Prognostic variables associated with improved outcomes in patients with stage III NSCLC treated with chemoradiation followed by consolidation Pembrolizumab: a subset analysis of a phase II study from the Hoosier Cancer Research Network LUN 14-179


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Prognostic variables associated with improved outcomes in patients 

with stage III NSCLC treated with chemoradiation followed by 

consolidation Pembrolizumab: a subset analysis of a phase II study 

from the Hoosier Cancer Research Network LUN 14-179 

Bilal Anouti1, Sandra Althouse2, Greg Durm3, Nasser Hanna3* 
1Indiana University Department of Internal Medicine, 1120 W Michigan St, Indianapolis, IN 46202, USA;

2Indiana University Department of Biostatistics, 410 W. 10th Street HITS 3000, Indianapolis, IN 46202, USA;

3Indiana University Simon Cancer Center, 535 Barnhill Dr., Indianapolis, IN 46202, USA 

*Corresponding author will be Dr. Nasser Hanna (nhanna@iu.edu)

___________________________________________________________________

This is the author's manuscript of the article published in final edited form as:
Anouti, B., Althouse, S., Durm, G., & Hanna, N. (2019). Prognostic variables associated with improved outcomes in 
patients with stage III NSCLC treated with chemoradiation followed by consolidation Pembrolizumab: A subset 
analysis of a phase II study from the Hoosier Cancer Research Network LUN 14-179. Clinical Lung Cancer, 0(0). 
https://doi.org/10.1016/j.cllc.2019.06.009

https://doi.org/10.1016/j.cllc.2019.06.009


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Abstract: 

Introduction 

HCRN LUN 14-179 is a phase II trial of consolidation pembrolizumab following 
concurrent chemoradiation for the treatment of patients with stage III NSCLC.  Time to 
metastatic disease, progression free survival and overall survival appear superior to historical 
controls of chemoradiation alone.  Unfortunately, not all patients benefit from consolidation 
immunotherapy.  We performed a univariate analysis evaluating variables associated with PFS, 
metastatic disease, and OS.    

Methods 

We conducted a retrospective analysis from patients enrolled on HCRN LUN14-179. 
Data collected included age, sex, stage, smoking status, PD-L1 status, >G2 vs <G1 adverse 
event, <G2 vs. >G3 pneumonitis, duration of pembrolizumab (<4 vs. >4 cycles), chemotherapy 
regimen, PS 0 vs 1, time to start pembrolizumab (4-6 vs. 6-8 weeks from radiation), V20 (<20% 
vs. >20%). Univariable Cox regression was performed to determine the variables associated with 
3 endpoints: TMDD; PFS; and OS.   

Results 

From April 2015 to December 2016, 93 patients were enrolled and 92 were included in 
the efficacy analysis (1 patient was ineligible). For TMDD, improved outcomes may be 
associated (p<0.1) with stage IIIA, non-squamous cell, >4 cycles of pembrolizumab, and V20< 
20%.  For PFS, improved outcomes (p<0.1) may be seen for >4 cycles of pembrolizumab, and 
V20< 20%. For OS, improved outcomes (p<0.1) may be seen for non-squamous histology, >4 
cycles of pembrolizumab.   

Conclusion 

Non-squamous NSCLC, longer duration of pembrolizumab, and V20< 20% may be 
associated with prolonged time to metastatic disease or death, PFS, and OS for patients with 
stage III NSCLC treated with chemoradiation followed by pembrolizumab.   

Keywords: 

Immunotherapy, Non-small cell lung cancer, Adjuvant therapy, Prognosis. 

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Introduction: 

Over the last 20 years, the 5 year survival rate for patients with stage IIIA and IIIB 

NSCLC has been 10-15% and 3-7%, respectively1. The standard of care for these patients during 

this period remained concurrent chemotherapy and radiation therapy2-4.  This standard has 

recently changed, based upon the results from the randomized, phase III PACIFIC trial.  In this 

study, patients with stage III NSCLC were treated with a variety of chemotherapy regimens 

concomitantly with radiation therapy and subsequently randomized in a 2:1 fashion to receive 

either durvalumab, a PD-L1 inhibitor, or placebo for up to 1 year.   Median progression-free 

survival for those receiving durvalumab was 16.8 compared with 5.6 months for placebo.  

