Supplementary material for:
Targeted Therapies for Lung Cancer:
Clinical Experience and Novel Agents
Jill E. Larsen, Ph.D.1, Tina Cascone, M.D.3, David E. Gerber, M.D.2 John V. Heymach3
and John D. Minna, M.D.1
1
Hamon Center for Therapeutic Oncology Research, Simmons Cancer Center, and 2Department
of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern
Medical Center, Dallas, TX; 3Department of Thoracic and Head and Neck Medical Oncology,
The University of Texas MD Anderson Cancer Center, Houston, Texas.
Correspondence:
John D. Minna, M.D.
Email: john.minna@utsouthwestern.edu; Tel: 1-214-648-4900; Fax: 1-214-648-4940
1
Supplementary Tables:
Supplementary Table 1: Completed and selected ongoing phase III* clinical trials of EGFR
inhibitors for NSCLC
Supplementary Table 2: Selected completed and ongoing clinical trials of anaplastic lymphoma
kinase (ALK) inhibitors for NSCLC
Supplementary Table 3: Completed and selected ongoing phase III* trials of anti-angiogenic
agents for NSCLC
Supplementary Table 4: Selected phase II and III clinical trials of targeted agents for NSCLC
Supplementary Table 5: Supplementary Table 1: Selected completed and ongoing phase II/III
clinical trials of novel targeted agents for small cell lung cancer (SCLC)
2
Supplementary Table 1: Completed and selected ongoing phase III* clinical trials of EGFR inhibitors for NSCLC
Trial
Target Population
FDA-approved agents for cancer treatment
Neoadjuvant
NCT01407822
EGFR
Stage IIIA-N2,
Phase II/III
EGFR mutant
Adjuvant — Early Stage
RADIANT
EGFR
Stage IB/IIIA,
NCT00373425
EGFR mutant
NCIC CTG
Unselected, stage
JBR.19
IB/IIIA
Treatment
No. of pts
Primary outcome(s)
Ref.
Erlotinib vs. CisplatinGemcitabine
Enrolling
ORR
1
Erlotinib x 2 yrs vs. placebo
Enrolling
DFS
1
Gefitinib vs. placebo
OS (Awaited)
1
NCT01405079
Stage II-IIIA,
EGFR mutant
Gefitinib vs. VinorelbinePlatinum
Closed after
500 (of 1,242
planned)
Enrolling
DFS
1
Unselected,
unresectable, stage
III
Unselected,
unresectable, stage
III
243
TTP: 21.6 mos (Erlotinib) vs. 13.1
(placebo) (P=0.12)
1
Closed after
243 (of 672
planned)
OS: 23 months (Gefitinib) vs. 35 months
(placebo) (P=0.01)
2
Enrolling
OS
1
Adjuvant — Locally Advanced
Rigas et al.
EGFR
(D0410)
NCT00153803
SWOG 0023
RTOG 0617
NCT00533949
First-line — Advanced
TALENT
EGFR
Unresectable,
stage IIIA/IIIB
Chemoradiation (CisplatinDocetaxel) ± maintenance
Erlotinib
Chemoradiation (CisplatinEtoposide) followed by
consolidation Docetaxel ±
maintenance Gefitinib
Chemo-radiation (CarboplatinPaclitaxel) ± Cetuximab
Unselected, stage
IIIB/IV
Cisplatin-Gemcitabine ±
Erlotinib
1,172
OS 10.8 mos (chemo + Erlotinib) vs. 11.0
mos (chemo alone) (P=0.49)
3
TRIBUTE
Unselected, stage
IIIB/IV
Stage IIIB/IV,
EGFR mutant
Carboplatin-Paclitaxel ±
Erlotinib
Erlotinib vs. Platinum-based
chemotherapy
1,059
4
Stage IIIB/IV,
EGFR mutant in
China
Erlotinib vs. CarboplatinGemcitabine
154
OS 10.6 mos (Erlotinib) vs. 10.5 mos
(placebo) (P=0.95)
PFS 9.4 mos (Erlotinib) vs. 5.2 mos
(chemo) (P<0.0001). [Secondary endpoints:
OS 22.9 mos (Erlotinib) vs.18.8 mos
(chemo) (P=0.42).
PFS 13.1 mos (Erlotinib) vs. 4.6 mos
(chemo) (P<0.0001).
EURTAC
OPTIMAL
153
3
5
6
760
Interim analysis after 340 deaths: HR of
death 1.40 in experimental arm (P=0.002);
OS 10.8 mos (standard arm) vs. 7.7 mos
(experimental arm)
7
Unselected, stage
IIIB/IV
Erlotinib followed at progression
by Cisplatin-Gemcitabine
(experimental arm) vs. CisplatinGemcitabine followed at
progression by Erlotinib
(standard arm)
Cisplatin-Gemcitabine ±
Gefitinib
1,093
8
INTACT-2
Unselected, stage
IIIB/IV
Carboplatin-Paclitaxel ±
Gefitinib
1,037
IPASS
East Asian, nonor former light
smoker, stage
IIIB/IV, adenoca
Stage IIIB/IV,
EGFR mutant in
Japan
Korean, neversmoker, stage
IIIB/IV
Stage IIIB/IV,
EGFR mutant in
Japan
Gefitinib vs.
Carboplatin-Paclitaxel
1,217
OS 9.9 mos (gefitinib 500 mg/d) vs. 9.9 mos
(Gefitinib 250 mg/d) vs. 10.9 mos (placebo)
(P=0.46)
OS 8.7 mos (gefitinib 500 mg/d) vs. 9.8 mos
(gefitinib 250 mg/d) vs. 9.9 mos (placebo)
(P=0.64)
PFS: 12-mo PFS rate 24.9% (gefitinib) vs.
