 268 9.4 54

Herbst et al., 201626 2014–2015 Atezolizumab 425 13.8 0.73 95%: 15

(OAK, all) 0.62 to 0.87
Docetaxel 425 9.6 43
Horn et al., 201725 2013–2015 Pembrolizumab 345 10.4 13
(KEYNOTE-010, 2 mg/kg
PD-L1≥1%) Pembrolizumab 346 12.7 16
10 mg/kg
Docetaxel 343 8.5 35

Rittmeyer et al., 201727 2015–2017 Avelumab 264 11.4 0.90 96%: 10

(JAVELIN Lung 200, 0.72 to 1.12
PD-L1≥1%) Docetaxel 265 10.3 49

Huang et al., 201822 2012–2013 Nivolumab 135 9.2 0.59 95%: 7

(CheckMate 017, squamous) 0.44 to 0.79
Docetaxel 137 6.0 57

HR = hazard ratio; CI = confidence interval.

nivolumab in patients with a higher tmb. Patients with the compared with 11.3 months in the chemotherapy–placebo
highest tmb and PD-L1 expression experienced the highest arm ( hr : 0.64; 95% ci : 0.49 to 0.85). A survival benefit
response rate. Several hypotheses have been put forward was seen at all levels of PD-L1 expression. The similarly
for why first-line nivolumab failed while pembrolizumab designed keynote-189 trial randomized 616 patients with
succeeded, including differences in the PD-L1 cut-off for treatment-naïve advanced nonsquamous nsclc and no
eligibility, the PD-L1 test used, and the criteria established ALK or EGFR mutation to 4 cycles of platinum–pemetrexed
for corticosteroid use and prior radiotherapy18,39. Differenc- followed by pemetrexed maintenance plus pembroli-
es between the treatment arms in CheckMate 026 might zumab or placebo32. Median os was not reached in the
also have contributed, including fewer patients with high chemotherapy–pembrolizumab arm; it was 11.3 months
PD-L1 in the nivolumab arm and better baseline prognosis in the chemotherapy–placebo arm ( hr : 0.49; 95% ci: 0.38 to
characteristics in the chemotherapy arm31,39. 0.64). As in the keynote-407 trial, a benefit was seen regard-
With the success of first-line pembrolizumab in pa- less of PD-L1 expression level. Those results established the
tients with a PD-L1 status of 50% or greater, the keynote-042 combination of chemotherapy and pembrolizumab as a
trial explored whether first-line pembrolizumab was su- soc in the first-line treatment of advanced nsclc ; however,
perior to platinum doublet chemotherapy in patients with whether chemotherapy is necessary in patients with PD-L1
advanced nsclc and a PD-L1 tumour proportion score of 1% expression of 50% or greater remains unclear.
or greater34. In patients meeting those criteria, os was 16.7 The IMpower150 trial explored the combination of che-
months for pembrolizumab compared with 12.1 months motherapy, bevacizumab, and atezolizumab for patients
for chemotherapy ( hr : 0.81; 95% ci: 0.71 to 0.93). The bene- with treatment-naïve advanced nonsquamous nsclc 37.
fit with pembrolizumab was greater with higher PD-L1 That 3-arm trial randomized patients to carboplatin–
proportion scores. Although those results are promising, paclitaxel chemotherapy plus bevacizumab, chemotherapy
an exploratory analysis in patients with a PD-L1 propor- plus bevacizumab and atezolizumab, or chemothera-
tion score of 1%–49% did not show a significant benefit py plus atezolizumab. Currently, the published compar-
with pembrolizumab compared with chemotherapy, sug- ison is for chemotherapy–bevacizumab compared with
gesting that the survival benefit seen in the overall study chemotherapy–bevacizumab–atezolizumab. For patients
population was driven primarily by patients with high without an EGFR or ALK mutation, os was 19.2 months in
PD-L1 expression. the chemotherapy–bevacizumab–atezolizumab arm and
The combination of chemotherapy and immunother- 14.7 months in the chemotherapy–bevacizumab arm
apy has been explored in multiple rcts. The keynote-407 ( hr : 0.78; 95% ci : 0.64 to 0.96). Although carboplatin–
trial randomized 559 patients with treatment-naïve paclitaxel–bevacizumab is not a commonly used regimen
adva nced squa mous-cel l ca rcinoma of t he lung to for nonsquamous nsclc in Canada, results validate the
carboplatin–taxane (paclitaxel or nab-paclitaxel) plus efficacy of chemotherapy and ici combinations. Results
either pembrolizumab or placebo, regardless of PD-L1 ex- from trials that are comparing atezolizumab combined
pression36. Patients received 4 cycles of chemotherapy and with various platinum doublet backbones (IMpower130,
up to 35 cycles of pembrolizumab or placebo. The os was 131, and 132) were presented in 2018, each suggesting a
15.9 months in the pembrolizumab–chemotherapy arm benefit for chemotherapy plus immunotherapy compared