Overall survival was also improved for those receiving durvalumab with a 24-month overall 

survival rate of 66.3% compared with 55.6% in the placebo group5.  A phase II study from the 

Hoosier Cancer Research Network (HCRN LUN 14-179) evaluated the role of consolidation 

pembrolizumab after chemoradiation in patients with stage III NSCLC. This study recruited 

patient from 14 sites in the U.S.   Results from this study indicated efficacy outcomes 

[progression free-survival (PFS), time to metastatic disease or death (TMDD), and overall 

survival (OS)] similar to those achieved with durvalumab in the PACIFIC trial with median 

TMDD of 22.4 months and a median PFS of 17 months in a similar study population. 

Prognostic variables associated with improved outcomes in patients with stage III 

NSCLC treated with chemoradiation are well characterized.  Performance status 0-1, absence of 

weight loss in the 3 months preceding the diagnosis of lung cancer, stage IIIA (compared with 

IIIB) disease, and volume of lung receiving at least 20 Gy of radiation (V20) < 20% are 

associated with improved outcomes6-8.  However, prognostic variables associated with improved 

efficacy from consolidation immunotherapy after chemoradiation therapy have not been defined.  

The anti-cancer mechanisms of checkpoint inhibitors is substantially different than conventional 

chemotherapy.  Furthermore, checkpoint inhibitors are associated with a vastly different side 

effect profile compared with conventional chemotherapy.  We, therefore, performed this 

retrospective subset analysis to evaluate potential prognostic variables associated with 

improvements in TMDD, PFS, and OS in patients with stage III NSCLC treated with 

chemoradiation followed by pembrolizumab from the HCRN LUN 14-179 clinical trial.   

 

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Methods: 

Study population 

We conducted a retrospective analysis from patients enrolled on HCRN LUN 14-179.  

This was a single arm, phase II trial of concurrent chemoradiation followed by consolidation 

pembrolizumab 200 mg IV every 3 weeks until disease progression, unacceptable toxicity, or up 

to 1 year of therapy was completed.  Patients were permitted to receive carboplatin plus 

paclitaxel, cisplatin plus etoposide, or cisplatin plus pemetrexed (non-squamous cell only) given 

concurrently with 59.4-66.6 Gy XRT.  Patients were also permitted up to 2 cycles of 

consolidation chemotherapy.  Patients with non-progression of disease were then enrolled onto 

the clinical trial.  Eligible patients had a PS of 0-1, stage IIIA or IIIB squamous or non-squamous 

NSCLC.  Patients with contraindications to checkpoint inhibitors were excluded, including a 

history of non-infectious pneumonitis or interstitial lung disease.  Patients were not excluded 

based upon pulmonary function, V20 or weight loss.  The primary objective of the overall study 

was to determine if consolidation pembrolizumab following concurrent chemoradiation improves 

time to death or metastatic disease in inoperable stage III NSCLC patients.  The efficacy and 

safety results of the overall study population have been reported9. The primary objective of this 

subset analysis was to determine prognostic variables associated with TMDD, PFS and OS.   

Prognostic variables 

Prognostic variables considered for this analysis included age, sex, stage of NSCLC (IIIA 

vs. IIIB), histology (squamous vs. non-squamous), smoking status (current vs. former vs. never 

smoker), PD-L1 status (>1% vs. < 1%), any adverse event grade ((≤ G2 vs. ≥ G3), pneumonitis 

(≤ G2 vs. ≥ G3), duration of treatment with pembrolizumab (< 4 vs. ≥ 4 cycles), chemotherapy 

regimen (carboplatin/paclitaxel vs. cisplatin/etoposide), ECOG performance status (0 vs. 1), 

interval between completion of radiation to start of pembrolizumab (4-6 weeks vs. 6-8 weeks) 

and volume of lung receiving at least 20 Gy of radiation (V20) (≤ 20% vs. >20%).   PD-L1 

testing was performed using modified proportion score (MPS).  This scoring system includes 

both PD-L1 positive mononuclear inflammatory cells (MIC), including macrophages and 

lymphocytes, and tumor cells.  It also evaluates MICs within the tumor-associated stroma, 

though this is not factored into the percent MPS score. 

