The Integration of Radiotherapy with Immunotherapy for the ...Non–Small Cell Lung Cancer Eric C....

Review

The Integration of Radiotherapy withImmunotherapy for the Treatment ofNon–Small Cell Lung CancerEric C. Ko1, David Raben2, and Silvia C. Formenti1

Abstract

Five-year survival rates for non–small cell lung cancer(NSCLC) range from 14% to 49% for stage I to stage IIIAdisease, and are

undergoing surgical resection (14, 15). A pooled analysis of 58medically operable stage I NSCLC patients from two phase IIItrials, STARS and ROSEL (which did notmeet their accrual goals),suggested that SBRT is better tolerated and may lead to improvedOS compared with surgery (16).

For patients with resectable locally advanced NSCLC, thestandard treatment is surgery followed by adjuvant chemotherapy(4). Adjuvant RT is indicated in patients with mediastinal nodalinvolvement and/or positive resection margins, with RT offeredeither sequentially or concurrently with adjuvant chemotherapy(4). Neoadjuvant chemoradiation and chemotherapy prior tosurgery are potential treatment options for select patients (4). Inpatients with locally advanced NSCLC who cannot undergosurgery, concurrent chemoradiationwith conventionally fraction-ated RT is typically recommended (4, 17). A meta-analysis of 25randomized clinical trials showed significantly decreased risk ofdeath with concurrent chemoradiation versus RT alone [hazardratio (HR), 0.71; 95% confidence interval (CI), 0.64�0.80] andversus sequential chemoradiation (HR, 0.74; 95%CI, 0.62�0.89)in patients with stage III NSCLC (17).

Failure pattern analyses have shown that not only are locallyadvanced NSCLC patients at a significant risk of developingdistant metastases, but a notable proportion of recurrentpatients also show locoregional failure (18). Thus, defining theRT dose and fractionation for optimal locoregional tumorcontrol remains an important area of investigation. The roleof RT dose escalation was addressed by RTOG 0617, a phase IIIstudy of patients with unresectable stage IIIA/B NSCLC thatdemonstrated that concurrent chemoradiation with high-doseRT (74 Gy) was associated with decreased overall survival (OS)and increased incidence of treatment-related deaths and severeesophagitis versus chemoradiation with standard dose RT(60 Gy; ref. 19). Consequently, based on current evidence,conventionally fractionated RT dose beyond 60 Gy shouldgenerally be avoided in the setting of concurrent chemoradia-tion. A meta-analysis of 10 randomized controlled trialsobserved that accelerated or hyperfractionated RT provided amodest OS benefit compared with conventional RT in locallyadvanced NSCLC (HR, 0.88; 95% CI, 0.80�0.97; P ¼ 0.009;ref. 20). A study of adaptive RT, with treatment fields informedby 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) conducted at mid-treatment, demonstrated improved locoregional tumor controlin patients with unresectable or inoperable stage II–III NSCLCwho were receiving concurrent chemotherapy (21). These resultshave provided the background for the ongoing phase II studyRTOG 1106, evaluating an individualized adaptive RT plan usedafter FDG-PET/CT compared with standard RT in unresectable orinoperable stage III NSCLC patients who receive concurrentchemotherapy. Multiple studies have also shown a positive localcontrol benefit of SBRT boost after concurrent chemoradiation inpatientswith locally advancedNSCLC,with no additional toxicitybeyond what is expected for conventional RT (22–25).

Despite improvements in clinical outcomes from current treat-ments (SBRT in early-stage node-negative NSCLC, and concurrentchemotherapy with conventionally fractionated RT in locallyadvanced NSCLC), there has been only a modest improvementin endpoints including freedom from progression, recurrence,and/ormetastasis aswell asOS (6, 7, 14, 15, 18). These limitationsprovide further rationale to support studies such as the combi-nation of RT or chemoradiation with immunotherapy.

Rationale for Integration of RT andImmunotherapy

In addition to providing effective local treatment at the irradi-ated tumor site, RT can also mediate an abscopal effect, a phe-nomenon in which tumor regression occurs in nonirradiatedlesions (26–28). Although the abscopal effect has been observedfor decades, the exact mechanisms underlying this phenomenonremained elusive for much of this time (27). Demaria andcolleagues were the first to link the abscopal effect of RT to animmune-mediated mechanism (29), and recent studies haveprovided further evidence that RT has the potential to activatea tumor-directed systemic immune response (26–28). With theadvent of immunotherapy, new areas of research have emerged,with significant recent interest in combining RT with immuno-therapeutic agents to potentially enhance the abscopal effect (26).

Preclinical evidence points to RT as a priming event for immu-notherapy. By modulating the host's immune system, RT canrender tumor cells more susceptible to T-cell–mediated attack(30). RT promotes the release of tumor neoantigens from dyingtumor cells, enhances MHC class I expression, and upregulateschemokines, cell-adhesion molecules, and other immunomodu-latory cell surface molecules, thereby potentiating an antitumorimmune response by triggering immunogenic cell death (Fig. 1;refs. 30, 31). The expression of programmed cell death ligand-1(PD-L1), a checkpoint activated by tumor cells to evade theimmune system, is upregulated in response to RT in preclinicalmodels of NSCLC and other tumors (Fig. 1; refs. 31–34). RT andPD-L1 blockade in mouse models of melanoma, colorectal can-cer, and breast cancer resulted in significantly delayed tumorgrowth, which was mediated by CD8þ T cells (32, 35). Similarsynergistic antitumor activity has also been noted in mousemodels of NSCLC (33, 34). Using a mouse model of coloncarcinoma, Dovedi and colleagues found that concurrent but notsequential administration of RT and anti–PD-1 therapy led totumor regression of distal nonirradiated lesions (36). In a studyusing amelanomamousemodel, RT given before or concurrentlywith CTLA-4 blockade delayed tumor growth and improvedsurvival, compared with mice treated with anti–CTLA-4 therapyalone (37). Importantly, when RT is combined with immunecheckpoint blockade, the dose per fraction of RT has been dem-onstrated in preclinical models to have an impact on its systemiceffects. RT-induced cytoplasmic double-stranded DNA is sensedby the cyclic GMP-AMP synthase (cGAS)-stimulator of interferongenes (STING) pathway to induce IFN-I, a key mediator ofdendritic cell recruitment and maturation (38–40). Vanpouille-Box and colleagues demonstrated a threshold dose per fraction ofRT administered beyond which TREX1 is induced (41); as anexonuclease, TREX1 digests cytosolic double-stranded DNA,thereby removing the substrate that triggers cGAS-STING signal-ing. These findings have significant clinical implications in theselection of dose and fractionation when RT is combined withimmunotherapy.

Immunotherapy for Systemic TumorControl

The advent of immunotherapy for NSCLC has provided oppor-tunities to enhance systemic tumor control by mechanisms dis-tinct from those that underlie the use of chemotherapy or agentsthat target tumor-driver mutations (Fig. 2; refs. 42, 43).

Radiotherapy and Immunotherapy in Non–Small Cell Lung Cancer

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Multiple agents are under active investigation in NSCLC(Fig. 3). Checkpoint molecules are regulators of T-cell activationthat deliver negative or positive regulatory signals (44), andactivation of inhibitory checkpoints may enable tumors to evadethe immune system (45). Within the lymph node, CTLA-4 acts asan inhibitory checkpoint on T cells (42, 44). Ipilimumab and

tremelimumab are anti–CTLA-4 antibodies that prevent the bind-ing of CTLA-4 on T cells with CD80 and CD86 on antigen-presenting cells, thereby enhancing T-cell activation (46). Ipili-mumab is approved for the treatment of patients withmelanoma(47), whereas tremelimumab is still investigational. Within thetumor microenvironment, PD-1 is an inhibitory checkpoint that

Macrophage

CytotoxicT cell

TNFa

HMGB-1

PD-1

PD-L1

Fas

ICAM-1

CalreticulinMHC I

TCR

APC Tumorneoantigens

Tumorcells

1. Increased antigen release

2. Upregulation of PD-L1

3. Upregulation of immunomodulatory cell surface molecules

4. Release ofsecretorymolecules

Figure 1.

Radiation-inducedimmunomodulatory mechanisms.APC, antigen-presenting cell;HMGB-1, high-mobility groupprotein B1; ICAM-1, intercellularadhesion molecule-1; TCR, T-cellreceptor. Adapted from Daly andcolleagues (2015, ref. 31),Copyright 2018, with permissionfrom Elsevier.

