Targeted Therapies for Advanced NSCLC - ceconcepts.com to the Future with... · 2016-06-09 ·...
Transcript of Targeted Therapies for Advanced NSCLC - ceconcepts.com to the Future with... · 2016-06-09 ·...
Targeted Therapies for Advanced NSCLC
Current Clinical Developments Friday, June 3, 2016
Supported by an independent educational grant from AstraZeneca
Not an official event of the 2016 ASCO Annual Meeting
Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation
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1. Review the molecular pathology of lung cancer and examine its relevance for clinical practice.
2. Outline the safety and efficacy of first-line therapies for advanced NSCLC, including first generation EGFR and ALK inhibitors.
3. Evaluate treatment approaches used to overcome EGFR and ALK resistance in advanced NSCLC, including the safety and efficacy of second- and third-line therapies and recommended molecular testing.
4. Appraise emerging concepts with EGFR TKIs and ALK inhibitors, including their role in adjuvant therapy, combination therapies, and other evolving data.
Learning Objectives
Looking to the Futurewith Targeted Therapies in NSCLC
Tony Mok, MD Li Shu Fan Medical FoundationProfessor of Clinical Oncology Department of Clinical OncologyThe Chinese University of Hong KongHong Kong, China
• I consult for ACA Biosciences, AstraZeneca, AVEO Oncology/Biodesix, BioMarin, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, geneDecode, GlaxoSmithKline, Janssen, Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche/Genentech, SFJ Pharmaceuticals Group, and Vertex
• I am a member of the speakers’ bureaus for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, and Roche/Genentech
• I am a major stock holder in Sanomics Ltd• I am not on any scientific advisory boards
Disclosures
Looking into the Future
"Those that fail to learn from history, are doomed to repeat it."
Winston Churchill
Looking to Next Five Years Based on History of The Past Five
20162011 to 2015 2017 to 2021
2011 to 2015
MADE IT DIDN’T MAKE IT• Crizotinib for ALK positive lung
cancer• Ramucirumab as second line
therapy• Necitumumab for squamous
cell carcinoma• Ceritinib/alectinib as second
line therapy for crizotinib failure
• Osimertinib for T790M positive lung cancer (post TKI failure)
• Nivolumab/pembrolizumab as second line therapy
• MAGE A3 vaccine as adjuvant therapy for resectable lung cancer
• Tecemotide for stage III lung cancer
• Bevacizumab as adjuvant therapy for resectable lung cancer
• Erlotinib as adjuvant therapy for resectable lung cancer
2011 to 2015
MADE IT DIDN’T MAKE IT• Crizotinib for ALK positive lung
cancer• Ramucirumab as second line
therapy• Necitumumab for squamous
cell carcinoma• Ceritinib/alectinib as second
line therapy for crizotinib failure
• Osimertinib for T790M positive lung cancer (post TKI failure)
• Nivolumab/pembrolizumab as second line therapy
• MAGE A3 vaccine as adjuvant therapy for resectable lung cancer
• Tecemotide for stage III lung cancer
• Bevacizumab as adjuvant therapy for resectable lung cancer
• Erlotinib as adjuvant therapy for resectable lung cancer
Why didn’t we make it?
Why didn’t we make it?
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 60 .0
0 .1
0 .2
0 .3
0 .4
0 .5
0 .6
0 .7
0 .8
0 .9
1 .0
O v e ra ll S u rv iv a l (M o n th s )
Ove
rall
Sur
viva
l Pro
babi
lity
E r lo tin ib P la c e b o
P la c e b o (1 3 e v e n ts )M e d ia n : n o t re a c h e d
E rlo tin ib (2 2 e v e n ts )M e d ia n : n o t re a c h e d
L o g -ra n k te s t: p = 0 .8 1 5 3
H R : 1 .0 9 (9 5 % C I: 0 .5 4 5 , 2 .1 6 1 )
N u m b e r a t R isk
5 69 4
5 39 1
3 04 3
5 71 0 0
5 91 0 2
5 18 8
5 08 6
4 17 5
2 42 6
57
00
1 41 5
P la c e b oE rlo tin ib
RADIANT
STARTMARGRIT
ECOG1505
EGFR by IHC or FISH
NoneMAGE-A3
expression by IHC
None
Biomarker-Based Adjuvant Studies
2016 2017 to 2021
Kelly K, et al. J Clin Oncol. 2015.