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Statistical analysis 

Data analysis was conducted using SAS software version 9.4 (SAS Institute Inc., Cary, 

NC). A p-value < .05 denoted statistical significance for all tests. Basic comparisons were made 

using Chi-Square Tests. Univariable Cox regression was performed to determine the variables 

associated with 3 endpoints: TMDD, PFS and OS. Variables found to have a P < 0.1 on 

univariable Cox regression analysis were included in a multivariable Cox regression model.  Due 

to a small sample size (n=92), we chose p < 0.1 as the cutoff in the univariable regression for 

inclusion into the multivariable regression model, to allow us to still develop hypothesis-

generating prognostic variables to be studied in larger trials in the future.. 

Results: 

From April 2015 to December 2016, 93 patients were enrolled and 92 were included in 

the efficacy analysis (1 patient was ineligible). The median follow-up was 30.5 months with a 

minimum follow-up of 26 months for patients who are alive.  Patient and disease characteristics 

are summarized in Table 1.  

For time to metastatic disease or death (TMDD), improved outcomes (p<0.1) were 

associated with stage IIIA (p=0.0922), non-squamous cell (p=0.0999), > 4 cycles of 

pembrolizumab (p<0.001), and V20 ≤ 20% (p=0.0716) according to the Univariable Cox 

regression model. A multivariable model was run with those variables and Stage IIIA (HR=2.9, 

p=0.02) and >4 cycles of pembrolizumab (HR=9.1, p<0.001) remained significant. On the other 

hand, smoking status was not associated with a difference in TMDD (p=0.7204) on univariable 

Cox regression model. PDL-1 status was also not associated with TMDD (p=0.3505) (Table 3). 

For PFS, improved outcomes (p<0.1) may be seen for >4 cycles of pembrolizumab 

(p<0.001), and V20≤ 20% (p=0.0630) according to the Univariable Cox regression model. A 

multivariable model was run with those variables and >4 cycles of pembrolizumab (HR=3.9, 

p<0.001) remained significant. Smoking status (p=0.9679), PDL-1 status (p=0.3261), and stage 

IIIA vs. IIIB (p=0.1444) were not associated with PFS. (Table 4). 

For OS, improved outcomes (p<0.1) may be seen for non-squamous histology 

(p=0.0829), and > 4 cycles of pembrolizumab (p<0.001) according to the univariable Cox 

regression model. A multivariable model was run with those variables and > 4 cycles of 

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pembrolizumab (HR=4.9, p<0.001) remained significant. Smoking status (p=0.6043), PDL-1 

status (p=0.1901) and stage of disease (p=0.1588) were not prognostic for OS (Table 5).  

 

Table 1: Baseline characteristics of study population (N=92) 

Characteristics Statistics 

Age (years), mean (std) 64 (8.6) 

Gender, n (%)  

Male 59 (64) 

Female 33 (36) 

Stage, n (%)  

IIIA 55 (60) 

IIIB 37 (40) 

Histology of NSCLC, n (%)  

Non-squamous 51 (55) 

Squamous 41 (45) 

Distant metastasis or death on follow-up*, n 

(%) 

 

Present 34 (37) 

Not present 57 (63) 

*One patient did not have an evaluable response for distant metastasis or death 

 

Table 2: Basic comparisons of outcomes 

Variable TMDD PFS OS 

IIIA (n=55) 

IIIB (n=37) 

69%   p=0.12 

51% 

56%   p=0.21 

41% 

75%  p=0.13 

59% 

Non-SCCA (n=51) 

