0. Continuous benefit counts
Module 2
Last updated: December 2016

1. Contents Introduction Defining “clinically meaningful improvement”
Continuous advances in advanced cancer
Histological subtype influences efficacy and tolerability in NSCLC
Recent treatment advances in NSCLC
Recent research on molecular targets for squamous NSCLC
NSCLC, non-small cell lung cancer

2. The treatment of patients with cancer is changing due to
Introduction
The treatment of patients with cancer is changing due to
Improvements in surgical techniques, radiotherapy, and adjuvant therapies1-3
The introduction of new chemotherapeutic regimens4,5
The use of antibody-drug conjugates and immunotherapies6,7
Development of therapies targeted against identified molecular drivers1,8,9
The treatment of patients with cancer is changing rapidly due to a number of surgical and therapeutic developments:
Improvements in surgical and radiotherapy techniques and adjuvant therapies1-3
The introduction of new chemotherapeutic regimens, antibody-drug conjugates, and immunotherapies4-7
The detailed characterization of tumor biology and subsequent development of therapies targeted against identified molecular drivers1,8,9
Continuous improvements have been observed in patients with cancers due to new therapeutic options1,10
References
Vickers M. Oncol Exchange 2013;12:30–3; p. 30, 1st col., 1st para.
Price A. Thorax 2003;58:447–52; abstract
Faria SL. Front Oncol 2014;4:229; abstract
Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3544, 1st col., 2nd para.; p. 3550, 1st col., 2nd para.
Paz-Ares LG et al. J Clin Oncol 2013;31:2895–902; p. 2901, 2nd col., 1st para.
Quinn DI et al. Urol Oncol 2015;33:245–60; p. 245, abstract, background
Klute K et al. Onco Targets Ther 2014;7:2227–36; p. 2228, table 1
Swain SM et al. N Engl J Med 2015;372:724–34; p. 724, abstract, background, results
Mok TS et al. N Engl J Med 2009;361:947–57; p. 948, 1st col., 2nd para.; p. 956, 1st col., 2nd para.
Rossi A et al. Cancer Treat Rev 2014;40:485–94; p. 488, 1st col., 3rd para.; p. 488, 1st col., 4th para.; p. 488, 2nd col., 1st para.; p. 488 , 2nd col., 2nd para.; p. 488, 2nd col., 3rd para.
However, the resulting improvements in outcomes have tended to occur mostly in small but continuous steps1,10
1. Vickers M. Oncol Exchange 2013;12:30–3;
2. Price A. Thorax 2003;58:447–52; 3. Faria SL. Front Oncol 2014;4:229; 4. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; 5. Paz-Ares LG et al. J Clin Oncol 2013;31:2895–902;
6. Quinn DI et al. Urol Oncol 2015;33:245–60; 7. Klute K et al. Onco Targets Ther 2014;7:2227–36; 8. Swain SM et al. N Engl J Med 2015;372:724–34; 9. Mok TS et al. N Engl J Med 2009;361:947–57; 10. Rossi A et al. Cancer Treat Rev 2014;40:485–94

3. Clinically meaningful improvement
Redefining what is meant by a “clinically meaningful improvement” (1 of 2)
A recent publication by ASCO working groups aims to achieve more meaningful results for patients by recommending a new definition of “clinically meaningful improvement”1
Selection of OS as the primary endpoint does not diminish the value of PFS and other surrogate endpoints, especially where a significantly prolonged PFS may provide meaningful palliation and improved QoL1
NSCLC population
Current baseline OS
Clinically meaningful improvement
Target hazard ratio
Squamous
10 months
2.5–3 months
0.77–0.80
Nonsquamous*
13 months
3.25–4 months
0.76–0.80
ǂThere 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 American Society of Clinical Oncology (ASCO) convened four disease-specific working groups to consider the design of future clinical trials that would produce results that are clinically meaningful to cancer patients; one of these working groups dealt with non-small cell lung cancer (NSCLC)1
In the report published in 2014, the ASCO working group recommends targets for clinically meaningful clinical trial goals, as summarized in the table on the slide1
In nonsquamous NSCLC, the current baseline survival in the first-line setting is 13 months. An improvement of 3.25–4 months over the current survival (target hazard ratio [HR] 0.76, 0.80) would be deemed by ASCO criteria to be clinically meaningful
In squamous NSCLC, current baseline survival in the first-line setting is 10 months. An improvement of 2.5–3 months over the current survival (target HR 0.77, 0.80) would be deemed by ASCO criteria to be clinically meaningful
The working group noted that selection of overall survival as the primary endpoint for future clinical trials of first-line therapy does not diminish the value of progression-free survival (PFS) and other surrogate endpoints, especially where a significantly prolonged PFS may provide meaningful palliation and improved quality of life1
The clinical meaningfulness of new treatments should be assessed in light of the efficacy benefits versus the current standard of care, the overall risk-benefit profile, and with consideration for the degree of unmet need and the challenges of advancing treatment in the squamous NSCLC setting
Reference
1. Ellis LM et al. J Clin Oncol 2014;32:1277–80; p. 1277, 2nd col., 2nd para.; p. 1277, 2nd col., 3rd para.; p. 1278, “Working group deliberations” 1st sent.; p. 1279, table 1
Clinical meaningfulness of new treatments should be assessed in light of the efficacy benefits vs the current standard of care, the overall risk:benefit profile, and with consideration for the degree of unmet need and the challenges of advancing treatment in the squamous NSCLC setting
ASCO, American Society of Clinical Oncology; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; QoL, quality of life
1. Ellis LM et al. J Clin Oncol 2014;32:1277–80

4. Minimum observed benefit
Redefining what is meant by a “clinically meaningful improvement” (2 of 2)
The ESMO-MCBS is a validated tool for measuring the clinical magnitude of anti-cancer treatments1
Primary outcome
Current baseline
Minimum observed benefit OS
≤12 months
≥3 months AND HR* ≤0.65 OR
≥10% increase in 2-year survival alone
>12 months
≥5 months AND HR* ≤0.70
≥10% increase in 3-year survival alone
PFS
≤6 months
≥1.5 months AND HR* ≤0.65
>6 months
The European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO- MCBS) is a validated tool for measuring the clinical magnitude of anti-cancer treatments and interventions1
The aim of the ESMO-MCBS evaluation was to assign scores to clinical trials to make appropriate grade adjustment to reflect the observed magnitude of benefit1
The score is based on having the adequate power for a relevant magnitude of benefit1
The ESMO-MCBS summarized in the table combines thresholds for the hazard ratio (HR) and the minimum observed benefit that could be considered as deserving the highest grade in the non-curative setting1
The ESMO-MCBS grades non-curative anti-cancer treatments from 1 through 5, where grades 5 and 4 represent a high level of proven clinical benefit1
When a new therapy is evaluated using overall survival (OS) as the primary outcome, a preliminary score takes HR, median survival gain, and late-survival advantage into consideration and is reported on a 4-point scale. A score of 5 can only be achieved when optimal survival outcomes are further enhanced by reduced toxicity or improved quality of life (QoL)1
When a new therapy is evaluated using progression-free survival as the primary outcome, the maximum preliminary score is 3. This score can be upgraded or downgraded based on secondary outcomes such as toxicity, improvement in OS, or data derived from QoL evaluation1
Reference
1. Cherny NI et al. Ann Oncol 2015;26:1547–73; p. 1548, 2nd col., 1st and 4th para.; p , 1st col., 1st and 2nd para., and table 2; p. 1550, 1st col., 2nd-5th para., and 2nd col., 1st para.
*Refers to the lower extreme of the 95% CI
ESMO-MCBS, European Society of Medical Oncology Magnitude of Clinical Benefit Scale; HR, hazard ratio; OS, overall survival; PFS, progression-free survival
1. Cherny NI et al. Ann Oncol 2015;26:1547–73