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TABLE III Randomized trials of immune checkpoint inhibitors in treatment-naïve advanced non-small-cell lung cancer

Reference Median Treatment arms HR 95% CI Median Grade 3 or greater

(trial name) follow-up OS treatment-related
(months) (months) adverse events (%)
Reck et al., 201618 Minimum Nivolumab–ipilimumab NR NR 31.2
(CheckMate 227, high TMB) 11.2
Platinum doublet 36.1

Remon et al., 201731 12.8 Pembrolizumab 0.81 0.71 to 0.93 16.7 17.8
(KEYNOTE-042, PD-L1≥1%)
Platinum doublet 12.1 41.0

Gandhi et al., 201832 20.0 (A) Paclitaxel–carboplatin– A vs. C: 0.64 to 0.96 19.2 58.5
(IMpower150, nonsquamous) bevacizumab–atezolizumab 0.78
B vs. C:
(B) Paclitaxel–carboplatin– 19.4
0.88
atezolizumab
(C) Paclitaxel–carboplatin– 14.7 50.0
bevacizumab

Jotte et al., 201833 19.0 Nab-paclitaxel–carboplatin– 0.79 0.64 to 0.98 18.6 74.9
(IMpower130) atezolizumab
Nab-paclitaxel–carboplatin 13.9 60.7

Lopes et al., 201834 7.8 Chemotherapy–pembrolizumab 0.64 0.49 to 0.85 15.9 69.8
(KEYNOTE-407, squamous)
Chemotherapy–placebo 11.3 68.2

Papadimitrakopoulou et al., 201835 17.1 (A) Nab-paclitaxel–carboplatin– B vs. C: 0.78 to 1.18 14.0
(IMpower131) atezolizumab 0.96
(B) Paclitaxel–carboplatin– NR 69
atezolizumab
(C) Nab-paclitaxel–carboplatin 13.9 58

Paz-Ares et al., 201836 10.5 Chemotherapy–pembrolizumab 0.49 0.38 to 0.64 NR 67.2

(KEYNOTE-189, nonsquamous)
Chemotherapy–placebo 11.3 65.8

Socinski et al.,201837 14.8 Pemetrexed–platinum CTx– 0.81 0.64 to 1.03 18.1 58

(IMpower132) atezolizumab
Pemetrexed–platinum CTx 13.6 42

Tan et al.,201830, and 25.2 Pembrolizumab 0.63 0.47 to 0.86 30.0 26.6
Camidge et al., 201917
Platinum doublet 14.2 53.3
(KEYNOTE-024, PD-L1≥50%

Reck et al., 201938 14.0 Nivolumab 1.02 0.80 to 1.30 14.4 18

(CheckMate 026, PD-L1≥1%)
Platinum doublet 13.2 51

HR = hazard ratio; CI = confidence interval; OS = overall survival; TMB = tumour mutational burden; NR = not reported.

