0. Unmet need in squamous non-small cell lung cancer (NSCLC)
Module 1
Last updated: December 2016

1. Epidemiology of lung cancer
Contents
Epidemiology of lung cancer
Risk factors and comorbidities associated with squamous NSCLC
Treatment options for squamous NSCLC
NSCLC, non-small cell lung cancer

2. Lung cancer is one of the most common cancers and is the most common cause of death by cancer worldwide1
Estimated age-standardized incidence and mortality rates (both sexes) based on 2012 data from the GLOBOCAN database1
Incidence
Mortality
Lung cancer is the most common cause of cancer- related death worldwide, accounting for 1.59 million deaths in 2012 (latest year for which data are available)1
Lung cancer deaths are expected to increase more than 1.8 times over the next 20 years1
Age-standardized rate (world) per 100,000
Age-standardized rate (world) per 100,000
The graphs show the incidence and mortality of all major cancers based on 2012 data from the GLOBOCAN database, which compiles estimates based on the most recent data available to the International Agency for Research on Cancer and on information publicly available on the Internet
The graph shows that globally in 2012, lung cancer had the third-highest incidence of all cancers, but was first in terms of mortality1
Worldwide in 2012, lung cancer accounted for approximately 1.59 million deaths1
Globally, the number of annual deaths due to lung cancer is expected to increase by more than 1.8 times over the next 20 years1
Reference
1. Ferlay J et al. GLOBOCAN Available at: (accessed October 15, 2014); top figure
1. Ferlay J et al. GLOBOCAN Available at: (accessed October 15, 2014)

3. Lung cancer is highly prevalent in the United States1
New cases*
Rank (%)
Deaths*
Total
224,390
1st (13.3)
158,080
1st (26.5)
Male
117,920
2nd (14.0)
85,920
1st (27.3)
Female
106,470
2nd (12.6)
72,160
1st (25.6)
*Includes estimates of both lung and bronchus cancer for 2016
5-year survival rate: 18% (patients diagnosed )
Over 220,000 new cases of lung cancer are estimated in the United States for the year 2016, making it the most diagnosed cancer among all patients
Over 155,000 deaths from lung cancer are estimated in the United States for the year 2016, making it the leading cause of cancer-related deaths in the United States
The 5-year survival rate for patients diagnosed from 2005–2011 was 18%
There was a statistically significant difference in rates between 1975 and 1977 and 2005 and 2011 (p<0.05)
Reference
1. Siegel RL et al. CA Cancer J Clin 2016;66:7-30; p. 6, table 1; p. 14, table 6, including footnote
1. Siegel RL et al. CA Cancer J Clin 2016;66:7-30

4. Lung cancer is highly prevalent and is the most common cause of death by cancer in Europe
Estimated number of new cancer cases
in Europe, 2012 (excludes sex-specific cancers)a
Estimated number of deaths from cancer
in Europe, 2012 (excludes sex-specific cancers)a
The graphs show the estimated incidence and mortality age-standardized rates from major cancers (excluding sex-specific cancers), based on data from 40 European countries in 20121
In Europe in 2012, in terms of absolute number of cases, lung cancer had the fourth-highest incidence of all cancers (410,000), following female breast cancer (464,000), colorectal cancer (447,000), and prostate cancer (417,000)
In Europe, again in terms of absolute numbers, lung cancer was the most common cause of death by cancer in 2012, accounting for 353,000 deaths1
Reference
Ferlay J et al. Eur J Cancer 2013;49:1374–403; p. 1379, table 3; p. 1382, right col., 2nd para.; p. 1385, right col., 1st para.
Age-standardized rate per 100,000
Age-standardized rate per 100,000
aTotal lung cancer cases: 410,000 in Europe in 2012
aTotal lung cancer deaths: 353,000 in Europe in 2012
1. Ferlay J et al. Eur J Cancer 2013;49:1374–403

5. Majority of patients with lung cancer are diagnosed with late-stage, locally advanced, or metastatic disease1-3 5%
16%
Lung cancer
SqNSCLC
22%
57%
Portugal 2000–2010 (n=9767)2
Spain 1997–1999
(n=186)3
Data based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program between 2005 and 20111
Early stage
Stage IIIB/IV
The pie chart on the left shows the disease stage at time of diagnosis for patients with lung cancer in the United States, based on data collected between 2005 and 2011 from the large-scale Surveillance, Epidemiology, and End Results program for cancer surveillance in the United States1
57% of patients had distant metastases at the time of diagnosis1
The pie charts on the right show the disease stage at time of diagnosis for patients with lung cancer in Portugal2 and Spain3
Based on data collected from 2000 to 2010, 77.8% of patients in Portugal were diagnosed with lung cancer in stages IIIB or IV2
Based on the retrospective analysis of data from 1997 to 1999, 68.1% of patients in Spain were diagnosed with non-small cell lung cancer in stages IIIB or IV3
References
Siegel RL et al. CA Cancer J Clin 2016;66:7–30; p.17, figure 5
Hespanhol V et al. Rev Port Pneumol 2013;19:245–51; p. 245, abstract
Prim JM et al. Eur J Cancer Care 2010;19:227–33; p. 227, abstract; p. 228, left col., 3rd para.
Disease stage at diagnosis in the United States (%)
Disease stage at diagnosis in Europe (%)
SqNSCLC, squamous non-small cell lung cancer 1. Siegel RL et al. CA Cancer J Clin 2016;66:7–30;
2. Hespanhol V et al. Rev Port Pneumol 2013;19:245–51;
3. Prim JM et al. Eur J Cancer Care 2010;19:227–33

6. Diagnoses of late-stage, locally advanced, or metastatic disease are associated with poor survival outcomes1,2
1.00
0.75
5-year relative survival, %
Proportion still alive
0.50
Stage I
Stage II
Stage III
Stage IV
All NSCLC
All lung cancer
0.25
The graph on the left shows the 5-year survival rate for patients with lung cancer in the United States by stage at diagnosis, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program between 2005 and 20111
Overall, 5-year survival was 17%, but only 4% for patients presenting with distant disease1
The graph on the right shows the survival patterns for patients with lung cancer in England and Wales during 20132
The median survival was 293 days for patients with stage III lung cancer and 100 days for patients with stage IV2
References
Siegel RL et al. CA Cancer J Clin 2016;66:7–30; p.18, figure 6, “Lung & bronchus”
HSCIC National Lung Cancer Audit: 2013 Patient Cohort. December 3, Available at: (accessed June 27, 2016); p. 46, figure 19 [Copyright © 2016, Re-used with the permission of the Health and Social Care Information Centre. All rights reserved.]
100
200
300
400
500
The standard error of the survival rate is between 5 and 10 percentage points. Data based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program between 2005 and 20111
Days
Survival study data from patients with lung cancer in England and Wales. The median survival for patients was 293 days for stage III disease and 100 days for stage IV in 20132
Re-used with permission of the Health and Social Care Information Centre, also known as NHS Digital.
All rights reserved
NSCLC, non-small cell lung cancer 1. Siegel RL et al. CA Cancer J Clin 2016;66:7–30; 2. HSCIC. National Lung Cancer Audit: 2013 Patient Cohort. Available at: (accessed June 27, 2016)