6.7% (chemo) (P<0.001)
Gefitinib vs. Cisplatin-Docetaxel
172
PFS 9.2 mos (Gefitinib) vs. 6.3 mos (chemo)
(P<0.001)
11
Gefitinib vs. CisplatinGemcitabine
313
OS 20.3 mos (Gefitinib) vs. 23.1 mos
(chemo) (P=0.43)
12
Gefitinib vs. CarboplatinPaclitaxel
200
13
EGFR+, stage
IIIB/IV
Unselected, stage
IIIB/IV
Cisplatin-Vinorelbine ±
Cetuximab
Carboplatin-Taxane ±
Cetuximab
1,125
Unselected, stage
IV or recurrent
disease after prior
surgery and/or
irradiation
Carboplatin-PaclitaxelBevacizumab ± Cetuximab
Enrolling
PFS 10.8 mos (gefitinib) vs. 5.4 mos (chemo
alone) (P<0.001)
[Secondary endpoints: RR 73.7% (Gefitinib)
vs. 30.7% (chemo) (P<0.001); OS 30.5 mos
(Gefitinib) vs. 23.6 mos (chemo) (P=0.31)
OS 11.3 mos (chemo + Cetuximab) vs. 10.1
mos (chemo alone) (P=0.04)
PFS 4.4 mos (chemo + Cetuximab) vs. 4.24
mos (chemo alone) (P=0.236) [Secondary
endpoint OS 9.69 mos (chemo + Cetuximab)
vs. 8.38 mos (chemo alone) (P=0.169)
OS and PFS
Unselected, stage
4 cycles platinum doublet
889
PFS 12.3 weeks (Erlotinib) vs. 11.1 weeks
16
TORCH
Unselected, stage
IIIB/IV
INTACT-1
WJTOG3405
First-SIGNAL
NEJ002
FLEX
BMS 099
SWOG
NCT00946712
Maintenance — Advanced
SATURN
EGFR
676
4
9
10
14
15
1
IIIB/IV
NCT01328951
Unselected, stage
IIIB/IV
ATLAS
Non-squamous,
stage IIIB/IV
WJTOG0203
Unselected, stage
IIIB/IV
IFCT-GFPC 05.02
NCT00300586
Unselected, stage
IIIB/IV
NCT01404260
Stage IIIB/IV,
non- or former
light smoker in
China, unknown
EGFR mutation
Stage IIIB-IV
NSCLC
EORTC
NCT00091156
NCT00820755
Second-line — Advanced
BR.21
EGFR
Unselected, stage
IIIB/IV
Unselected, stage
IIIB/IV
chemotherapy followed by
maintenance Erlotinib vs.
placebo
Erlotinib vs. Erlotinib at Time
of Disease Progression in pts who
have not progressed following 4
cycles of Platinum-based
chemotherapy
4 cycles Platinum doublet chemo
followed by maintenance
Bevacizumab ± Erlotinib
Six cycles platinum-doublet
chemotherapy (arm A) vs. three
cycles platinum-doublet
chemotherapy followed by
Gefitinib until progression (arm
B)
After 4 to 6 cycles of standard
chemotherapy: observation vs.
gemcitabine maintenance
vs. Erlotinib immediately given
after the end of first-line
chemotherapy
Gemcitabine- Carboplatin ±
intercalating and maintenance
Gefitinib
Open , not
recruiting
(placebo) (P<0.0001).
[Secondary endpoint OS 12 mos (Erlotinib)
vs. 11 mos (placebo) (P<0.05)]
OS
1
768
PFS 4.8 mos (Bevacizumab + Erlotinib) vs.
3.7 mos (Bevacizumab alone) (P=0.001)
17
604
OS HR, 0.86 (arm B) (P=0.11).
[Secondary endpoint: PFS HR 0.68 (arm B)
(P<0.001).
18
Enrolling
PFS
1
Active, not
recruiting
ORR RECIST
1
Follow Up With or Without
Adjuvant Gefitinib Following
Chemotherapy
Cetuximab (250 mg/m2 Weekly
and 500 mg/m2 Every Two
Weeks) Maintenance Therapy
After Platinum-based
Chemotherapy in Combination
With Cetuximab)
Ongoing
OS
[Secondary endpoints PFS, Toxicity]
1
Active, not
recruiting
OS
1
Erlotinib vs. placebo
731
OS 6.7 mos (Erlotinib) vs. 4.7 mos (placebo)
(P<0.001)
19
5
ISEL
INTEREST
NCT00095199
Unselected, stage
IIIB/IV
Unselected, stage
IIIB/IV
Stage IIIB/IV
OS 5.6 mos (Gefitinib) vs. 5.1 mos (placebo)
(P=0.09)
OS 7.6 mos (Gefitinib) vs. 8.0 mos
(Docetaxel) (P<0.05)
PFS (Awaited)
20
585
OS HR Death 1.077 P=0.74;
PFS 3.3 mos (afatinib) vs.1.1 mos (placebo)
P<0.0001
22
Active, not
enrolling
PFS
1
Enrolling
PFS
1
167
Low activity of neratinib in all patients (RR,
2%).
Pronounced RR in rare EGFR G719X
mutant tumors (75%).
23
188
RR 17.1% vs. 4.3% P=0.008; PFS 2.9 mos
vs. 1.9 mos, P=0.017
24
65 (ongoing)
Patients with adeno or nonadeno refractory
NSCLC receiving PF299 experience clinical
benefit
25
Gefitinib vs. placebo
1,692
Gefitinib vs. Docetaxel
1,466
Docetaxel or Pemetrexed ±
Cetuximab after progression on
prior platinum-based
chemotherapy
Novel non-FDA-approved agents for cancer treatment
LUX-LUNG 1
EGFR, Stage IIIB/IV,
Afatinib (BIBW 2992) + BSC
NCT00656136
HER2
Failing 1-2 lines
vs. Placebo + BSC
chemo and
Erlotinib or
Gefitinib
LUX-LUNG 5
NSCLC, Failing
Afatinib + Paclitaxel vs.