CytotoxicT cell

ActivatedT cells

T cell T cellT cell

MemoryT cells

APCAPC

APCAPC

Tumorneoantigens

Tumorcell

tumor targets destruction of tumor cells4. Tumor-specific activated T cells and memory T cells are generated

3. Dendritic cell–mediated presentation oftumor-specific antigens to T cells

2. Dendritic cell–mediated phagocytosis of dying tumor cell

Figure 2.

Generation of an antitumorimmune response. APC, antigen-presenting cell. Adapted fromChen and Mellman (2013, ref. 42),Copyright 2018, with permissionfrom Elsevier.

Ko et al.

Clin Cancer Res; 24(23) December 1, 2018 Clinical Cancer Research5794




downregulates effector T cells (45). Nivolumab and pembrolizu-mab are anti–PD-1 antibodies that bind and block PD-1 receptorson activated T cells, whereas durvalumab, atezolizumab, andavelumab are anti–PD-L1 antibodies that bind and block PD-L1on tumor cells (45). Blockade of the PD-1/PD-L1 pathway enablesT cells to recognize and destroy tumor cells (45). To date, only thePD-1 blockers pembrolizumab and nivolumab and the PD-L1blocker atezolizumab are FDA-approved for the treatment ofmetastatic NSCLC (10–12), with PD-L1 expression as a selectioncriteria for treatment with pembrolizumab (11). Durvalumab hasbeen recently approved by the FDA for the treatment of unresect-able stage III NSCLC patients whose disease has not progressedfollowing concurrent platinum-based chemoradiation (13). Ave-lumab is currently being tested in clinical trials in NSCLC.

Other targets for immunotherapy include OX-40 (48, 49), toll-like receptors (TLR; refs. 50, 51), IDO1 (52, 53), and cytokines(54). OX-40 agonists, TLR agonists, IDO1 inhibitors, cytokines,and cytokine blockers are currently in clinical development, andsome of these agents are being tested in combination with RT.

Safety and Efficacy of RT Combined withImmunotherapyCheckpoint blockers

The integration of RT with checkpoint inhibitors may presentoverlapping toxicities such as pneumonitis (10–12) and, poten-tially, myocarditis (55). Recent data from clinical trials andsecondary or retrospective analyses include patients with locally

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Activatingreceptor orligand

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GM-CSFThymosin-a1IL2ADV/HSV-tkFresolimumab

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IMO-2125MotolimodMEDI9197GSK1795091CMB305GLA-SEPUL-042EntolimodSD-101ResiquimodPolyICLCM-VM3MGN1703

Other immunotherapies

Figure 3.

Positive and negative immune regulators and therapeutic agents in clinical development. Bold: agents investigated in combination with RT in clinical trials.Yellow highlighting: agents investigated in combination with RT in NSCLC in clinical trials. � , PD-L1/PD-L2/VISTA antagonist small molecule. †, Bispecific anti–PD-1and anti–LAG-3DARTprotein. x, Soluble formof LAG-3. z, Soluble formof Flt3L. �� , DARTmolecule that recognizes bothB7-H3andCD3. APC, antigen-presenting cell;NK, natural killer. Adapted from Mellman and colleagues (2011, ref. 44), copyright 2018, by permission from Macmillan Publishers Ltd.






advanced or metastatic NSCLC. Durvalumab is the only check-point blocker with phase III data following definitive platinum-based concurrent chemoradiation in locally advanced, unresect-able stage III NSCLC patients without evidence of disease pro-gression (56). The phase III randomized PACIFIC study investi-gated durvalumab versus placebo in 713 patients with unresect-able stage III NSCLC who did not have disease progression after�2 cycles of platinum-based chemoradiation (56). The incidenceof adverse events (AE) of any cause was similar for durvalumabversus placebo for AEs of any grade (97% vs. 95%), grade 3/4 AEs(30% vs. 26%), and serious AEs (SAEs; 29% vs. 23%; ref. 56).Treatment-related AEs of all grades were reported in 68% ofdurvalumab-treated patients versus 53% of placebo-treatedpatients, and the incidence of grade 3/4 AEs was 12% versus4%, respectively (56). The most frequent grade 3/4 AEs of anycausewere pneumonia (4% in each arm) andpneumonitis (3% ineach arm), which were expected after definitive chemoradiation(56). The incidence of treatment-related grade 3/4 pneumonitiswas comparable at 1% in each arm (56). A planned interimanalysis of the PACIFIC trial showed that durvalumab signifi-cantly extended both the median progression-free survival (PFS)versus placebo (16.8 vs. 5.6months;HR, 0.52; 95%CI, 0.42–0.65;P

20.6 months; HR, 0.78; 95% CI, 0.64–0.95; P ¼ 0.016) amongthe 806 patients who had received prior concurrent chemo-radiation (64). The phase III STOP study investigated vacci-nation with belagenpumatucel-L as maintenance therapyafter platinum-based frontline chemotherapy with or withoutRT in stage III/IV NSCLC patients (n ¼ 532; ref. 66). Inthis trial, 5 treatment-related SAEs were reported, 3 in thebelagenpumatucel-L arm and 2 in the placebo arm (66).Although this trial did not meet its primary endpoint ofOS in all randomized patients, maintenance therapy withbelagenpumatucel-L was associated with significantly longermedian OS than placebo (28.4 vs. 16.0 months; HR, 0.61;95% CI, 0.38–0.96; P ¼ 0.032) among the 161 patients whohad received prior chemoradiation (66).

In a phase III study of adjuvant chemotherapy or RT fol-lowed by lymphokine-activated killer (LAK) cell adoptiveimmunotherapy in NSCLC patients (n ¼ 170; 63% with stageIII; 69 curative cases and 101 noncurative cases), there wereno serious side effects other than fever and rigors associatedwith LAK cell administration (67). In this study, RT followedby LAK immunotherapy resulted in improved 9-year survivalversus no adjuvant therapy, or adjuvant chemotherapy or RTalone (52% vs. 24%; P < 0.001; ref. 67).

In a phase II study investigating telomerase peptide vaccinationwith GV1001 after chemoradiation in inoperable stage III NSCLCpatients (n ¼ 23), no treatment-related SAEs were observed (68).Vaccination with GV1001 after chemoradiation led to specificimmune responses in 16 of 20 (80%) evaluable patients, with atrend toward longer median PFS in responders when comparedwith nonresponders (12.2 vs. 6.0 months; P ¼ 0.20; ref. 68). In aphase II study testing granulocyte-macrophage colony-stimulat-ing factor (GM-CSF) with concurrent chemoradiation in 41patients withmetastatic solid tumors (n¼ 18withNSCLC), grade3/4 AEs of fatigue and hematologic findings were the mostcommon AEs observed in 6 and 10 patients, respectively (69).One patient experienced a grade 4 SAE of pulmonary embolismthat emerged during GM-CSF administration; however, nopatient discontinued treatment due to toxicity (69). GM-CSFcombined with concurrent chemoradiation resulted in abscopalresponses in 4 of 18 NSCLC patients (69). Finally, in a phase Ibdose-escalation study investigating RT followed by the immu-nocytokine NHS-IL2 in metastatic NSCLC patients (n ¼ 13)attaining disease control (at least stable disease) after first-lineplatinum-based chemotherapy, there were only 3 grade 3 AEsrelated to NHS-IL2 (70). Although no objective responses wereobserved in this study, long-term survival occurred in 2 of 13patients with good performance status 4 years after the start offirst-line chemotherapy, including 1 patient with long-termtumor control (70).

Ongoing TrialsPlanned or ongoing clinical trials investigating RT combined

with immunotherapy (including concurrent and sequentialapproaches) in patients with NSCLC are presented in Table 1.The majority of these trials are phase I or phase II studiesinvestigating RT combined with checkpoint blockers. The onlyphase III study (RTOG 3505), which is currently recruitingpatients, is investigating the use of nivolumab versus placeboafter concurrent chemoradiation in patients with stage III unre-sectable NSCLC.

Areas of Investigation and FutureDirections

Although early evidence points to the clinical viability ofcombining RT and immunotherapy inNSCLC,many unansweredquestions remain. For example, at what stage of NSCLC is thistreatment approach most effective? In addition to the metastaticand locally advanced NSCLC settings, it is conceivable thatpatients with early-stage diseasemay also potentially benefit fromthese treatment combinations. Patients with early-stage NSCLCstill have high rates of relapse after definitive resection or SBRT, asevidenced by 5-year survival rates of 30% to 49%; thus, therecontinues to be an unmet need for postresection adjuvant therapyand post-SBRT maintenance/consolidation therapy (3, 71).