SCCA (n=41) 

69%   p=0.11 

54% 

55%   p=0.21 

44% 

75%   p=0.16 

61% 

PD-L1 [-] (n=11) 

PD-L1 [+] (n=42) 

82%   p=0.13 

57% 

64%   p=0.19 

40%  

91%   p=0.07 

62% 

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> 4 pembro (n=77) 

< 4 pembro (n=15) 

68%   p=0.01 

33% 

55%   p=0.04 

27% 

75%   p=0.001 

33% 

V20 ≤ 20% (n=19) 

V20 > 20% (n=59) 

79%   p=0.07 

54% 

63%    p=0.08 

39% 

79%   p=0.15 

61% 

G < 2 pneumonitis (n=87) 

G > 3 pneumonitis (n=5) 

63%   p=0.28 

40% 

51%   p=0.61 

40% 

70%   p=0.16 

40% 

Female (n=33) 

Male (n=59) 

67%   p=0.37 

59% 

67%   p=0.11 

59% 

73%   p=0.51 

66% 

<65 years old (n=43) 

≥65 years old (n=49) 

56%   p=0.32 

67% 

49%   p=0.99 

51% 

65%   p=0.52 

71% 

Current Smoker (n=16) 

Former Smoker (n=71) 

Never Smoker (n=5) 

50%   p=0.42 

66% 

40% 

50%   p=0.99 

51% 

40% 

56%   p=0.44 

72% 

60% 

Any AE Grade ≤2 (n=46) 

Any AE Grade ≥3 (n=46) 

70%   p=0.17 

54% 

56%   p=0.29 

43% 

76%   p=0.12 

61% 

Carboplatin/Paclitaxel (n=66) 

Cisplatin/Etoposide (n=24) 

59%   p=0.57 

67% 

44%   p=0.15 

63% 

65%   p=0.38 

75% 

Rad Interval 4-6 weeks (n=17) 

Rad Interval 6-8 weeks (n=75) 

53%   p=0.56 

64% 

41%   p=0.71 

52% 

59%   p=0.34 

71% 

ECOG=0 (n=40) 

ECOG=1 (n=52) 

68%   p=0.40 

58% 

55%   p=0.38 

46% 

73%   p=0.47 

65% 

 

Table 3: Univariate analysis for prognostic variables associated with time to metastatic 

disease or death 

  Univariable Results Multivariable Results 

Variable Comparison* 

Hazard Ratio 

(95% CI) p-value 

 

Hazard Ratio 

(95% CI) 

 

p-value 

Age <65 vs. ≥65 years old 1.00 (0.96, 1.04) 0.9678   

Gender Female vs Male 0.97 (0.46, 2.04) 0.9401   

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  Univariable Results Multivariable Results 

Variable Comparison* 

Hazard Ratio 

(95% CI) p-value 

 

Hazard Ratio 

(95% CI) 

 

p-value 

Stage IIIB vs IIIA 1.79 (0.91, 3.52) 0.0922 2.87 (1.21, 6.81) 0.0165 

Histology non-squamous vs 
squamous 

0.57 (0.29, 1.12) 0.0999 0.63 (0.30, 1.32) 0.2192 

Smoking status Current vs Former 1.39 (0.62, 3.10) 0.7204   

 Current vs Never 1.21 (0.25, 5.74)    

 Former vs Never 0.87 (0.20, 3.71)    