RADIANT EGFRm Subgroup Disease-Free Survival
0 6 12 18 24 30 36 42 48 54 60 660.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Disease-free Survival (Months)
Dise
ase-
free
Surv
ival P
roba
bility
PlaceboErlotinib
Placebo (32 events)Median: 28.5 m
Erlotinib (39 events)Median: 46.4 m
Log-rank test: p=0.0391
HR: 0.61 (95% CI: 0.384, 0.981)
Number at Risk4380
3576
1222
4994
59102
3068
2356
1535
1010
00
00
53
PlaceboErlotinib
The difference is not
statistically significant
Kelly K, et al. J Clin Oncol. 2015.
RADIANT EGFRm Subgroup Overall Survival
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 60 .0
0 .1
0 .2
0 .3
0 .4
0 .5
0 .6
0 .7
0 .8
0 .9
1 .0
O v e ra ll S u rv iv a l (M o n th s )
Ove
rall
Su
rviv
al P
rob
ab
ility
E r lo tin ib P la c e b o
P la c e b o (1 3 e v e n ts )M e d ia n : n o t re a c h e d
E rlo tin ib (2 2 e v e n ts )M e d ia n : n o t re a c h e d
L o g -ra n k te s t: p = 0 .8 1 5 3
H R : 1 .0 9 (9 5 % C I: 0 .5 4 5 , 2 .1 6 1 )
N u m b e r a t R isk
5 69 4
5 39 1
3 04 3
5 71 0 0
5 91 0 2
5 18 8
5 08 6
4 17 5
2 42 6
57
00
1 41 5
P la c e b oE rlo tin ib
CTONG1104 Phase III Trial Adjuvant Gefitinib vs Chemotherapy
EGFR M+ Post-surgical Stage II and Stage III A
NSCLC
Adjuvant gefitinib (24 months)
Adjuvant vinorelbine plus platinum chemotherapy (4 cycles)
Primary:Disease Free
Survival
Secondary:OS
DDFSSafety
QoL
1:1 randomization
• Sample size was estimated to be 220 when HR of DFS; the primary endpoint was estimated to be 0.6; the enrollment period was to be 2 years; the period of follow-up after the final enrollment was to be 5 years; statistically significant level (α) was to be 0.05; the statistical power was to be 80%; the estimated total events is 122 from 208 analysed patients.
NCT01405079
FPI: Sept 15, 2011
24 sites, 41 patients randomized (2012/9)
Stage II-IIIA (N1-N2) NSCLC with EGFR activating mutation (ADJUVANT)
IMPACT: WJOG6410L
Cisplatin80 mg/m2 d1Vinorelbine
25 mg/m2 d1, 8
q3 weeksX 4 courses
Gefitinib250 mg/day for 2
yearsPatients• Completely
resected, stage II-III NSCLC
• EGFR mutation (exon 19 del or L858R)
• NO T790M
Stratification• Institution• Stage• Gender• Age
Endpoints1 ̊ Disease free survival2 ̊ OS Safety Recurrence Pattern
Off studyNo mutation
N=115
N=115
Assumptions:• DFS for chemo 28 months• HR=0.65• Alpha=0.0025(0ne sided), beta=0.2• Necessary DFS events=169• Registration 3y, f/u 5y• Sample size=217
PI: Hitohito Tada, MD
CDDP/VNRMedian PFS=28 monthsMedian DFS=43 monthsHR=0.65
Potential problems with both studies:1. DFS as primary endpoint2. Not powered for overall survival3. Duration of exposure to TKI at 2 years
Gefitinib for Mutation+ Lung Cancer as Adjuvant Chemotherapy (A randomized phase III trial of adjuvant gefitinib versus cisplatin and vinorelbine in completely
resected (stage II-III) NSCLC patients with mutated EGFR)
ALCHEMIST-Screening Study Trial Schema
Trials conducted at sites in theNCI Clinical Trials Networks: NCTN & NCORPNon-squamous NSCLC (n=6000 to 8000 pts)Clinical/Pathologic Stage IB (>4cm), II, IIIAPost-Op cohort with negative surgical margins