The optimal sequence and timing of RT and immunotherapyremain investigational. Available data in NSCLC showed clinicalbenefit when immunotherapy was given after RT (� chemother-apy; refs. 56, 57, 67, 68). A subgroup analysis of the PACIFIC studyfound that the PFS improvement in favor of durvalumab wasmore pronounced among patients who had their last RT dose 14 days from RT completion. To date, few studies have testedconcomitant administration of immunotherapy with RT (69, 72,73), and only a few case reports have described a treatment benefitwith RT after immunotherapy (62, 63). The type of immunother-apy used in combinationwith RT is likely to play a role inwhethera concurrent or sequential strategy is more efficacious. For exam-ple, RT may elicit more effective antitumor immunity if admin-istered concurrently with anti–CTLA-4 therapy (as both therapiesact at the early stage of the antitumor immune response), whereasin other cases, RT may be more effective if administered prior toanti–PD-1/PD-L1 therapy, as PD-1/PD-L1 signaling typically actsat a later stage of the antitumor immune response. Clinical trialsthat evaluate the optimal therapeutic sequence are needed, as arepreclinical data to better understand the underlying mechanismsat play.

There are conflicting data on changes in PD-L1 expressionafter chemoradiation. A small retrospective analysis in locallyadvanced NSCLC (n ¼ 15) found that neoadjuvant chemoradia-tion led to a decrease in PD-L1 expression (74), whereas retro-spective analyses in patients with other tumor types foundthat neoadjuvant chemoradiation increased PD-L1 expression(75, 76). It is possible that the differential effects could beaccounted for by differences in tumor types, staging, and/ortreatment. Additional studies are needed to clarify this issue andits therapeutic implications.

The optimal RT dose and schedule to ensure adequate primingfor immunotherapy, and the extent of tumor that should beirradiated while minimizing local toxicity, remain to be defined.Preclinical studies using breast and colon carcinoma mousemodels (41, 77) and a clinical study in patients with melanoma(78) suggest that fractionated dosing is preferred to a single-dosestrategy to elicit an abscopal response when paired with anti–CTLA-4 antibodies. However, among fractionated strategies,it is not clear if the dosing should be modeled after ablative






Table

1.Ong

oingstud

iesofim

mun

otherap

yin

combinationwithRTin

NSCLC

NCTnu

mber/

trialna

me

Stud

ypha

seDisea

sestag

eTrialdesign

RTdetails

(dose,fractiona

tion,

number

oflesions

tobetrea

ted,

timingrelative

toim

mun

otherap

y)Line

oftherap

yStatus

Estim

ated

primary

completiondate

Early-stageNSC

LCNCT03110978

I-SABR

2RInoperab

lestag

eIan

dIIA

immun

otherap

y-na€ �veNSCLC

(N¼

140)

SBRTalone

vs.SBRTþnivo

lumab

given

within36

hoursbefore

ora

fter

thefirst

SBRTfraction

SBRTdelivered

at50

Gyin4fractions,or,if

thiscann

otmee

tno

rmal-tissuedose-

volumeco

nstraints,70

Gyin10

fractions

ove

r1–2wee

ks

Any

line

Recruiting

June

2022

NCT029

04954

2RResectable

stag

eI–IIIANSCLC

(N¼

60)

Neo

adjuva

ntdurva

lumab

�SBRT,

follo

wed

bysurgery,

follo

wed

by

postoperativemonthlymainten

ance

durva

lumab

SBRTdelivered

at24

Gyin3dailyfractions

starting

concurrently

withthefirstcycle

ofdurvalumab

Neo

adjuva

nt/adjuva

nt/

mainten

ance

Recruiting

Janu

ary20

20

NCT032

17071

Pem

broX

2RResectable

stag

eI–IIIANSCLC

(N¼

40)

Neo

adjuva

ntpem

brolizum

ab�

SBRT

SBRTdelivered

at12

Gyin1fractionto

50%

oftheprimarytumoronly,ad

ministered

within1wee

k(�

3day

s)follo

wingthe

seco

ndad

ministrationof

pem

brolizum

ab

Neo

adjuva

ntRecruiting

Sep

tember

2019

NCT028

18920

TOP1501

2Resectable

stag

eIB,IIA/B

,IIIA

NSCLC

(N¼

32)

Neo

adjuva

ntpem

brolizum

ab,follo

wed

bysurgery,

follo

wed

bystan

dard

adjuvant

chem

otherap

y�

RT,

follo

wed

byad

juva

ntpem

brolizum

ab

N/A

Neo

adjuva

nt/adjuva

nt

Recruiting

Janu

ary20

20

NCT0314832

71/2R

Inoperab

lestag

eI/IIA

NSCLC

(N¼

105)

Durva

lumab

þSBRTvs.S

BRTalone

SBRTdelivered

at54

Gyin3fractions,ora

t50

Gyin

4fractions,o

rat

65Gyin

10fractions,a

dministeredwithin10

days

afterdurvalumab

firstdose

1LRecruiting

June

2020

NCT025

81787

SABR-A

TAC

1/2

StageIA/B

NSCLC

under

considerationforSBRTas

defi

nitive

primarytherap

y(N

¼60)

Freso

limum

abonday

s1,15,3

6þ

SBRT

SBRTdelivered

in4fractions,b

etwee

nday

s8an

d12

1LRecruiting

Janu

ary20

20

NCT030

5055

41/2

Inoperab

lestag

eINSCLC

(N¼

56)

Ave

lumab

�SBRT

SBRTdelivered

at48Gyin4fractions,ora

t50

Gyin

5fractions

(given

everyother

day

ove

r10–12day

s)

Adjuva

ntRecruiting

March

2020

NCT025

99454

1Inoperab

lestag

eINSCLC

(N¼

33)

Atezo

lizum

abþ

SBRT

SBRTdelivered

at50

Gyin4fractions

(for

periphe

rally

locatedtumors)orin

5fractions

(forcentrally

locatedtumors)

ove

rday

s1–5ofcycle3,

administered

within24

–48ho

ursafterreceiving

atezolizum

ab

N/A

Recruiting

Nove

mber

2017

Locally

adva

nced

stag

eNSC

LCNCT027

6855

8RTOG35

05

3RInoperab

leorun

resectab

lestag

eIIIA/B

(notmetastatic)

immun

otherap

y-na€�veNSCLC

(N¼

660)

Che

moradiation(cisplatin/etoposideþ

RT),follo

wed

bynivo

lumab

vs.

placebo

60GyofthoracicRT(3D-CRTorIM

RT)

N/A

Recruiting

October

2022

NCT023

439

52HCRNLU

N14-

179

2Inoperab

leorun

resectab

lestag

eIIIA/B

NSCLC

(not

metastatic;

N¼

93)

Che

moradiation(eithe

rcisplatin/

etoposideorcarboplatin/paclitaxel

þRT),follo

wed

byco

nsolid

ation

pem

brolizum

ab

RTdelivered

at59

.4–6

6.6

Gy

Consolid

ation

Ong

oing

not

recruiting

March

2018

(58)

NCT024

34081

NICOLA

S2

Locally

advanced

stag

eIIIA/B

NSCLC

(notmetastatic;

N¼

78)

Nivolumab

þstan

dardchem

oradiation

N/A

1LOng

oing

not

recruiting

Aug

ust20

20

(Continue

donthefollowingpag

e)

Ko et al.