5. Improvement in OS* (months)
Many historical studies do not meet the new definition of a “clinically meaningful improvement”1-4
Pivotal studies of many of the agents in the current therapeutic armamentarium for 1st-line treatment of advanced NSCLC did not provide an OS improvement that meets the ASCO working group criteria or the ESMO-MCBS5,6
Phase III randomized, open-label studies of 1st-line treatment in advanced NSCLC
Treatments
Histology
Improvement in OS* (months) HR
Gemcitabine-cisplatin vs cisplatin1
All
1.5 NR
Paclitaxel-carboplatin vs paclitaxel2
2.1
0.91
Pemetrexed-cisplatin vs gemcitabine-cisplatin3
Nonsquamousǂ
1.4
0.81
Nab-paclitaxel-carboplatin vs paclitaxel-carboplatin4
0.9
0.92
The data in the table summarize improvements in survival with first-line therapies in advanced non-small cell lung cancer (NSCLC)
In a Phase III randomized, open-label trial of gemcitabine plus cisplatin compared with cisplatin alone in patients with stage IIIB/IV NSCLC (n=522), the difference in median survival was 1.5 months; the hazard ratio (HR) was not reported1
In a Phase III randomized, open-label trial of paclitaxel-carboplatin compared with paclitaxel in patients with stage IIIB/IV NSCLC (n=561), the HR for improvement in overall survival (OS), the primary endpoint, with the doublet was 0.91, with a difference in median survival of 2.1 months compared with paclitaxel alone2
In a Phase III randomized, open-label trial of pemetrexed-cisplatin compared with gemcitabine-cisplatin in patients with stage IIIB/IV NSCLC, the HR for improvement in survival, the primary endpoint, in those with nonsquamous histology (n=1000) was 0.81, with an improvement in median survival of 1.4 months3
In a Phase III randomized, open-label trial of nab-paclitaxel-carboplatin versus paclitaxel-carboplatin in patients with stage IIIB/IV NSCLC (n=1052), the HR for improvement in OS, a secondary endpoint, with nab-paclitaxel-carboplatin was 0.92, with a median improvement in OS of 0.9 months (p=0.271)4
These data demonstrate that many pivotal studies of agents in the current therapeutic armamentarium for first-line treatment of advanced NSCLC did not provide an OS improvement that meets the American Society of Clinical Oncology working group criteria, as no trial reported an OS improvement of ≥2.5 months or HR ≤0.805
These agents also did not provide an OS improvement that meets the European Society of Medical Oncology Magnitude of Clinical Benefit Scale, as no trial reported an OS improvement of ≥3 months with a target of HR ≤0.65 or ≥5 months with a target of HR ≤0.706
References
Sandler AB et al. J Clin Oncol 2000;18:122–30; p. 122, abstract
Lilenbaum RC et al. J Clin Oncol 2005;23:190–6; p. 190, abstract; p. 191, 1st col., p. 191, eligibility criteria, treatment plan; p. 192, 1st col., 1st para.
Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3543, abstract, patients and methods; p. 3544, introduction, last sent.; p. 3546, 2nd col., last para., 1st sent.
Socinski MA et al. J Clin Oncol 2012;30:2055–62; p.2055, abstract, purpose; patients and methods, results, 3rd sent.; p. 2057, assessment of efficacy and safety endpoints, 3rd sent.
Ellis LM et al. J Clin Oncol 2014;32:1277–80; p. 1279, table 1
Cherny NI et al. Ann Oncol 2015;26:1547–73; p. 1549, table 2
*Primary endpoint;13 Secondary endpoint4
ǂThere 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
ASCO, American Society of Clinical Oncology; HR, hazard ratio; NR, not reported; NSCLC, non-small cell lung cancer; OS, overall survival
1. Sandler AB et al. J Clin Oncol 2000;18:122–30; 2. Lilenbaum RC et al. J Clin Oncol 2005;23:190–6;
3. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; 4. Socinski MA et al. J Clin Oncol 2012;30:2055–62; 5. Ellis LM et al. J Clin Oncol 2014;32:1277–80; 6. Cherny NI et al. Ann Oncol 2015;26:1547–73

6. 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

7. Continuous improvements in survival with 1st-line treatment of advanced / metastatic NSCLC (1 of 4)
Study
Regimen
Median OS, months
All NSCLC histologies
Single-agent platinum chemotherapy
EST 1583 (n=699)a,1
Carboplatin
7.3
Platinum doublet chemotherapy
Wozniak et al (n=432)b,2
Cisplatin
Vinorelbine-cisplatin 6 8
(p=0.018)
Sandler et al (n=522)c,d,3
Gemcitabine-cisplatin
7.6
9.1
(p=0.004)
aStage IV NSCLC, only data for carboplatin arm shown; bAdvanced NSCLC PS 0–1;
cAdvanced NSCLC; dquality of life deteriorated equally in both groups
This slide and the three subsequent slides summarize the therapeutic advances observed in non-small cell lung cancer (NSCLC) over recent years in various treatment settings and include survival by histology where reported
The table on this slide provides data on overall survival (OS) with single-agent platinum chemotherapy1 and two comparative studies of single versus doublet platinum chemotherapy2-3
In a Phase III study, previously untreated patients with stage IV NSCLC (n=699) treated with carboplatin had a median OS of 7.3 months1
In a randomized study in patients with advanced NSCLC and performance status 0–1 (n=432), vinorelbine plus cisplatin was associated with improved OS compared with cisplatin alone (8 versus 6 months, respectively; p=0.018)2
In a Phase III study in patients with advanced NSCLC (n=522), treatment with gemcitabine plus cisplatin was also associated with an improved OS versus cisplatin alone (9.1 versus 7.6 months, respectively; p=0.004)3
The effects of cisplatin and gemcitabine-cisplatin on quality of life were assessed among 72.4% of study participants (n=378) in the Phase III study.3 Similar decreases in total Functional Assessment of Cancer Therapy–Lung and Health-Related Quality of Life scores were observed for patients in both study arms3
References
1. Bonomi PD et al. J Clin Oncol 1989;7:1602–13; p. 1602, abstract
Wozniak AJ et al. J Clin Oncol 1998;16:2459–65; p. 2459, abstract
Sandler AB et al. Clin Oncol 2000;18:122–30; p. 122, abstract, p. 127, right col., 1st para.
NSCLC, non-small cell lung cancer; OS, overall survival; PS, performance status
1. Bonomi PD et al. J Clin Oncol 1989;7:1602–13; 2. Wozniak AJ et al. J Clin Oncol 1998;16:2459–65; 3. Sandler AB et al. Clin Oncol 2000;18:122–30

8. Continuous improvements in survival with 1st-line treatment of advanced / metastatic NSCLC (2 of 4)
Study
Regimen
Median OS, months
All
Nonsquamous*
Squamous
Platinum doublet chemotherapy (continued)
ECOG 1594 (n=1207)a,1,2
Platinum doublet
Paclitaxel-cisplatin
Gemcitabine-cisplatin
Docetaxel-cisplatin
Paclitaxel-carboplatin
7.9
7.8
8.1
7.4 –
9.1b
8.1b
7.7b
7.6b
6.9
9.4
9.3
Rosell et al (n=618)a,c,3
8.2
9.8
(HR 1.22; p=0.019)
aStage IIIb/IV PS 0–2; bAdenocarcinoma only; cNo differences in global health status or functional scales between the groups
*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
This is the second of a series of four slides summarizing the therapeutic advances observed in non-small cell lung cancer (NSCLC) over recent years in various treatment settings and includes survival by histology where reported
The table on this slide provides data on overall survival (OS) from comparative studies of different platinum doublets1-3
In a Phase III study that compared four platinum doublets in 1207 patients with stage IIIb/IV NSCLC and performance status (PS) 0–2, median OS was 7.9 months with no significant difference between the regimens in the overall population or in a subsequent post-hoc analysis by histology (adenocarcinoma and squamous NSCLC)1,2
A Phase III study in patients with advanced NSCLC and PS 0–2 (n=618) demonstrated a significantly longer OS with paclitaxel-cisplatin compared with paclitaxel-carboplatin (median 9.8 versus 8.2 months)3
Quality of life was assessed in the study comparing paclitaxel-carboplatin and paclitaxel- cisplatin. No significant differences were observed in global health status or functional scales between the two groups3
References
Schiller JH et al. N Engl J Med 2002;346:92–8; p. 92, abstract, methods; p. 95, table 3
Hoang T et al. Lung Cancer 2013;81:47–52; p. 1, abstract, methods; p. 13, table 3
3. Rosell R et al. Ann Oncol 2002;13:1539–49; p. 1539, abstract, background, results; p , right col., 1st para., last sent.
HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PS, performance status
1. Schiller JH et al. N Engl J Med 2002;346:92–8; 2. Hoang T et al. Lung Cancer 2013;81:47–52; 3. Rosell R et al. Ann Oncol 2002;13:1539–49

