1. Evidence-Based Strategies for Challenging Squamous NSCLC Cases
Suresh S. Ramalingam, MD
Professor of Hematology and Medical Oncology
Director, Division of Medical Oncology
Assistant Dean for Cancer Research
Emory University School of Medicine
Deputy Director, Winship Cancer Institute
Atlanta, Georgia
NSCLC, non-small-cell lung cancer.

2. Case 1: Newly Diagnosed Squamous NSCLC
68-yr-old man, former smoker with 30 pack-yr history, presented with chest pain on his right side
PMH: HTN and COPD
Imaging studies identified 5-cm lesion in upper right lobe and mediastinal LN enlargement
PET scan identified lesions in bones and adrenal gland
Brain MRI negative
Biopsy identified squamous NSCLC
ECOG PS 1
COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; HTN, hypertension; LN, lymph node; NSCLC, non-small-cell lung cancer; PMH, past medical history; PS, performance status.

3. Case 1: Expert Recommendations
68-yr-old man diagnosed with metastatic squamous NSCLC; former heavy smoker, ECOG PS 1
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status.

4. Recommended First-line Chemotherapy Regimens for Squamous NSCLC
PS 0/1
PS 2
Carboplatin/nab-paclitaxel
Carboplatin/docetaxel
Carboplatin/etoposide
Carboplatin/gemcitabine
Carboplatin/paclitaxel
Carboplatin/vinorelbine
Cisplatin/docetaxel
Cisplatin/etoposide
Cisplatin/gemcitabine
Cisplatin/gemcitabine/necitumumab
Cisplatin/paclitaxel
Cisplatin/vinorelbine
Gemcitabine/docetaxel
Gemcitabine/vinorelbine
Nab-paclitaxel
Docetaxel
Etoposide
Gemcitabine
Irinotecan
Paclitaxel
NSCLC, non-small-cell lung cancer; PS, performance status.
NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v
Slide credit: clinicaloptions.com

5. Therapeutic Plateau in Metastatic NSCLC ECOG 1594
100
Cisplatin/paclitaxel
Cisplatin/gemcitabine
Cisplatin/docetaxel
Carboplatin/paclitaxel 80 60
OS (%) 40 20
NSCLC, non-small-cell lung cancer. 10 20 30 40
Mos
Slide credit: clinicaloptions.com
Schiller JH, et al. N Engl J Med. 2002;346:92-98.

6. Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine: OS by Histology
Nonsquamous
Squamous
C/P C/G C/P vs C/G
Median Survival, Mos
11.8
10.4
Adjusted HR: 0.81 (95% CI: )
Median Survival, Mos
1.0
1.0
C/P C/G C/P vs C/G
9.4
10.8
0.8
0.8
Adjusted HR: 1.23 (95% CI: )
0.6
0.6
Survival Probability
Survival Probability
0.4
0.4
0.2
0.2
C/G, cisplatin/gemcitabine; C/P, cisplatin/pemetrexed; NSCLC, non-small-cell lung cancer. 6 12 18 24 30 6 12 18 24 30
Mos
Mos
No difference in overall group between study arms: C/P 10.3 mos vs C/G 10.3 mos; adjusted HR: 0.94 (95% CI: )
Slide credit: clinicaloptions.com
Scagliotti GV, et al. J Clin Oncol. 2008;26: 6

7. SQUIRE: Overall Survival
Cisplatin/ Gemcitabine + Necitumumab (n = 545)
100
Cisplatin/ Gemcitabine (n = 548)
Pts censored, n (%)
Median OS, mos (95% CI)
Stratified P value (log rank)
Stratified HR (95% CI)
127 (23)
11.5 ( )
.01
0.84 ( )
106 (19)
9.9 ( ) 80 60
OS (%) 40 20
Cisplatin/gemcitabine + necitumumab
Censored pts
Cisplatin/gemcitabine 4 8 12 16 20 24 28 32 36 40
Mos
Slide credit: clinicaloptions.com
Thatcher N, et al. Lancet Oncol. 2015;16:

8. SQUIRE: Progression-Free Survival
Cisplatin/ Gemcitabine Necitumumab, n/Events
Cisplatin/ Gemcitabine, n/Events
HR (95% CI)
Age group, yrs
< 65
≥ 65 to < 70
≥ 70
332/258
105/79
108/81
340/277
111/94
97/71
0.88 ( )
0.63 ( )
1.03 ( )
Sex
Women
Men
95/77
450/341
90/72
458/370
0.88 ( )
0.84 ( )
Race
White
Nonwhite
457/355
88/63
456/369
92/73
0.86 ( )
0.78 ( )
Smoking status
Never/light exsmoker
Current smoker
44/34
500/383
53/44
495/398
0.82 ( )
0.85 ( )
ECOG PS 1 2
164/117
332/260
49/41
180/139
320/261
47/42
0.82 ( )
0.85 ( )
0.78 ( )
Overall ITT population
545/418
548/442
0.84 ( )
ECOG, Easter Cooperative Oncology Group; ITT, intent to treat; PS, performance status.
0.45 1
1.5
Favors necitumumab plus cisplatin/gemcitabine
Favors cisplatin/gemcitabine
Slide credit: clinicaloptions.com
Thatcher N, et al. Lancet Oncol. 2015;16:

9. SQUIRE: Adverse Events Possibly Related to Necitumumab
Cisplatin/Gemcitabine + Necitumumab
Overall (N = 538)
Cisplatin/Gemcitabine Overall (N = 541)
Grade 1/2
Grade ≥ 3
Skin reactions 71 8 11
< 1
Rash 69 7 10
Hypomagnesemia 22 9 15 1
Venous thromboembolic events 4 5 3
Slide credit: clinicaloptions.com
Thatcher N, et al. Lancet Oncol. 2015;16:

10. Carboplatin/Nab-Paclitaxel vs Carboplatin/ Paclitaxel in Advanced NSCLC: Responses
Carboplatin/nab-paclitaxel Carboplatin/paclitaxel
P < .001 RRR: 1.680 50
Response Rate (%)
P = .005 RRR: 1.31
41% 40
P = .808 RRR: 1.034
33% 30
26%
25%
24%
25% 20
ITT, intent to treat; NSCLC, non-small-cell lung cancer; RRR, response rate ratio. 10
n =
521
531
229
221
292
310
ITT
Squamous
Nonsquamous
Less neuropathy reported with nab-paclitaxel vs paclitaxel
Slide credit: clinicaloptions.com
Socinski MA, et al. J Clin Oncol. 2012;30:

11. Doublet vs Single-Agent Chemotherapy in Pts With Advanced NSCLC and PS 2
CALGB 9730 trial compared carboplatin/paclitaxel vs single- agent paclitaxel
18% of pts with a PS of 2
40% reduction for risk of death with doublet (P = .016)
IFCT-0501 trial compared carboplatin/paclitaxel vs gemcitabine or vinorelbine
37% reduction for risk of death with doublet in PS 2 pts (n = 123)
Regimen
Pts With PS 2, n
Median OS, Mos
1-Yr Survival Rate, %
Carboplatin/paclitaxel 49
4.7 18
Paclitaxel 50
2.4 10
NSCLC, non-small-cell cancer; PS, performance status.
Lilenbaum RC, et al. J Clin Oncol. 2005;23:
Quoix E, et al. Lancet. 2011;378:
Slide credit: clinicaloptions.com

12. Case 2: Progressive Squamous NSCLC
72-yr-old man diagnosed with squamous NSCLC 6 mos ago
ECOG PS 1
Treated with carboplatin/paclitaxel for 4 cycles; achieved stable disease
Recent follow-up identified disease progression in lungs, adrenal gland, and bones
Biopsy tissue testing revealed PD-L1 positive with 63% staining of tumor cells
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell cancer; PS, performance status.

13. Case 2: Expert Recommendations
72-yr-old man with progressive metastatic squamous NSCLC, ECOG PS 1, previous carboplatin/paclitaxel, PD-L1 positive
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell cancer; PS, performance status.