Table

1.Ong

oingstud

iesofim

mun

otherap

yin

combinationwithRTin

NSCLC

(Cont'd)

NCTnu

mber/

trialna

me

Stud

ypha

seDisea

sestag

eTrialdesign

RTdetails

(dose,fractiona

tion,

number

oflesions

tobetrea

ted,

timingrelative

toim

mun

otherap

y)Line

oftherap

yStatus

Estim

ated

primary

completiondate

NCT025

72843

2Resectable

stag

eIIIANSCLC

(N¼

68)

Neo

adjuvant

chem

otherap

y(cisplatin/

docetaxel),follo

wed

byne

oad

juvant

durva

lumab

,follo

wed

bysurgery,

follo

wed

byad

juva

ntdurva

lumab

for

R0patientsorstan

dardRTpriorto

adjuvant

durva

lumab

forR1/R2

patients

N/A

Neo

adjuvant/adjuvant

Recruiting

March

2021

NCT031022

42

2Unresectable

stag

eIIIA/B

NSCLC

,elig

ible

for

chem

oradiationwithcurative

intent

(N¼

63)

Neo

adjuva

ntatez

olizum

abþ

chem

oradiation(carboplatin/

paclitaxelþRT),follo

wed

byad

juva

ntatez

olizum

ab

RTdelivered

at60Gyin

30daily

fractions

ove

r6wee

ks,inco

njun

ctionwith

chem

otherap

yan

dim

mun

otherap

y

Neo

adjuva

nt/adjuva

nt

Notye

trecruiting

March

2020

NCT030

877

60

2NSCLC

patientswho

have

received

previous

chem

otherap

yan

dco

ncurrent

intratho

racicRT

withdefi

nitive

intent

andha

veatumorrecurren

cein

orne

arthepriorirradiationfields

(N¼

41)

Pem

brolizum

abmono

therap

yNomore

than

74Gyin

37daily

fractions

(2Gyea

ch)ofpriorRT

Consolid

ation

Recruiting

July

2019

NCT025

2575

7DETERRED

2Unresectable

stag

eII/III

NSCLC

(notmetastatic;

N¼

40)

Stand

ardchem

oradiation(carboplatin/

paclitaxel

þRT)�

atez

olizum

abfor

6–7

wee

ks,follo

wed

bya3–

4-w

eek

rest

period(nochem

oradiation)

�atez

olizum

ab,follo

wed

by

consolid

ationtherap

ywith

atez

olizum

abþ

chem

otherap

yfor2

cycles,follo

wed

bymainten

ance

therap

ywithatez

olizum

abalone

60–6

6Gydelivered

in30

–33

daily

fractions

ove

r6–7

wee

ks1L

Recruiting

Janu

ary20

20

NCT030

53856

2StageIIIANSCLC

(N¼

37)

Neo

adjuvant

chem

oradiation(cisplatin/

paclitaxel

þRT),follo

wed

bysurgery,

follo

wed

byad

juva

ntpem

brolizum

ab

RTdelivered

at44Gyin

22daily

fractions

ove

r5wee

ksAdjuva

ntNotye

trecruiting

May

2021

NCT032

3737

72

Resectable

stag

eIIIANSCLC

(N¼

32)

Neo

adjuva

ntdurva

lumab

�trem

elim

umab

þRT,follo

wed

by

surgery

Tho

racicRTdelivered

at45Gyin

25daily

fractions

ove

r5wee

ksNeo

adjuva

ntNotye

trecruiting

Sep

tember

2019

NCT029

879

98

CASE4516

1Resectable

stag

eIIIANSCLC

(N¼

20)

Neo

adjuvant

chem

oradiation(cisplatin/

etoposideþ

RT)þ

pem

brolizum

ab,

follo

wed

byco

nsolid

ation

pem

brolizum

ab

RTdelivered

at45Gyin

25daily

fractions

(1.8

Gyea

ch)

Neo

adjuva

nt/consolid

ation

Recruiting

Janu

ary20

19

Stag

eIV

(metastatic)

NSC

LCNCT029

929

12SABR-PD-L1

2Metastaticsolid

tumor,includ

ing

NSCLC

,CRC,orR

CC(N

¼180)

Atezo

lizum

abþ

SBRT

SBRTdelivered

at45Gyin

3fractions

(15Gyea

ch)

2Lþ

(forNSCLC

)Recruiting

Nove

mber

2018

NCT028

8874

32R

MetastaticNSCLC

and

metastaticCRC(N

¼180)

Durva

lumab

þtrem

elim

umab

�RT

(eithe

rhigh-dose

orlow-dose)

RTstarts

atwee

k2:either

high-dose

RTin

upto

3daily

fractions

ove

r10

day

s,or

low-dose

RTev

ery6ho

urstw

iceper

day

onwee

ks2,

6,10,a

nd14

2Lþ

(forNSCLC

:after

progressionto

anti–P

D-1/

PD-L1therap

y)

Recruiting

Decem

ber

2020

NCT030

44626

FORCE

2Metastaticno

nsqua

mous

NSCLC

(N¼

130)

Nivolumab

þco

ncurrent

RT(for

patientsne

cessitatingRT)or

nivo

lumab

alone

(forpatientswitho

utthene

cessityofRT)

RTdelivered

at20

Gyin

5fractions

(4Gy

each)to

1target

lesionove

r2wee

ks,

administeredwithin3daysafter

nivo

lumab

firstdose

2/3L

Recruiting

Aug

ust20

19

(Continue

donthefollowingpag

e)






Table

1.Ong

oingstud

iesofim

mun

otherap

yin

combinationwithRTin

NSCLC

(Cont'd)

NCTnu

mber/

trialna

me

Stud

ypha

seDisea

sestag

eTrialdesign

RTdetails

(dose,fractiona

tion,

number

oflesions

tobetrea

ted,

timingrelative

toim

mun

otherap

y)Line

oftherap

yStatus

Estim

ated

primary

completiondate

NCT030

50060

2StageIV

NSCLC

,stageIV

melan

oma,ormetastaticRCC

(N¼

120)

Nelfina

virmesylateþ

immun

otherap

y(pem

brolizum

abornivo

lumab

or

atez

olizum

ab)þ

RT

Hyp

ofractiona

tedIGRTad

ministeredove

r3–

14days,starting

afterco

urse

1an

dbefore

course

3ofim

mun

otherap

y

Priorim

mun

otherap

yor

chem

otherap

yallowed

Recruiting

Decem

ber

2021

NCT03176

173

2MetastaticNSCLC

undergoing

stan

dardim

mun

otherap

y(N

¼85)

Immun

otherap

y(nivolumab

or

pem

brolizum

aboratez

olizum

ab)�

concurrent

IGRT

Rad

ical-dose

IGRTad

ministereddaily

for

upto

10day

s(w

ithin2wee

ks)

Patientsmustha

vebee

nreceivingan

ti–P

D-1or

anti–P

D-L1therap

yforat

least4wee

ks

Recruiting

June

2020

NCT024

925

68

PEMBRO-RT

2RStageIV

(metastatic)

NSCLC

(N¼

74)

Pem

brolizum

abafterSBRTvs.

pem

brolizum

abalone

SBRTdelivered

at24

Gyin3fractions

(1–2

wee

kspriorto

startofpem

brolizum

ab)

2Lþ

Recruiting

October

2017

NCT026

2359

52

StageIV

NSCLC

(N¼

60)

GM-CSF

daily

from

days1to

14þ

SBRT

SBRTdelivered

at50

Gyin

5fractions

to1

lung

lesionfrom

day

s1to

53L

þ(progressionafter

stan

dard2L

chem

otherap

y)

Recruiting

May

2019

NCT029

78404

2StageIV

NSCLC

,orRCC(w

ith

brain

metastases;N¼

60)

Nivolumab

þSRS

SRSdelivered

at15–2

0Gyin

1fractionto

brain

metastases,ad

ministered1–2

wee

ksafterreceivingthefirstdose

of

nivo

lumab

1-4L

Recruiting

June

2020

NCT030

04183

STOMP

2MetastaticNSCLC

orTNBC

(N¼

57)

Insitu

oncolyticvirustherap

y(A

DV/

HSV

-tkonday

0þ

valacyclovirfrom

days1to

15)þ

SBRT,follo

wed

by

pem

brolizum

ab(startingonday

17)

SBRTdelivered

at30

Gyin5fractions

(6Gy

each)ove

r2wee

ksfrom

days2to

161L

(immun

otherap

yan

dchem

otherap

yna€�ve)

Recruiting

May

2022

ForNSCLC

:EGFRorALK

wtor

withEGFRorALK

aberrations

afterfailure

totargeted

therap

y

2L(1priorregim

enof

platinu

m-containing

chem

otherap

yor,if

carrying

EGFRorALK

aberrations

afterfailure

totargeted

therap

y)NCT033

13804

2Adva

nced

ormetastaticNSCLC

,orHNSCC(N

¼57

)Im

mun

otherap

y(nivolumab

or

pem

brolizum

aboratez

olizum

ab)þ

concurrent

RT

RT(SBRTor3D

-CRT)ad

ministeredwithin

14day

sofreceivingthefirstdose

of

immun

otherap

yto

1target

lesion(non-

CNS):either

SBRTto

achiev

eBED>100

Gyor30

Gyoffractiona

ted3D

-CRT

ForNSCLC

:1L

orrelapsed

Recruiting

June

2018

NCT029

40990

2RStageIV

(metastatic)