9. Continuous improvements in survival with 1st-line treatment of advanced / metastatic NSCLC (3 of 4)
Study
Regimen
Median OS, months
All
Nonsquamous*
Squamous
Platinum doublet chemotherapy (continued)
TAX 326 (n=1218)a,b,1
Vinorelbine-cisplatin
Docetaxel-cisplatin
10.1
11.3
(p=0.044)
Lilenbaum et al (n=561)c,2
Paclitaxel
Paclitaxel-carboplatin
6.7
8.8
(HR 0.91; p=0.25)
GLOB3 (n=380)d,e,3
 Vinorelbine-cisplatin
9.9
9.8
(p=0.58)
11.7g
11.6g
8.9
SWOG (n=792)f,4
 Paclitaxel-carboplatin
9.1g
8.1g
6.9
This is the third of a series of four slides summarizing the therapeutic advances observed in non-small cell lung cancer (NSCLC) over recent years in various treatment settings and includes survival by histology where reported
The table summarizes further comparative studies of platinum doublet regimens, including combinations of platinum agents with vinorelbine and also a study of a platinum doublet versus single-agent taxane therapy
In a Phase III study in patients with stage IIIb/IV NSCLC (n=1218), docetaxel plus cisplatin was associated with longer overall survival (OS) than vinorelbine plus cisplatin, achieving a median OS of months1
In a Phase III study in patients with stage IIIb/IV NSCLC performance status 0–2 (n=561), carboplatin plus paclitaxel was associated with a longer survival compared with paclitaxel alone2
In contrast, the smaller GLOB3 study (n=380) showed no difference in OS between vinorelbine (alternating treatment intravenously and by mouth) plus cisplatin versus docetaxel plus cisplatin.3 When the results were evaluated by histology, patients with adenocarcinoma survived for longer than those with squamous NSCLC in both treatment arms3
Pooled data from three randomized Phase III studies of standard-of-care regimens (paclitaxel-carboplatin; vinorelbine-cisplatin) involving patients with advanced disease (n=792) showed longer OS with paclitaxel plus carboplatin compared with vinorelbine plus cisplatin in both adenocarcinoma and squamous NSCLC patients4
Quality of life was assessed in two of these studies. In the study of Fossella et al comparing docetaxel plus cisplatin and vinorelbine plus cisplatin, there was consistent improvement in global quality of life (QoL) in the docetaxel-cisplatin group, as assessed by the European QoL questionnaire and the QoL Lung Cancer System Scale (LCSS) questionnaire, but deterioration in QoL for patients in the vinorelbine-cisplatin group.1 In the study by Tan et al, the QoL LCSS questionnaire showed similar worsening of the global score from baseline for both the vinorelbine-cisplatin and docetaxel-cisplatin groups3
References
Fossella F et al. J Clin Oncol 2003;21:3016–24; p. 3016, abstract; p. 3020, left col., last para.
Lilenbaum RC et al. J Clin Oncol 2005;23:190–6; p. 190, Abstract; p. 191, 1st col., eligibility criteria
Tan EH et al. Ann Oncol 2009;20:1249–56; p. 1249, abstract; p. 1250, eligibility criteria, 1st para.; p. 1252, left col., 1st para.
Kelly K et al. Clin Lung Cancer 2013;14:627–35; abstract; p. 4, last para.; p. 13, figure 3A; p. 14, figure 4A
aStage IIIb/IV; bQuality of life improved in the docetaxel-cisplatin group and deteriorated in the vinorelbine-cisplatin group; cStage IIIb/IV PS 0–2;
dStage IIIb/IV KPS ≥80%; eQuality of life deteriorated equally in both groups; fStage IIIb (pleural infusion only)/IV PS 0–1; gAdenocarcinoma only
*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
HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PS, performance status
1. Fossella F et al. J Clin Oncol 2003;21:3016–24; 2. Lilenbaum RC et al. J Clin Oncol 2005;23:190–6; 3. Tan EH et al. Ann Oncol 2009;20:1249–56; 4. Kelly K et al. Clin Lung Cancer 2013;14:627–35

10. Continuous improvements in survival with 1st-line treatment of advanced / metastatic NSCLC (4 of 4)
Study
Regimen
Median OS, months
All
Nonsquamous*
Squamous
Platinum doublet chemotherapy (continued)
Scagliotti et al (n=1725)a,1
Pemetrexed-cisplatin
Gemcitabine-cisplatin
10.3
(HR 0.94)
11.8
10.4
(HR 0.81)
9.4
10.8
(HR 1.23)
Socinski et al (n=1052)a,2
Nab-paclitaxel-carboplatin
Paclitaxel-carboplatin
12.1
11.1
(HR 0.92)
13.1
13.0
10.7
9.5
(HR 0.89)
Shukuya et al (n=355)a,3
Nedaplatin-docetaxel
Cisplatin-docetaxel
13.6
11.4
Targeted therapies
Sandler et al (n=878)a,4
Bevacizumab + paclitaxel-carboplatin
10.3b
14.2b
(HR 0.69)
This is the final slide of a series of four slides summarizing the therapeutic advances observed in non-small cell lung cancer (NSCLC) over recent years in various treatment settings, including survival by histology where reported. The table summarizes the results of studies with newer cytotoxics and also of the Phase II bevacizumab trial in patients with adenocarcinoma
In a Phase III study in 1725 chemotherapy-naive patients with stage IIIb/IV NSCLC and performance status (PS) 0–1 (n=1725), pemetrexed-cisplatin significantly improved median overall survival (OS) compared with gemcitabine-cisplatin in patients with nonsquamous NSCLC, with a median OS of 11.8 months (versus 10.4 months),1 whereas in patients with squamous histology, median OS with gemcitabine-cisplatin was longer than with the pemetrexed combination (10.8 versus 9.4 months)
In a Phase III study in 1052 patients with stage IIIb/IV NSCLC and PS 0–1, nab- paclitaxel-carboplatin was associated with a numerical (nonsignificant) increase in OS in patients with squamous NSCLC2
In a Phase III study in 355 Japanese patients with stage IIIb/IV or recurrent squamous NSCLC and previously untreated with chemotherapy (although adjuvant chemotherapy >1 year previously was permitted), nedaplatin (a cisplatin derivative) combined with docetaxel significantly improved OS compared with cisplatin plus docetaxel (hazard ratio 0.81; 95% confidence interval 0.65, 1.02; p=0.037, one-sided log-rank test); median survival was 13.6 versus 11.4 months3
In a Phase III study in patients with nonsquamous NSCLC with no antecedent history of hemoptysis (n=878), bevacizumab, in combination with paclitaxel and carboplatin, demonstrated a survival benefit compared with paclitaxel-carboplatin alone in the adenocarcinoma subset (14.2 versus 10.3 months)4
References
Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3543, abstract, patients and methods, results; p. 3546, 2nd col., 4th para.
Socinski MA et al. J Clin Oncol 2012;30:2055–62; p. 2055, abstract, purpose, patients and methods; p. 2059, 1st col., 1st para.; figure 2
Shukuya T et al. Lancet Oncol 2015;16:1630–8; p. 1630, abstract, methods and findings
Sandler A et al. J Thorac Oncol 2010;5:1416–23; p. 1416, abstract; p. 1417, patient population and histologies, 1st para.; table 1
aStage IIIb/IV PS 0–1; bAdenocarcinoma only (n=602)
*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
HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PS, performance status
1. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; 2. Socinski MA et al. J Clin Oncol 2012;30:2055–62;
3. Shukuya T et al. Lancet Oncol 2015;16:1630–38; 4. Sandler A et al. J Thorac Oncol 2010;5:1416–23