NCT01085136
Erlotinib or
chemotherapy following Afatinib
Gefitinib
monotherapy
Stage IIIB/IV,
Afatinib vs. CisplatinEGFR activating
Gemcitabine
mutation
NCT00266877
Progressed,
Neratinib (HKI-272)
Phase II
advanced NSCLC
with ≥12 weeks of
EGFR TKI ±
EGFR mutation;
or EGFR TKI
naïve,
adenocarcinoma,
≤20 pys smoking,
current nonsmoker
NCT00769067
EGFR, Stage IIIB/IV,
PF0299804 (Pan-Her Inhibitor)
Phase II
HER2, NSCLC, prior
vs. Erlotinib
HER4
chemo therapy but
not EGFR TKIs
NCT00548093
KRAS wild-type,
PF0299804
Phase II
advanced NSCLC,
failure of 1 CT
regimen and
6
800
21
1
SQUIRE
NCT00981058
EGFR
erlotinib
Untreated, Stage
IV squamous
NSCLC
Advanced NSCLC
Gemcitabine-Cisplatin ±
Necitumumab (IMC-11F8)
947 (ongoing)
OS
1
1
INSPIRE
Pemetrexed-Cisplatin ±
634 (active,
OS
NCT00982111
not enrolling)
Necitumumab
This table is adapted, in part, from Oxford American Pocket Notes: Targeted Therapy in Non-Small Cell Lung Cancer.26
BMS, Bristol-Myers Squibb; BR, Bronchus; DFS, Disease-Free Survival; First-SIGNAL, First-line Single agent Iressa versus Gemcitabine and cisplatin Trial in
Never-smokers with Adenocarcinoma of the Lung; FLEX, First-line in Lung cancer with ErbituX; INTACT, Iressa NSCLC Trial Assessing Combination
Treatment; ISEL, Iressa Survival Evaluation in Lung Cancer; INTEREST, Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere; IPASS, Iressa
Pan-Asia Study; NEJ, North-East Japan; SATURN, Sequential Tarceva in Unresectable NSCLC; SWOG, Southwest Oncology Group; TALENT, Tarceva Lung
Cancer Investigation; TRIBUTE, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin; WJTOG, West Japan Thoracic Oncology Group; SWOG,
Southwest Oncology Group; TORCH, Tarceva or Chemotherapy.
DFS, disease free survival; HR, hazards ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PD,
progressive disease, RR, response rate; SD, stable disease; TTP, time to progression
*Unless otherwise noted.
7
Supplementary Table 2: Selected completed and ongoing clinical trials of anaplastic lymphoma kinase (ALK) inhibitors for
NSCLC
Trial
Population
Treatment
NCT01441128
Phase I
NCT01121575
Phase I
Dose Escalation
Phase I
expansion cohort
Stage IIIB/IV NSCLC
Crizotinib (PF-02341066) +
PF0299804 (Pan-ERBB inhibitor)
Crizotinib + PF00299804 vs.
PF00299804 alone until progression
followed by MTD of both agents
Crizotinib
NCT00932451
Phase II
PROFILE 1007
NCT00932893
Phase III
Advanced NSCLC with translocation
or inversion of ALK gene
Advanced NSCLC with ALK gene
fusion progressed after platinum-based
chemotherapy
Stage IIIB/IV NSCLC
Advanced NSCLC with ALK gene
fusion (most previously treated)
Crizotinib
Crizotinib
vs. Docetaxel or Pemetrexed
No. of
patients
Enrolling
Primary outcome(s)
Ref.
Safety and PK
1
Enrolling
Safety
[Secondary endpoints
PK, PD and ORR]
RR 57%
SD 33%
6-mos PFS 72%
ORR and Safety
1
PFS
1
82
400 planned
(Enrolling)
318 planned
(Enrolling)
PROFILE 1014
Previously untreated nonsquamous
Crizotinib vs. Pemetrexed-Cisplatin or
314 planned
PFS
NCT01154140
advanced NSCLC with ALK gene
Pemetrexed-Carboplatin
(Enrolling)
Phase III
fusion
This table is adapted, in part, from Oxford American Pocket Notes: Targeted Therapy in Non-Small Cell Lung Cancer.26
ORR, overall response rate; PFS, progression-free survival; PK, pharmacokinetics; PD, progressive disease, RR, response rate; SD, stable disease
8
27
1
1
Supplementary Table 3: Completed and selected ongoing phase III* trials of anti-angiogenic agents for NSCLC
Trial
Target
Population
FDA-approved agents for cancer treatment
Early stage — adjuvant
ECOG 1505
VEGF
Unselected
NCT00324805
stage IB/IIIA
Advanced — first line
ECOG 4599
VEGF
Nonsquamous
stage IIIB/IV
AVAiL
Nonsquamous
stage IIIB/IV
NCT00946712
Nonsquamous
stage IV or
recurrent
NCT00976456
Nonsquamous
stage IIIB/IV
elderly patients
(>65 yo)
Unselected
stage IIIB/IV
ESCAPE
NExUS
NCT00449033
VEGFR1/2,
PDGFRα/β,
FLT-3, cKIT,
RAF
Advanced—second line
BeTA
VEGF
Unselected
stage IIIB/IV
Unselected
stage IIIB/IV
Treatment
No. of pts
Primary outcome(s)
Ref.
4 cycles adjuvant
chemo ±
Bevacizumab
Enrolling
OS
1
CarboplatinPaclitaxel ±
Bevacizumab
CisplatinGemcitabine ±
Bevacizumab
878
OS 12.3 mos (chemo + BV) vs. 10.3 mos (chemo alone)
(P=0.003)
28
1,043
29
CarboplatinPaclitaxel ±
Bevacizumab ±
Concurrent
Cetuximab
BevacizumabPemetrexed ±
Carboplatin
Enrolling
PFS 6.7 mos (chemo + Bevacizumab 7.5 mg/kg)
(P=0.003 vs. chemo alone) vs. 6.5 mos (chemo +
Bevacizumab 15 mg/kg) (P=0.03 vs. chemo alone) vs.
6.1 mos (chemo alone) [Secondary endpoint OS 13.6 mos
(chemo + Bevacizumab 7.5 mg/kg) (P=0.42 vs. chemo
alone) vs. 13.4 mos (chemo + Bevacizumab 15 mg/kg)
(P=0.76 vs. chemo alone) vs. 13.1 mos (chemo alone)]
OS, PFS
Enrolling
PFS
1
CarboplatinPaclitaxel ±
Sorafenib
CisplatinGemcitabine ±
Sorafenib
926
OS 10.7 mos (chemo plus sorafenib) vs. 10.6 mos
(chemo alone) (P=0.93)
30
900
OS (not met)
1
Erlotinib ±
Bevacizumab
636
OS 9.3 mos (Erlotinib + Bevacizumab) vs. 9.2 mos
(Erlotinib) (P=0.75); PFS 3.4 mos (Erlotinib +
Bevacizumab) vs. 1.7 mos (Erlotinib) HR 0.62; ORR
Objective response 13% (Erlotinib + Bevacizumab) vs.