PDL-1 status Negative vs Positive 0.50 (0.12, 2.16) 0.3505   

Any adverse 
event 

Grade <=2 vs Grade >=3 0.65 (0.33, 1.29) 0.2194   

Pneumonitis 
grade 

Grade <=2 vs Grade >=3 0.57 (0.17, 1.86) 0.3493   

Duration of 
treatment with 
pembrolizumab 

<4 cycles vs >=4 cycles of 
treatment 

5.98 (2.75, 13.00) <.0001 9.14 (3.35, 24.92) <.0001 

Type of chemo Carboplatin/Paclitaxel vs 
Cisplatin/Etoposide 

1.36 (0.61, 3.03) 0.4462   

ECOG 0 vs 1 0.63 (0.31, 1.29) 0.2035   

Time between 
radiation to 
pembrolizumab 

4-6 weeks vs 6-8 weeks 1.40 (0.61, 3.24) 0.4315   

V20 <=20% vs >20% 0.38 (0.13, 1.09) 0.0716 0.64 (0.21, 1.95) 0.4346 

*reference category is the second category 

Table 4: Univariate analysis for prognostic variables associated with progression-free 
survival 

  Univariable Results Multivariable Results 

Variable Comparison* 

Hazard Ratio 

(95% CI) p-value 

 

Hazard Ratio 

(95% CI) 

 

p-value 

Age <65 vs. ≥65 years old 1.00 (0.97, 1.04) 0.8557   

Gender Female vs Male 0.80 (0.41, 1.55) 0.5065   

Stage IIIB vs IIIA 1.56 (0.86, 2.83) 0.1444   

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  Univariable Results Multivariable Results 

Variable Comparison* 

Hazard Ratio 

(95% CI) p-value 

 

Hazard Ratio 

(95% CI) 

 

p-value 

Histology non-squamous vs 
squamous 

0.72 (0.41, 1.31) 0.2859   

Smoking status Current vs Former 1.04 (0.48, 2.25) 0.9679   

 Current vs Never 1.22 (0.26, 5.80)    

 Former vs Never 1.18 (0.28, 4.93)    

PDL-1 status Negative vs Positive 0.59 (0.20, 1.70) 0.3261   

Any adverse 
event 

Grade <=2 vs Grade >=3 0.78 (0.43, 1.41) 0.4031   

Pneumonitis 
grade 

Grade <=2 vs Grade >=3 0.83 (0.26, 2.67) 0.7472   

Duration of 
treatment with 
pembrolizumab 

<4 cycles vs >=4 cycles of 
treatment 

4.25 (2.11, 8.59) <.0001 3.87 (1.82, 8.25) 0.0005 

Type of chemo Carboplatin/Paclitaxel vs 
Cisplatin/Etoposide 

1.65 (0.79, 3.44) 0.1839   

ECOG 0 vs 1 0.71 (0.38, 1.30) 0.2665   

Time between 
radiation to 
pembrolizumab 

4-6 weeks vs 6-8 weeks 1.44 (0.66, 3.11) 0.3599   

V20 <=20% vs >20% 0.46 (0.20, 1.04) 0.0630 0.57 (0.25, 1.33) 0.1929 

*reference category is the second category 

Table 5: Univariate analysis for prognostic variables associated with overall survival 

  Univariable Results Multivariable Results 

Variable Comparison* 

Hazard Ratio 

(95% CI) p-value 

 

Hazard Ratio 

(95% CI) 

 

p-value 

Age <65 vs. ≥65 years old 1.01 (0.96, 1.05) 0.7975   

Gender Female vs Male 0.84 (0.38, 1.85) 0.6634   

Stage IIIB vs IIIA 1.69 (0.81, 3.52) 0.1588   

Histology non-squamous vs squamous 0.52 (0.25, 1.09) 0.0829 0.64 (0.30, 1.35) 0.2390 

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  Univariable Results Multivariable Results 

Variable Comparison* 

Hazard Ratio 

(95% CI) p-value 

 

Hazard Ratio 

(95% CI) 

 

p-value 

Smoking status Current vs Former 1.55 (0.66, 3.67) 0.6043   

 Current vs Never 1.48 (0.31, 7.18)    

 Former vs Never 0.95 (0.22, 4.11)    