with chemotherapy alone33,35,40. The full publications from and 5.5 months with chemotherapy (hr : 0.58; 97.5% ci: 0.41
those trials had not been released at time of writing, and so to 0.81). A benefit in pfs was seen regardless of PD-L1 ex-
details are not included for those publications. pression. The os results were immature, but encouraging.
Combination immunotherapy is also being studied Although those results are promising, it remains to be
in advanced nsclc. CheckMate 227 is a complex multipart seen whether combination immunotherapy is superior to
study that randomized patients with PD-L1 expression of monotherapy or the combination of immunotherapy and
1% or greater to nivolumab–ipilimumab, nivolumab mono- chemotherapy. Further trials are ongoing.
therapy, or platinum doublet chemotherapy19. Patients
with PD-L1 expression less than 1% were randomized to Duration of Treatment
nivolumab–ipilimumab, nivolumab plus chemotherapy, The optimal duration of treatment with icis for patients
or chemotherapy alone. The protocol was amended to add with advanced nsclc remains an open question. Trials of
a co-primary endpoint of pfs for nivolumab–ipilimumab nivolumab and atezolizumab in previously treated patients
compared with chemotherapy in patients with a high tmb were designed with unlimited continuation of treatment
(defined as at least 10 mutations per megabase). The results until disease progression or lack of tolerance23,24,27. On
of the biomarker analysis showed that the pfs in the high the other hand, trials of pembrolizumab stopped treat-
tmb subgroup was 7.2 months with nivolumab–ipilimumab ment after a maximum of 2 years 26 . After 43 months’