31
9
1
ZEAL
6% (Erlotinib)
PFS 4.4 mos (Pemetrexed + Vandetanib) vs. 3.0 mos
(Pemetrexed alone) (HR 0.86; 97.58% CI, 0.69 to 1.06;
P=0.108). [Secondary endpoint
OS (HR, 0.86; 97.54% CI, 0.65 to 1.13; P=0.219). ORR
(19% vs. 8%; P<0.001)
PFS 2.6 mos (Vandetanib) vs. 2.0 mos (Erlotinib), HR
0.98 (95% CI, 0.87–1.1; P=0.72) [Secondary endpoints
OS HR, 1.01; 95% CI, 0.89–1.16; (P=0.83)
PFS 4.3 mos (Docetaxel + Vandetanib) vs. 3.5 mos
(Docetaxel alone) (P<0.001) [Secondary endpoint HR for
death 0.91; P=0.196]
Overall 8-week DCR 46%.
Overall PFS 1.9 mos,
Overall OS
8.8 months and 1-year survival
35%.
Overall
8-week DCRs 34% erlotinib, 33% vandetanib, 50%
erlotinib + bexarotene, and 58% sorafenib
32
Unselected
stage IIIB/IV
Pemetrexed ±
Vandetanib
534
ZEST
Unselected
stage IIIB/IV
Vandetanib vs.
Erlotinib
1,240
ZODIAC
NCT00312377
Unselected
stage IIIB/IV
Docetaxel ±
Vandetanib
1,391
NSCLC, prior
EGFR TKI,
median of 2
prior
chemotherapies
ErlotinibVandetanibErlotinib +
Bexarotene or
Sorafenib
244
Second-line,
Stage IIIB/IV
NSCLC
Pemetrexed or
Sunitinib or
Pemetrexed +
Sunitinib
Sunitinib
(SU11248) 50 mg/d
for 4 weeks
followed by 2
weeks of no
treatment in 6 week
treatment cycles
Enrolling
18-week PFS
1
63
ORR 11.1%; Median PFS 12.0 weeks; Median OS 23.4
weeks
36
PemetrexedCarboplatin
followed by
Pemetrexed or
PaclitaxelCarboplatinBevacizumab
Enrolling
PFS
1
BATTLE
Phase II
CALGB30704
NCT00698815
Phase II
VEGFR2,
EGFR
VEGFR2,
EGFR
(Vandetanib).
VEGFR1/2,
FLT-3,
PDGFRα/β,
RAF, MEK,
cKIT
(Sorafenib)
VEGFR1/2,/3
PDGFRα/β,
FLT-3, cKIT,
RET
Socinski et al.
Phase II
Advanced – maintenance
NCT00948675
VEGF
Second-line,
Stage IIIB/IV
NSCLC, failure
failure of
chemotherapy
Nonsquamous
stage IIIB/IV
10
33
34
35
AVAPERL1
NCT00961415
Nonsquamous
stage IIIB/IV
NCT00762034
Nonsquamous
stage IIIB/IV
NCT01107626
Nonsquamous
stage IIIB/IV
NCT01351415
Nonsquamous
Stage IIIB/IV,
First-line
Platinum
DoubletChemotherapy
± Bevacizumab
Advanced/Meta
static NSCLC
NCT00265317
SUN 1058
Phase II
NCT00457392
SUN 1087
NCT00693992
VEGFR1/2,/3
PDGFRα/β,
FLT-3, cKIT,
RET
Advanced/Meta
static NSCLC
Stage III/IV
followed by
Bevacizumab
4 cycles
Bevacizumab +
CisplatinPemetrexed
followed by
Bevacizumab ±
Pemetrexed
PemetrexedCarboplatinBevacizumab
followed by
PemetrexedBevacizumab vs.
PaclitaxelCarboplatinBevacizumab
followed by
Bevacizumab
Bevacizumab or
Pemetrexed alone
or in combination
following
CarboplatinPaclitaxelBevacizumab
Standard of Care ±
Continuous
Bevacizumab
Treatment Beyond
Disease
Progression
Enrolling
PFS
1
Enrolling
OS
1
Enrolling
OS
1
Enrolling
OS
1
Erlotinib ±
Sunitinib
Ongoing
OS
1
Erlotinib ±
Sunitinib
Sunitinib
Ongoing
OS
1
Enrolling
PFS
1
11
NSCLC, prior
maintenance vs.
combination
placebo
chemotherapy
1
MAPPING
VEGFR1/2/3, Stage IIB/IV,
Pazopanib vs.
Enrolling
OS
(EORTC Lung
PDGFRα/β,
non progressive Placebo
Group Study)
cKIT
with first-line
Phase II/III
therapy
1
NCT00775307
Stage I
Adjuvant
Enrolling
Post-surgical DFS
Phase II/III
NSCLC, Tumor Pazopanib vs.
Size ≤5cm, N0
Placebo
Novel non-FDA-approved agents for cancer treatment
1
LUME-Lung1
FGFR,
Stage IIIB/IV
Ongoing,
PFS
Vargatef (BIBF
NCT00805194
PDGFR,
1120) + Docetaxel
not
VEGFR
vs. Placeborecruiting
Docetaxel
1
LUME-Lung2
Advanced/Recu Vargatef +
Ongoing,
PFS
NCT00806819
rrent
Pemetrexed vs.
not
Nonsquamous
Placebo +
recruiting
NSCLC,
Pemetrexed
Failure of firstline therapy
1
NCT00532155
VEGF
Locally
Ongoing,
OS
Aflibercept
advanced or
(AVE005) +
not
metastatic
docetaxel vs.
recruiting
NSCLC
placebo + docetaxel
1
MONET1
Advanced
CarboplatinOngoing,
OS
NCT00460317
NSCLC
Paclitaxel ± AMG
not
recruiting
706
This table is adapted, in part, from Oxford American Pocket Notes: Targeted Therapy in Non-Small Cell Lung Cancer.26
AVAiL, Avastin in Lung; ECOG, Eastern Cooperative Oncology Group; ESCAPE, Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC;
ZEAL, Zactima Efficacy with Alimta in Lung Cancer; ZEST, Zactima Efficacy Study versus Tarceva; ZODIAC, Zactima in cOmbination with Docetaxel In nonsmAll cell lung cancer; BATTLE, Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; NExUS, NSCLC research Experience
Utilizing Sorafenib.