7. Incidence and early death of lung cancer are associated with socioeconomic deprivation in the UK
Incidence of lung cancer per 100,000 people / years (95% CI)1
p=0.017
OR (95% CI) for death within 90 days of diagnosis2
The graph on the top shows the overall incidence of lung cancer per 100,000 people/year in the UK between 2000 and 2009 by socioeconomic status, which was measured using the Townsend Deprivation Index1
The incidence of lung cancer among the most socioeconomically deprived patients was 2.2 times higher than that of the least socioeconomically deprived patients1
The graph on the bottom shows the odds ratio for death within 90 days of diagnosis by socioeconomic status for patients with lung cancer in the UK between 2000 and 20132
The odds of an early death were higher in patients diagnosed with lung cancer who had higher levels of socioeconomic deprivation compared with those who were more affluent2
References
Iyen-Omofoman B et al. BMC Public Health 2011;11:857; p. 4, right col., 3rd para.; p. 5, table 3
O’Dowd EL et al. Thorax 2015;70:161–8; p. 164, left col., 1st para.; p. 163, abstract; p. 166, table 3
n=165
n=190
n=201
n=269
n=224
Townsend Deprivation Index Quintile
1Data taken from a UK database (THIN), a computerised, longitudinal, primary care dataset with cases extracted from January 2000–January 2009
CI, confidence interval; OR, odds ratio; THIN, The Health Improvement Network
1. Iyen-Omofoman B et al. BMC Public Health 2011;11:857;
2. O’Dowd EL et al. Thorax 2015;70:161–8
2Multivariate analysis using data taken from a UK database (THIN), with cases extracted from January 200–January 2013

8. HR (95% CI) for overall death2
Incidence and survival after lung cancer are associated with socioeconomic deprivation in North America and Europe
Age-standardized incidence rate of lung cancer per 100,000 people / years (95% CI)1
Income quintile
HR (95% CI) for overall death2
The graph on the top shows the aged-standardized overall incidence of lung cancer per 100,000 people/year in Canada between 1991 and 2003 by socioeconomic status1
The incidence of lung cancer among the most socioeconomically deprived male patients was 2.11 times higher than that of the least socioeconomically deprived patients1
The graph on the bottom shows the hazard ratio for death by socioeconomic status for patients with high-stage lung cancer in Denmark between 2004 and 20102
Survival time was defined as the time between diagnosis and death from any cause (overall survival) or the end of follow-up (December 31, 2011), whichever occurred first
The hazard ratio of dying for patients with high-stage lung cancer and low-to-medium income was 8–12% higher compared with those with higher incomes, after adjustment for age, gender, and period, and further adjustment for potential mediating factors (stage at diagnosis, receipt of first-line treatment, comorbidity, and performance status)2
References
Mitra D et al. Health Rep 2015;26:12–20; p. 12, abstract; p.13, 3rd col., 2nd para.; p.15, table1
Dalton SO et al. Acta Oncol 2015;54:797–804; p.797, abstract; p. 799, 1st col., 3rd para.; p. 800, 1st col., 1st para. and 2nd col., 1st para.
Income level
1Prospective analysis using data taken from the Canadian Census Cohort, with cases extracted from 1991 to 2003
CI, confidence interval; HR, hazard ratio
1. Mitra D et al. Health Rep 2015;26:12–20;
2. Dalton SO et al. Acta Oncol 2015;54:797–804
2Multivariate logistic regression analysis using data taken from the Danish Lung Cancer Register, with cases extracted from 2004 to 2010

9. Prevalence of NSCLC subtypes1
Epidemiology of NSCLC
NSCLC represents ~85% of all cases of lung cancer1
Prevalence of NSCLC subtypes1
Non-small cell lung cancer (NSCLC) represents approximately 85% of all cases of lung cancer, based on patients diagnosed in the United States between 2004 and 2009 from the population-based Surveillance, Epidemiology, and End Results program1
The pie chart shows the prevalence of NSCLC by histology based on population-based data from over one million cases of lung cancer diagnosed in the United States between 2004 and 2009, with approximately 20–30% of all NSCLC cases being squamous disease and 70–80% being nonsquamous. Adenocarcinoma is the most frequent type of nonsquamous lung cancer, accounting for 45% of NSCLC1
Based on data gathered in Australia, Canada, France, Korea, Sweden, the UK, and the United States between 1998 and 2002 from the International Agency for Research on Cancer, squamous NSCLC accounts for 27–46% of NSCLC in men, and 11–28% of cases in women2
References
Houston KA et al. Lung Cancer 2014;86:22–8; p.23, 2nd col., 4th para.; p. 24, table 2
Youlden DR et al. J Thorac Oncol 2008;3:819–31; p. 823, table 2
Data based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program between 2004 and 20091
Globally, squamous NSCLC accounts for 27–46% of NSCLC cases in men and 11–28% of cases in women2
NSCLC, non-small cell lung cancer; nos, not otherwise specified 1. Houston KA et al. Lung Cancer 2014;86:22–8; 2. Youlden DR et al. J Thorac Oncol 2008;3:819–31

10. Adenocarcinoma vs squamous cell carcinoma in NSCLC: pathology
H-E stain X150
H-E stain X150
Images used with permission of the Radiological Society of North America
Presence of glands and papillary structures (*)
Neoplastic cells with round to oval nuclei, prominent nucleoli, and moderate amounts of cytoplasm
Positive for mucin, TTF-1, cytokeratin 7
Flattened appearance (i.e., “squamous”)
Intercellular bridges
Individual cell keratinization (arrowhead)
Keratin pearls
Positive for p63, p40, cytokeratin 5/6
Adenocarcinoma is characterized pathologically by the presence of glands and papillary structures, neoplastic cells with round/oval and prominent nuclei, and moderate amounts of cytoplasm1,4
A high-power micrograph of adenocarcinoma is shown on the left1
Squamous non-small cell lung cancer is characterized pathologically by its flattened appearance and intracellular bridges and relatively high degree of keratinization1,4
A high-power micrograph of squamous carcinoma is shown on the right1
Adenocarcinomas typically stain for mucin, thyroid transcription factor 1, and cytokeratin 7, whereas squamous tumors typically stain for p63, p40, and cytokeratin 5/62-4
References
Rosado-de-Christenson ML et al. Radiographics 1994;14:429–46; p.431, figure 1A and 2nd col., 2nd para.; p.436 figure 8A and 1st para.; p.437, 1st col., 1st sentence [Source: Images used with permission. Radiographics 1994;14: © Radiological Society of North America]
Oliver TG et al. Am J Clin Oncol 2015;38:220–6; p.3, 1st col., last para.
Bishop JA et al. Mod Pathol 2012;25:405–15; p.409, 1st col., 2nd para.
Travis WD et al. J Thorac Oncol 2015;10:1243–60; p. 1247, 1st col., 1st para.
NSCLC, non-small cell lung cancer; TTF-1, thyroid transcription factor 1 1. Rosado-de-Christenson ML et al. Radiographics 1994;14:429–46;
2. Oliver TG et al. Am J Clin Oncol 2015;38:220–6; 3. Bishop JA et al. Mod Pathol 2012;25:405–15;
4. Travis WD et al. J Thorac Oncol 2015;10:1243–60