PDL-1 status Negative vs Positive 0.26 (0.03, 1.96) 0.1901   

Any adverse 
event 

Grade <=2 vs Grade >=3 0.55 (0.26, 1.17) 0.1208   

Pneumonitis 
grade 

Grade <=2 vs Grade >=3 0.37 (0.11, 1.23) 0.1034   

Duration of 
treatment with 
pembrolizumab 

<4 cycles vs >=4 cycles of 
treatment 

5.40 (2.43, 12.02) <.0001 4.91 (2.18, 11.06) 0.0001 

Type of chemo Carboplatin/Paclitaxel vs 
Cisplatin/Etoposide 

1.58 (0.64, 3.90) 0.3225   

ECOG 0 vs 1 0.71 (0.33, 1.54) 0.3862   

Time between 
radiation to 
pembrolizumab 

4-6 weeks vs 6-8 weeks 1.54 (0.65, 3.63) 0.3225   

V20 <=20% vs >20% 0.51 (0.17, 1.48) 0.2136   

*reference category is the second categor 

  

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Discussion: 

Prognostic variables associated with better or worse outcomes for patients with stage III 

NSCLC treated with concurrent chemoradiation are well characterized7.  However, prognostic 

variables associated with outcomes are not well defined in this patient population receiving 

consolidation PD-1 or PD-L1 inhibition. The analysis performed from HCRN LUN 14-179 

reported here indicates that receiving 4 or more cycles of consolidation pembrolizumab is 

associated with improved PFS, TMDD, and OS compared with receiving fewer than 4 cycles. 

The interpretation of this, however, should be undertaken with caution.  It is possible (and even 

likely) that this simply represents a patient population who tolerated therapy well and may have 

had more favorable tumor biology.  It should be noted, though, that duration of pembrolizumab 

therapy remained prognostic when factoring in other variables, including stage, PD-L1 score, 

histology, V20, and PS, which can influence efficacy outcomes.   The optimal duration of 

consolidation PD-1 or PD-L1 inhibition after chemoradiation is not defined.  The PACIFIC trial 

and the HCRN LUN 14-179 trials each permitted up to 1 year of consolidation checkpoint 

inhibition.  Approximately 40% of patients on each study were able to receive 1 year of therapy, 

and the median duration of consolidation therapy received in both studies was approximately 9 

months5.   

Other known prognostic variables for patients with stage III NSCLC were evaluated in 

the current study.  V20 < 20% is associated with less toxicity and better outcomes for patients 

treated with chemoradiation for stage III NSCLC10.  Based upon the current analysis, it appears 

that V20 < 20% is also associated with improved PFS and TMDD with consolidation 

pembrolizumab. Lower V20 may simply be a surrogate for lower volume of disease, selecting 

out patients who may be more curable.   Furthermore, non-squamous NSCLC was also 

associated with improved survival with consolidation pembrolizumab.   

Subset analyses from the PACIFIC trial suggested that patients with PD-L1 expression of 

< 1% may not have improved survival with consolidation durvalumab compared with placebo, 

although PFS was improved with durvalumab in that  analysis5.  The HCRN LUN 14-179 trial 

utilized a PD-L1 testing platform that assessed PD-L1 expression in tumor cells along with other 

cells in the microenvironment.  Utilizing this assay, PD-L1 expression of < 1% was not 

associated with inferior survival with consolidation pembrolizumab. It is possible that the 

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utilization of different assays resulted in disparate results between HCRN LUN 14-179 and the 

PACIFIC trial.  The optimal therapy for patients with PD-L1 scores of 1% remains undefined. 

In addition, a subset analysis from the PACIFIC trial suggested that initiating 

consolidation durvalumab within 2 weeks of completing chemoradiation was associated with 

improved outcomes5.  In contrast, patients enrolled onto HCRN LUN 14-179 were required to 

wait a minimum of 4 weeks and a maximum of 8 weeks after completing chemoradiation prior to 

initiating pembrolizumab.  The current study evaluated the differences in outcomes of patients 

initiating pembrolizumab 4-6 weeks after chemoradiation versus those initiating pembrolizumab 

6-8 weeks after chemoradiation.  No difference was detected in efficacy outcomes (PFS, TMDD, 

OS) between these subgroups.  It is possible that patients receiving durvalumab within 2 weeks 

of chemoradiation on the PACIFIC trial represented patients with fewer medical problems, 

improved tolerance to therapy, and better performance status.  Furthermore, smoking status, age, 

gender, chemotherapy regimen, and development of pneumonitis during consolidation 

immunotherapy do not appear to be associated with outcomes in this patient population.   