BV, bevacizumab; DFS, disease free survival; HR, hazards ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK,
pharmacokinetics; PD, progressive disease, RR, response rate; SD, stable disease
*Unless otherwise noted.
12
Supplementary Table 4: Selected phase II and III clinical trials of targeted agents for NSCLC
Trial
Target
Phase,
Setting
Patient Population
Treatment
No. of pts
Primary outcome(s)
Ref.
II
Stage IIIB/IV and
performance status (PS) 2
Docetaxel + Cetuximab
(D+C) or Docetaxel +
Bortezomib (D+B)
64 enrolled
59 included in
analysis
ORR 13.3% (D+C)
vs.10.3% (D+B)
PFS 3.4 mos (D+C) vs.
1.9 mos (D+B)
OS 5.0 mos (D+C) vs. 3.9
mos (D+B)
37
cMET
II
Previously treated,
advanced NSCLC; MET
IHC, EGFR and KRAS
mutation
Erlotinib + MetMAb
vs. Erlotinib + placebo
128
38
cMET
II
Previously treated patients
with EGFR TKI-naive
advanced NSCLC
Erlotinib + Tivantinib
(ARQ 197) vs.
Erlotinib + Placebo
167
Nonsquamous stage IIIB/IV
Erlotinib ± Tivantinib
Enrolling
High MET tumors: PFS:
HR=0.47, P=0.01; 1.5 mo
(EP) vs. 3.0 mo (EM)
OS: HR=0.37, P=0.002;
4.6 mo (EP) vs. 12.6 mo
(EM)
Low MET tumors: OS:
HR=3.02, P=0.01; 9.2 mo
(EP) vs. 5.5 mo (EM)
PFS 3.8 mos for ET vs.
2.3 mos for EP [HR],
0.81; (P=0.24). PFS in pts
with KRAS mutations
[HR] 0.18, interaction
P=0.006).
ORR 10% on ET, 7% on
EP
OS
Nonsquamous stage IIIB/IV
with Wild-type EGFR
Erlotinib ± Tivantinib
Enrolling
OS
1
Metastatic lung and/or
pancreatic cancers
GSK1120212 + either
Docetaxel, Erlotinib,
Pemetrexed,
PemetrexedCarboplatin, or nab-
Enrolling
Safety, tolerability, and
RP2D of each
GSK1120212-based
treatment combination
1
Proteasome inhibitors
CALGB30402
26S
NCT00118183
proteasome
Phase II
MET inhibitors
OAM4558g
NCT00854308
Phase II
Sequist et al.
Phase II
NCT01244191
cMET
III
Phase III
NCT01377376
cMET
III
Phase III
RAS/RAF/MEK/ERK pathway inhibitors
NCT01192165
MEK
I
Phase I
13
39
1
NCT01324258
Phase I
MEK
I
Advanced Solid Tumors in
Japan
NCT00687622
Phase I
MEK
I
Advanced Solid tumors
NCT00955773
Phase IB/II
NCT01362296
Phase II
MEK
IB/II
Advanced Solid Tumors
MEK
II
Hainsworth et al.
Phase II
MEK
II
Subjects With Targeted
Mutations (KRAS, NRAS,
BRAF, MEK1) in Locally
Advanced or Metastatic
NSCLC Stage IIIB/IV
Stage IIIB/IV With KRAS
Mutation Positive Locally
Advanced Metastatic
NSCLC 2nd line
NCT00890825
Phase II
MEK
II, 2ndline
Paclitaxel
GSK1120212 vs.
GSK1120212 +
Gemcitabine
GSK1120212 (PO,
QD)
Enrolling
Safety and tolerability
1
162
MTD, recommended
phase II doses (RP2D),
minimum biological
activity using
PD assessments
Safety, PK, PD and ORR
40
Efficacy and Safety
1
41
1
GSK1120212 + Oral
Everolimus
GSK1120212 vs.
Docetaxel in 2nd Line
Active, not
recruiting
Enrolling
Selumetinib
(AZD6244, ARRY142886) vs. Pemetrexed
84
Stage IIIB/IV NSCLC Pts
With KRAS Mutation
Positive
Previously Treated Patients
With Advanced NSCLC
Selumetinib +
Docetaxel vs.
Docetaxel Alone
Erlotinib, Erlotinib +
MK-2206, MK-2206 +
Selumetinib, Sorafenib
Completed
Disease progression
events in 28 pts (70%)
with AZD6244 and 26 pts
(59%) with Pemetrexed
PFS 67 days with
AZD6244 vs. 90 days
with Pemetrexed HR 1.08,
P=0.79).
OS (Awaited)
Enrolling
8-week DCR
1
MTD was reached at
cixutumumab 6 mg/kg IV
and temsirolimus25 mg
IV
RR
42
Phase Ib: safety,
tolerability, MTD and
RP2D of CP-751,8971
1
BATTLE-2
MEK
NCT01248247
Phase II
IGF pathway inhibitors
Naing et al.
IGF-1R
Phase I
II
I
Advanced solid tumors
Cixutumumab (IMCA12) + Temsirolimus
42
NCT00799240
Phase II
NCT00147537
Phase Ib/II
IGF-1R
II
IB/II
Pemetrexed + Cisplatin
± MK-0646
Phase Ib: PaclitaxelCarboplatin ± Erlotinib
± Figitumumab (CP-
Enrolling
IGF-1R
Stage IIIB/ IV metastatic
non-squamous
Advanced stage IIB/IV
NSCLC
14
Completed
1
1
Karp et al.