11. Key differences between adenocarcinoma and squamous NSCLC
Parameter
Adenocarcinoma
Squamous cell carcinoma
Patient demographics
Over twice as common as any other lung cancer histology in women; most common histology in nonsmokers; patients tend to be younger1-4
More prevalent in men; stronger association with smoking; patients tend to be slightly older1-4
Tumor location
Peripheral5,6
Central (higher incidence of hemorrhages from blood vessel invasion and bronchial obstruction)5-7
Cavitation
Not typical5,6
Typical5,6
Disease stage at presentation
Metastatic disease often presents before symptom development8
More likely to be detected at localized stage due to earlier onset of symptoms8
Metastasis
Brain metastases are more common9
Brain metastases are less common9
The table summarizes a number of differences between adenocarcinoma and squamous non-small cell lung cancer (NSCLC)
Adenocarcinoma is the most common histology in nonsmokers and is more than twice as common as any other lung cancer histology in women, while squamous NSCLC is more prevalent in men compared with women and has a stronger association with smoking1-4
Patients with adenocarcinoma tend to be diagnosed at a slightly younger age than those with squamous disease: mean age 64 versus 67 years1 and 60 versus 62 years3 in two large population-based studies conducted in the United States and Poland, respectively
Adenocarcinoma is typically located peripherally, whereas squamous tumors most commonly arise centrally and are more likely to result in hemorrhages from blood vessel invasion and cause bronchial obstruction than adenocarcinoma5-7
Cavitation is less common in adenocarcinoma than in squamous disease5,6
Patients with adenocarcinoma usually present with metastatic disease before symptom development, and metastases to the brain are more common than in squamous disease8,9
References
Cetin K et al. Clin Epidemiol 2011;3:139–48; p. 141, table 1
Pesch B et al. Int J Cancer 2012;131:1210–9; p. 4, 3rd para.
3. Radzikowska E et al. Ann Oncol 2002;13:1087–93; p. 1088, table 1; p. 1089, table 2
Houston KA et al. Lung Cancer 2014;86:22–8; p. 24, table 2
Rosado-de-Christenson ML et al. Radiographics 1994;14:429–46; p. 432, 1st col., 1st para. p. 437, 1st col., 2nd and 4th para.; 2nd col., 3rd para.
Nichols L et al. Arch Pathol Lab Med 2012;136:1552–7; p. 1556, 2nd col., 1st para.
Ito M et al. BMC Cancer 2012;12:27; p. 2, 2nd col., 3rd para.
Hirsch FR et al. J Thorac Oncol 2008;3:1468–81; p. 1469, 2nd col., 2nd and 3rd para.
Mujoomdar A et al. Radiology 2007;242:882–8; p. 885, 1st col. on to 2nd col. and p. 886, table 2
NSCLC, non-small cell lung cancer 1. Cetin K et al. Clin Epidemiol 2011;3:139–48; 2. Pesch B et al. Int J Cancer 2012;131:1210–9; 3. Radzikowska E et al. Ann Oncol 2002;13:1087–93; 4. Houston KA et al. Lung Cancer 2014;86:22–8; 5. Rosado-de-Christenson ML et al. Radiographics 1994;14:429–46; 6. Nichols L et al. Arch Pathol Lab Med 2012;136:1552–7; 7. Ito M et al. BMC Cancer 2012;12:27; 8. Hirsch FR et al. J Thorac Oncol 2008;3:1468–81; 9. Mujoomdar A et al. Radiology 2007;242:882–8

12. Advanced squamous NSCLC is an aggressive cancer associated with a worse prognosis than nonsquamous NSCLC, irrespective of treatment1-6
Based on recent clinical trials, median OS in patients with advanced squamous NSCLC following 1st-line therapy is 9–11 months4,6 compared with 12–14 months for those with advanced nonsquamous* disease3-6
~30%
Median OS, months
Squamous
Nonsquamous*
Advanced squamous non-small cell lung cancer (NSCLC) is an aggressive cancer that grows quickly, with a median doubling time significantly shorter than adenocarcinoma1,2
The figure demonstrates that in recent clinical trials of various first-line therapies, median overall survival (OS) of patients with advanced squamous disease was approximately 30% shorter than that of patients with nonsquamous disease3-6
There are four main pathological types of lung cancer (adeno-, squamous cell, small cell and large cell carcinoma). For reasons of clinical consequences, different pathological types of lung cancer are sometimes grouped into a category (non-small cell carcinoma or nonsquamous non-small cell carcinoma) when it is necessary or useful to consider them in the same way, even if the tumors are pathologically different3-6
In patients with squamous disease, median OS was ~9–11 months, compared with ~12–14 months for nonsquamous disease3-6
In a Phase III trial, patients with stage IIIb/IV nonsquamous disease receiving a combination of paclitaxel, carboplatin, and bevacizumab (n=433) as first-line therapy had a median OS of 12.3 months3
In a Phase III trial, patients with advanced nonsquamous histology receiving pemetrexed/cisplatin induction therapy followed by placebo maintenance (n=180) had a median OS of 14.0 months5
In a Phase III trial, patients with stage IIIb/IV adenocarcinoma (n=847) receiving first-line cisplatin/pemetrexed or cisplatin/gemcitabine had a median OS of 12.6 and 10.9 months, respectively.6 In the same trial, patients with squamous disease (n=473) had a median OS of 9.4 and 10.8 months following treatment with cisplatin/pemetrexed and cisplatin/gemcitabine, respectively6
In a Phase III trial of first-line albumin-bound nab-paclitaxel versus solvent-based paclitaxel (both in combination with carboplatin), patients with advanced squamous disease (n=450) had a median OS of 10.7 and 9.5 months, respectively, while patients with advanced nonsquamous disease (n=602) had an OS of 13.1 and 13.0 months, respectively4
References
1. Wilson DO et al. Am J Respir Crit Care Med 2012;185:85–9; p. 87, table 2
2. Veronesi G et al. Ann Intern Med 2012;157:776–84; p. 780, table 1
3. Sandler A et al. N Engl J Med 2006;355:2542–50; p. 2543, 1st col., last para., 2nd col., 1st para.; p. 2546, 2nd col., 2nd para.; p. 2546, table 1
4. Socinski MA et al. J Clin Oncol 2012;30:2055–62; p. 2057, table 1; p. 2059, 1st col., 1st para.
5. Paz-Ares LG et al. J Clin Oncol 2013;31:2895–902; p. 2897, 2nd col., 2nd para.; figure 2A; p. 2899, figure 3; table A1
6. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3544, table 1; p. 3546, 2nd col., 4th para.
Data based on Phase III clinical trials of different 1st-line interventions in advanced NSCLC3-6 The shaded portion of each bar represents the range
*There are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell and large cell carcinoma). For reasons of clinical consequences, different pathological types of lung cancer are sometimes grouped into a category (non-small cell carcinoma or nonsquamous non-small cell carcinoma) when it is necessary or useful to consider them in the same way, even if the tumors are pathologically different
NSCLC, non-small cell lung cancer; OS, overall survival 1. Wilson DO et al. Am J Respir Crit Care Med 2012;185:85–9; 2. Veronesi G et al. Ann Intern Med 2012;157:776–84; 3. Sandler A et al. N Engl J Med 2006;355:2542–50; 4. Socinski MA et al. J Clin Oncol 2012;30:2055–62; 5. Paz-Ares LG et al. J Clin Oncol 2013;31:2895–902; 6. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51