Pre-opcohort
Post-opcohort
Completeresection+ standardadj therapyper treatingphysician
CentralEGFR & ALKgenotyping
FFPE tissue &blood specimen
EGFR-mutation:Phase III trial of erlotinibvs placebo x 2 years(n=410) after any adj txALK-rearranged:Phase III trial of crizotinibvs placebo x 2 years(n=360) after any adj tx
Without MolecularAlterations: Followedq6 months x 5 years afterany adj tx
FFPE tissue from biopsydone at recurrence
Advanced genomics at the NCI
ALCHEMISTEGFR Treatment Trial A081105
ResectedNSCLC tissue
tested onALCHEMISTScreening
Trial
Patients withtumors with
an EGFRmutation
RANDOM IZE
Erlotinib150 mg po BID x
2 years
Placebopo BID x2 years
Long TermFollow-up
Long TermFollow-up
1 cycle = 21 days
Primary endpoint is overall survival
ALCHEMISTALK Treatment Trial E4512
Accrual has been slow!!
ResectedNSCLC tissue
tested onALCHEMISTScreening
Trial
Patients withtumors with
an ALKre-arrangement
RANDOMIZE
Crizotinib250 mg po BID x
2 years
Placebopo BID x2 years
Long TermFollow-up
Long TermFollow-up
1 cycle = 21 days
Primary endpoint is overall survival
ADAURA Phase III Trial Osimertinib vs Placebo
Placebo
Stage IB-IIIAPrimary NSCLC
EGFR mutation positive including
the atypical mutations
WHO PS0,1Completed resection
and adjuvant chemotherapy
Osimertinib
•Primary endpoint: disease-free survival (DFS)•Secondary endpoints: OS, DFS and OS in patients with del19/L858R
2:1 2 yr treatment period
ClinicalTrials.gov Identifier: NCT02511106.
2011 to 2015
MADE IT DIDN’T MAKE IT• Crizotinib for ALK positive lung
cancer• Ramucirumab as second line
therapy• Necitumumab for squamous
cell carcinoma• Ceritinib/alectinib as second
line therapy for crizotinib failure
• Osimertinib for T790M positive lung cancer (post TKI failure)
• Nivolumab/pembrolizumab as second line therapy
• MAGE A3 vaccine as adjuvant therapy for resectable lung cancer
• Tecemotide for stage III lung cancer
• Bevacizumab as adjuvant therapy for resectable lung cancer
• Erlotinib as adjuvant therapy for resectable lung cancer
What is the reason(s) for success?
Best % change from baseline in target lesionsLDK378 400–750 mg/day
Crizotinib
Ceritinib
Osimertinib
Kwak. N Engl J Med. 2011; Shaw AT, et al. N Engl J Med. 2014; Jänne PA, et al. N Engl J Med. 2015.
• Specific biomarker selection• Expanded phase I program
Should we combine EGFR/ALK TKI with other agent(s)?
Antiangiogenesis Chemotherapy
EGFR/ALK TKI
Immunotherapy
Potential Combination(s)
Antiangiogenesis Chemotherapy
EGFR/ALK TKI
Immunotherapy
Potential Combination(s)
Seto T, et al. Lancet Oncol. 2014.
JO25567 Phase II TrialErlotinib +/- Bevacizumab
Assessed for eligibility
Withdrew before treatment started:Thrombosis: 1Pleural effusion: 1
Randomized (N=154)
Received EB and eligible for analysis
(N=75)
Received E and eligible for analysis
(N=77)
E monotherapy(N=77)
EB combination(N=77)
Seto T, et al. Lancet Oncol. 2014.