Phase II
IGF-1R
II
Unselected IIIB/IV
treatment-naïve NSCLC
PI3K/AKT/mTOR pathway
NCT01294306
AKT
Phase II
II
Advanced NSCLC with
progression after response
to erlotinib
Previously Treated Patients
With Advanced NSCLC
BATTLE-2
NCT01248247
Phase II
NCT01363232b
Phase I/II
AKT
II
pan-PI3K
I/II
NCT01297491
Phase II
NCT00974584
Phase I
II
Phase 2: ORR
(Awaited)
156
ORR 54% PCI vs. 42%
PC. PFS HR 0.8 to 0.56
P<0.001
43
MK-2206 + Erlotinib
Enrolling
ORR of patients with
EGFR mutation and DCR
1
Erlotinib, Erlotinib +
MK-2206, MK-2206 +
Selumetinib, Sorafenib
BKM120 + MEK162
Enrolling
8-week DCR
1
Enrolling
Incidence of Dose
Limiting Toxicities
1
Squamous: BKM120 or
Docetaxel;
Nonsquamous:
BKM120 or Docetaxel
or Pemetrexed
GDC-0941 in
combination with
Paclitaxel-Carboplatin
± Bevacizumab
GDC-0941 + Erlotinib
Enrolling
PFS
1
Enrolling
AEs and ORR
1
Enrolling
AEs and Tumor responses
1
MTD was reached at
cixutumumab 6 mg/kg IV
and temsirolimus25 mg
IV
RR and toxic effects
(awaited)
Safety and tolerability
42
3-month PFS
1
I
Advanced NSCLC
I
Advanced Solid Tumors
I
Advanced solid tumors
Cixutumumab +
Temsirolimusa (CCI779)
42
NCT00079235
Phase II
NCT00406276
Phase I/II
II
Advanced NSCLC
Temsirolimusa
Completed
I/II
Recurrent NSCLC
Ongoing, not
recruiting
NCT01317615
II, 1st-
Advanced (Stage IV) Large
Everolimus (Affinitor,
RAD001) + Docetaxel
vs. Docetaxel alone
Everolimus +
NCT00975182
Phase I
Naing et al.
Phase I
PI3K
Adult Patients With
Selected Advanced Solid
Tumors with KRAS, NRAS,
and/or BRAF mutations
Metastatic NSCLC With
Activated PI3K Pathway
751,871)
Phase II:
Paclitaxel-Carboplatin
± Figitumumab
Figitumumab +
Paclitaxel-Carboplatin
(PCI) vs. PaclitaxelCarboplatin (PC)
mTOR
15
Ongoing, not
1
1
Phase II
line
Soria et al.
Phase II
II
TRAIL inhibitors
Soria et al.
Phase IB
rhApo2L/T
RAIL
NCT00508625
Phase II
Greco et al.
NCT00092924
Phase II
TRAIL-R1
TRAIL-R2
NCT00534027
Phase IB/II
DNA repair inhibitors
NCT01082549
PARP
Phase III
HDAC inhibitors
NCT00907179
pan-DAC
Paclitaxel-Carboplatin
as 1st line treatment
recruiting
Everolimus 10 mg/day
until progression or
unacceptable toxicity
85
ORR 4.7% (7.1% stratum
1; 2.3% stratum 2).
Overall DCR 47.1%.
PFS 2.6 (stratum 1) and
2.7 mos (stratum 2)
44
Previously untreated,
nonsquamous, stage IIIb
(with pleural effusion)/IV or
recurrent NSCLC
Previously Untreated Stage
IIIb/IV NSCLC
24
Well-tolerated and ORR
56%
45
Active, not
recruiting
ORR
1
32
46
II
Subjects With Relapsed or
Refractory NSCLC
Paclitaxel-CarboplatinBevacizumab (PCB) +
Dulanermin
(AMG 951)
Dulanermin +
Carboplatin-Paclitaxel
 Bevacizumab
Mapatumumab
(TRM-1)
II
Untreated Stage IIIB-IV
advanced primary NSCLC
Carboplatin-Paclitaxel
 Mapatumumab
111
I
Advanced solid tumors
Conatumumab (AMG
655)
16
IB/II
First-Line Treatment of
Advanced NSCLC
Paclitaxel-Carboplatin
 Conatumumab
Completed
Well tolerated.
0/32 treated pts showed a
response. Nine pts (29%)
had SD
Addition of
Mapatumumab to PC did
not improve RR or PFS.
No DLTs or
Conatumumab-related
serious AEs. MTD was
not reached.
OR in one patient with
46% reduction in tumor
volume
PFS (Awaited)
Untreated Stage IV
Squamous NSCLC
GemcitabineCarboplatin ± Iniparib
(SAR240550)
Enrolling
OS
1
Previously-Treated Patients
Pemetrexed and
Enrolling
MTD
1
II
NCT00583830
Phase II
LoRusso et al.
Phase I
IB
Cell Lung Cancer With
Neuroendocrine
Differentiation (LC-NEC)
Stage IIIb/IV NSCLC, with
2 or < prior chemotherapy
regimens, one platinum
based (stratum 1) or both
chemotherapy and EGFR
TKIs (stratum 2)
I/II
16
47
48
1
Phase I/II
NCT01413750
Phase II
With Stage IIIB-IV NSCLC
Enrolling
PFS
1
94
RR 34% (vorinostat) vs.
12.5% (P=0.02)
PFS 6.0 (vorinostat) vs.
4.1 mos (P=0.48)
OS 13.0 (vorinostat) vs.
9.7 mos (P=0.17)
Efficacy
Safety
49
1 DLT; No grade 4 AEs;
grade 3 AEs included
diarrhea (9%), non-septic
arthritis (3%), AST
elevation (3%) and
thrombocytopenia (3%).