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median follow-up in keynote-010, 79 of 690 patients re- behaves differently from EGFR-mutated nsclc upon expos-
ceived pembrolizumab for the maximal 2 years, and 25 ure to immunotherapy remains an area of active research.
(32%) developed progressive disease after stopping41. Of Concerns have also been raised about benefit from icis
the 14 patients re-treated with pembrolizumab, 11 experi- for lung cancer in older adults and in patients with a poor
enced a partial re-response or disease stabilization. The performance status (ps). Older adults experience changes in
most rigorous study to assess treatment duration (Check- the immune system that might blunt immune responsive-
Mate 153) randomized patients still receiving nivolumab ness45. A meta-analysis of six trials showed a net survival
after 1 year to observation or continuation42. Of 1245 initial advantage for immunotherapy compared with chemother-
patients, 220 were still receiving treatment at 1 year, and 163 apy in patients 65 or more years of age (hr: 0.72; 95% ci: 0.58
with stable or responding nsclc were included in an efficacy to 0.89) 22. In a real-world setting, older patients (65–75
analysis. The pfs was superior in the continuation arm (not years and >75 years) experience outcomes similar to those
reached vs. 10.3 months), and a statistically nonsignifi- in patients on trials, the median os being approximately
cant trend toward better os was observed ( hr : 0.63; 95% 12 months46,47. Patients with a poor ps were not included in
ci : 0.33 to 1.20). Of the 87 patients who stopped nivolumab, the landmark clinical trials. A phase ii trial of nivolumab
43 (49%) developed progressive disease. In 34 patients who for such patients (Eastern Cooperative Oncology Group
received nivolumab re-treatment, the median duration ps 2–4) with advanced nsclc showed a ps improvement in
of re-treatment at data cut-off was 3.8 months (range: 29% of patients and an os of 9.3 months in those with EGFR
0.1–17.5 months). The data available to judge duration of wild-type nsclc48. Those data suggest that patients with a
immunotherapy treatment and the value of re-treatment poor ps can still benefit; however, the trial included only
are inadequate to reach firm conclusions. It is possible 33 patients, and so caution and further research are still
that 1 year is too early a stopping point. CheckMate 153 required before this approach can be adopted.
does not demonstrate a statistically significant survival
benefit, although it was underpowered for that outcome. Stage III NSCLC
Currently, the best recommendation is to follow the trial The soc treatment in stage iii nsclc is concurrent chemo-
protocols for each drug. radiotherapy. The chemotherapy component typically
involves one of three regimens: cisplatin–etoposide,
Special Populations cisplatin–vinorelbine, or carboplatin–paclitaxel5. Consol-
Patients whose nsclc carries an EGFR or ALK mutation idative chemotherapy does not appear to improve survival
appear to benefit much less from icis than do patients with after concurrent chemoradiotherapy49. Although treatment
a wild-type profile. Subgroup analyses from landmark for metastatic nsclc has evolved markedly since 2009, no
rct s establishing monotherapy with nivolumab, pem- major advances in systemic therapy for stage iii nsclc had
brolizumab, or atezolizumab showed no evidence of im- been made until the pacific trial. That trial randomized 713
proved survival in patients with EGFR mutations23,24,26,27. patients to receive either standard chemoradiotherapy plus
A meta-analysis of EGFR-mutated nsclc from four trials placebo or soc plus 1 year of consolidative durvalumab.
showed no benefit ( hr : 1.11; 95% ci : 0.80 to 1.53), reducing Interim analysis showed that, compared with soc alone,
the likelihood that the lack of benefit is simply attributable the addition of durvalumab was associated with superi-
to a small sample size22. Patients with ALK-translocated or 24-month survival (66.3% vs. 55.6%) and os ( hr : 0.68;
nsclc were also included in those trials, but no publica- 99.73% ci: 0.47 to 0.997) 50. Benefit appeared to be similar
tions have reported on that subgroup. Patients with EGFR in most subgroups, including different levels of PD-L1,
and ALK mutations were excluded from most first-line with the main uncertainty being efficacy in patients
immunotherapy trials, but the IMpower150 trial, discussed with EGFR-mutated nsclc . From a safety perspective,
earlier, included 80 patients with EGFR-mutated nsclc and grades 3–4 toxicities were observed in 29.9% of patients in
34 with ALK-translocated nsclc37. When combined, those the durvalumab group compared with 26.1% of those in
subgroups experienced superior pfs with the inclusion of the placebo group. Most importantly, the rate of pneumo-
atezolizumab ( hr : 0.59; 95% ci : 0.37 to 0.94). That benefit nitis was 33.9% for the durvalumab group compared with
raises the question of adding immunotherapy to targeted 24.8% for the placebo group, but grades 3–4 pneumonitis
therapy—the typical first-line standard for targetable mu- occurred in only 3.4% and 2.6% respectively51. The pacific
tations. However, combinations of icis with gefitinib and trial thus created a new soc for patients with stage iii nsclc.
crizotinib have caused severe hepatotoxicity, and combin-
ations with osimertinib have caused severe pneumonitis, SCLC
curtailing enthusiasm for those combinations 43,44. The In patients with sclc, results for immunotherapy, including
relative insensitivity of EGFR- and ALK-mutated nsclc to PD1/PD-L1 inhibitors, have been more mixed than they
immunotherapy might be related to a comparatively low have for patients with nsclc. The single-arm keynote-158
tmb, lower levels of PD-L1, and the ongoing presence of a trial assessed the effect of pembrolizumab monotherapy
growth signal once targeted therapy has been stopped. in patients with extensive-stage sclc after failure of stan-
Interestingly, the exception to that trend of decreased dard therapy 52. Encouragingly, patients showing PD-L1
efficacy with driver mutations is seen with KRAS-mutated positivity responded to pembrolizumab 35.7% of the
nsclc. In individual rcts and systematic reviews alike, the time and had a median os of 14.9 months. The benefit in
likelihood of response and improved os are higher when PD-L1–negative sclc was minimal. Additional trials for
KRAS-mutated nsclc is treated with icis rather than with treatment-refractory sclc are ongoing. Combination im-
chemotherapy 21,22. The reason that KRAS-mutated nsclc munotherapy with nivolumab–ipilimumab, tested in the

Current Oncology, Vol. 27, Supp. 2, April 2020 © 2020 Multimed Inc. S83
 IO IN LUNG CANCER, Dawe et al.

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