11. Histological subtype influences efficacy and tolerability in advanced NSCLC1-3
Studies of 1st-line therapies for NSCLC have demonstrated an interaction between histological subtype and treatment response, OS, or toxicity1-3
Majority highlighted efficacy or tolerability advantages in patients with nonsquamous* not squamous NSCLC
A Phase II randomized trial of addition of bevacizumab to carboplatin + paclitaxel demonstrated a higher response rate with bevacizumab; however, patients with squamous histology had an increased risk of major hemoptysis3
Phase III study of chemotherapy-naive patients with stage IIIB/IV NSCLC (n=1725)2
HR 1.23
(95% CI 1.00, 1.51)
HR 0.81
(95% CI 0.70, 0.94)
Median OS, monthsa
aPrimary trial endpoint
Clinical trials of first-line therapies for non-small cell lung cancer (NSCLC) have demonstrated an interaction between histological subtype and treatment response, overall survival (OS), or toxicity1-3
The majority of these studies have highlighted advantages in efficacy or tolerability in patients with nonsquamous rather than squamous NSCLC
The figure summarizes data for the primary endpoint, OS, from a Phase III noninferiority, randomized study of patients with stage IIIB/IV NSCLC (n=1725) treated with cisplatin- pemetrexed or cisplatin-gemcitabine2
In patients with squamous histology, median OS was shorter with cisplatin- pemetrexed (n=244) at 9.4 months, compared with 10.8 months with cisplatin- gemcitabine (n=229) [hazard ratio [HR] 1.23; 95% confidence interval [CI] 1.00, 1.51]2
In contrast, in patients with nonsquamous histology (n=1000), median OS was longer with cisplatin-pemetrexed at 11.8 months, compared with 10.4 months with cisplatin- gemcitabine (HR 0.81; 95% CI 0.70, 0.94)2
A Phase II randomized trial (n=99) of the addition of bevacizumab to carboplatin plus paclitaxel in patients with advanced NSCLC demonstrated a higher response rate with bevacizumab; however, patients with squamous histology had an increased risk of major hemoptysis3
References
1. Al-Farsi A, Ellis PM. Front Oncol 2014;4:157; p. 157, 2nd col., 2nd para.
2. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51; p. 3543, abstract; table 1; p. 3544, 1st col., 2nd para.; p. 3546, 2nd col., 4th para., 1st and 2nd sent.
3. Johnson DH et al. J Clin Oncol 2004;22:2184–91; p. 2184, 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
CI, confidence interval; cis, cisplatin; gem, gemcitabine; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; pem, pemetrexed 1. Al-Farsi A, Ellis PM. Front Oncol 2014;4:157; 2. Scagliotti GV et al. J Clin Oncol 2008;26:3543–51;
3. Johnson DH et al. J Clin Oncol 2004;22:2184–91

12. 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 a further 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

13. Understanding of oncogenic drivers specific to squamous NSCLC is limited1-3
Molecular characterization of squamous NSCLC has only recently begun in earnest2
A genomic and epigenetic analysis of squamous NSCLC suggests that squamous NSCLC tumors are genetically complex, identifying:3
TP53 mutations in almost all samples
HLA-A loss-of-function mutations
Alterations in the FGFR kinase family
Frequent alterations in pathways involved in cell cycle control, response to oxidative stress, apoptotic signaling, and / or squamous cell differentiation
The potential of these mutations as molecular targets in the treatment of squamous NSCLC is currently unknown3
Our understanding of oncogenic drivers that are specific to squamous non-small cell lung cancer (NSCLC) is currently limited, and in contrast to lung adenocarcinoma, the molecular characterization of squamous NSCLC has only recently begun in earnest1,2
The Cancer Genome Atlas Research Network conducted a genomic and epigenetic analysis of 178 squamous NSCLC tumors and found that squamous NSCLC is characterized by complex genetic alterations, including:3
Tumor protein 53 mutations in almost all samples
Human leukocyte antigen A loss-of-function mutations that had previously been unreported
Alterations in the fibroblast growth factor receptor kinase family
Frequent alterations in pathways involved in cell cycle control, response to oxidative stress, apoptotic signaling, and/or squamous cell differentiation
The potential of these molecular targets in the treatment of squamous NSCLC is currently unknown3
References
1. Gerber DE et al. Am Soc Clin Oncol Educ Book 2014;e353–65; p. e354, 1st col., 2nd para.; p. e355, table 1, last 4 rows
2. Liao RG et al. Lung Cancer Manag 2012;1:293–300; p. 1, last para.; p.4, other kinases
3. Cancer Genome Atlas Research Network. Nature 2012;489:519–25; p. 1, summary; p. 7, discussion, 1st para., 2nd para., 3rd para.
FGFR, fibroblast growth factor receptor; HLA-A, human leukocyte antigen A; NSCLC, non-small cell lung cancer; TP53, tumor protein 53
1. Gerber DE et al. Am Soc Clin Oncol Educ Book 2014;e353–65; 2. Liao RG et al. Lung Cancer Manag 2012;1:293–300; 3. Cancer Genome Atlas Research Network. Nature 2012;489:519–25

14. Recent advances in systemic therapies for advanced / metastatic NSCLC: 1st-line and maintenance
Therapy
Nonsquamous* NSCLC
Squamous NSCLC
EGFR and ALK TKIs
Provide benefits in patients who carry EGFR mutations and ALK translocations, respectively1,2
Tumors that harbor an EGFR or ALK mutation are rare in squamous NSCLC3
Pemetrexed
Approved for 1st-line and maintenance4,5
Not an approved indication4,5
Bevacizumab
Provides improvements in OS compared with chemotherapy alone6
Associated with an increased risk of pulmonary hemorrhage7
Necitumumab
Not an approved indication8,9
Approved as 1st-line therapy in combination with gemcitabine-cisplatin for:8,9
metastatic squamous NSCLC (U.S.)
locally advanced / metastatic EGFR–expressing squamous NSCLC (EU)
Pembrolizumab
Approved for 1st-line in patients whose tumors express PD-L1 in ≥50% of cells and who do not have any EGFR mutations and ALK translocations10,11
The table summarizes the advances in first-line and maintenance therapeutics observed in nonsquamous non-small cell lung cancer (NSCLC) over recent years in various treatment settings, compared with squamous NSCLC
The epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are effective in patients with tumors carrying EGFR mutations and ALK translocations, respectively.1,2 They are approved in patients with squamous NSCLC tumors that harbor these mutations; however, such mutations are rare in these tumors3
Pemetrexed is approved for first-line and maintenance settings in nonsquamous NSCLC, but it is not approved for treatment of squamous NSCLC4,5
Bevacizumab is associated with improvements in overall survival in nonsquamous NSCLC,6 but is associated with an increased risk of pulmonary hemorrhage in squamous NSCLC7
Necitumumab is approved as first-line therapy in combination with gemcitabine-cisplatin for metastatic squamous NSCLC in the United States and for locally advanced/metastatic EGFR-expressing squamous NSCLC in Europe8,9
The National Comprehensive Cancer Network does not include necitumumab + gemcitabine-cisplatin as a treatment option10
Pembrolizumab is approved as first-line therapy in for high-expressing PD-L1 metastatic NSCLC without any EGFR mutations or ALK translocations11,12
References
Mok TS et al. N Engl J Med 2009;361:947–57; abstract, p. 948, 2nd col., 2nd para.; p. 951, 1st col., 2nd para. on to 2nd col.
Kwak E et al. N Engl J Med 2010;363:1693–703; p. 1695, 2nd col., results; last sent. on to p. 1696; p. 1700, 2nd col., discussion, 1st sent.
Pao W, Girard N. Lancet Oncol 2011;12:175–80; p. 176, table 1
FDA. Pemetrexed. Highlights of prescribing information. Available at: (accessed June 20, 2016); p. 1, Indications and Usage
EMA. Pemetrexed summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications
Sandler A et al. J Thorac Oncol 2010;5:1416–23; p. 1416, abstract
Johnson DH et al. J Clin Oncol 2004;22:2184–91; p. 2189, 2nd col., 3rd para., 2nd sent.
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
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; p. MS-26, 2nd col., 2nd para. [please access ref via NCCN website: NCCN does not permit its distribution]
FDA. Pembrolizumab. Highlights of prescribing information. Available at (accessed June 20, 2016). p. 1, Indications and Usage
EMA Summary of opinion (post authorisation). Available at: (accessed on February, 2017); p. 1, 3rd para.
*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
Necitumumab + gemcitabine-cisplatin is FDA / EMA approved for metastatic squamous NSCLC;8,9 the NCCN does not include necitumumab + gemcitabine-cisplatin as a treatment option12
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor
Mok TS et al. N Engl J Med 2009;361:947–57; 2. Kwak E et al. N Engl J Med 2010;363:1693–703; 3. Pao W, Girard N. Lancet Oncol 2011;12:175–80; 4. FDA. Pemetrexed. Highlights of prescribing information. Available at: (accessed June 20, 2016); 5. EMA. Pemetrexed summary of product characteristics Available at: (accessed June 20, 2016); 6. Sandler A et al. J Thorac Oncol 2010;5:1416–23; 7. Johnson DH et al. J Clin Oncol 2004;22:2184–91; 8. FDA. Necitumumab. Highlights of prescribing information. Available at: (accessed June 20, 2016); 9. EMA. Necitumumab summary of product characteristics Available at: (accessed June 20, 2016); 10. FDA. Pembrolizumab. Highlights of prescribing information. Available at: EMA Summary of opinion (post authorisation). Available at:
(accessed February 22, 2017); 12. 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.