No ORs in 32 evaluable
pts;. 15 pts (47%) had SD;
17 pts (53%) had PD
ORR
[Secondary endpoints
PFS, TTP
OS]
Anti-tumor activity
50
PFS
[Secondary endpoints
TTP
OS]
ORR of 7% (5/76), 10%
(4/40) in pts with EGFR
wt, and 4% (1/28) with
EGFR mutations. 2/3 pts
1
II
Advanced NSCLC
NCT00473889
Phase II/III
II/III
1st Line Therapy of stage
IIIB-IV NSCLC
NCT00005093
Phase III
III
Second-Line Treatment of
Patients With Advanced
NSCLC
CI-994 (Tacedinaline)
Capsules +
Gemcitabine Infusion
vs. Placebo Capsules +
Gemcitabine Infusion
Ongoing
I
Refractory Solid Tumors
and Lymphomas
SNX-5422
(PF04929113) dosed
twice weekly
33
NCT01427946
Phase I/II
I/II
KRAS Mutant NSCLC
Retaspimycin (IPI504) and Everolimus
Enrolling
NCT01228435
Phase II
NCT01362400
Phase II
II
Stage IIIB/IV NSCLC with
ALK Translocations
Previously Treated Stage
IIIB/IV NSCLC
Retaspimycin
Active, not
recruiting
Enrolling
Sequist et al.
Phase II
II
Advanced, molecularly
defined NSCLC after EGFR
TKI therapy
Retaspimycin
HSP inhibitors
NCT00644072
Phase I,
Dose-escalation
HDAC
Panobinostat
(LBH589)
Vorinostat or Placebo
+ CarboplatinPaclitaxel
Carboplatin-Paclitaxel
± Vorinostat or
Placebo
HSP90
II
Retaspimycin +
Docetaxel
vs. Placebo + Docetaxel
17
76
1
1
1
51
NCT01031225
Phase II
GALAXY
NCT01348126
Phase II/III
Telomerase inhibitors
NCT01137968
Telomerase
Phase II
II
Stage IIIB/IV NSCLC
II/III
Stage IIIB/IV NSCLC
Ganetespib (STA9090)
Ganetespib +
Docetaxel vs.
Docetaxel alone
Enrolling
Enrolling
with ALK rearrangement,
had partial responses and
the third had prolonged
SD (7.2 mos, 24%
reduction in tumor size).
PFS
PFS, OS
[Secondary endpoints
ORR, AEs]
1
1
1
Maintenance therapy after
Observation/Bevacizum Enrolling
PFS
chemotherapy for advanced
ab  Imetelstat (GRNNSCLC
163L)
AVAiL, Avastin in Lung; BATTLE, Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; BMS, Bristol-Myers Squibb; BR,
Bronchus; CALGB, Cancer And Leukemia Group B; First-SIGNAL, First-line Single agent Iressa versus Gemcitabine and cisplatin Trial in Never-smokers with
Adenocarcinoma of the Lung; ECOG, Eastern Cooperative Oncology Group; ESCAPE, Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC;
FLEX, First-line in Lung cancer with ErbituX; INTACT, Iressa NSCLC Trial Assessing Combination Treatment; ISEL, Iressa Survival Evaluation in Lung
Cancer; INTEREST, Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere; IPASS, Iressa Pan-Asia Study; NEJ, North-East Japan; NExUS,
NSCLC research Experience Utilizing Sorafenib; SATURN, Sequential Tarceva in Unresectable NSCLC; SWOG, Southwest Oncology Group; TALENT,
Tarceva Lung Cancer Investigation; TRIBUTE, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin; WJTOG, West Japan Thoracic Oncology
Group; SWOG, Southwest Oncology Group; TORCH, Tarceva or Chemotherapy; ZEAL, Zactima Efficacy with Alimta in Lung Cancer; ZEST, Zactima
Efficacy Study versus Tarceva; ZODIAC, Zactima in cOmbination with Docetaxel In non-smAll cell lung cancer
AEs, Adverse Events; DCR, disease control rate; DFS, disease free survival; DLT, Dose Limiting Toxicities; HR, hazards ratio; MTD, maximum tolerated dose;
ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PD, progressive disease, RP2D, Recommended Phase II
Dose; RR, response rate; SD, stable disease; TTP, time to progression
*Unless otherwise noted.
II
18
Supplementary Table 5: Selected completed and ongoing phase II/III clinical trials of novel targeted agents for small cell lung
cancer (SCLC)
Trial
Target
Population
Treatment
NCT00308529
Phase II
NCT00755157
Phase II
NCT00930891
Phase II/III
VEGF
Limited Stage
Irinotecan, Carboplatin,
Bevacizumab, and Radiation
Metronomic Docetaxel +
Bevacizumab
Bevacizumab + Chemotherapy vs.
Chemotherapy: PCDE (cisPlatinCyclophosphamideepiDoxorubicin-Etoposide) or PE
(cisPlatin-Etoposide)
Cisplatin, Irinotecan and
Bevacizumab
Unselected
Extensive-Disease,
responded to
chemotherapy
CALGB
NCT00118235
Phase II
NCT00698516
Phase II
Hoosier
Oncology Group
Phase II
SALUTE
Phase II
National Cancer
Institute #7097
NCT00245063
Phase II
NCT00726986
Phase II
NCT00726986
Untreated, Extensive
Stage
Previously treated,
relapsed
Relapsed, chemosensitive
No. of
patients
Ongoing
Primary outcome(s)
Ref.
PFS
1
Ongoing
ORR
1
Ongoing
ORR
1
Ongoing
OS
Oral Topotecan + Bevacizumab
50
Paclitaxel + Bevacizumab
34
3-month PFS 65% (95% CI
49.3 to 76.9); P=0.017
PFS
1
1
52
Untreated Extensive stage
VEGFR1/2,
PDGFRα/β,
FLT-3, cKIT,
Chemotherapy + Bevacizumab
100
53
Previously treated,
progression after prior
platinum-based
chemotherapy only
Extensive stage
Cediranib (AZD2171)
Cisplatin-Etoposide ± Sorafenib
Ongoing
PFS
1
Extensive stage
Cisplatin-Etoposide ± Sorafenib
Ongoing
PFS
1
19
25
PFS: 5.5 mos (BV) vs. 4.4
mos (placebo) [HR 0.53, CI
0.32-0.86].