13. The location of squamous NSCLC tumors makes them challenging to treat1,2
Squamous NSCLC is typically centrally located close to blood vessels1 and may be more likely to invade larger blood vessels, potentially resulting in fatal hemorrhages2
Peripherally located squamous NSCLC usually presents when the tumor is larger and has invaded the chest wall3
Squamous
cell
carcinoma
Squamous non-small cell lung cancer (NSCLC) is usually located centrally and, as a result, may be more likely to invade larger blood vessels, resulting in potentially fatal hemorrhages1,2
Squamous NSCLC that presents peripherally usually does so once the tumor has grown larger and invaded the chest wall3
References
1. Rosado-de-Christenson ML et al. Radiographics 1994;14:429–46; p. 437, 1st col., 2nd para.
2. Nichols L et al. Arch Pathol Lab Med 2012;136:1552–7; p. 1556, 2nd col., 1st para.
3. Rubin E, Reisner HM (eds). Essentials of Rubin’s Pathology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009; p. 268, 2nd col., 4th para. (local effects)
NSCLC, non-small cell lung cancer 1. Rosado-de-Christenson ML et al. Radiographics 1994;14:429–46; 2. Nichols L et al. Arch Pathol Lab Med 2012;136:1552–7; 3. Rubin E, Reisner HM (eds). Essentials of Rubin’s Pathology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009

14. Smoking has a stronger association with squamous NSCLC than other NSCLC and impacts on outcome1-4
Tobacco consumption is peaking in non-western countries where the incidence of lung cancer is expected to rise1
Active tobacco smoking has a stronger association with squamous NSCLC than with other NSCLC2,3
In a pooled analysis of >13,000 case-control studies, the OR for squamous disease in current vs never smokers was 45.6 vs for adenocarcinoma3
Mortality rates for patients with squamous NSCLC who have ever smoked are twice those for adenocarcinoma4
Indirect estimates are based on a systematic review of 148 studies4
In countries where the smoking epidemic has more recently peaked or is still increasing, such as in China, the incidence of lung cancer is expected to rise over the coming decades1
Active tobacco smoking has a greater association with squamous non-small cell lung cancer (NSCLC) than with other NSCLC2
In a pooled analysis of over 13,000 patient cases from Europe and Canada, the age-adjusted odds ratio for squamous cell carcinoma, estimated with logistic regression, was 45.6 in current versus never smokers, compared with 10.8 for adenocarcinoma3
Based on a systematic review of relative-risk estimates derived from 148 studies, the mortality rate for patients with squamous NSCLC who had ever smoked was per 100,000/year, compared to 58.5 for patients with adenocarcinoma who had ever smoked4
References
1. Torre LA et al. CA Cancer J Clin 2015;65:87–108; p. 9; 2nd col., 1st para.
2. Khuder A. Lung Cancer 2001;31:139–48; abstract
3. Pesch B et al. Int J Cancer 2012;131:1210–9; abstract and 4th page, 3rd para.
Lee PN, Forey BA. BMC Cancer 2013;13:189; p. 1, ‘Methods’ and p. 22, table 11
NSCLC, non-small cell lung cancer; OR, odds ratio
1. Torre LA et al. CA Cancer J Clin 2015;65:87–108; 2. Khuder A. Lung Cancer 2001;31:139–48; 3. Pesch B et al. Int J Cancer 2012;131:1210–9;
4. Lee PN, Forey BA. BMC Cancer 2013;13:189

15. Role of age and comorbidity in NSCLC1,2
Both squamous and adenocarcinoma NSCLC are associated with increased age1
Serious comorbidities (i.e., cardiovascular disease and COPD) are more prevalent in lung cancer patients aged ≥70 years2
In patients aged ≥70 years, those with squamous NSCLC have a higher incidence of comorbidity compared with adenocarcinoma, large-cell undifferentiated carcinoma, and small-cell carcinoma2
Advanced squamous and nonsquamous non-small cell lung cancer (NSCLC) are associated with advanced age, and based on data from 51,749 patients diagnosed in the United States between 1998 and 2003 as part of the Surveillance, Epidemiology, and End Results program, approximately 60% of patients with squamous NSCLC are aged ≥65 years when diagnosed, compared with 50% of patients with adenocarcinoma1
In a registry study of 3864 lung cancer patients, increased age (≥70 years) was associated with a higher prevalence of serious comorbidity in patients with NSCLC, including chronic obstructive pulmonary disorder or cardiovascular disease.2 In the same study, patients aged ≥70 years with squamous NSCLC had a higher incidence of comorbidity than those with adenocarcinoma, large cell undifferentiated carcinoma, and small cell carcinoma2
References
1. Cetin K et al. Clin Epidemiol 2011;3:139–48; p. 141, table 1
2. Janssen-Heijnen ML et al. Lung Cancer 1998;21:105–13; p. 105, abstract; p. 107, 1st col., last para. and 2nd col., 2nd para.; p. 109, table 3
Data taken from 51,749 patients diagnosed in the US between
1998 and 2003 as part of the NCI’s SEER program1
Data based on a population-based registry of
3864 patients with lung cancer2
COPD, chronic obstructive pulmonary disease; NCI, National Cancer Institute;
NSCLC, non-small cell lung cancer; SEER, Surveillance, Epidemiology, and End Results
1. Cetin K et al. Clin Epidemiol 2011;3:139–48; 2. Janssen-Heijnen ML et al. Lung Cancer 1998;21:105–13