14. CheckMate-017: OS 100 80 60 40 20 OS (%) 3 6 9 12 15 18 21 24 Mos
Median OS,
Mos (95% CI) 9.2 ( )
6.0 ( )
1-Yr OS,
% 42 24
18-Mo OS,
% 28 13
Nivolumab Docetaxel
HR: 0.59 (95% CI: ; P < .001)
OS (%) 3 6 9 12 15 18 21 24
Mos
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

15. CheckMate-017: OS by PD-L1 Expression
1% PD-L1 Expression Level
5% PD-L1 Expression Level
10% PD-L1 Expression Level
Median OS, Mos
Median OS, Mos
Median OS, Mos
PD-L1 ≥ 1%
PD-L1 < 1%
Nivolumab
9.3
8.7
Docetaxel
7.2
5.9
PD-L1 ≥ 5%
PD-L1 < 5%
Nivolumab
10.0
8.5
Docetaxel
6.4
6.1
PD-L1 ≥ 10%
PD-L1 < 10%
Nivolumab
11.0
8.2
Docetaxel
7.1
6.1
100 80 60
OS (%) 40 20 6 12 18 24 6 12 18 24 6 12 18 24
Mos
Mos
Mos
Nivolumab PD-L1+
Nivolumab PD-L1-
Docetaxel PD-L1+
Docetaxel PD-L1-
Slide credit: clinicaloptions.com
Brahmer J, et al. N Engl J Med. 2015;373:

16. KEYNOTE-001: Pembrolizumab Efficacy by PD-L1 Expression
ORR
Pts, n
All Cohorts, % (95% CI)
Percent PD-L1 staining
≥ 50% 73
45.2 ( )
1% to 49%
103
16.5 ( )
< 1% 28
10.7 ( )
100
PFS
100 OS 80 80
PS ≥ 50% (n = 119) 60 60
PFS (%)
OS (%) 40
PS, proportion score.
PS ≥ 50% (n = 119) 40
PS 1-49% (n = 161)
PS < 1% (n = 76) 20
PS < 1% (n = 76) 20
PS 1-49% (n = 161) 2 4 6 8 10 12 14 16 18 20 22 24 26 4 8 12 16 20 24 28
Mos
Mos
Slide credit: clinicaloptions.com
Garon EB, et al. N Engl J Med. 2015;372:

17. KEYNOTE-010: OS All pts experienced OS benefit from pembrolizumab
PD-L1 TPS ≥ 1%
PD-L1 TPS ≥ 50%
100 80 60 40 20
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
100 80 60 40 20
OS (%)
OS (%)
TPS, tumor proportion score. 5 10 15 20 25 5 10 15 20 25
Mos
Mos
Slide credit: clinicaloptions.com
Herbst RS, et al. Lancet. 2016;387:

18. POPLAR: Atezolizumab vs Docetaxel in NSCLC Updated OS, Biomarker AnalysesHR
(95% CI)
P Value n
Median OS,
Mos
ITT
144
12.6
143
9.7
0.69 ( )
.011
TC3 or IC3 24
Not estimable 23
11.1
0.45 ( )
.033
TC2/3 or IC2/3 50
15.1 55
7.4
0.50 ( )
.003
TC1/2/3 or IC1/2/3 93
102
9.2
0.59 ( )
TC0 and IC0 51
9.7 41
0.88 ( )
.601
IC, immune cell; ITT, intent to treat; NSCLC, non-small-cell lung cancer; TC, tumor cell.
Squamous 49
10.1 48
8.6
0.66 ( )
.075
Nonsquamous 95
14.8
10.9
0.69 ( )
.039
Slide credit: clinicaloptions.com
Smith DA, et al. ASCO Abstract 9028.