NSCLC

with>5

metastasesan

dpan

-ne

gativefordrive

rmutations

(N¼

50)

Stand

ardtw

o-drugplatinu

m-containing

chem

otherap

y(carboplatinor

cisplatinþ

pem

etrexedordocetaxel

orpaclitaxel

oretoposideor

gem

citabineorvino

relbineorna

b-

paclitaxel)alone

vs.stand

ardtw

o-

drugplatinu

m-containing

chem

otherap

yþ

SBRTþ

GM-CSF

SBRTto

primarylesions

ormetastatic

lesions

N/A

Notye

trecruiting

Decem

ber

2019

NCT029

7674

02

StageIV

(metastatic)

NSCLC

(N¼

48)

GM-CSF

daily

from

days1to

14þ

thym

osin-a1from

wee

ks1to

12þ

SBRT

SBRTdelivered

at50

Gyin

4–10fractions

to1lung

lesionfrom

days1to

103L

þ(after

progressionto

stan

dard2L

chem

otherap

y)

Recruiting

June

2019

NCT026

58097

CASE1516

2RStageIV

(metastatic)

NSCLC

(N¼

48)

SFRTfollo

wed

bypem

brolizum

abvs.

pem

brolizum

abalone

SFRTdelivered

at8Gyin

1fractiononthe

firstday

ofpem

brolizum

abtherap

y2L

þRecruiting

Decem

ber

2018

NCT027

874

47

2MetastaticNSCLC

withEGFR

mutations

withSDafter3

months

oftargeted

therap

y(N

¼46)

Gefi

tiniborerlotiniboricotinibþ

RTþ

thym

osin-a1(startingat

wee

k2)

Tho

racichy

pofractiona

tedRTdelivered

at40–4

5Gyin

5–15

fractions

(startingat

wee

k1)

Consolid

ation

Recruiting

Decem

ber

2017

(Continue

donthefollowingpag

e)


Ko et al.




Table

1.Ong

oingstud

iesofim

mun

otherap

yin

combinationwithRTin

NSCLC

(Cont'd)

NCTnu

mber/

trialna

me

Stud

ypha

seDisea

sestag

eTrialdesign

RTdetails

(dose,fractiona

tion,

number

oflesions

tobetrea

ted,

timingrelative

toim

mun

otherap

y)Line

oftherap

yStatus

Estim

ated

primary

completiondate

NCT03113851

2StageIV

(metastatic)

NSCLC

(N¼

40)

GM-CSF

daily

from

day

s1to

14,e

very

3wee

ksþ

SBRT

SBRTdelivered

at35

Gyin10

fractions

to1

lung

lesionove

r2wee

ksConsolid

ation(forpatients

withresponseorSDafter

1Lchem

otherap

y)

Recruiting

Aug

ust20

18

or

3Lþ

(forpatientswith

disea

seprogressionafter

stan

dard2L

chem

otherap

y)NCT028

31933

ENSIGN

2StageIV

(metastatic)

NSCLC

(N¼

29)

Insitu

gen

etherap

y(A

DV/H

SV-tkon

day

0þva

lacyclovirfrom

days1to15)

þSBRT,follo

wed

bynivo

lumab

(startingonday

17)

SBRTdelivered

at30

Gyin5fractions

(6Gy

each)ove

r2wee

ksfrom

days2to

162/3L

þRecruiting

Decem

ber

2021

NCT028

3926

52

StageIII/IVNSCLC

nota

men

able

tocurative

therap

y(N

¼29

)CDX-301dailyfor5daysþ

concomitan

tSBRT

SBRTdelivered

toasing

lelung

lesion,

starting

onthesameday

of

immun

otherap

y

2Lþ

(atleastone

stan

dard

chem

otherap

yregim

enor

targeted

therap

y)

Recruiting

July

2020

34Gyin

1fraction(forperiphe

raltum

ors

smallertha

n2cm

andno

tadjacent

tothe

chestwall),o

r54

Gyin

3fractions

(for

periphe

raltum

ors

noteligible

for34

Gy

in1fraction),o

r50

Gyin

5fractions

(for

centraltumors)

NCT022

39900

1/2R

Metastaticsolid

tumors,

includ

ingpatientswithlung

metastases(N

¼120)

Ipilimum

abþ

SBRT(concurrent

vs.

seque

ntial)

SBRTdelivered

to1–4lung

lesion(s)

ateither

50Gyin4fractions

or60Gyin10

fractions

2Lþ

Recruiting

Aug

ust20

19(73)

NCT024

4474

11/2R

Allstag

esNSCLC

forpha

seI;

stag

eIV

(metastatic)

NSCLC

forpha

seII(N

¼104)

Pem

brolizum

abþ

RT(SBRTvs.W

FRT)

SBRTdelivered

at50

Gyin4dailyfractions

WFRTdelivered

at45Gyin

15daily

fractions

N/A

Recruiting

Sep

tember

2020

NCT0316973

8QUILT-3.044

1/2

NSCLC

(N¼

85)

Nan

tNSCLC

vaccineco

nsisting

of

immun

otherap

yco

mbinationtherap

ywith:

avelum

ab,b

evacizum

ab,

capecitab

ine,

cisplatin,

cyclopho

spha

mide,

5-fluo

rouracil,

fulvestran

t,leucovo

rin,na

b-paclitaxel,

nivo

lumab

,lovaza,o

xalip

latin,

RT,

ALT

-803,

ETBX-011,E

TBX-021,

ETBX-051,E

TBX-061,GI-4000,

GI-620

7,GI-630

1,an

dha

nk

SBRT

2Lþ

(after

progressionto

anti–P

D-1/PD-L1therap

y)Notye

trecruiting

Janu

ary20

19

Inductionpha

se,follo

wed

bya

mainten

ance

pha

seforpatientswith

complete

response

NCT026

96993

1/2

StageIV

(metastatic)

NSCLC

withbrainmetastasis(N

¼80)

Nivolumab

�ipilimum

abþRT(SBRTor

WBRT)

SBRTorWBRTad

ministeredtheday

after

thefirstad

ministrationof

immun

otherap

yorwithinthefirst2

wee

ks

N/A

Recruiting

Decem

ber

2020

SBRTdelivered

in1fraction(dose

determined

bytrea

ting

phy

sician

)WBRTdelivered

at30

Gyin

10daily

fractions

(Continue

donthefollowingpag

e)






Table

1.Ong

oingstud

iesofim

mun

otherap

yin

combinationwithRTin

NSCLC

(Cont'd)

NCTnu

mber/

trialna

me

Stud

ypha

seDisea

sestag

eTrialdesign

RTdetails

(dose,fractiona

tion,

number

oflesions

tobetrea

ted,

timingrelative

toim

mun

otherap

y)Line

oftherap

yStatus

Estim

ated

primary

completiondate

NCT024

07171

1/2

MetastaticNSCLC

(anti–PD-1/

PD-L1the

rapy–

na€ �vepatients)

orm

etastaticmelan

oma(after

progressionto

anti–P

D-1

therap

y;N¼

60)

Foran

ti–P

D-1/PD-L1therap

y–na€ �ve

NSCLC

patients:pem

brolizum

abmono

therap

yun

tilPD,the

nSBRT,

follo

wed

bypem

brolizum

abmono

therap

y

Startingdose:3

0Gyin

5fractions

to1

target

lesion

ForNSCLC

:anti–PD-1/PD-L1

therap

yna€ �ve

Recruiting

Decem

ber

2018

Other

dose

coho

rts:30

Gyin3fractions

to1

target

lesion;10

Gyin1fractionto

1target

lesion

NCT03168464

1/2

MetastaticNSCLC

(N¼

45)

Ipilimum

abþRT(both

starting

atday

1),

follo

wed

byad

ditionofn

ivolumab

(on

day

22)

Nona

blative

RTdelivered

at30

Gyin

5fractions

to1lesion

2Lþ

Recruiting

Decem

ber

2021

NCT032

12469

ABBIM

UNE

1/2

MetastaticNSCLC

,HNSCC,o

resopha

gea

lcancer

(N¼

40)