JO25567 Phase II Trial PFS by Independent Review
EB E
Median (months)
HR 0.54 (95% CI, 0.36–0.79)
P value*
75 72 69 64 60 53 49 38 30 20 13 8 4 4 077 66 57 44 39 29 24 21 18 12 10 5 2 1 0
00
1.0
EEBNumber at risk Time (months)
4 8 122 6 10 14 18 22 2616 20 24 28
0.2
0.4
0.6
0.8
PFS
prob
abili
ty
9.7 16.0
EB
E
*log-rank test, two-sided
NEJ026 Phase III TrialErlotinib +/- Bevacizumab
Non-sq NSCLCPreviously untreated
Age 20 or aboveEGFR M+
N=214
Erlotinib + Bevacizumab
Recommend Pem/Platinum +
Bevacizumab
RecommendPem/Platinum
Erlotinib
PD1
PD1
Primary endpoint: PFSSecondary endpoint: OS, RR, Safety
RELAY Phase III Trial Erlotinib +/- Ramucirumab
• Age >18• Stage IV NSCLC• EGFR exon
19/21 +ive• T790m -ive• Measurable
disease
N=462
Ramucirumab10 mg/kg
every 2 wks +Erlotinib
150 mg daily
Placebo +Erlotinib
150 mg daily
Primary endpoint: PFS
Started in May 2015
Antiangiogenesis Chemotherapy
EGFR/ALK TKI
Immunotherapy
Potential Combination(s)
Wu YL, et al. Lancet Oncol. 2013.
FASTACT-2 Phase III Trial Intercalated Chemotherapy and Erlotinib
Stage IIIB/IV untreated NSCLC
EGFR Mutation
EGFR Wild Type
Erlotinib (49 patients)Placebo (48 patients)
Prog
ress
ion
free
su
rviv
al (%
)
100
80
60
40
20
0Number at risk
ErlotinibPlacebo
4948
4840
46 45 42 37 33 29 25 22 19 16 11 9 6 4 0035 27 16 8 5 4 4 3 2 2 2 1 1 1
Erlotinib (69 patients)Placebo (67 patients)
Prog
ress
ion
free
su
rviv
al (%
)
100
80
60
40
20
0
Number at riskErlotinibPlacebo
69 564645 0
0165 3
22 2
1 1 1123335967 55 33
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
0001
111
1357101536 0
Time (months)38
Cheng Y, et al. WCLC. 2015.
JMIT 05 Phase II East-Asian Trial Gefitinib +/- Pemetrexed
• Planned enrollment of 188 patients for 145 PFS events with 70% power to detect an HR=0.79 with a one-sided α level of 0.2
• Tumor samples were collected for biomarker analyses• Patients were followed up approximately every 90 days (±14 days) after study treatment
discontinuation for survival
Inclusion Criteria•Adult patients ≥18 years (≥20 years in Japan and Taiwan)•Confirmed advanced (Stage IV) or recurrent NS NSCLC•Activating EGFR mutations•ECOG PS ≤1•No prior systemic chemotherapy, immunotherapy, or biological therapy
•Enrollment period: February 2012 – August 2013•Data cut-off date: 22 April 2015
Oral gefitinib 250mg daily + pemetrexed 500 mg/m2
IV on Day 1 every 3-week cycle (N=126)
Standard folic acid and Vitamin B12
supplementationN=191
2:1
Oral gefitinib250 mg daily
(N=65)
RANDOMIZE
Until disease progression, unacceptable
toxicity, or another
permitted reason for study discontinuation
Primary Endpoint: PFSKey Secondary Endpoints: Overall survival (OS), Overall response, Disease control rate (DCR), Duration of response (DoR), Quality of life (QoL), Safety
Cheng Y, et al. WCLC. 2015.
JMIT 05 Phase II East-Asian Trial PFS (Primary End Point)
Significantly prolonged median PFS in the gefitinib + pemetrexed arm (15.8 months) vs the gefitinib arm (10.9 months)
Prob
abili
ty
10.90.80.70.60.50.40.30.20.1
00 6 12 18 24 30 36
Progression-Free Survival (Months)
GefitinibGefitinib + Pemetrexed
Median PFS, months (95% Cl)
15.8 (12.6, 18.3)10.9 (9.7, 13.9)
Adjusted HRAdjusted P-value 1-sided=0.01; 2-sided=0.03
0.68 (0.48, 0.96)
Patients at RiskGefitinib + PemetrexedGefitinib
12665 51 17
1828
11
006
69 4997
Han B, et al. ELCC. 2016.