19. REVEL: Ramucirumab + Docetaxel vs Docetaxel in Pts With PD After Chemo: OS
FDA approved ramucirumab (12/14) in combination with docetaxel in metastatic NSCLC with disease progression on or after platinum-based chemotherapy 20 40 60 80
100
Median OS, Mos (95% CI)
Ram + doc
Pbo + doc
Ram + doc vs pbo + doc HR: (95% CI: ; P = .023)
10.5 ( )
9.1 ( )
OS (%)
Doc, docetaxel; Pbo, placebo; PD, progressive disease; Ram, ramucirumab.
Ram + doc
Pbo + doc
Censored 3 6 9 12 15 18 21 24 27 30 33 36
Mos
Slide credit: clinicaloptions.com
Garon EB, et al. Lancet. 2014;384:

20. Docetaxel + Ramucirumab Overall (N = 627) Docetaxel Overall (N = 618)
REVEL: Adverse Events
AEs, %
Docetaxel + Ramucirumab Overall (N = 627)
Docetaxel Overall (N = 618)
Any AEs 98 95
Grade ≥ 3 AEs
Fatigue
Neutropenia
Febrile neutropenia 79 14 49 16 71 10 39
Serious AEs 43 42
AEs of special interest
Bleeding/hemorrhage
Hypertension
Any grade 29 11
Grade ≥ 3 2 6 15 5
AE, adverse event.
Slide credit: clinicaloptions.com
Garon EB, et al. Lancet. 2014;384:

21. Case 3: Suspected Pneumonitis
68-yr-old man diagnosed with stage IV squamous NSCLC
Experienced disease progression following platinum- based doublet chemotherapy
Started pembrolizumab
After 4 mos, experienced progressive dyspnea
No fever, no hemoptysis
Examination revealed hypoxia with oxygen saturation of 86% to 88% on rom air
Chest x-ray identified hazy infiltrates in both lungs
NSCLC, non-small-cell lung cancer.

22. Immune-Related Pneumonitis: Signs and Symptoms
Shortness of breath
Dry cough
New or increasing oxygen requirements
May be detected just on imaging
Decreasing oxygen saturation on room air
11/15/2013: Prepneumonitis
1/21/14: Pneumonitis
2/21/14: Improved with steroids; taper completed 3/7/14
Slide credit: clinicaloptions.com

23. Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities
Onset: average is 6-12 wks after initiation of therapy
Can occur within days of the first dose, after several mos of treatment, and after discontinuation of therapy
Occasional (5% to 20%)
Fatigue, headache, arthralgia, fevers, chills, lethargy
Rash: maculopapular, pruritus, vitiligo
Topical treatments
Diarrhea/colitis
Initiate steroids early, taper slowly
Hepatitis, liver/pancreatic enzyme abnormalities
Infusion reactions
Endocrinopathies: thyroid, adrenal, hypophysitis
Rare (< 5%)
Pneumonitis
Grade 3/4 toxicities uncommon
Low grade reversible with steroids and discontinuation
Anemia
Villadolid J, et al. Transl Lung Cancer Res. 2015;4:
Weber JS, et al. J Clin Oncol. 2015;33:
Slide credit: clinicaloptions.com

24. General Principles of Immune-Related Toxicity Management
Management generally based on severity of symptoms
Grade 1: supportive care; ± withhold drug
Grade 2: withhold drug, consider restarting if toxicity resolves to grade ≤ 1; low-dose corticosteroids (prednisone 0.5 mg/kg/day or equivalent) if symptoms do not resolve within 1 wk
Grade 3/4: discontinue drug; high-dose corticosteroids (prednisone 1-2 mg/kg/day or equivalent) tapered over ≥ 1 mo once toxicity resolves to grade ≤ 1
Ipilimumab adverse reaction management guide. Nivolumab adverse reaction management guide. Pembrolizumab adverse reaction management guide.
Slide credit: clinicaloptions.com

25. Conclusions
The therapeutic landscape in advanced squamous NSCLC has changed dramatically over the last few yrs
In first-line therapy, cisplatin/gemcitabine + necitumumab improves OS without significantly increasing adverse events
In second-line therapy, immune checkpoint inhibitors including nivolumab and pembrolizumab are now a standard of care
Vigilance is important for the management of uncommon but potentially serious complications associated with these agents