16. Squamous NSCLC is associated with challenging comorbidities that make treatment of the disease more difficult1-4
Many patients with squamous NSCLC have age- and smoking-related comorbidities at the time of diagnosis1-3
Patients with squamous NSCLC have a 64% incidence of comorbid disease at diagnosis vs 52% for those with other lung cancers1
Comorbid conditions increase the difficulty of treating patients
The presence of comorbidities has been associated with poorer survival2,3
In a NSCLC study, patients with severe comorbidities had a higher incidence of specific grade 3 / 4 adverse events following chemotherapy4
Adverse event (grade 3 / 4)
Patients with severe comorbidities
Patients with no severe comorbidities
p value
Neutropenic fevers
12% 5%
0.01
Death from neutropenic fever 3% 0%
0.03
Thrombocytopenia
46%
36%
Patients with squamous non-small cell lung cancer (NSCLC) have a high incidence of concomitant disease, and in a registry study of 3864 newly diagnosed lung cancer patients, 64% of those with squamous histology had a concomitant disease compared with approximately 52% of patients with nonsquamous NSCLC1
Older patients with NSCLC have a higher prevalence of comorbid disease such as cardiovascular disease or chronic obstructive pulmonary disorder (COPD)1
In a combined analysis of two randomized trials involving a total of 1255 patients with NSCLC in the adjuvant/palliative setting, the presence of a comorbid condition was associated with poorer survival.2 A Charlson Comorbidity Index Score (CCIS) of ≥1 was associated with shorter survival; for example, for CCIS 1 versus 0, the hazard ratio was 1.28 (95% confidence interval 1.09, 1.50; p=0.003)
Based on data from 34,203 patients with lung adenocarcinoma and 26,967 patients with squamous cell lung carcinoma collected as part of the Surveillance, Epidemiology, and End Results program, the presence of comorbid chronic obstructive pulmonary disease was found to adversely influence survival outcomes in patients with stage I-IIIa disease3
In a Phase III study of 402 patients with advanced NSCLC treated with first-line chemotherapy, those with severe comorbidities had similar survival to other patients, but had a significantly greater incidence of grade 3/4 neutropenic fever, thrombocytopenia, and death due to neutropenic infections4
References
1. Janssen-Heijnen ML et al. Lung Cancer 1998;21:105–13; p.105, abstract; p. 107, 1st col., results, 2nd para.; p. 109, table 3 and p. 110, 1st col., 2nd para.
2. Asmis TR et al. J Clin Oncol 2008;26:54–9; p. 54, abstract; p. 56, 1st col., 2nd para.
3. Putila J, Guo NL. PLoS One 2014;9:e100994; p. 1, abstract and p. 4, 1st col., 2nd para.
4. Grønberg BH et al. Eur J Cancer 2010;46:2225–34; p. 2225, abstract and p. 2231, 1st col., 3rd para.
NSCLC, non-small cell lung cancer 1. Janssen-Heijnen ML et al. Lung Cancer 1998;21:105–13; 2. Asmis TR et al. J Clin Oncol 2008;26:54–9;
3. Putila J, Guo NL PLoS One 2014;9:e100994; 4. Grønberg BH et al. Eur J Cancer 2010;46:2225–34

17. In addition to lung cancer, smoking is associated with many other diseases1
Smoking is formally established as a causative link to 21 diseases, including COPD and CVD,1 but in addition, pooled data from 5 cohort studies (n=954,029 patients aged ≥55 years) has now highlighted excess mortality from causes not previously recognized as being associated with smoking
The additional potential disease burden due to smoking further increases the challenge of managing squamous NSCLC
Disease
RR (95% CI) for mortality
Renal failure
2.0 (1.7, 2.3)
Hypertensive heart disease
2.4 (1.9, 3.0)
Intestinal ischemia
6.0 (4.5, 8.1)
Infections
2.3 (2.0, 2.7)
Other respiratory disordersa
2.0 (1.6, 2.4)
Prostate cancer
1.4 (1.2, 1.7)
Breast cancer
1.3 (1.2, 1.5)
Liver cirrhosis
3.1 (2.6, 3.7)
Smoking is formally established as a causative link to 21 diseases, including chronic obstructive pulmonary disease (COPD) and cardiovascular disease;1 however, recent data link smoking with many other diseases1
Pooled data from five cohort studies (n=954,029 patients aged ≥55 years) highlight excess mortality from causes not previously recognized as being associated with smoking, including renal failure (relative risk [RR] 2.0), hypertensive heart disease (RR 2.4), intestinal ischemia (RR 6.0), infections (RR 2.3), other respiratory disorders (excluding pneumonia, influenza, COPD, and pulmonary fibrosis; RR 2.0), liver cirrhosis (RR 3.1), prostate cancer (RR 1.4), and breast cancer (RR 1.3)1
The data suggest that patients with squamous non-small cell lung cancer may have comorbidities, such as renal dysfunction, that complicate treatment
Reference
1. Carter BD et al. N Engl J Med 2015;372:631–40; p. 631, abstract and p. 632, 1st col., 1st para. and p. 636, 1st col., 1st para.
aExcludes pneumonia, influenza, COPD, and pulmonary fibrosis
CI, confidence interval; COPD, chronic obstructive pulmonary disorder; CVD, cardiovascular disease; NSCLC, non-small cell lung cancer
1. Carter BD et al. N Engl J Med 2015;372:631–40

18. Nearly 50% of patients have a performance status of 2–4 at diagnosis
In a recent survey of patients diagnosed in 2013 in the UK, 19.6% had a PS of 2, 18% had a PS of 3, and 6.4% had a PS of 4
Patients may not receive a full diagnostic evaluation due to poor PS or cancer staging
PS of patients in England and Walesa in 2013, %
(n>30,000)
As noted in previous slides, patients with lung cancer tend to be older and have comorbidities, and their performance status even at initial diagnosis can be poor. For example, nearly 50% of patients diagnosed with lung cancer in England and Wales in 2013 had a performance status of 2–4, which may limit their treatment options1
Many patients with lung cancer do not even undergo full diagnostic evaluation. For example, in England and Wales in 2013, approximately 25% of patients did not have a full histological/cytological evaluation.1 Poor performance status is one reason for this; advanced disease stage is another
Reference
HSCIC National Lung Cancer Audit: 2013 Patient Cohort. December 3, Available at: (accessed June 27, 2016); figure 7; p. 50
aData were collected from various strategic clinical networks throughout England and Wales for patients first diagnosed with lung cancer PS, performance status
HSCIC. National Lung Cancer Audit: 2013 Patient Cohort. Available at: (accessed June 27, 2016)

19. Improvements in survival over recent decades have been greater in stage IV adenocarcinoma vs squamous NSCLC1
Stage IV NSCLC 1-year survival: adenocarcinoma vs squamous1
Stage IV NSCLC 2-year survival: adenocarcinoma vs squamous1 *
Based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program for patients diagnosed between 1990 and 2005 with stage IV NSCLC1; *p=0.02
Survival has been improving since 1990 for NSCLC of all histologies1
Survival significantly increased for patients diagnosed in 2002–2005 with adenocarcinoma compared with those diagnosed with squamous NSCLC1
The figures show 1- and 2-year survival for four periods based on 129,337 patients from the Surveillance, Epidemiology, and End Results program for cancer surveillance in the United States1
Although survival has been improving since 1990 for patients diagnosed with stage IV non-small cell lung cancer (NSCLC) of all histologies, these improvements were significantly greater for adenocarcinoma compared with squamous cell disease between 2002 and 20051
Improved outcomes in patients diagnosed since 2002 with adenocarcinoma compared with those diagnosed with squamous cell carcinoma may partly reflect the approval of epidermal growth factor receptor-tyrosine kinase inhibitors, which have increased activity in adenocarcinoma compared with squamous NSCLC1
Reference
1. Morgensztern D et al. J Thorac Oncol 2009;4:1524–9; p. 1524, abstract and p. 1526, table; p. 1527, table 5; p. 1528, 1st col., 2nd para.
NSCLC, non-small cell lung cancer 1. Morgensztern D et al. J Thorac Oncol 2009;4:1524–9