Gefitinib +/- Pemetrexed/Carboplatin Randomized Phase II Study
Advanced NSCLC• Adenocarcinoma• EGFR exon 19/21
mut+• First-line treatment• PS 0-1
RANDOMIZE
Pem/carbo +Gefitinib day 5 to 21
x 6 cycles
Pem/carbo x 6 cycles
N=121 patients
Primary endpoint in
PFS
Gefitinib
PFS 18.8 monthRR 83%
PFS 5.8 monthsRR 33%
PFS 12 monthsRR 66%
Is Pemetrexed + Gefitinib better?
Pem/carbo + Gefitinib: Median PFS 16 months
Gefitinib: Median PFS 10 months Pem/carbo: PFS 6 months
Antiangiogenesis Chemotherapy
EGFR/ALK TKI
Immunotherapy
Potential Combination(s)
What can we expect from anti-PD-1/PD-L1 therapy in patients with EGFR/ALK driver
oncogenes?
PD-1/PD-L1 InhibitorsMGH Retrospective Analysis Characteristic EGFR-Mutant or ALK-Positive
(N=26)EGFR WT or ALK-Negative
(N=28) P Value
Age at DiagnosisMedianRange
54.536-75
64.552-77
.004
Smoking History – no. (%) NeverLight (≤10 pack-years)Heavy (>10 pack-years)
14 (54)6 (23)6 (23)
1 (4)1 (4)
26 (93)
<.001
HistologyAdenocarcinomaSquamous
25 (96)1 (4)
20 (71)7 (25)
.036
Molecular Genotype – no. (%) EGFR MutationALK RearrangementKRAS MutationOther/Unknown
20 (77)6 (23)0 (0)0 (0)
0 (0)0 (0)
10 (36)18 (64)b
<.001
Prior Lines of TherapyMedianRange
30-8
20-4
.006
Prior TKIs – no. (%) 22 (85) 5 (18) <.001
PD-1 vs. PD-L1 InhibitorsPD-1 InhibitorsPD-L1 Inhibitors
21 (81)5 (19)
19 (68)9 (32)
.358
PD-1/PD-L1 InhibitorsResponse by Mutation or Smoking Status
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
EGFR-mutant orALK-positive
EGFR WT/ALKnegative
P=.052
ORR
(%)
Objective Response Rate by Mutation Status
3.8%
25%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
Never/LightSmokers
Heavy SmokersO
RR (%
)
P=.122
Objective Response Rate by Smoking Status
4.5%
21.9%
PD-1/PD-L1 InhibitorsPFS by Mutation Status
Months
EGFR Mut or ALK+EGFR WT or ALK -
Median 95% CI 1.93 months 1.87-2.30 months2.20 months 1.93-5.80 months
P=0.041Hazard Ratio 0.577
Progression-Free Survival
Months
Endpoint
Surv
ival
Pro
babi
lity
(%)
No. at Risk
Group 1
Group 2
26
28
3 1 1 1 1 0
0233610
ALK TKI with Immunotherapy Cohorts
[-1 dose cohort] ceritinib 300 mg daily + nivolumab (3 mg/kg every 2 weeks) [1st dose cohort] ceritinib 450 mg daily + nivolumab (3 mg/kg every 2 weeks)
[starting doselevel]
[2nd dose cohort] ceritinib 600 mg daily + nivolumab (3 mg/kg every 2 weeks)
Dose-escalation phase Dose expansion phase
N=30Nivolumab + Ceritinib
(at MTD or RDE)ALK inhibitor-treated
(ALK inhibitor aslast therapy excluding ceritinib)
N=30Nivolumab + Ceritinib
(at MTD or RDE)ALK inhibitor naïve
N=3-6Ceritinib 300 mg +
Nivolumab3mg/kg
N=3-6Ceritinib 450 mg +
Nivolumab 3mg/kg
N=3-6Ceritinib 600 mg +
Nivolumab 3mg/kg Dose Level 1
Starting Dose
2nd Dose Level
TATTONMulti-Arm Osimertinib Phase IB Trial
Ahn M, et al. ELCC. 2016.
