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Continuous
benefit counts
Module 2
Last updated: December 2016
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
1
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 antibodydrug conjugates and
immunotherapies6,7
Development of
therapies targeted
against identified
molecular drivers1,8,9
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
2
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
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
NSCLC population
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
•
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
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
3
Redefining what is meant by a “clinically
meaningful improvement” (2 of 2)
•
Primary
outcome
The ESMO-MCBS is a validated tool for measuring the clinical
magnitude of anti-cancer treatments1
Current baseline
Minimum observed benefit
≤12 months
≥3 months AND HR* ≤0.65
OR
≥10% increase in 2-year survival alone
OS
>12 months
≥5 months AND HR* ≤0.70
OR
≥10% increase in 3-year survival alone
PFS
≤6 months
≥1.5 months AND HR* ≤0.65
PFS
>6 months
≥3 months AND HR* ≤0.65
OS
*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
4
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 ESMOMCBS5,6
Phase III randomized, open-label studies of 1st-line treatment in advanced NSCLC
Histology
Improvement
in OS* (months)
HR
Gemcitabine-cisplatin vs cisplatin1
All
1.5
NR
Paclitaxel-carboplatin vs paclitaxel2
All
2.1
0.91
Nonsquamousǂ
1.4
0.81
All
0.9
0.92
Treatments
Pemetrexed-cisplatin vs gemcitabine-cisplatin3
Nab-paclitaxel-carboplatin vs paclitaxel-carboplatin4
*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
5
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
Median OS, months
NSCLC (all histologies)
18
16
14
12
10
8
6
4
2
0
Single-agent
platinum
1980s1,2
Platinumbased
doublets
1990–20053-5
Squamous
Platinumbased
doublets
Nonsquamous
Histologydirected therapy
Platinum-triplet
therapy (BEV)
New
strategies
Platinumbased
doublets
2005–20096-8
2010–20159,10
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
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
6
Continuous improvements in survival with 1st-line
treatment of advanced / metastatic NSCLC (1 of 4)
Median OS, months
Study
Regimen
All NSCLC histologies
Carboplatin
7.3
Wozniak et al (n=432)b,2
Cisplatin
Vinorelbine-cisplatin
6
8
(p=0.018)
Sandler et al (n=522)c,d,3
Cisplatin
Gemcitabine-cisplatin
7.6
9.1
(p=0.004)
Single-agent platinum chemotherapy
EST 1583 (n=699)a,1
Platinum doublet chemotherapy
aStage
IV NSCLC, only data for carboplatin arm shown; bAdvanced NSCLC PS 0–1;
NSCLC; dquality of life deteriorated equally in both groups
cAdvanced
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
7
Continuous improvements in survival with 1st-line
treatment of advanced / metastatic NSCLC (2 of 4)
Median OS, months
Study
Regimen
All
Nonsquamous*
Squamous
–
9.1b
8.1b
7.7b
7.6b
–
6.9
9.4
8.1
9.3
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
8.1
Rosell et al
(n=618)a,c,3
Paclitaxel-carboplatin
Paclitaxel-cisplatin
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
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
8
Continuous improvements in survival with 1st-line
treatment of advanced / metastatic NSCLC (3 of 4)
Median OS, months
Study
Regimen
All
Nonsquamous*
Squamous
11.7g
11.6g
8.9
9.8
9.1g
8.1g
8.8
6.9
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
Docetaxel-cisplatin
9.9
9.8
(p=0.58)
SWOG
(n=792)f,4
Paclitaxel-carboplatin
Vinorelbine-cisplatin
aStage
dStage
IIIb/IV; bQuality of life improved in the docetaxel-cisplatin group and deteriorated in the vinorelbine-cisplatin group; cStage IIIb/IV PS 0–2;
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
9
Continuous improvements in survival with 1st-line
treatment of advanced / metastatic NSCLC (4 of 4)
Median OS, months
Study
Regimen
All
Nonsquamous*
Squamous
Platinum doublet chemotherapy (continued)
Scagliotti et al
(n=1725)a,1
Pemetrexed-cisplatin
Gemcitabine-cisplatin
10.3
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
(HR 0.81)
Targeted therapies
Sandler et al
(n=878)a,4
aStage