20. In contrast to nonsquamous
In contrast to nonsquamous* NSCLC, survival in advanced squamous NSCLC has remained relatively unchanged for more than 2 decades1-10
Examples of OS from start of 1st-line therapy in advanced NSCLC patients
NSCLC (all histologies)
Squamous
Nonsquamous
Single-agent platinum
Platinum- based doublets
Histology- directed therapy Platinum-triplet therapy (BEV)
New strategies 18 16 14 12 10 8 6 4 2
1980s1,2
1990–
2005–
2010–20159,10
Median OS, months
Pemetrexed and bevacizumab are contraindicated in SqCLC histology; there are no oncogene-directed targeted therapy in squamous histology to date
*There are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell and large cell carcinoma). For reasons of clinical consequences, different pathological types of lung cancer are sometimes grouped into a category (non-small cell carcinoma or nonsquamous non-small cell carcinoma) when it is necessary or useful to consider them in the same way, even if the tumors are pathologically different
The figure shows an approximation of median survival from clinical trials conducted since the 1980s in patients with advanced non-small cell lung cancer (NSCLC) receiving various first-line treatments1-10
Despite a number of trials, very few treatment options have been specifically approved for the first-line treatment of squamous NSCLC11
References
Bonomi PD et al. J Clin Oncol 1989;7:1602–13; abstract
Eagan RT et al. J Clin Oncol 1988;6:5–8; abstract
Schiller JH et al. N Engl J Med 2002;346:92–8; p. 95, table 3
Sandler AB et al. J Clin Oncol 2000;18:122–30; abstract
Spira A, Ettinger DS. N Engl J Med 2004;350:379–92; p. 386, 1st col., 2nd and 3rd para.
Sandler A et al. N Engl J Med 2006;355:2542–50; p. 2543, 2nd col., 1st para. and p. 2546, 2nd col., 2nd para.
Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3546, 2nd col., 4th para.
Scagliotti G et al. Oncologist 2009;14:253–63; p. 259, figure 1
Socinski MA et al. J Clin Oncol 2012;30:2055–62; p. 2057, table 1 and p. 2059, 1st col., 1st para.
Paz-Ares LG et al. J Clin Oncol 2013;31:2895–902; p. 2898, figure 2A and p. 2898, 2nd col., 2nd para.
Socinski MA et al. J Thorac Oncol 2016;11:1411–22; p. 1412, 1st col., 3rd para. and p. 1412, 2nd col., 1st para.
Very few new 1st-line treatment options have been approved for patients with squamous NSCLC11
BEV, bevacizumab; NSCLC, non-small cell lung cancer; OS, overall survival; Pem, pemetrexed.
1. Bonomi PD et al. J Clin Oncol 1989;7:1602–13; 2. Eagan RT et al. J Clin Oncol 1988;6:5–8; 3. Schiller JH et al. N Engl J Med 2002;346:92–8; 4. Sandler AB et al. J Clin Oncol 2000;18:122–30; 5. Spira A, Ettinger DS. N Engl J Med 2004;350:379–92; 6. Sandler A et al. N Engl J Med 2006;355:2542–50; 7. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; 8. Scagliotti G et al. Oncologist 2009;14:253–63; 9. Socinski MA et al. J Clin Oncol. 2012;30:2055–62; 10. Paz-Ares LG et al. J Clin Oncol. 2013;31:2895–902; 11. Socinski MA et al. J Thorac Oncol 2016;11:1411–22

21. Treatment in advanced NSCLC is driven by histological subtype, performance status, and oncogenic testing according to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)1
Histological subtype
Oncogenic testing
1st line
Adenocarcinoma, large cell, NSCLC NOS
EGFR-mutation positive
Erlotinib or afatinib or gefitinib (all category 1)
ALK-mutation positive
Crizotinib (category 1)
EGFR- / ALK-mutation negative
PS 0–1: doublet chemotherapy (category 1) or PT-doublet + bevacizumab
PS 2: chemotherapy
Stable disease / overall response:
continuation or switch maintenance or close observation
Squamous
Testing should be considered in patients who have never been smokers, have a small biopsy specimen, or have mixed histology
PS 0–1: doublet chemotherapy (category 1)
Stable disease / overall response: continuation or switch maintenance or close observation
The table summarizes the 2016 National Comprehensive Cancer Network (NCCN) treatment guidelines for patients with non-small cell lung cancer (NSCLC).1 All recommendations for first-line treatment are category 2A unless otherwise noted
In patients with adenocarcinoma, large cell, or NSCLC not otherwise specified histology, screening for mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) is recommended to guide the most appropriate therapy, with EGFR and ALK inhibitors recommended in patients with mutation-positive disease (category 1)
In patients with squamous histology, consider EGFR mutation and ALK testing in never smokers or small biopsy specimens, or mixed histology. Recommended first-line treatment is doublet chemotherapy for patients with performance status (PS) 0–1 (category 1) and chemotherapy for patients with PS 2
Necitumumab + gemcitabine-cisplatin is approved for treatment of patients with metastatic squamous NSCLC; the NCCN does not include necitumumab + gemcitabine-cisplatin as a treatment option2,3
NCCN categories of evidence and consensus are defined as the following:
Category 1: based on high-level evidence, there is uniform NCCN consensus that the intervention is appropriate
Category 2A: based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate
Category 2B: based on lower-level evidence, there is NCCN consensus that the intervention is appropriate
Category 3: based on any level of evidence, there is major NCCN disagreement that the intervention is appropriate
Reference
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed February 21, To view the most recent and complete version of the guideline, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any away. [please access ref via NCCN website: NCCN does not permit its distribution]
FDA. Necitumumab. Highlights of prescribing information. Available at: (accessed June 20, 2016); p. 2, Indications and Usage
EMA. Necitumumab summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications
Necitumumab + gemcitabine-cisplatin is FDA / EMA approved for metastatic SqCLC.2,3 The NCCN does not include necitumumab + gemcitabine-cisplatin as a treatment option1
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; NOS, not otherwise specified; PS, performance status; PT, platinum based; SqCLC, squamous cell lung cancer; TKI, tyrosine kinase inhibitor
1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed February 21, To view the most recent and complete version of the guideline, go online to NCCN.org.
The NCCN Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a
statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or
consult any NCCN Guidelines® is expected to use independent medical judgement in the context of individual clinical circumstances to determine
any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content,
use, or application and disclaims any responsibility for their application or use in any way;
2. FDA. Necitumumab. Highlights of prescribing information. Available at:
(accessed June 20, 2016);
3. EMA. Necitumumab summary of product characteristics Available at:
(accessed June 20, 2016).