Part A – dose escalationPatient with progression on any EGFR TKI Part B – dose expansion
Osimertinib + durvalumab (anti-PD-L1 mAb) First-line: osimertinib + durvalumab
Osimertinib + selumetinib (MEK1/2 inhibitor)
T790M-directed EGFR-TKI progressors, cMET negative: osimertinib + selumetinib
>Second-line, cMET negative: osimertinib + selumetinib
Osimertinib + savolitinib (MET inhibitor)
>Second-line, cMET positive: osimertinib + savolitinib
T790M-directed EGFR-TKI progressors, cMET positive: osimertinib + savolitinib
TATTON Phase IB TrialOsimertinib + Durvalumab
Ahn M, et al. ELCC. 2016.
Characteristic, n
Part A Part BOsimertinib 80 mg daily/durvalumab
3 mg/kg every 2 weeks(N=10)
Osimertinib 80 mg daily/durvalumab10 mg/kg every 2
weeks (N=13)
Osimertinib 80 mg daily/durvalumab
10 mg/kg every 2 weeks (N=11)
GenderMale/Female 3/7 6/7 6/5
Age, median (range), years 67 (46-78) 58 (44-73) 57 (46-70)
Treatment location and ethnicityAsia/USAJapanese/Asian Black/White
6/43/5/1/1
7/62/8/1/2
10/15/6/0/0
SmokerCurrent/Former/Never/Unknown 0/3/7/0 1/1/9/2 1/5/5/0
Therapy line, median (range) 3.5 (2-10) 3 (2-5) N/A: all treatment naïve
Immediate prior therapyGefitinib/Erlotinib/Afatinib/Other 4/1/3/2 2/5/1/5 N/A: all treatment naïve
EGFRmEx19 del/L858R/Unknown 6/4/0 5/7/1 8/2/1
T790M statusNegative/Positive 7/3 7/6 11/10
TATTON Phase IB TrialOsimertinib + Durvalumab: Toxicity
Ahn M, et al. ELCC. 2016.
AE by preferred term, occurring in >3 patients at any dose, n
Part A Part B
Osimertinib 80 mg daily/durvalumab
3mg/kg every 2 weeks (N=10)
Osimertinib 80 mg daily/durvalumab10mg/kg every 2
weeks (N=13)
Osimertinib 80 mg daily/durvalumab10mg/kg every 2
weeks (N=11)
Any Grade Grade >3 Any Grade Grade >3 Any Grade Grade >3
Rash (grouped terms) 5 1 6 0 7 0
ILD (grouped terms) 2 1 4 1 7* 3
Diarrhea 3 0 3 0 5 0
Pyrexia 2 0 2 0 4 0
Stomatitis 1 0 1 0 4 0
Nausea 3 0 5 0 3 0
Anemia 4 0 4 1 1 0
Vomiting 7 1 2 0 0 0
Decreased appetite 3 1 4 0 1 0
TATTON Phase IB TrialOsimertinib + Durvalumab: Tumor Response
Ahn M, et al. ELCC. 2016.
Investigator-assessed ORR was 67% (6/9) and 21% (3/14) in patient with T790M positiveAnd T790M negative NSCLC, respectively, and 70% (7/10) in EGFRm treatment-naïve patients
Best
per
cent
age
chan
ge fr
om b
asel
ine
in ta
rget
lesi
on si
ze (%
)
Best percentage change in target lesion size
Part A T790M positive Part A T790M negative Part B First-line therapy
40
20
0
-20
-40
-60
-80
-100
Long List of Early Trials
• Durvalumab + Gefitinib in EGFR mut+ NSCLC
• Durvalumab + Osimertinib in EGFR mut+ NSCLC [part of TATTON]
• Nivolumab + Erlotinib in EGFR mut+ Erlotinib failure [part of Checkmate 012]
• Nivolumab + Ceritinib in ALK translocated Crizotinib failure
• Atezolizumab + Erlotinib in EGFR mut+ NSCLC
• Atezelizumb + Alectinib in ALK translocated Crizotinib failure
• Pembrolizumab + Rociletinib in EGFR mut+ Erlotinib failure
• Pembrolizumab + Afatinib in EGFR mut+ Pembrolizumab failure
• Pembrolizumab + Crizotinib in ALK translocated NSCLC
• Pembrolizumab + Dabrafenib/Trametinib in KRAS mut+ NSCLC
ClinicalTrials.gov. March 29, 2016.