OS: 9.4 mos (BV) vs. 10.9
mos (placebo) [HR 1.16, CI
0.66-2.04].
ORRs 58% (CI, 43-71%) (BV)
and 48% (CI, 34-62%)
(placebo)
9 pts had SD
PFS 2 mos
OS 6 mos
54
Phase II
NCT00453154
Phase IB/II
NCT00695292
Phase II
NCT00613626
Hoosier
Oncology Group
LUN06-113
Phase II
National Cancer
Institute of
Canada Clinical
Trials Group
Study BR.20
Phase II
NCT00248482
Phase II
RAF
VEGFR1/2,/3
PDGFRα/β,
FLT-3, cKIT,
RET
VEGFR2,
EGFR
KIT, BCRABL, PDGFR
KIT, BCRABL, PDGFR
CALGB 30602
Phase II
BCR-ABL,
Src
ECOG (E1500)
Phase II
Untreated, ExtensiveStage
Untreated, ExtensiveStage
Combination Chemotherapy ±
Maintenance Sunitinib
Irinotecan, Carboplatin, and
Sunitinib
Cisplatin-Etoposide ± Concurrent
Vandetanib
Ongoing
RP2D of Sunitinib
1
Ongoing
1-year PFS
1
Ongoing
TTP
1
CALGB and
NCCTG
NCT00052949
Phase II
NCT00374140
Phase II
Extensive Stage
mTOR
After CR or PR to
induction chemotherapy
with or without radiation
therapy
Vandetanib vs. Placebo
c-kit positive, Extensive
disease
Imatinib maintenance therapy
after irinotecan + cisplatin
c-KIT+ (≥1+ by IHC)
Arm A: PD <3mos. Arm
B: PD ≥3mos after
previous treatment
Imatinib
Chemosensitive, relapsed
Dasatinib (BMS-354825)
107
(46 limited
disease and
61 extensive
disease)
Median PFS 2.7 mos
(vandetanib) and 2.8 mos
(placebo) (P=0.51). OS
vandetanib 10.6 vs. 11.9 mos
placebo P=0.9)
14
PR: 8 pts. Median number of
weeks on imatinib was 6.1
(range, 4.1-25.1 weeks). DS: 3
pts (21%) for 12, 15, and 25
wks.
PFS: 4.3 mos (95% CI, 2.9-4.8
mos). OS: 7.8 mos (95% CI,
5.7-10.0 mos)
PD (29%), early death (29%),
patient refusal (42%).
No ORs and no SD ≥6 wks in
either arm. PFS 16 wks in 1
patient
No ORR among the initial 27
patients, 13 instances of
PFS≥6 wks. OS 17.0 wks and
PFS 5.9 wks, for the 43
eligible and treated patients
6-weeks DCR: 26%. 1 (3%)
PR, 8 (23%) SD, 26 (74%) DP
29
Previously treated,
relapsed
Everolimus (Affinitor, RAD001)
Extensive-stage,
responding or SD after
induction chemotherapy
Temsirolimus (Torisel, CCI-779)
25 mg vs. 250 mg
20
45
Ongoing,
not
recruiting
87
PFS: 2.2 mos median, 4.7% 1year; PFS (25mg) 1.9 mos,
(250mg) 2.5 mos
55
56
57
58
59
60
NCT01387386
Phase II
NCT00869752
Phase II
NCT01173523
Phase II
NCT00702962
Phase I/II
NCT00887159
Phase II
IGF-1R
Relapsed
OSI-906 vs. Topotecan
Ongoing
PFS
1
Extensive stage
Etoposide + Cisplatin + MK-0646
PFS
1
HSP90
Relapsed or refractory
Ganetespib (STA-9090)
Active, not
recruiting
Ongoing
8-week PFS
1
HDAC
Extensive Stage
Ongoing
MTD
1
SMO (Vis.)
IGF-1R (Cix.)
Extensive Stage
Carboplatin + Etoposide +
Vorinostat
Cisplatin + Etoposide ±
Vismodegib (GDC-0449) or
Cixutumumab (IMC-A12)
Bortezomib (PS-341)
Ongoing
PFS
1
SWOG S0327
26S
Platinum-treated
56
PD 91% of patients; PFS 1
61
NCT00068289
proteasome
(recurrent or refractory)
mo, OS 3 mos
Phase II
Extensive Stage SCLC
AVAiL, Avastin in Lung; BATTLE, Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; BMS, Bristol-Myers Squibb; BR,
Bronchus; CALGB, Cancer And Leukemia Group B; First-SIGNAL, First-line Single agent Iressa versus Gemcitabine and cisplatin Trial in Never-smokers with
Adenocarcinoma of the Lung; ECOG, Eastern Cooperative Oncology Group; ESCAPE, Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC;
FLEX, First-line in Lung cancer with ErbituX; INTACT, Iressa NSCLC Trial Assessing Combination Treatment; ISEL, Iressa Survival Evaluation in Lung
Cancer; INTEREST, Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere; IPASS, Iressa Pan-Asia Study; NEJ, North-East Japan; NExUS,
NSCLC research Experience Utilizing Sorafenib; SATURN, Sequential Tarceva in Unresectable NSCLC; SWOG, Southwest Oncology Group; TALENT,
Tarceva Lung Cancer Investigation; TRIBUTE, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin; WJTOG, West Japan Thoracic Oncology
Group; SWOG, Southwest Oncology Group; TORCH, Tarceva or Chemotherapy; ZEAL, Zactima Efficacy with Alimta in Lung Cancer; ZEST, Zactima
Efficacy Study versus Tarceva; ZODIAC, Zactima in cOmbination with Docetaxel In non-smAll cell lung cancer
AEs, Adverse Events; CI, confidence interval; CR, clinical response; DCR, disease control rate; DFS, disease free survival; DLT, Dose Limiting Toxicities; DP,
disease progression; HR, hazards ratio; MTD, maximum tolerated dose; ORR, overall response rate; OS, overall survival; PD, progressive disease, PFS,
progression-free survival; PK, pharmacokinetics; PR, partial response; RP2D, Recommended Phase II Dose; RR, response rate; SD, stable disease; TTP, time to
progression
*Unless otherwise noted.
21
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