Paclitaxel-carboplatin
Bevacizumab + paclitaxelcarboplatin
10.3b
14.2b
(HR 0.69)
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
10
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
Phase III study of chemotherapy-naive patients with stage IIIB/IV NSCLC (n=1725)2
Median OS, monthsa
14
aPrimary
trial endpoint
•
HR 1.23
(95% CI 1.00, 1.51)
10.8
12
10
9.4
HR 0.81
(95% CI 0.70, 0.94)
cis-pem
11.8
10.4
cis-gem
8
6
4
2
0
Squamous
Nonsquamous
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
*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
11
Oncogenic drivers with effective treatments are
rare in squamous NSCLC vs adenocarcinoma1-3
Adenocarcinoma1
EGFR M+
15–20%
Unknown oncogenic
drivers or oncogenic
drivers without
proven treatments
Squamous NSCLC2,3
EGFR M+ or
EML4-ALK+
<5%
EML4-ALK+
3–7%
Unknown oncogenic
drivers or oncogenic
drivers without
proven treatments
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
12
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
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
13
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
Pembrolizumab
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)
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
*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
1. 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: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021462s039lbl.pdf (accessed June 20, 2016);
5. EMA. Pemetrexed summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000564/WC500025611.pdf
(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: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125547s000lbl.pdf (accessed June 20, 2016); 9. EMA. Necitumumab summary of product characteristics. 2016.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003886/WC500202694.pdf (accessed June 20, 2016);
10. FDA. Pembrolizumab. Highlights of prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf
11. EMA Summary of opinion (post authorisation). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003820/WC500218016.pdf
(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.3.2017.
© National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed February 21, 2017. 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 Guidel ines® 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.
14
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
EGFR
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
EGFR
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
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
15
Advances in 1st-line therapy for advanced
squamous NSCLC: EGFR ‒ necitumumab
Necitumumab treatment setting: Approved as 1st-line therapy in combination with gemcitabinecisplatin 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
HR (95% CI)
Median OS
Median PFS
11.5
a
9.9
5.7
b
or bsecondary endpoint
4
Gem / cis (n=548)
0.85 (0.74, 0.98)
p=0.02
5.5
0
aPrimary
0.84 (0.74, 0.96)
p=0.01
Necitumumab
+ gem / cis (n=545)
8
12
Time (months)
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:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125547s000lbl.pdf (accessed June 20, 2016);
2. EMA. Necitumumab summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/003886/WC500202694.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.3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved.
Accessed February 21, 2017. 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 regardi ng their content,
Use, or application and disclaims any responsibility for their application or use in any way
16
Recent advances in systemic therapies for
advanced / metastatic NSCLC: 2nd- and 3rd-line
Therapy
Erlotinib
Nonsquamous* NSCLC
Squamous NSCLC
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
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor
1. FDA. Erlotinib. Highlights of prescribing information.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021743s019lbl.pdf. Accessed February 12, 2015;
2. EMA. Erlotinib summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000618/WC500033994.pdf (accessed June 20, 2016); 3. FDA. Afatinib. Highlights of prescribing information.