While this was the first attempt to evaluate prognostic variables utilizing immunotherapy 

after chemoradiation for patients with stage III NSCLC, it is important to recognize the 

limitations of this analysis.  This analysis was retrospective and unplanned.  Secondly, a p value 

of <1% was utilized as a cut-off for utilization in the multivariate model.  Third, the sample size 

of this study is relatively small.  Fourth, the PD-L1 assay utilized is not standard.  Fifth, PFS can 

be challenging to define in a patient population treated with radiation due to the difficulty of 

interpreting local progression.  Nevertheless, despite these significant limitations, this study 

serves as hypothesis generating to test variables in larger studies of this patient population..  

In conclusion, this is the first dedicated report assessing prognostic variables associated 

with outcomes in patients with stage III NSCLC treated with chemoradiation followed by 

consolidation pembrolizumab.  Efforts are underway to build off the success of the PACIFIC and 

HCRN LUN 14-179 trials.  Given the increased risks and costs associated with consolidation 

immunotherapy in this setting, it is essential to define the optimal duration of immunotherapy 

and to identify prognostic markers associated with benefit (or detriment) with this strategy.  One 

such effort is underway through the BIG10 Cancer Research Consortium (NCT03285321) which 

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will evaluate multiple clinical factors, radiation treatment variables, and molecular biomarkers 

associated with outcomes in patients treated with consolidation immunotherapy strategies. 

  

  

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References: 

1. National Cancer Institute NC. Non-Small Cell Lung Cancer Treatment. Available at 
https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq#section/_4889. 2018. 
2. Albain KS, Crowley JJ, III ATT, et al. Concurrent Cisplatin, Etoposide, and Chest Radiotherapy 
in Pathologic Stage IIIB Non–Small-Cell Lung Cancer: A Southwest Oncology Group Phase II Study, 
SWOG 9019. Journal of Clinical Oncology 2002;20:3454-3460. 
3. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy 
followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest 
Oncology Group phase II study 8805. Journal of Clinical Oncology 1995;13:1880-1892. 
4. (NCCN) NCCN. NCCN Clinical practice guidelines in oncology. Available at 
https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf Accessed February 20 2019. 
5. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–
small-cell lung cancer. New England Journal of Medicine 2017;377:1919-1929. 
6. Berghmans T, Paesmans M, Sculier JP. Prognostic factors in stage III non-small cell lung cancer: 
a review of conventional, metabolic and new biological variables. Therapeutic advances in medical 
oncology 2011;3:127-138. 
7. Urvay SE, Yucel B, Erdis E, et al. Prognostic Factors in Stage III Non-Small-Cell Lung Cancer 
Patients. Asian Pacific journal of cancer prevention : APJCP 2016;17:4693-4697. 
8. Sloan JA, Zhao X, Novotny PJ, et al. Relationship between deficits in overall quality of life and 
non-small-cell lung cancer survival. J Clin Oncol 2012;30:1498-1504. 
9. Durm GA, Althouse SK, Sadiq AA, et al. Phase II trial of concurrent chemoradiation with 
consolidation pembrolizumab in patients with unresectable stage III non-small cell lung cancer: Hoosier 
Cancer Research Network LUN 14-179. Journal of Clinical Oncology 2018;36:8500-8500. 
10. Ramella S, Trodella L, Mineo TC, et al. Adding ipsilateral V20 and V30 to conventional 
dosimetric constraints predicts radiation pneumonitis in stage IIIA–B NSCLC treated with combined-
modality therapy. International Journal of Radiation Oncology* Biology* Physics 2010;76:110-115. 

 

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