15. Advances in 1st-line therapy for advanced NSCLC with agents targeted against oncogenic drivers: EGFR
Results from Phase III randomized, open-label trials for EGFR mutation positive patients
Target
Approved drug
PFSa OS
EGFR
Erlotinib
Longer PFS vs cis + D / gem
(HR 0.37; 95% CI 0.25, 0.54; p<0.0001)1
Comparable OS vs cis + D / gem
(HR 1.04; 95% CI 0.65, 1.68; p=0.87)1
Gefitinib
Longer PFS vs CP
(HR 0.48; 95% CI 0.36, 0.64; p<0.001)2,b
Comparable OS vs CP
(HR 0.90; 95% CI 0.79, 1.02; p=0.109)3
Afatinib
Longer PFS vs cis-pem
(HR 0.47; 95% CI 0.34, 0.65; p=0.001)4,b,c
Significantly longer OS vs cis-pem (HR 0.54; 95% CI 0.36, 0.79; p=0.0015)5,b,c
aPrimary trial endpoint; bIn adenocarcinoma only; cPre-planned subgroup analysis of EGFR+ patients
Majority of patients with squamous NSCLC are EGFR mutation negative6
Significant advances have been made with first-line therapies for nonsquamous non-small cell lung cancer (NSCLC) with agents targeted against tumors harboring epidermal growth factor receptor (EGFR) mutations1-3
The table provides clinical trial data on progression-free survival (PFS), the primary endpoint, and overall survival for erlotinib, gefitinib, and afatinib, each of which are approved for the first-line treatment of EGFR mutation-positive metastatic NSCLC
In the EURTAC study, a Phase III randomized, open-label trial in EGFR+ patients (positive for the EGFR exon 19 deletion or L858R mutation) with stage IIIB/IV NSCLC (n=173), PFS was significantly improved with erlotinib compared with cisplatin plus docetaxel/gemcitabine (median 9.7 versus 5.2 months; hazard ratio [HR] 0.37; 95% confidence interval [CI] 0.25, 0.54; p<0.0001).1 Overall survival (OS) was similar for both arms1
EGFR+ patients with stage IIIB/IV adenocarcinoma (n=261) had a significantly longer PFS with gefitinib compared with carboplatin-paclitaxel (HR 0.48; 95% CI 0.36, 0.64; p<0.001) in a Phase III randomized, open-label study.2 OS was similar for both arms3
The LUX-Lung 3 study was an open-label Phase III trial of 345 patients with stage IIIB/IV lung adenocarcinoma randomized to receive afatinib or cisplatin plus pemetrexed chemotherapy. In EGFR+ patients (n=308), median PFS was 13.6 months with afatinib, compared with 6.9 months with cisplatin-pemetrexed (HR 0.47; 95% CI 0.34, 0.65; p=0.001).4 OS was significantly longer for patients with lung adenocarcinoma carrying an exon 19 deletion in EGFR who were treated with afatinib compared with cisplatin plus pemetrexed chemotherapy5
The majority of patients with squamous NSCLC do not carry mutations on EGFR6
References
1. Rosell R et al. Lancet Oncol 2012;13:239–46; p. 239, abstract; p. 240, 2nd col., study design and participants, 2nd sent.; p. 243, 1st col., results, 1st para., 3rd sent.; p. 244, 2nd col., 4th para.
Mok TS et al. N Engl J Med 2009;361:947–57; p. 947, abstract; p. 948, 2nd col., 2nd para.
Fukuoka M et al. J Clin Oncol 2011;29:866–74; p. 2866, abstract; p. 2869, 2nd col., 2nd para.
Sequist LV et al. J Clin Oncol 31:3327–34; p. 3327, abstract, patients and methods, results; p , 1st col., study design and patients; p. 3329, 1st col., last para.
Yang JC et al. Lancet Oncol 2015;16:141–51; p.141, abstract
Cancer Genome Atlas Research Network. Nature 2012;489:519–25; p. 522, 1st col., 3rd para.; p. 523, figure 5
C, carboplatin; CI, confidence interval; cis, cisplatin; D, docetaxel; EGFR, epidermal growth factor receptor; gem, gemcitabine; HR, hazard ratio; NSCLC, non-small-cell lung cancer; OS, overall survival; P, paclitaxel; pem, pemetrexed; PFS, progression-free survival 1. Rosell R et al. Lancet Oncol 2012;13:239–46; 2. Mok TS et al. N Engl J Med 2009;361:947–57;
3. Fukuoka M et al. J Clin Oncol 2011;29:866–74; 4. Sequist LV et al. J Clin Oncol 2013;31:3327–34;
5. Yang JC et al. Lancet Oncol 2015;16:141–51; 6. Cancer Genome Atlas Research Network. Nature 2012;489:519–25

16. necitumumab + gemcitabine-cisplatin as a treatment option4
Advances in 1st-line therapy for advanced squamous NSCLC: EGFR ‒ necitumumab
Necitumumab treatment setting: Approved as 1st-line therapy in combination with gemcitabine-cisplatin for metastatic squamous NSCLC (US)1 or locally advanced / metastatic EGFR-expressing squamous NSCLC (EU)2
Results from a randomized Phase III clinical trial:3
aPrimary or bsecondary endpoint
Time (months)
Improvements in first-line therapy for advanced squamous non-small cell lung cancer (NSCLC) have been demonstrated with the epidermal growth factor receptor (EGFR) antibody necitumumab1
Necitumumab is approved as first-line therapy in combination with gemcitabine-cisplatin for metastatic squamous NSCLC in the United States and for locally advanced/metastatic EGFR-expressing squamous NSCLC in Europe2,3
The National Comprehensive Cancer Network does not consider necitumumab + gemcitabine-cisplatin an appropriate treatment option4
In a randomized Phase III study of 1093 patients with previously untreated stage IV squamous NSCLC, the primary endpoint of overall survival (OS) for necitumumab plus gemcitabine-cisplatin therapy was significantly longer compared with gemcitabine-cisplatin therapy (median 11.5 versus 9.9 months; hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.74, 0.96; p=0.01). Median progression-free survival was 5.7 months with necitumumab plus gemcitabine-cisplatin therapy versus 5.5 months with gemcitabine-cisplatin therapy (HR 0.85; 95% CI 0.74, 0.98; p=0.02)1
References
Thatcher N et al. Lancet Oncol 2015;16:763–74; p. 763, abstract; p. 765, 1st col., 2nd and 4th para.; 2nd col., last para; p. 766, 1st col., 1st para.; p. 767, 1st col., 1st para.; p. 768, 1st col., 3rd para. and table 2; p. 769, figure 2
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: _Product_Information/human/003886/WC pdf (accessed June 20, 2016); p. 2, Therapeutic Indications
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; p. MS-26, 2nd col., 2nd para. [please access ref via NCCN website: NCCN does not permit its distribution]
Necitumumab + gemcitabine-cisplatin is FDA / EMA approved for metastatic squamous NSCLC;1,2 the NCCN does not include
necitumumab + gemcitabine-cisplatin as a treatment option4
CI, confidence interval; cis, cisplatin; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency;
FDA, Food and Drug Administration; gem, gemcitabine; HR, hazard ratio; NCCN, National Comprehensive Cancer Network;
NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival
1. FDA. Necitumumab. Highlights of prescribing information. Available at:
(accessed June 20, 2016);
2. EMA. Necitumumab summary of product characteristics Available at: document_library/EPAR_-_Product_Information/human/003886/WC pdf (accessed June 20, 2016); 3. Thatcher N et al. Lancet Oncol 2015;16:763–74; 4. 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