22. Currently approved therapies in NSCLC often have reduced efficacy or greater toxicity in squamous vs nonsquamous1-8
Distinctions between adenocarcinoma and squamous NSCLC are becoming increasingly important in predicting therapeutic response and toxicity1,2
The efficacy of systemic therapies in nonsquamous* NSCLC is often reduced in squamous NSCLC
A 1st-line chemotherapy doublet increased survival in patients with nonsquamous* NSCLC vs an established chemotherapy combination but failed to do so in patients with squamous NSCLC3
EGFR and ALK TKIs are effective in mutation-positive NSCLC4-6; however, these mutations are extremely rare in squamous NSCLC6,7
Squamous histology is also a predictor of poor local control8
The histological distinction between adenocarcinoma and squamous cell carcinoma has become increasingly important, as histology may predict response and/or toxicity to certain therapies1,2
Therapies demonstrating efficacy in nonsquamous non-small cell lung cancer (NSCLC) have demonstrated reduced efficacy in squamous NSCLC
In a Phase III trial, patients with advanced adenocarcinoma (n=847) receiving cisplatin/pemetrexed as first-line therapy had a median overall survival of 12.6 months, compared with 9.4 months for patients with advanced squamous disease (n=473)3
Targeted therapies, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors, have demonstrated efficacy in mutation-positive nonsquamous NSCLC but not in squamous NSCLC4-6
The use of these agents in squamous cell carcinoma is limited due to the very low frequency of EGFR and ALK mutations in squamous tumors6,7
EGFR mutations are associated with adenocarcinoma and with patients who have never smoked6
Squamous histology is also a predictor of poor local control.8 In a study of reirradiation therapy in 102 patients with recurrence, squamous histology, T4 disease, and Eastern Cooperative Oncology Group performance status score >1 were identified as predictors of poor local control
References
Zugazagoitia J et al. J Thorac Dis 2014;6(Suppl 5):S526–36; p. s533, 1st col., 1st para; p. s534, 1st col., 2nd para.
Perez-Moreno P et al. Clin Cancer Res 2012;18:2443–51; p. 2443, 1st col., 1st para.
Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3546, 2nd col., 4th para.
Mok T et al. N Engl J Med 2009;361:947–57; p. 947, abstract
Kwak E et al. N Engl J Med 2010;363:1693–703; p. 1693, abstract and p. 1697, table 1
6. Pao W et al. Proc Natl Acad Sci USA 2004;101:13306–11; p , abstract and p , 1st col., 4th para and p , 2nd col., 3rd para.
7. Liao RG et al. Lung Cancer Manag 2012;1:293–300; p. 1, 2nd para.
8. McAvoy S et al. Int J Radiat Oncol Biol Phys 2014;90:819–27; abstract
*There are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell and large cell carcinoma). For reasons of clinical consequences, different pathological types of lung cancer are sometimes grouped into a category (non-small cell carcinoma or nonsquamous non-small cell carcinoma) when it is necessary or useful to consider them in the same way, even if the tumors are pathologically different
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor 1. Zugazagoitia J et al. J Thorac Dis 2014;6(Suppl 5):S526–36; 2. Perez-Moreno P et al. Clin Cancer Res 2012;18:2443–51; 3. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; 4. Mok T et al. N Engl J Med 2009;361:947–57; 5. Kwak E et al. N Engl J Med 2010;363:1693–703; 6. Pao W et al. Proc Natl Acad Sci USA 2004;101:13306–11; 7. Liao RG et al. Lung Cancer Manag 2012;1:293–300; 8. McAvoy S et al. Int J Radiat Oncol Biol Phys 2014;90:819–27

23. Chemotherapy, % of patients
Fewer patients with stage IV squamous NSCLC receive chemotherapy (1 of 2)
In a large study conducted in the Netherlands, fewer patients with stage IV squamous NSCLC received chemotherapy compared with those with stage IV adenocarcionoma1
Chemotherapy use in stage IV NSCLC in the Southern Netherlands, 2001–20121
Histology n
Chemotherapy, % of patients
Squamous
985 38
Adenocarcinoma
2,112 52
In addition to adenocarcinoma diagnosis, factors associated with treatment were younger age, higher socioeconomic status, no comorbidities, and recent diagnosis1
Patients who received chemotherapy had improved survival:
For those aged 65–74 years, 64% survived at 6 months with chemotherapy, compared with only 19% without chemotherapy1
In a study from the Netherlands, fewer patients with newly diagnosed advanced squamous non-small cell lung cancer received chemotherapy compared with patients with advanced adenocarcinoma (38% versus 52%; p<0.0001)
For patients aged 65–74 years, survival at 6 months was 64% for those who received chemotherapy, compared with 19% for those who did not1
Reference
Aarts MJ et al. Int J Cancer 2015;136:E387–95; p. E387, abstract; p. E389, table 1; p. E392, table 3
NSCLC, non-small cell lung cancer
1. Aarts MJ et al. Int J Cancer 2015;136:E387–95

24. Fewer patients with stage IV squamous NSCLC receive chemotherapy1 (2 of 2)
In a study of 8113 Canadian patients with stage IV NSCLC, most patients did not receive systemic therapy1
Patients with squamous NSCLC and older patients were less likely to receive chemotherapy
The use of systemic therapy for treatment of patients increased from 19% in 2005 to 26% in 2009 (p<0.0001)
A large, retrospective, population-based study of all patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in Canada between 2005 and 2009 (n=8113) found that only 24% of patients received first-line chemotherapy1
Use of chemotherapy increased over the period of 2005–2009 (from 19% to 26%)
Of those receiving first-line chemotherapy, only 31% subsequently received second-line therapy
Patients with adenocarcinoma were more likely to receive systemic therapy than patients with squamous NSCLC (odds ratio 1.3; p<0.0001)
Patients aged ≥70 years were less likely to receive systemic therapy than younger patients (odds ratio 0.3; p<0.0001)
Reference
Sacher AD et al. Cancer 2015;121:2562–2569; p. 2562, abstract; p. 2564, table 1
Data for treatment utilization was based on 8113 Canadian patients who were identified as having stage IV NSCLC between 2005 and 20091
NSCLC, non-small cell lung cancer
1. Sacher AD et al. Cancer 2015;121:2562–9

25. EGFR M+ or EML4-ALK+ <5%
Oncogenic drivers with effective treatments are rare in squamous NSCLC vs adenocarcinoma1-3
Adenocarcinoma1
Squamous NSCLC2,3
EGFR M+ or EML4-ALK+ <5%
EGFR M+ 15–20%
Unknown oncogenic drivers or oncogenic drivers without proven treatments
Unknown oncogenic drivers or oncogenic drivers without proven treatments
EML4-ALK+ 3–7%
The pie charts show that in nonsquamous non-small cell lung cancer (NSCLC), 15–20% of patients have an epidermal growth factor receptor (EGFR) mutation and an additional 3–7% have an anaplastic lymphoma kinase (ALK) rearrangement1
In squamous NSCLC, however, <5% of patients have either an EFGR or ALK abnormality2,3
The development of targeted agents in squamous NSCLC is therefore limited by the lack of known oncogenic drivers in squamous disease
References
Gerber DE et al. Am Soc Clin Oncol Educ Book 2014:e353–65; p. e354, figure 1A
Pao W, Girard N. Lancet Oncol 2011;12:175–80; p. 176, table 1
Perez-Moreno P et al. Clin Cancer Res 2012;18:2443–51; p. 2445, table 1
ALK, anaplastic lymphoma kinase;
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer
1. Gerber DE et al. Am Soc Clin Oncol Educ Book 2014:e353–65; 2. Pao W, Girard N. Lancet Oncol 2011;12:175–80; 3. Perez-Moreno P et al. Clin Cancer Res 2012;18:2443–51

26. Research into 1st-line treatments for squamous NSCLC has proved extremely challenging1-7
Treatments that target numerous pathways have failed in clinical trials in squamous NSCLC patients:
Antiangiogenics1
Multikinase inhibitors2,3
Protein modifiers4
IGF-1R mAb5
EGFR mAb6-9
Reasons for failure in clinical trials can include: failure to meet primary endpoint, unacceptable toxicity, and unfavorable risk:benefit ratio
Trial design, chemotherapy backbone, and the patient population can also contribute to trial failure
Multiple studies of various agents for squamous non-small cell lung cancer (NSCLC) have been undertaken in the last 10–15 years, but have failed in clinical trials and/or not been approved by regulatory authorities due to an unfavorable risk-benefit ratio. These include antiangiogenics, multikinase inhibitors, protein-modifying agents, and epidermal growth factor receptor and IGR-1R monoclonal antibodies1-9
Reasons for failure in clinical trials can include trial design, chemotherapy backbone, the patient population, and lack of efficacy
References
1. Johnson DH et al. J Clin Oncol 2004;22:2184–91; p. 2184, abstract and p. 2189, 2nd col., 3rd para.
2. Scagliotti GV et al. J Clin Oncol 2012;30:2829–36; p. 2830, 1st col., 3rd para.
3. Scagliotti G et al. J Clin Oncol 2010;28:1835–42; p. 1835, abstract and p. 1839, 1st col., 1st para.
Sanofi. Press release, June 3, Available at: (accessed October 15, 2014); p. 1, 2nd para.; 6th para.
Langer CJ et al. J Clin Oncol 2014;32:2059–66; abstract
6. Pirker R et al. Lancet 2009;373:1525–31; p. 1525, abstract and 1st col., 2nd para.
European Medicines Agency. Assessment Report for Erbitux. London, UK: 2010, p. 43, last para.
Pirker R et al. Lancet Oncol 2012;13:33–42; p. 1, abstract
European Medicines Agency. Withdrawal Assessment Report for Erbitux. London, UK: 2012, p. 47, last para.
EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; NSCLC, non-small cell lung cancer
1. Johnson DH et al. J Clin Oncol 2004;22:2184–91; 2. Scagliotti GV et al. J Clin Oncol 2012;30:2829–36; 3. Scagliotti G et al. J Clin Oncol 2010;28:1835–42; 4. Sanofi. Press release, June 3, Available at: Accessed October 15, 2014; 5. Langer CJ et al. J Clin Oncol 2014;32:2059–66; 6. Pirker R et al. Lancet 2009;373:1525–31; 7. European Medicines Agency. Assessment Report for Erbitux. London, UK: 2010; 8. Pirker R et al. Lancet Oncol 2012;13:33–42;
9. European Medicines Agency. Withdrawal Assessment Report for Erbitux. London, UK: 2012

27. Radiation therapy can provide palliation of thoracic symptoms irrespective of systemic therapy
Substantial evidence supports the efficacy of external beam radiotherapy (RT), either alone or in combination with concurrent chemotherapy, in the palliation of thoracic symptoms such as hemoptysis, cough, chest pain, and airway obstruction1,2
RT may be the primary or only option for patients with poor performance status and advanced disease and for those who have declined or progressed despite systemic therapy
In patients with advanced disease, palliative thoracic RT ≥35 Gy10 significantly improved total symptom score and survival compared with lower doses2
Patients should be informed of the potential disadvantages of high-dose RT (higher incidence of esophagitis and greater time investment)
Patients with short expected survival can be treated with short-course palliative RT with minimal toxicity and inconvenience
Data from two systematic reviews of the literature support the efficacy of external beam radiation therapy (EBRT) in combination with concurrent chemotherapy in the palliation of thoracic symptoms such as hemoptysis, cough, chest pain, and airway obstruction1,2
Data from a systematic review that included 13 randomized controlled trials of palliative thoracic radiation therapy (RT) showed that in patients with advanced disease, palliative thoracic RT ≥35 Gy10 significantly improved total symptom score and survival compared with lower doses1
Patients should be informed of the potential disadvantages of high-dose RT, including a higher incidence of esophagitis and greater time investment
Patients with short expected survival can be treated with short-course palliative RT, with minimal toxicity and inconvenience
Thoracic EBRT is indicated for palliation of symptoms that include hemoptysis, cough, chest pain, dyspnea, obstructive pneumonia, dysphagia related to esophageal compression, superior vena cava syndrome, hoarseness, and stridor2
Guidelines do not recommend palliative thoracic EBRT for symptoms caused by malignant pleural effusion, lymphangitic carcinomatosis, or multilobar parenchymal disease
Patients with poor performance status and advanced disease or those who have declined or progressed despite systemic therapy may only be eligible to receive RT1
References
Fairchild A et al. J Clin Oncol 2008;26:4001–11; p. 4001, abstract; p. 4007, left col., 2nd para.; p. 4007, right col., 1st and 2nd para.; p. 4008, left col., 1st para.; p. 4008, right col., 1st and 2nd para.
Rodrigues G et al. Pract Radiat Oncol 2011;1:60–71; p. 60–61, abstract; p. 62, right col., 2nd para.
1. Rodrigues G et al. Pract Radiat Oncol 2011;1:60–71;
2. Fairchild A et al. J Clin Oncol 2008;26:4001–11

28. Conclusions
Squamous NSCLC is an aggressive and difficult-to-treat form of NSCLC, with 30% lower OS than nonsquamous* NSCLC
Advancing age and smoking are the predominant risk factors in squamous NSCLC, and the comorbidities associated with these factors make the disease challenging to treat
Treatment in advanced NSCLC is driven by histological subtype and oncogenic testing
There are fewer treatment options for squamous compared with nonsquamous* NSCLC
Platinum-based chemotherapy has been the only 1st-line treatment option for most patients with squamous NSCLC for the last 2 decades, reflecting a significant unmet need for treatment advances in this patient population
*There are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell and large cell carcinoma). For reasons of clinical consequences, different pathological types of lung cancer are sometimes grouped into a category (non-small cell carcinoma or nonsquamous non-small cell carcinoma) when it is necessary or useful to consider them in the same way, even if the tumors are pathologically different
NSCLC, non-small cell lung cancer; OS, overall survival