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf (accessed June 20, 2016); 4. EMA. Afatinib
summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002280/WC500152392.pdf (accessed June 20, 2016)
5. FDA. Pemetrexed. Highlights of prescribing information. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021462s039lbl.pdf (accessed June 20, 2016);
6. EMA. Pemetrexed summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000564/WC500025611.pdf (accessed June 20, 2016); 7. FDA. Ramucirumab. Highlights of prescribing
information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s007lbl.pdf (accessed June 20, 2016);
8. EMA. Ramucirumab summary of product characteristics. 2016.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002829/WC500180724.pdf
(accessed June 20, 2016)
17
Advances in other treatment settings in
advanced NSCLC: EGFR
Results from a randomized Phase III trial
Approved drug
Erlotinib
Afatinib
Treatment setting
Median PFS
Maintenance in patients PFS benefit for erlotinib vs placebo
with EGFR–activating
after progression
mutations1,2
(HR 0.10; 95% CI 0.04, 0.25;
p<0.0001)2,a
Median OS
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
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
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:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021743s025lbl.pdf (accessed December 12, 2016);
2. EMA. Erlotinib summary of product characteristics. 2016. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000618/WC500033994.pdf
(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: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf (accessed June 20, 2016);
5. EMA. Afatinib summary of product characteristics. 2016. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002280/WC500152392.pdf
(accessed June 20, 2016); 6. Soria JC et al. Lancet Oncol 2015;16:897–907
18
Advances in other treatment settings for advanced
NSCLC with agents targeted against oncogenic
drivers: ALK
Target
Approved
drugs
Median PFS from
clinical trials
Median OS from
clinical trials
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
--
--
Treatment setting
Crizotinib
ALK translocation
aPrimary
endpoint; bSecondary endpoint; cRandomized, open-label Phase III trial; dExtended Phase I study; ePhase II
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: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202570s016lbl.pdf (accessed June 20, 2016);
2. EMA. Crizotinib summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002489/WC500134759.pdf (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:
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm395386.htm. Accessed January 27, 2014;
6. EMA. Ceritinib summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/
en_GB/document_library/EPAR_-_Product_Information/human/003819/WC500187504.pdf (accessed June 20, 2016);
7. FDA. Alectinib. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf (accessed June 20, 2016);
8. Cancer Genome Atlas Research Network. Nature 2012;489:519–25
19
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 EGFRor 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
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
1. FDA. Nivolumab. Highlights of prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf
(accessed June 20, 2016); 2. EMA. Nivolumab BMS summary of product characteristics. 2015. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003840/WC500190648.pdf (accessed June 20,
2016); 3. FDA. Pembrolizumab.
Highlights of prescribing information. Available at: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf (accessed June 20,
2016); 4. EMA Summary of opinion (post authorisation). Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003820/WC500218016.pdf
(accessed February 22 2017); 5. FDA. Atezolizumab. Highlights of prescribing information. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf (accessed December 12, 2016).
20
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
Nivolumab (n=135)
Docetaxel (n=137)
HR (95% CI)
Median OS
9.2
a
0.59 (0.44, 0.79)
p<0.001
6.0
3.5
Median PFS b
0.62 (0.47, 0.81)
p<0.001
2.8
0
4
8
12
Time (months)
aPrimary
or bsecondary endpoint
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:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf
(accessed June 20, 2016); 2. EMA. Nivolumab BMS summary of product characteristics. 2015.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003840/WC500190648.pdf (accessed
June 20, 2016); 3. Brahmer J et al. N Engl J Med 2015;373:123–35
21
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 EGFRor 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
Pembrolizumab 10 mg/kg (n=346)
Pembrolizumab 2 mg/kg (n=345)
3,a
Median OS
TPS ≥50%
4,a
Median OS
8.5
4,a
10.4
0.54 (0.39, 0.73)
12.7
4.0
3.9
4.0
Median
PFS
0
aPrimary
18.8
15.8
8.2
endpoint
4
Docetaxel (n=343)
HR (95% CI)
8
12
Time (months)
16
0.48 (0.35, 0.66)
0.71 (0.58, 0.88)
p=0.0008
0.61 (0.49, 0.75)
p<0.0001
0.88 (0.74, 1.05)
p=0.07
0.79 (0.66, 0.94)
p=0.004
20
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 http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
(accessed December 12, 2016); 2. EMA Summary of opinion (post authorization). Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003820/WC500218016.pdf
(accessed February 22, 2017); 3. Herbst R et al. ESMO Congress 2016. Abstract LBA48; 4. Herbst RS et al. Lancet 2016;387:1540–50
22
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
Atezolizumab (n=425)
Docetaxel (n=425)
HR (95% CI)
15.6
*Nonsquamous
NSCLC
0.73 (0.60, 0.89)
p=0.0015
11.2
8.9
Squamous
NSCLC
0.73 (0.54, 0.98)
p=0.0383
7.7
0
4
8
Time (months)
12
16
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
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:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf (accessed December 12, 2016);
2. Barlesi F et al. ESMO Congress 2016;Abstract LBA44.
23
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
24