17. Recent advances in systemic therapies for advanced / metastatic NSCLC: 2nd- and 3rd-line
Therapy
Nonsquamous* NSCLC
Squamous NSCLC
Erlotinib
Approved as 2nd-/3rd-line therapy, irrespective of histology1,2
Afatinib
Not an approved indication3,4
Approved as a 2nd-line therapy3,4
Pemetrexed
Approved as a 2nd-line therapy5,6
Not an approved indication5,6
Ramucirumab
Approved for 2nd-line therapy in combination with docetaxel, irrespective of histology7,8
*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 table summarizes the therapeutic advances observed in nonsquamous non-small cell lung cancer (NSCLC) over recent years in various treatment settings, compared with squamous NSCLC
The epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) erlotinib is also approved for second-/third-line settings in patients with nonsquamous and squamous NSCLC1,2
Afatinib is approved in patients with advanced squamous NSCLC who experience progression on or after platinum-based chemotherapy3,4
Pemetrexed is approved for first-line, maintenance, and second-line settings in nonsquamous NSCLC, but it is not approved for treatment of squamous NSCLC5,6
Ramucirumab is approved in NSCLC for second-line settings in combination with docetaxel, irrespective of histology7,8
References
FDA. Erlotinib. Highlights of prescribing information. Available at: (accessed February 12, 2015); p. 1, Indications and Usage
EMA. Erlotinib summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications
FDA. Afatinib. Highlights of prescribing information. Available at: (accessed June 20, 2016). p. 1, Indications and Usage
EMA. Afatinib summary of product characteristics Available at: (accessed June 20, 2016). p. 3, Therapeutic Indications
FDA. Pemetrexed. Highlights of prescribing information. Available at: (accessed June 20, 2016); p. 1 , Indications and Usage
EMA. Pemetrexed summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications
FDA. Ramucirumab. Highlights of prescribing information. Available at: (accessed June 20, 2016); p. 1, Indications and Usage
EMA. Ramucirumab summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor
1. FDA. Erlotinib. Highlights of prescribing information.
Available at: Accessed February 12, 2015; 2. EMA. Erlotinib summary of product characteristics Available at: (accessed June 20, 2016); 3. FDA. Afatinib. Highlights of prescribing information. Available at: (accessed June 20, 2016); 4. EMA. Afatinib summary of product characteristics Available at: (accessed June 20, 2016)
5. FDA. Pemetrexed. Highlights of prescribing information. Available at: (accessed June 20, 2016);
6. EMA. Pemetrexed summary of product characteristics Available at: (accessed June 20, 2016); 7. FDA. Ramucirumab. Highlights of prescribing information. Available at: (accessed June 20, 2016);
8. EMA. Ramucirumab summary of product characteristics
(accessed June 20, 2016)

18. Advances in other treatment settings in advanced NSCLC: EGFR
Results from a randomized Phase III trial
Approved drug
Treatment setting
Median PFS
Median OS
Erlotinib
Maintenance in patients with EGFR–activating mutations1,2
PFS benefit for erlotinib vs placebo after progression (HR 0.10; 95% CI 0.04, 0.25; p<0.0001)2,a
OS benefit of erlotinib vs placebo
after progression
(HR 0.83;
95% CI 0.34, 2.02)2,b
Metastatic NSCLC after failure of ≥1 prior chemotherapy regimen1,2
2.2 vs 1.8 months (HR 0.61; 95% CI 0.51, 0.74; p<0.001)3,b
6.7 vs 4.7 months (HR 0.70; 95% CI 0.58, 0.85; p<0.001)3,a
Afatinib
Metastatic SqNSCLC after progression with platinum-based chemotherapy4,5
2.6 vs 1.9 months with erlotinib (HR 0.81; 95% CI 0.69, 0.96; p=0.0103)6,a,c
7.9 vs 6.8 months with erlotinib (HR 0.81; 95% CI 0.69, 0.95; p=0.0077)6,b
Improvements in outcomes in advanced non-small cell lung cancer (NSCLC) have also been demonstrated with the epidermal growth factor receptor (EGFR) inhibitor erlotinib in other treatment settings, as summarized in the table
Erlotinib has been approved for maintenance therapy in patients with metastatic NSCLC harboring EGFR-activating mutations.1,3 In a predefined exploratory analysis in patients with metastatic NSCLC who had tumors with EGFR-activating mutations (n=49), erlotinib showed benefits in progression-free survival (hazard ratio [HR]=0.10, 95% confidence interval [CI], 0.04, 0.25; p<0.0001) and in overall survival (OS) [HR=0.83; 95% CI, 0.34, 2.02].3
Based on the results from the IUNO trial, erlotinib is not indicated in Europe for maintenance therapy in patients with metastatic NSCLC who do not carry an EGFR-activating mutation. No differences were observed between erlotinib for first-line erlotinib maintenance therapy and erlotinib after progression for the primary endpoint of OS (HR 0.94; 95% CI 0.80, 1.11; p=0.48). Similarly, no differences were observed between erlotinib for first-line erlotinib maintenance therapy and erlotinib after progression for the secondary endpoint of PFS (HR 1.02; 95% CI 0.85, 1.22; p=0.82)3
Erlotinib is also approved in the second-line setting in patients with metastatic NSCLC after failure of at least one prior chemotherapy regimen.1,3 In a Phase III randomized, double-blind trial in patients with stage IIIB/IV NSCLC who had failed one or two prior chemotherapy regimens (n=731), erlotinib was associated with a median PFS of 2.2 months, versus 1.8 months with placebo (HR 0.61; 95% CI 0.51, 0.74; p<0.001) and a median OS of 6.7 versus 4.7 months (HR 0.70; 95% CI 0.58, 0.85; p<0.001);3 the primary endpoint in this trial was OS, with PFS as a secondary endpoint4
Afatinib is approved for therapy after progression with platinum-based chemotherapy in patients with metastatic squamous NSCLC.5,6 In a Phase III randomized trial in patients with stage IIIB/IV squamous NSCLC who had progressed after at least four cycles of platinum-based chemotherapy (n=795), afatinib was associated with a median PFS of 2.6 months versus 1.9 months with erlotinib (HR 0.81; 95% CI 0.69, 0.96; p=0103) and a median OS of 7.9 versus 6.8 months (HR 0.81; 95% CI 0.69, 0.95; p<0.0077);7 the primary endpoint in this trial was PFS, with OS as a secondary endpoint7
References
1. FDA. Erlotinib. Highlights of prescribing information. Available at: (accessed December 12, 2016); Indications and Usage, 2nd and 3rd bullets
Cohen MH et al. Oncologist 2010;15:1344–51; p. 1344–1345, abstract; p. 1345, 2nd col., patients and methods, 1st sent.; table 1 and table 4
EMA. Erlotinib summary of product characteristics Available at: (accessed December 12, 2016); p. 2, Therapeutic Indications; p. 15, 2nd para.
Shepherd FA et al. N Engl J Med 2005;353:123–32; p. 123, abstract; p. 124, 2nd col., methods, study design, 2nd para.; p. 127, 1st col., 2nd para.
FDA. Afatinib. Highlights of prescribing information. Available at: (accessed June 20, 2016); p. 1, Indications and Usage
EMA. Afatinib summary of product characteristics Available at: (accessed June 20, 2016); p. 3, Therapeutic Indications
Soria JC et al. Lancet Oncol 2015;16:897–907; p. 897, abstract
aPrimary or bsecondary endpoint;
cAt the time of primary analysis of OS
CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; SqNSCLC, squamous non-small cell lung cancer
1. FDA. Erlotinib. Highlights of prescribing information. Available at:
(accessed December 12, 2016);
2. EMA. Erlotinib summary of product characteristics Available at:
(accessed December 12, 2016); 3. Shepherd FA et al. N Engl J Med 2005;353:123–32; 4. FDA. Afatinib. Highlights of prescribing information.
Available at: (accessed June 20, 2016);
5. EMA. Afatinib summary of product characteristics Available at:
(accessed June 20, 2016); 6. Soria JC et al. Lancet Oncol 2015;16:897–907