Durva

lumab

�trem

elim

umab

þco

ncurrent

RT

SBRTad

ministeredat

day

15ofcycle1

2Lþ

Recruiting

Feb

ruary20

18

NCT032

23155

1RStageIV

NSCLC

(N¼

80)

SBRT,follo

wed

bynivo

lumab

þipilimum

abbetwee

n1and

7day

safter

completionofSBRT

SBRTdelivered

in3–

5fractions

to2–

4sites

1LRecruiting

Decem

ber

2020

vs.

nivo

lumab

þipilimum

abþ

concurrent

SBRTto

beco

mpletedwithin2wee

ks(priorto

seco

nddose

ofnivo

lumab

)NCT023

039

90

RADVAX

1Advanced

andmetastatic

cancersinclud

ingNSCLC

,melan

oma(w

hoha

vefailed

anti–P

D-1therap

y),b

reast

cancer,pan

crea

ticcancer,and

other

cancers(w

hoha

veprogressed

afterat

leastone

priorsystem

ictherap

y;N¼

70)

Pem

brolizum

abþ

RT

Hyp

ofractiona

tedRTto

anisolatedlesion

2Lþ

Recruiting

Feb

ruary20

17

NCT025

874

55PEAR

1Tho

racictumors

includ

ing

NSCLC

(immun

otherap

yna€ �ve;

N¼

48)

Pem

brolizum

abþ

palliative

RT

Low-dose

orhigh-dose

RT

N/A

Recruiting

June

2018

NCT024

00814

1StageIV

(metastatic)

or

recurren

tNSCLC

(N¼

45)

Atezo

lizum

abþ

SBRT(both

starting

on

day

1ofcycle1)

SBRTdelivered

in5fractions,2–3

times

per

wee

kove

r1.5

–2wee

ks2L

þRecruiting

Decem

ber

2017

or

atez

olizum

ab(startingonday

1ofcycle

1),follo

wed

bySBRT(startingonday

1ofcycle3)

or

SBRT(startingonday

1ofcycle1),

follo

wed

byatez

olizum

ab(startingon

day

1ofcycle2)

NCT028

58869

1StageIV

NSCLC

,ormelan

oma

(withbrain

metastases;

N¼

43)

Pem

brolizum

abþ

SRS

SRSdelivered

at30

Gyin5fractions

(6Gy

each),orat

27Gyin

3fractions

(9Gy

each)betwee

nday

s2an

d15ofcycle1,or

at18–21Gyin

1fractionbetwee

nday

s2

and3ofcycle1

1Lþ

Recruiting

October

2019

NCT023

1877

11

Recurrent/m

etastaticlung

cancer,H

NSCC,R

CC,o

rmelan

oma(N

¼40)

RTfollo

wed

bypem

brolizum

ab(3–16

dayslater)

or

8Gyin

1fraction(day

1)N/A

Recruiting

Janu

ary20

20or

pem

brolizum

abþ

concomitan

tRT

20Gyin5fractions

of4

Gyea

ch(day

s1–5)

or

pem

brolizum

abþ

concomitan

tRT,

follo

wed

bypem

brolizum

ab

(Continue

donthefollowingpag

e)

Ko et al.





Table

1.Ong

oingstud

iesofim

mun

otherap

yin

combinationwithRTin

NSCLC

(Cont'd)

NCTnu

mber/

trialna

me

Stud

ypha

seDisea

sestag

eTrialdesign

RTdetails

(dose,fractiona

tion,

number

oflesions

tobetrea

ted,

timingrelative

toim

mun

otherap

y)Line

oftherap

yStatus

Estim

ated

primary

completiondate

NCT026

0838

51

Advanced

metastaticsolid

tumors

includ

ingNSCLC

(N¼

35)

Pem

brolizum

abþ

SBRT

SBRTdelivered

in3–

5fractions

N/A

Ong

oing

not

recruiting

Decem

ber

2017

NCT030

35890

N/A

StageIV

(metastatic)

NSCLC

(N¼

33)

Immun

otherap

y(nivolumab

or

pem

brolizum

aboratez

olizum

ab)þ

concurrent

RT

Response-ad

aptedhy

pofractiona

tedRT

delivered

ateither

24–4

5Gyin

3fractions

(8–15Gyea

ch),or30

–50Gyin

5fractions

(6–10Gyea

ch)ove

r3–

10day

s

2Lþ

(priorchem

otherap

y�

RT)

Recruiting

Decem

ber

2017

NCT033

077

59SABRseq

1MetastaticPD-L1þ

NSCLC

(N¼

32)

RTfollo

wed

bypem

brolizum

abSBRT

1Lþ

Notye

trecruiting

Nove

mber

2021

or

pem

brolizum

abfollo

wed

byRTafter

cycle1

NCT032

24871

1(pilot)

MetastaticNSCLC

afterfailure

toan

ti–P

D-1/PD-L1therap

y(N

¼30

)

Che

ckpointinhibition(nivolumab

or

pem

brolizum

ab)þ

concurrent

RTþ

interlesiona

lIL2(starting1–3day

saftertheco

mpletionofRTan

dto

be

completedbyday

21)

Hyp

ofractiona

tedRTdelivered

at24

Gyin

3fractions

(8Gyea

ch)daily

orev

ery

other

day

duringthefirstwee

kof

therap

y

N/A

Recruiting

July

2020

NCT026

2139

81

Inoperab

lestag

eII,IIIA/B

NSCLC

(N¼

30)

Che

moradiation(carboplatin/paclitaxel

þRTfrom

wee

ks1to

6)þ

pem

brolizum

ab(from

wee

ks5to

6)

3D-CRTorIM

RToncedaily

5day

sawee

kfor6wee

ks1L

Ong

oing

not

recruiting

Sep

tember

2018

NCT026

39026

1MetastaticNSCLC

,melan

oma,

breastcancer,o

rpan

crea

tic

aden

ocarcinoma(N

¼30

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Abbreviations:3D-CRT,3-dim

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(SABR/SBRT) or subablative RT strategies (41). In addition, incases where high doses of RT are warranted, the use of noveltechnologies that cause less damage to healthy tissues, such asproton beam RT (4), should be taken into consideration aspotential combination partners for immunotherapy.

The optimal RT field size also remains undefined. For example,if RT is utilized in combination with immunotherapy in settingswhere the malignancy is not confined to just one region, it is notclear if all gross disease or only a specific site (e.g., the primarytumor) should be irradiated, as large-field irradiation may have anegative impact on circulating immune cells and may alsoincrease the risk of toxicity (79).

As more clinical research on the integration of RT with immu-notherapy evolves, it will be important to establish and validatepredictive biomarkers to identifywhichpatientswouldbenefit themost from RT and immunotherapy.

ConclusionsCurrently available data, though limited, suggest that the pairing

of RT with immunotherapy may be a safe and viable treatment

approach in patients with NSCLC. Ongoing clinical trials will addto the growing evidence on this promising combination.

Disclosure of Potential Conflicts of InterestD. Raben reports receiving consulting fees from AstraZeneca, EMD Serono,

Genentech, Merck, Nanobiotix, and Suvica, and is a consultant/advisory boardmember for AstraZeneca and Genentech. S.C. Formenti reports receiving com-mercial research grants from Bristol-Myers Squibb, Eisai, Janssen, Merck,Regeneron, and Varian, and honoraria from AstraZeneca, Bristol-Myers Squibb,Dynavax, Eisai, Elekta, GlaxoSmithKline, Janssen, Merck, Regeneron, andVarian. No potential conflicts of interest were disclosed by the other author.

AcknowledgmentsMedical writing support was provided by Robert Schupp, PharmD, CMPP,

and Francesca Balordi, PhD, of The Lockwood Group, in accordance withGood Publication Practice (GPP3) guidelines, and funded by AstraZeneca.

The costs of publication of this articlewere defrayed inpart by the payment ofpage charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received February 13, 2018; revised April 5, 2018; accepted June 22, 2018;published first June 26, 2018.

References1. National Cancer Institute. SEER cancer stat facts: lung and bronchus cancer

[cited 13 Jan 2018]. Available from: https://seer.cancer.gov/statfacts/html/lungb.html.

2. American Cancer Society. What is non-small cell lung cancer? [cited 13Jan 2018]. Available from: https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html.

3. Cancer.net, Lung cancer - non-small cell: statistics [cited 13 Jan 2018].Available from: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics.