Looking into the Future
ARCHER 1050 Phase III Study Dacomitinib vs Gefitinib
Advanced NSCLC• Adenocarcinoma• EGFR exon 19/21
mut+• First-line treatment• PS 0-1
RANDOMIZE
Dacomitinib45 mg daily
Gefitinib250 mg daily
1
1
N=440 patients
Primary endpoint in
PFS14.8 vs 9.5
months
Stratification- Race- Exon 19 v 21
Completed accrual in March 2015
FLAURA Phase III Study Osimertinib vs Gefitinib or Erlotinib
Randomize patients 1:1
Enrollment by local*
or central#EGFR
mutation testing of
biopsy sample
Stratified by:
Asian/non-Asian
Ex19del/L858R
RECIST 1.1 assessment
every 6 weeks until
objective progressive
disease
Patients randomized to standard of care may
receive AZD9291
after progression§
Primary objective:
efficacy by PFS
Osimertinib (80 mg po daily)
EGFR-TKI standard of care##: gefitinib
(250 mg po daily) or erlotinib (150 mg po
daily)
*With central laboratory assessment performed for sensitivity#cobasTM EGFR Mutation Test (Roche Molecular Systems)##Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation§Patients randomized to the standard of care treatment arm may receive open-label treatment with AZD9291 on central confirmation
Targeting EGFR MutationsFuture Advanced stage NSCLC
EGFRm(by tissue or blood)
Gefitinib Erlotinib+/-Bev Afatinib DacomitinibOsimertinib
OsimertinibRociletinibHMI 61713
PD
Chemo +/-Bev
T790m+ T790m-
Rebiopsy
Continue TKI beyond RECIST
PD
Anti-C797S Tx
? role of ICI
ASCEND-4 Phase III Study Ceritinib vs Chemotherapy
Ceritinib 750 mg(N=174)
Pemetrexed/cisplatinOR
Pemetrexed/carboplatin every 3 weeks
(N=174)
Pemetrexedevery 3 weeks
Eligibility criteria:• ALK-positive locally
advanced/metastatic non-squamous NSCLC
• No prior treatment for advanced disease
RANDOMIZE
Primary endpoint = PFS
Eligibility criteria:• ALK-positive
locally advanced/metastatic NSCLC
• No prior treatment for advanced disease
RANDOMIZE
Alectinib 600 mg BID (N=143)
Crizotinib 250 mg BID (N=143)
Primary endpoint = PFS by IRR*J-ALEX
ASCO 2016
ALEX Phase III Study Alectinib vs Crizotinib
*Closed by IDMC at preplanned interim analysis after primary end-point of PFS met.
Targeting ALK TranslocationsFuture
Crizotinib/ceritinib/alectinib CNS met
Alectinib/ceritinib if prior
crizotinib
Re-biopsy
Y
N
Gate-keeper mut
2nd
generation according to sensitivity
Chemo
Others G1202R
Loratinib
Summary • Biomarker driven adjuvant studies
− EGFR: Two Asian studies on DFS, ALCHEMIST study on OS− ALK: ALCHEMIST study on OS (slow)
• Combination strategies − With anti-angiogenesis: NEJ26− With chemotherapy: FASTACTII, pemetrexed/carboplatin− With immunotherapy: uncertain efficacy/toxicity
• Second/third generation TKI as first line therapy− EGFR: dacomitinib, osimertinib− ALK: ceritinib, alectinib
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