19. Median PFS from clinical trials Median OS from clinical trials
Advances in other treatment settings for advanced NSCLC with agents targeted against oncogenic drivers: ALK
Target
Approved drugs
Treatment setting
Median PFS from clinical trials
Median OS from clinical trials
ALK trans-
location
Crizotinib
ALK+ metastatic NSCLC1,2
10.9 vs 7.0 months with pem-cis/carboplatin (HR 0.45; 95% CI 0.35, 0.60; p<0.001)3,a,c
NYR for either group (HR for death with crizotinib 0.82;
95% CI 0.54, 1.26;
p=0.36)3,b,c
ROS1+ metastatic NSCLC1
19.2 months
(95% CI 14.4, NYR)4,d --
Ceritinib
ALK+ metastatic NSCLC and progression on / intolerance to crizotinib5,6
5.7 months
(95% CI 5.3, 7.4)6,b,e
14.0 months
(95% CI 10.3,14.0) 6,b,e
Alectinib
ALK+ metastatic NSCLC and progression on / intolerance to crizotinib7
aPrimary endpoint; bSecondary endpoint; cRandomized, open-label Phase III trial; dExtended Phase I study; ePhase II
Improved outcomes in advanced non-small cell lung cancer (NSCLC) have also been demonstrated with the anaplastic lymphoma kinase (ALK) inhibitors crizotinib and ceritinib in first-line therapy and other settings
Crizotinib is approved in patients with ALK+ metastatic NSCLC.1,2 In a Phase III randomized, open-label study of patients with previously untreated, locally advanced, recurrent or metastatic nonsquamous NSCLC positive for ALK rearrangements (n=343), progression-free survival (PFS), the primary endpoint, was significantly longer with crizotinib than with pemetrexed in combination with cisplatin or carboplatin (median 10.9 versus 7.0 months; hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.35, 0.60; p<0.001).3 Median OS, the secondary endpoint, was not yet reached for either group (HR for death with crizotinib, 0.82; 95% CI 0.54,1.26; p=0.36)3
Crizotinib is also approved in the United States in patients with Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1)+ metastatic NSCLC.1 In an expanded Phase I study that included 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement, the median PFS (primary endpoint) for treatment with crizotinib was 19.2 months (95% CI 14.4, not reached)4
Ceritinib is approved in patients with ALK+ metastatic NSCLC with progression on, or who are intolerant to, crizotinib.5,6 In an extended Phase I study in patients with advanced or metastatic ALK+ NSCLC previously treated with an ALK inhibitor (n=163), median PFS for treatment with ceritinib was 6.9 months (95% CI 5.6, 8.7) and the median OS was 16.7 months (95% CI 14.8, not yet reached) [both secondary outpoints].6 In a Phase II study in patients with advanced or metastatic ALK+ NSCLC previously treated with an ALK inhibitor (n=140), median PFS for treatment with ceritinib was 5.7 months (95% CI 5.3, 7.4) and the median OS was 14.0 months (95% CI 10.3, 14.0) [both secondary outpoints]6
Alectinib is approved in patients with ALK+ metastatic NSCLC with progression on, or who are intolerant to, crizotinib.7 The objective response rate per Independent Review Committee was 38% (95% CI 28, 49) in one Phase II North American study of 87 patients with ALK+ advanced NSCLC and 44% (95% CI 36, 53) in another Phase II international study of 138 patients with ALK+ advanced NSCLC7
Patients with squamous NSCLC do not typically present with mutations in ALK8
References
FDA. Crizotinib. Available at: (accessed June 20, 2016); p. 1, Indications and Usage
EMA. Crizotinib summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications
Solomon BJ et al. N Engl J Med 2014;371:2167–77; p. 2167, abstract; p. 2168, methods, 1st col., 1st para.; p. 2169, 1st col., 2nd para.
Shaw AT et al. N Engl J Med 2014;371:1963–71; p. 1, abstract; p. 3, 3rd para.
FDA. Ceritinib. Available at: (accessed January 27, 2014); p. 1, Indications and Usage
EMA. Ceritinib summary of product characteristics Available at: (accessed June 20, 2016); p. 2, Therapeutic Indications; p. 13, 6th and 7th para.; p. 14, 1st para. and table 13
FDA. Alectinib. Available at: (accessed June 20, 2016); p. 1, Indications and Usage; p. 11, 10th and 11th para.; p. 12, 1st para. and table 5
Cancer Genome Atlas Research Network. Nature 2012;489:519–25; p. 519, 1st col., 1st para.
ALK mutations are rare in squamous NSCLC8
ALK, anaplastic lymphoma kinase; CI, confidence interval; doc, docetaxel; HR, hazard ratio; NSCLC, non-small cell lung cancer; pem, pemetrexed; NYR, not yet reached; PFS, progression-free survival; ROS1, Proto-Oncogene 1, Receptor Tyrosine Kinase
1. FDA. Crizotinib. Available at: (accessed June 20, 2016);
2. EMA. Crizotinib summary of product characteristics Available at: (accessed June 20, 2016)
3. Solomon BJ et al. N Engl J Med 2014;371:2167–77; 4. Shaw AT et al. N Engl J Med 2014;371:1963–71; 5. FDA. Ceritinib. Available at: Accessed January 27, 2014;
6. EMA. Ceritinib summary of product characteristics Available at: en_GB/document_library/EPAR_-_Product_Information/human/003819/WC pdf (accessed June 20, 2016); 7. FDA. Alectinib. Available at: (accessed June 20, 2016);
8. Cancer Genome Atlas Research Network. Nature 2012;489:519–25

20. Recent advances in immunotherapies for advanced / metastatic NSCLC: 2nd and 3rd line
Therapy
Nonsquamous* NSCLC
Squamous NSCLC
Nivolumab
Approved in patients with progression during / after platinum-based chemotherapy, irrespective of histology1,2
Pembrolizumab
Approved in patients with progression during / after platinum-based chemotherapy, irrespective of histology, and whose tumours express PD-L1 in ≥1% of cells; patients with EGFR- or ALK-positive tumor mutations should also have received prior therapy for these mutations3,4
Atezolizumab
Approved in patients with progression during / after platinum-based chemotherapy, irrespective of histology; patients with EGFR- or ALK-positive tumor mutations should have progressed on approved therapy for these mutations5
*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 table summarizes the therapeutic advances observed in nonsquamous non-small cell lung cancer (NSCLC) over recent years in various treatment settings, compared with squamous NSCLC
Nivolumab is approved in patients with advanced squamous or nonsquamous NSCLC who experience progression on or after platinum-based chemotherapy1,2
Pembrolizumab is approved in patients with advanced squamous or nonsquamous NSCLC whose tumours express programmed death-ligand 1 in ≥1% of cells and who experience progression on or after platinum-based chemotherapy; patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive tumor mutations should also have received prior therapy for these mutations (EU) 3,4
Atezolizumab is approved in patients with progression during/after platinum-based chemotherapy, irrespective of histology; patients with EGFR- or ALK-positive tumor mutations should have progressed on approved therapy for these mutations5
References
FDA. Nivolumab. Highlights of prescribing information. Available at: (accessed June 20, 2016); p.1, Indication and Usage
EMA. Nivolumab BMS summary of product characteristics Available at: _Product_Information/human/003840/WC pdf (accessed June 20, 2016); p. 2, Therapeutic Indications
FDA. Pembrolizumab. Highlights of prescribing information. Available at: (accessed June 20, 2016). p.1, Indication and Usage
EMA. Summary of opinion (post authorisation). Available at: WC pdf (accessed February ); p.1, 5th para.
FDA. Atezolizumab. Highlights of prescribing information. Available at: (accessed December 12, 2016). p.1, Indications and Usage
ALK, anaplastic lymphoma kinase; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival
FDA. Nivolumab. Highlights of prescribing information. Available at: (accessed June 20, 2016); 2. EMA. Nivolumab BMS summary of product characteristics Available at: (accessed June 20, 2016); 3. FDA. Pembrolizumab. Highlights of prescribing information. Available at: (accessed June 20, 2016); 4. EMA Summary of opinion (post authorisation). Available at:
(accessed February ); 5. FDA. Atezolizumab. Highlights of prescribing information. Available at: (accessed December 12, 2016).