4. NCCN.org. NCCN clinical practice guidelines in oncology (NCCN Guide-lines�) for non-small cell lung cancer V.3.2018. � National Comprehen-sive Cancer Network, Inc.; 2018.

5. Stanic S, Paulus R, Timmerman RD, Michalski JM, Barriger RB, Bezjak A,et al. No clinically significant changes in pulmonary function followingstereotactic body radiation therapy for early-stage peripheral non-small celllung cancer: an analysis of RTOG 0236. Int J Radiat Oncol Biol Phys2014;88:1092–9.

6. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, et al.Stereotactic body radiotherapy (SBRT) for operable stage I non-small-celllung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol BiolPhys 2011;81:1352–8.

7. Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al.Stereotactic body radiation therapy for inoperable early stage lung cancer.JAMA 2010;303:1070–6.

8. Ahn JS, Ahn YC, Kim JH, Lee CG, Cho EK, Lee KC, et al. Multinationalrandomized phase III trial with or without consolidation chemotherapyusing docetaxel and cisplatin after concurrent chemoradiation in inoper-able stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol2015;33:2660–6.

9. Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R,et al. Phase III study of cisplatin, etoposide, and concurrent chest radiationwith or without consolidation docetaxel in patients with inoperable stageIII non-small-cell lung cancer: the Hoosier Oncology Group and U.S.Oncology. J Clin Oncol 2008;26:5755–60.

10. OPDIVO (nivolumab) injection [prescribing information]. Princeton, NJ:Bristol-Myers Squibb Company; 2018.

11. KEYTRUDA (pembrolizumab) for injection [prescribing information].Whitehouse Station, NJ: Merck & Co., Inc.; 2017.

12. TECENTRIQ (atezolizumab) injection [prescribing information]. SouthSan Francisco, CA: Genentech, Inc.; 2017.

13. IMFINZI (durvalumab) injection [prescribing information]. Wilmington,DE: AstraZeneca Pharmaceuticals LP; 2017.

14. Crabtree TD,Denlinger CE,Meyers BF, ElNaqa I, Zoole J, Krupnick AS, et al.Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2010;140:377–86.

15. Grills IS, Mangona VS, Welsh R, Chmielewski G, McInerney E, Martin S,et al. Outcomes after stereotactic lung radiotherapy or wedge resection forstage I non-small-cell lung cancer. J Clin Oncol 2010;28:928–35.

16. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al.Stereotactic ablative radiotherapy versus lobectomy for operable stage Inon-small-cell lung cancer: a pooled analysis of two randomised trials.Lancet Oncol 2015;16:630–7.

17. O'Rourke N, Roqu�e IFM, Farr�e Bernad�o N, Macbeth F. Concurrent che-moradiotherapy in non-small cell lung cancer. CochraneDatabase Syst Rev2010:CD002140.

18. Aup�erin A, Le P�echoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al.Meta-analysis of concomitant versus sequential radiochemotherapy in locallyadvanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181–90.

19. Bradley JD, Paulus R, Komaki R,Masters G, BlumenscheinG, Schild S, et al.Standard-dose versus high-dose conformal radiotherapy with concurrentand consolidation carboplatin plus paclitaxel with or without cetuximabfor patientswith stage IIIA or IIIB non-small-cell lung cancer (RTOG0617):a randomised, two-by-two factorial phase 3 study. Lancet Oncol2015;16:187–99.

20. Mauguen A, Le P�echoux C, Saunders MI, Schild SE, Turrisi AT, BaumannM, et al. Hyperfractionated or accelerated radiotherapy in lung cancer:an individual patient data meta-analysis. J Clin Oncol 2012;30:2788–97.

21. Kong FM, Ten Haken RK, Schipper M, Frey KA, Hayman J, Gross M, et al.Effect of midtreatment PET/CT-adapted radiation therapy with concurrentchemotherapy in patients with locally advanced non-small-cell lung can-cer: a phase 2 clinical trial. JAMA Oncol 2017;3:1358–65.

22. Feddock J, Arnold SM, Shelton BJ, Sinha P, Conrad G, Chen L, et al.Stereotactic body radiation therapy can be used safely to boost residualdisease in locally advanced non-small cell lung cancer: a prospective study.Int J Radiat Oncol Biol Phys 2013;85:1325–31.

23. Hepel JT, Leonard KL, Safran H, Ng T, Taber A, Khurshid H, et al. Stereo-tactic body radiation therapy boost after concurrent chemoradiation forlocally advanced non-small cell lung cancer: a phase 1 dose escalationstudy. Int J Radiat Oncol Biol Phys 2016;96:1021–7.

24. Higgins KA, Pillai RN, Chen Z, Tian S, Zhang C, Patel P, et al. Concomitantchemotherapy and radiotherapywith SBRT boost for unresectable, stage IIInon-small cell lung cancer: a phase I study. J Thorac Oncol 2017;12:1687–95.

Ko et al.




https://seer.cancer.gov/statfacts/html/lungb.htmlhttps://seer.cancer.gov/statfacts/html/lungb.htmlhttps://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.htmlhttps://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.htmlhttps://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statisticshttps://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statisticshttp://clincancerres.aacrjournals.org/

25. Kumar S, Feddock J, Li X, Hall L, Shelton BJ, Arnold S, et al. Anupdate of a prospective study of SBRT for postchemoradiation resid-ual disease in stage II/III nonsmall cell lung cancer. Radiat Oncol2017;99:652–9.

26. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on theabscopal effect. Curr Probl Cancer 2016;40:25–37.

27. GrassGD,KrishnaN,KimS. The immunemechanisms of abscopal effect inradiation therapy. Curr Probl Cancer 2016;40:10–24.

28. Ng J, Dai T. Radiation therapy and the abscopal effect: a concept comes ofage. Ann Transl Med 2016;4:118.

29. Demaria S,Ng B,DevittML, Babb JS, KawashimaN, Liebes L, et al. Ionizingradiation inhibition of distant untreated tumors (abscopal effect) isimmune mediated. Int J Radiat Oncol Biol Phys 2004;58:862–70.

30. Hodge JW, Guha C, Neefjes J, Gulley JL. Synergizing radiation therapyand immunotherapy for curing incurable cancers. Opportunities andchallenges. Oncology (Williston Park) 2008;22:1064–70; discussion1075, 1080–1, 1084.

31. DalyME,MonjazebAM,Kelly K. Clinical trials integrating immunotherapyand radiation for non-small-cell lung cancer. J Thorac Oncol 2015;10:1685–93.

32. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al.Irradiation and anti-PD-L1 treatment synergistically promote antitumorimmunity in mice. J Clin Invest 2014;124:687–95.

33. Gong X, Li X, Jiang T, Xie H, Zhu Z, Zhou F, et al. Combined radiotherapyand anti-PD-L1 antibody synergistically enhances antitumor effect in non-small cell lung cancer. J Thorac Oncol 2017;12:1085–97.

34. Herter-SprieGS, Koyama S, KorideckH,Hai J,Deng J, Li YY, et al. Synergy ofradiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight2016;1:e87415.

35. Dovedi SJ, Adlard AL, Lipowska-Bhalla G,McKenna C, Jones S, Cheadle EJ,et al. Acquired resistance to fractionated radiotherapy can be overcome byconcurrent PD-L1 blockade. Cancer Res 2014;74:5458–68.

36. Dovedi SJ, Cheadle EJ, Popple AL, Poon E, Morrow M, Stewart R,et al. Fractionated radiation therapy stimulates antitumor immunitymediated by both resident and infiltrating polyclonal T-cell popula-tions when combined with PD-1 blockade. Clin Cancer Res 2017;23:5514–26.

37. Twyman-Saint Victor C, Rech AJ,Maity A, Rengan R, Pauken KE, Stelekati E,et al. Radiation and dual checkpoint blockade activate non-redundantimmune mechanisms in cancer. Nature 2015;520:373–7.

38. Deng L, LiangH, XuM, Yang X, Burnette B, Arina A, et al. STING-dependentcytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity2014;41:843–52.

39. Harding SM, Benci JL, Irianto J,DischerDE,MinnAJ,Greenberg RA.Mitoticprogression following DNA damage enables pattern recognition withinmicronuclei. Nature 2017;548:466–70.

40. Mackenzie KJ, Carroll P, Martin CA,Murina O, Fluteau A, SimpsonD, et al.cGAS surveillance ofmicronuclei links genome instability to innate immu-nity. Nature 2017;548:461–5.

41. Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM,Schneider RJ, et al. DNA exonuclease Trex1 regulates radiotherapy-inducedtumour immunogenicity. Nat Commun 2017;8:15618.

42. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunitycycle. Immunity 2013;39:1–10.

43. Shekarian T, Valsesia-Wittmann S, Caux C, Marabelle A. Paradigm shift inoncology: targeting the immune system rather than cancer cells. Mutagen-esis 2015;30:205–11.

44. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age.Nature 2011;480:480–9.

45. Anagnostou VK, Brahmer JR. Cancer immunotherapy: a future paradigmshift in the treatment of non-small cell lung cancer. Clin Cancer Res2015;21:976–84.

46. ADIS R&D Profile. Tremelimumab. Drugs R D 2010;10:123–32.47. YERVOY (ipilimumab) injection [prescribing information]. Princeton, NJ:

Bristol-Myers Squibb Company; 2017.48. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle

A. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer 2016;52:50–66.

49. Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combinationimmunotherapy: putting the pedal to the metal. Front Oncol 2015;5:34.

50. Wang K,Wang J,Wei F, Yang F, Ren X. Expression of TLR4 in non-small celllung cancer is associated with PD-L1 and poor prognosis in patientsreceiving pulmonectomy. Front Immunol 2017;8:456.

51. Kaczanowska S, Joseph AM, Davila E. TLR agonists: our best frenemy incancer immunotherapy. J Leukoc Biol 2013;93:847–63.

52. Maleki Vareki S, Chen D, Di Cresce C, Ferguson PJ, Figueredo R, PampilloM, et al. IDO downregulation induces sensitivity to pemetrexed, gemci-tabine, FK866, and methoxyamine in human cancer cells. PLoS One2015;10:e0143435.

53. Yue EW, Sparks R, PolamP,ModiD,Douty B,WaylandB, et al. INCB24360(Epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase1 (IDO1) inhibitor for immuno-oncology. ACS Med Chem Lett 2017;8:486–91.

54. Kang J, Demaria S, Formenti S. Current clinical trials testing the combi-nation of immunotherapy with radiotherapy. J Immunother Cancer2016;4:51.

55. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al.Fulminant myocarditis with combination immune checkpoint blockade.N Engl J Med 2016;375:1749–55.

56. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lungcancer. N Engl J Med 2017;377:1919–29.

57. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW,Formenti SC, et al. Previous radiotherapy and the clinical activity andtoxicity of pembrolizumab in the treatment of non-small-cell lung cancer: asecondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18:895–903.

58. DurmGA, JohnsonC, Jalal SI, Sadiq AA, Jabbour SS, ZonR, et al. Safety andfeasibility of consolidation pembrolizumab following concurrent chemor-adiation for unresectable stage III non-small cell lung cancer: HoosierCancer Research Network LUN14-179. J Clin Oncol 2017;35(suppl):abstr8523.

59. Tamiya A, Tamiya M, Nakahama K, Taniguchi Y, Shiroyama T, Isa SI, et al.Correlation of radiation pneumonitis history before nivolumabwith onsetof interstitial lung disease and progression-free survival of patients withpre-treated advanced non-small cell lung cancer. Anticancer Res 2017;37:5199–205.

60. Kataoka Y, Ebi N, Fujimoto D, Hara S, Hirano K, Narabayashi T, et al.Prior radiotherapy does not predict nivolumab response in non-small-cell lung cancer: a retrospective cohort study. Ann Oncol 2017;28:1402.

61. Bang A, Wilhite TJ, Pike LRG, Cagney DN, Aizer AA, Taylor A, et al.Multicenter evaluation of the tolerability of combined treatment withPD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiationtherapy. Int J Radiat Oncol Biol Phys 2017;98:344–51.

62. Yuan Z, Fromm A, Ahmed KA, Grass GD, Yang GQ, Oliver DE, et al.Radiotherapy rescue of a nivolumab-refractory immune response in apatient with PD-L1-negative metastatic squamous cell carcinoma of thelung. J Thorac Oncol 2017;12:e135–6.

63. Komatsu T, Nakamura K, Kawase A. Abscopal effect of nivolumab in apatient with primary lung cancer. J Thorac Oncol 2017;12:e143–4.

64. Butts C, SocinskiMA,Mitchell PL, Thatcher N,Havel L, KrzakowskiM, et al.Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage IIInon-small-cell lung cancer (START): a randomised, double-blind, phase 3trial. Lancet Oncol 2014;15:59–68.

65. Mitchell P, Thatcher N, Socinski MA, Wasilewska-Tesluk E, Horwood K,Szczesna A, et al. Tecemotide in unresectable stage III non-small-cell lungcancer in the phase III START study: updated overall survival andbiomarkeranalyses. Ann Oncol 2015;26:1134–42.

66. Giaccone G, Bazhenova LA, Nemunaitis J, TanM, Juh�asz E, Ramlau R, et al.A phase III studyof belagenpumatucel-L, an allogeneic tumour cell vaccine,as maintenance therapy for non-small cell lung cancer. Eur J Cancer2015;51:2321–9.

67. Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2lymphokine-activated killer cell immunotherapy combined with chemo-therapy or radiotherapy after curative or noncurative resection of primarylung carcinoma. Cancer 1997;80:42–9.

68. Brunsvig PF, Kyte JA, Kersten C, Sundstrøm S, Møller M, Nyakas M, et al.Telomerase peptide vaccination in NSCLC: a phase II trial in stage IIIpatients vaccinated after chemoradiotherapy and an 8-year update on aphase I/II trial. Clin Cancer Res 2011;17:6847–57.






69. Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, et al. Local radiotherapy and granulocyte-macrophagecolony-stimulating factor to generate abscopal responses in patients withmetastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015;16:795–803.

70. van denHeuvel MM, Verheij M, Boshuizen R, Belderbos J, Dingemans AM,De Ruysscher D, et al. NHS-IL2 combined with radiotherapy: preclinicalrationale and phase Ib trial results in metastatic non-small cell lung cancerfollowing first-line chemotherapy. J Transl Med 2015;13:32.

71. Taunk NK, Rimner A, Culligan M, Friedberg JS, Brahmer J, Chaft J.Immunotherapy and radiation therapy for operable early stage and locallyadvanced non-small cell lung cancer. Transl Lung Cancer Res 2017;6:178–85.

72. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopalresponse to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013;1:365–72.

73. Tang C, Welsh JW, de Groot P, Massarelli E, Chang JY, Hess KR, et al.Ipilimumabwith stereotactic ablative radiation therapy: phase I results andimmunologic correlates fromperipheral T cells. Clin Cancer Res 2017;23:1388–96.

74. FujimotoD,Uehara K, Sato Y, Sakanoue I, ItoM, Teraoka S, et al. Alterationof PD-L1 expression and its prognostic impact after concurrent chemor-

adiation therapy in non-small cell lung cancer patients. Sci Rep 2017;7:11373.

75. HechtM, Buttner-Herold M, Erlenbach-Wunsch K, HaderleinM, Croner R,Gr€utzmann R, et al. PD-L1 is upregulated by radiochemotherapy in rectaladenocarcinoma patients and associated with a favourable prognosis. Eur JCancer 2016;65:52–60.

76. Lim SH, HongM, Ahn S, Choi YL, Kim KM,OhD, et al. Changes in tumourexpression of programmed death-ligand 1 after neoadjuvant concurrentchemoradiotherapy in patients with squamous oesophageal cancer. Eur JCancer 2016;52:1–9.

77. DewanMZ,GallowayAE, KawashimaN,Dewyngaert JK, Babb JS, FormentiSC, et al. Fractionated but not single-dose radiotherapy induces animmune-mediated abscopal effect when combined with anti-CTLA-4antibody. Clin Cancer Res 2009;15:5379–88

78. Chandra RA,Wilhite TJ, Balboni TA, Alexander BM, Spektor A,Ott PA, et al.A systematic evaluation of abscopal responses following radiotherapy inpatients with metastatic melanoma treated with ipilimumab. Oncoimmu-nology 2015;4:e1046028.

79. Schoenhals JE, Seyedin SN, Anderson C, Brooks ED, Li YR, Younes AI, et al.Uncovering the immune tumor microenvironment in non-small cell lungcancer to understand response rates to checkpoint blockade and radiation.Transl Lung Cancer Res 2017;6:148–58.


Ko et al.




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