21. Advances in other treatment settings in advanced NSCLC: nivolumab immunotherapy
Nivolumab treatment setting: Approved for metastatic NSCLC on progression or after platinum-based chemotherapy1,2
Results from a randomized Phase III clinical trial:3 a b
Improved outcomes in advanced non-small cell lung cancer (NSCLC) have also been demonstrated with the programmed cell death protein 1 (PD-1) antibody nivolumab.1-3 Nivolumab is approved in patients with advanced squamous or nonsquamous NSCLC who experience progression on or after platinum-based chemotherapy1,2
In a randomized, open-label, Phase III study of 272 patients with stage IIIB/IV squamous NSCLC previously treated with platinum-based chemotherapy, the primary endpoint of overall survival for nivolumab therapy was significantly longer compared with docetaxel therapy (median 9.2 versus 6.0 months; hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.44, 0.79; p<0.001). Median progression-free survival was 3.5 months with nivolumab therapy versus 2.8 months with docetaxel therapy (HR 0.62; 95% CI 0.47, 0.81; p<0.001)3
References
FDA. Nivolumab. Highlights of prescribing information. Available at: (accessed June 20, 2016). p.1, Indications and Usage
EMA. Nivolumab BMS summary of product characteristics Available at: _Product_Information/human/003840/WC pdf (accessed June 20, 2016).p.2, Therapeutic Indications
Brahmer J et al. N Engl J Med 2015;373:123–35; p. 123, abstract; p. 124, 1st col., last para.; p. 125, 1st col., 1st para.; p. 128, figure 1; p. 130, figure 2B
Time (months)
CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival
1. FDA. Nivolumab. Highlights of prescribing information. Available at:
(accessed June 20, 2016); 2. EMA. Nivolumab BMS summary of product characteristics (accessed June 20, 2016); 3. Brahmer J et al. N Engl J Med 2015;373:123–35

22. Advances in other treatment settings in advanced NSCLC: pembrolizumab immunotherapy
Pembrolizumab treatment setting: Indicated for first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 in ≥50% of cells and who do not have EGFR- or ALK-positive tumor mutations. Also indicated for patients with locally advanced or metastatic NSCLC progressing after ≥1 prior chemotherapy regimen and whose tumors express PD-L1 with ≥1% of cells. Patients with EGFR- or ALK-positive tumor mutations should also have received targeted therapy prior to treatment with pembrolizumab1,2
Results from a randomized Phase III clinical trial:3,4
3,a
0.48 (0.35, 0.66)
4,a
0.61 (0.49, 0.75)
p<0.0001
Improved outcomes in advanced non-small cell lung cancer (NSCLC) have also been demonstrated with pembrolizumab,1,2 another programmed cell death protein 1 (PD-1) antibody
Pembrolizumab 200 mg every 3 weeks is approved in patients with advanced squamous or nonsquamous NSCLC whose tumors express programmed cell death ligand-1 (PD-L1) in ≥1% and who experience progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor- or anaplastic lymphoma kinase-positive tumor mutations should also have received prior therapy for these mutations1,2
In a randomized, open-label, Phase II/III trial of 1034 patients with NSCLC whose tumors expressed PD-L1 (≥1% tumor cells) and who had been previously treated, the primary endpoint overall survival (OS) for pembrolizumab 2 mg/kg therapy was significantly longer compared with docetaxel therapy (median 10.4 versus 8.5 months; hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.58, 0.88; p=0.0008). The OS for pembrolizumab 10 mg/kg therapy was also significantly longer compared with docetaxel therapy (median 12.7 versus 8.5 months; HR 0.61; 95% CI 0.49, 0.75; p<0.0001). The primary endpoint of progression-free survival was 3.9 for pembrolizumab 2 mg/kg and 4.0 months for both pembrolizumab 10 mg/kg and docetaxel therapy (HR 0.88; 95% CI 0.74, 1.05; p=0.07 and HR 0.79; 95% CI 0.66, 0.94; p=0.004, respectively)3
In analyses from a 6-month follow-up study, OS for pembrolizumab 2 mg/kg therapy continued to be superior compared with docetaxel therapy in patients with a PD-L1 tumor progression score of ≥50 (median 15.8 versus 8.2 months; HR 0.54; 95% CI 0.39, 0.73). The OS for pembrolizumab 10 mg/kg therapy was also significantly longer compared with docetaxel therapy in these patients (median 18.8 versus 8.2 months; HR 0.48; 95% CI 0.35, 0.66)4
References
FDA. Pembrolizumab. Highlights of prescribing information. Available at (accessed June 20, 2016). p. 1, Indications and Usage; p. 1, Dosage and Administration
EMA Summary of opinion (post authorisation). Available at: C pdf (accessed on February 2017); p. 1, 3rd and 5th para.
Herbst RS et al. Lancet 2016;387:1540–50; p. 1540, abstract
Herbst R et al. ESMO Congress Abstract LBA48
0.79 (0.66, 0.94)
p=0.004
Time (months)
ALK, anaplastic lymphoma kinase; CI, confidence interval; EGFR, epidermal growth factor receptor;
HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival;
PD-L1, programmed cell death ligand-1; TPS, tumor proportion score
1. FDA. Pembrolizumab. Highlights of prescribing information. Available at (accessed December 12, 2016); 2. EMA Summary of opinion (post authorization). Available at:
(accessed February 22, 2017); 3. Herbst R et al. ESMO Congress Abstract LBA48; 4. Herbst RS et al. Lancet 2016;387:1540–50

23. Advances in other treatment settings in advanced NSCLC: atezolizumab immunotherapy
Atezolizumab treatment setting: Approved for metastatic NSCLC with progression on or after platinum-based chemotherapy; patients with EGFR- or ALK-positive tumor mutations should have progressed on approved therapy for these mutations1
OS results from a randomized Phase III clinical trial:2
15.6
11.2
8.9
7.7
Improved outcomes in advanced non-small cell lung cancer (NSCLC) have also been demonstrated with azetolizumab, a further programmed death ligand-1 (PD-L1) antibody1,2
Atezolizumab is approved in patients with metastatic squamous or nonsquamous NSCLC who experience progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor- or ALK-positive tumor mutations should have progressed on approved therapy for these mutations1
In a randomized, open-label, Phase III study of an initial 450 patients with NSCLC previously treated with platinum-based chemotherapy, the primary endpoint of overall survival (OS) for atezolizumab therapy was significantly longer compared with docetaxel therapy (median versus 9.6 months; hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.62, 0.87; p= ). Median OS in patients with squamous NSCLC was 8.9 months with atezolizumab therapy versus 7.7 months with docetaxel therapy (HR 0.73; 95% CI 0.54, 0.98; p=0.0383). Median OS in patients with nonsquamous NSCLC was 15.6 months with atezolizumab therapy versus 11.2 months with docetaxel therapy (HR 0.73; 95% CI 0.60, 0.89; p=0.0015)2
References
1. FDA. Atezolizumab. Highlights of prescribing information. Available at: (accessed December 12, 2016); p. 1, Indications and Usage
2. Barlesi F et al. ESMO Congress 2016; Abstract LBA44. Abstract, table
Time (months)
ALK, anaplastic lymphoma kinase; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival
1. FDA. Atezolizumab. Highlights of prescribing information. Available at: (accessed December 12, 2016);
2. Barlesi F et al. ESMO Congress 2016;Abstract LBA44.

24. Conclusions
Improved survival over recent decades in NSCLC has resulted from, and will continue to result from, continuous advances in therapy
Significant advancements have been made in nonsquamous NSCLC in recent years with the approval of pemetrexed and antiangiogenic agents, and therapies targeting EGFR M+ mutations and the EML4-ALK translocation
Such oncogenic drivers are rare in squamous NSCLC
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer