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Non-Small-Cell Lung Cancer: Transformations in the Care of Metastatic Disease
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clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
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Core Faculty
Corey J. Langer, MD, FACPDirector, Thoracic OncologyAbramson Cancer CenterProfessor of MedicineHematology-Oncology DivisionUniversity of PennsylvaniaPhiladelphia, Pennsylvania
Heather Wakelee, MDAssociate Professor of Medicine, OncologyDepartment of Medicine/OncologyStanford UniversityStanford, California
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Faculty Disclosures
Corey J. Langer, MD, FACP, has disclosed that he has received funds for research support from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Nektar, OSI, and Pfizer and consulting fees from Abbott, Abraxis, Amgen, AstraZeneca, Bayer/Onyx, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Caris Dx, Celgene, Clarient, Genentech, ImClone, Lilly, Morphotek, Novartis, Pfizer, sanofi-aventis, Synta, and Vertex and served on a DSMC for Amgen, Agennix, Lilly, and Synta.
Heather Wakelee, MD, has disclosed that she has received consulting fees from Peregrine and funds for research support (paid to Stanford) from AstraZeneca, Bristol-Myers Squibb, Celgene, Clovis, Exelixis, Genentech/Roche, Lilly, Novartis, Pfizer, Regeneron, and Xcovery.
Individualizing Therapy for Advanced/Metastatic NSCLC
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Adeno LCC-NOS SqCC SCLC
EGFR mutants ALK ROS/RET
HER2
BRAF KRAS
KRAS
Changes in the Therapeutic Landscape of Stage IV Lung Cancer
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Tissue sent to pathology
Morphologic analysis
IHC, special stains
Tumor genotyping
Tumor biomarkers
Paradigm Shift in Pathology . . .
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
NSCLC Biopsy: Key Factors Adequate tissue for molecular analysis is critical to best
select first-line NSCLC therapy
Determination of EGFR mutation and ALK translocation status is indicated
– Should other genes be evaluated? ROS1, KRAS, BRAF, HER2, others
Rebiopsy at time of progression helpful in determining resistance mechanisms
Bone biopsy less ideal due to decalcification and degradation of DNA
Liquid biopsies in development
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Circulating Tumor DNA Tumors continually shed DNA into the circulation
ctDNA analysis (liquid biopsy or blood sample)
– Can identify both genetic and epigenetic aberrations
– Can provide the genetic landscape of all cancerous lesions (primary and metastases)
– Opportunity to systematically track genomic evolution
– Potential utility in inaccessible lesions and bone-only tumor
Crowley E, et al. Nat Rev Clin Oncol. 2013;10:472-484.
Tumor Histology
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Histology in Management of Advanced- Stage Non-Oncogene–Driven NSCLC What is the current treatment
algorithm in the absence of a known and targetable oncogenic driver?
Is NSCLC histologic subtype prognostic (ie, portends pt outcome independent of therapeutic intervention)?
Is NSCLC histologic subtype predictive of differential benefit from available therapies?
Large Cell
Squamous
Adenocarcinoma
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Pathologic Assessment of Histology Helps Determine Optimal Treatment Histology still guides the therapeutic choice for the vast
majority of pts
Classify pts as squamous or nonsquamous
Adenocarcinomas are TTF1 positive (70% to 90%) and generally negative for p63 (70%) and p40 (97%)[1-4]
Squamous cells are typically p63 (or p40) positive and TTF1 negative[1-4]
All pts who do not have bona fide squamous NSCLC should be considered nonsquamous
1. Di Loreto C, et al. J Clin Pathol. 1997;50:30-32. 2. Fabbro D, et al. Eur J Cancer. 1996;32A:512-517. 3. Rekhtman N, et al. Mod Pathol. 2011;24:1348-1359. 4. Bishop JA, et al. Mod Pathol. 2012;25:405-415.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Histologic Subtypes of NSCLC: US
Wahbah M, et al. Ann Diagn Pathol. 2007;11:89-96.American Cancer Society database.
Decreasing Incidence of Squamous Cell Subtype Over Time
85% of lung cancers are NSCLC
AdenocarcinomaSquamous cell carcinomaLarge cell carcinomaOther or not otherwise specified
40%20%
10% to 15%
25% to 30%
AdenocarcinomaSquamous cellLarge cell
454035302520151050
Can
cer I
ncid
ence
(%)
Yr of Diagnosis (3-Yr Moving Average)
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
Tumor Molecular Profile
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Frequency of Driver Abnormalities in NSCLC, %
AKT1 1
ALK 3-7
BRAF 1-3
EGFR 10-35
HER2 2-4
KRAS 15-25
MEK1 1
NRAS 1
PIK3CA 1-3
RET 1-2
ROS1 1
BRAFHER2
MEK1
AKT1
ALK
PIK3CA
NRAS
ROS1RET
www.mycancergenome.org.
Molecular Subsets of Lung Cancer Defined by Driver Abnormalities*
UnknownKRAS
EGFR
*Double mutations are rare (< 3%)
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Selection for Molecular Testing in NSCLC All pts with an adenocarcinoma
component should be tested Pure SCC diagnosis is appropriate for
EGFR mutation and ALK testing in some clinical settings[1]
– Young, never, or light smoker
– Poor quality/small sample
– East Asian ethnicity (EGFR mut testing)
Primary tumors and metastatic lesions are equally suitable for testing[1]
– Discordance between mut status primary tumor and metastases uncommon for EGFR mut and ALK translocation (in previously untreated pts)[3]
If sensitizing EGFR mutation or ALK is unknown, consider ROS1 testing[4]
1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859. 2. D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070. 5. Yatabe Y, et al. J Clin Oncol. 2011;29:2972-2977. 4. NCCN. Lung cancer. v5.2015.
Pack-Yrs[2] EGFR Mutation, % 95% CI
Never 52 48-56
1-5 34 25-43
6-10 34 26-44
11-15 18 11-26
16-25 11 7-16
26-50 8 6-11
51-75 9 5-13
> 75 4 2-8
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Molecular Testing Guideline: EGFR and ALK Pts SHOULD NOT be treated with first-line EGFR and
ALK inhibitors based on clinical characteristics alone
– If one uses clinical characteristics alone, EGFR inhibitors will be inappropriately given first line to 40% to 60% of pts
Pts SHOULD NOT be offered or denied testing based on clinical characteristics alone
Pathologic sample preparations using heavy metal fixatives or acidic solutions compromise molecular testing[1]
– eg, avoid bone biopsy for molecular testing due to decalcifying solutions, which denature the DNA
1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859.
Selecting Therapy Based on Tumor Histology
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
1.0
0.8
0.6
0.4
0.2
0
Cis/Gem vs Cis/Pem in Advanced NSCLC: OS by Histology
Mos
Surv
ival
Pro
babi
lity
SquamousNonsquamous
Mos
Surv
ival
Pro
babi
lity
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
C/PC/G
C/P vs C/G
Median Survival11.8 mos10.4 mosAdjusted HR: 0.81(95% CI: 0.70-0.94)
C/PC/G
C/P vs C/G
Median Survival9.4 mos10.8 mosAdjusted HR: 1.23(95% CI: 1.00-1.51)
1.0
0.8
0.6
0.4
0.2
0300 6 12 18 24 300 6 12 18 24
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Carbo/Albumin-Bound Paclitaxel vs Carbo/Paclitaxel in Advanced NSCLC
Phase IIIPrimary endpoint: ORRSecondary endpoints: PFS, OS, safety
Pts with stage IIIb/IV NSCLC, ECOG PS
0-1, no previous chemotherapy for metastatic disease
(N = 1050)
Nab-Paclitaxel 100 mg/m2 on Days 1, 8, 15 +Carboplatin AUC 6 on Day 1
No premedication
Paclitaxel 200 mg/m2 on Day 1 +Carboplatin AUC 6 on Day 1
Premedication: dexamethasone, antihistamines
Stratified by stage (IIIb vs IV), age (< 70 yrs vs > 70 yrs), sex,
histology (squamous vs nonsquamous), geographic region
21-day cycles
Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
P = .005RRR: 1.3133%
25%
Intent to Treat
Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.
Carbo/Nab-Paclitaxel vs Carbo/Paclitaxel in Advanced NSCLC: Responses*
Carboplatin/albumin-bound-paclitaxelCarboplatin/paclitaxel
Res
pons
e R
ate
(%)
P < .001RRR: 1.680
P = .808RRR: 1.034
41%
26%24% 25%
0
10
20
30
40
50
Squamous† Nonsquamous†
229 221 292 310
*Independent radiological review. †Not a prespecified endpoint. Interaction P value for histology = .036
521 531n =
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Bevacizumab-Containing Regimens in Advanced Nonsquamous NSCLCOutcome E4599[1]
(N = 878)AVAiL[2,3]
(N = 1043; P values vs placebo)JO19907[4]
(N = 180)PCB PC CGB
(7.5 mg/kg)CGB
(15 mg/kg)Placebo +
CGPCB Placebo
+ PCORR, % 35 15 37.8 34.6 21.6 60.7 31.0
P < .001 P < .0001 P = .0002 P = .001
HR for PFS 0.66P < .001
0.75P = .0003
0.85P = .046
0.61P = .009
Median PFS, mos 6.2 4.5 6.7 6.5 6.1 6.9 5.9
HR for OS 0.79P = .003
0.93P = NS
1.03P = NS
0.99P = .95
Median OS, mos 12.3 10.3 13.6 13.4 13.1 22.8 23.4
1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234.3. Reck M, et al. Ann Oncol. 2010;21:1804-1809. 4. Niho S, et al. Lung Cancer. 2012;362-367.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Maintenance Therapy for Pts With Nonprogressive Disease*
Pts with at least SD after 4 cycles
of CT, PS 0-1
Continuation Maintenance
Observation
Switch Maintenance
Observation
Early 2nd-line Therapy
Observation
Bevacizumab, cetuximab, or pemetrexed (cat 1)
Bevacizumab + pemetrexed
Gemcitabine (2B)
Category 2B:Docetaxel,Pemetrexed,Erlotinib,Gefitinib
NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.
Options:
*After initial platinum-based chemotherapy.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
NSCLC Maintenance Therapy: Advantages and Disadvantages
Advantages
Maintains disease control
Improves PFS
Improves OS
Maintains quality of life
Opportunity to treat more pts
Pts support maintenance therapy
Disadvantages
Induction regimens of 4 vs 6 cycles may achieve the same improvement in PFS
Careful follow-up reveals more pts available for second-line therapy than initially estimated by early reports
Cumulative toxicity with Grade 3/4 AEs in 30% to 40% of pts
Cost
Lack of reliable predictive biomarkers
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Second-line (or Third-line) Therapy for Advanced NSCLC (Non-Oncogene Driven) Commonly used options
– Docetaxel ± ramucirumab
– Pemetrexed
– Erlotinib
– Gemcitabine
– Nivolumab
Multiple investigational options
Adapted from NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
100
80
60
40
20
0
REVEL: Docetaxel ± VEGFR2 Antibody Ramucirumab in 2nd-Line NSCLC
First study in the second-line setting to show an OS advantage for the addition of a “targeted” agent to docetaxel compared with docetaxel alone
First and only study of angiogenesis inhibition in advanced NSCLC to show a benefit in a squamous cell cancer cohort
Overall Survival Phase III Study
Ram + Doc
Pl + Doc
P Value
ORR,%(95% CI)
22.9(19.7-26.4)
13.6(11.0-16.5)
< .001
Median PFS, mos(95% CI)
4.5 (4.2-5.4)
3.0 (2.8-3.9)
HR: 0.72
< .0001
Perol M, et al. ASCO 2014. Abstract LBA8006^.
0 3 6 9 12 15 18 21 24 27 30 33 36Survival Time (Mos)
OS
(%)
Ram + Doc 10.5 (9.5-11.2) 31.8%Pl + Doc 9.1 (8.4-10.0) 27.0%Ram + Doc vs Pl + Doc:Stratified HR: 0.857 (95% CI: 0.751-0.979)Stratified log-rank P = .0235
Median (95% Cl) Censoring Rate
Ram + DocPl + Doc
Selecting Therapy Based on Tumor Molecular Profile
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Activity of Crizotinib in Pts With ROS1 Fusions: Best Overall Response
Shaw AT, et al. N Engl J Med. 2014;371:1963-1971.
ORR: 72%
100
80
60
40
20
0
-20
-40
-60
-80
-100
Cha
nge
From
Bas
elin
e (%
)
PDSDPRCR
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Targeted Therapy Focuses on Driver Gene Alterations: “Oncogenic Addiction”
Gefitinib[1,2] Erlotinib[3,4] Afatinib[5,6] Crizotinib[7-9]
Activity EGFR EGFR EGFR(ErbB family) ALK, ROS1, MET
Target EGFR EGFR EGFR ALK
RR, % 60-80 50-80 ~ 60 ~ 60
PFS, mos 10-11 10-14 ~ 11 ~ 10
TRD, % 1~2 1~2 1.7 < 1
EGFR mutants ALK ROS/RET
1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334. 6. Wu YL, et al. Lancel Oncol. 2014;15:213-222. 7. Camidge DR, et al. Lancet Oncol 2012;10:1011-1019. 8. Kim DW, et al. ASCO 2012. Abstract 7533. 9. Shaw AT, et al. N Engl J Med 2013;368:2385-2394.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Johnson B, et al. ASCO 2013. Abstract 8019.
Lung Cancer Mutation Consortium: OS by Mutation and Treatment
Driver mutation + targeted therapy (n = 313; median OS: 3.5 yrs)Driver mutation + no targeted therapy (n = 265; median OS: 2.4 yrs)No driver mutation (n = 361; median OS: 2.1 yrs)
100
80
60
40
20
0
OS
(%)
0 1 2 3 4 5Yrs
Targeted therapy vs no targeted therapy; P < .0001
EGFR Mutation
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Paclitaxel 200 mg/m2/
Carboplatin AUC 5 or 6‡
Gefitinib†
250 mg/day
*Never smokers (< 100 cigarettes in lifetime) or light ex-smokers(stopped 15 yrs ago and smoked 10-pack yrs).†Carboplatin/paclitaxel was offered to gefitinib pts upon progression.‡Limited to a maximum of 6 cycles.
Pts Chemo naive Aged ≥ 18 yrs Adenocarcinoma
histology Never or light ex-
smokers* Life expectancy
≥ 12 wks PS 0-2 Measurable stage
IIIB/IV disease
EndpointsPrimary PFS (noninferiority) Secondary ORR OS Quality of life Disease-related symptoms Safety and tolerability
Exploratory Biomarkers
– EGFR mutation
– EGFR gene copy number
– EGFR expression
Mok TS, et al. N Engl J Med. 2009;361:947-957. Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.
IPASS: First-line Gefitinib vs Paclitaxel/ Carboplatin
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
IPASS: PFS by EGFR Mutation Status Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)
PFS: gefitinib superior to carboplatin/paclitaxel in ITT population
EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel
Mok TS, et al. N Engl J Med. 2009;361:947-957.
EGFR Mutation Positive
HR: 0.48 (95% CI: 0.36-0.64; P < .001)
Prob
abili
ty o
f PFS
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
00 4 8 12 16 20 24
EGFR Mutation Negative
HR: 2.85 (95% CI: 2.05-3.98; P < .001)
Prob
abili
ty o
f PF
S
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
00 4 8 12 16 20 24
GefitinibPac/carbo
GefitinibPac/carbo
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605
Favors EGFR TKI Favors Chemo
Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS
StudyHR
(95% CI)HR
(95% CI)
EGFRmut (first-line therapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUX LUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal
0.37 (0.25-0.54)0.54 (0.27-1.10)1.08 (0.24-4.90)0.55 (0.19-1.60)0.48 (0.36-0.64)0.58 (0.43-0.78)0.32 (0.24-0.44)0.16 (0.11-0.26)0.59 (0.21-1.67)0.90 (0.39-2.06)0.49 (0.20-1.20)0.52 (0.38-0.72)0.43 (0.38-0.49)
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Phase II Study: Erlotinib ± Bevacizumab in Advanced NSCLC With EGFR Mutations
Open-label study
Primary endpoint: PFS (independent review; RECIST)
Secondary endpoints: OS, tumor response; QoL, safety
Seto T, et al. Lancet Oncol. 2014;15:1236-1244. Kato T, et al. ASCO 2014. Abstract 8005.
Pts with chemo-naive, nonsquamous
NSCLC and EGFR mutations (del 19, L858R), no brain
mets(N = 154)
Treat until disease
progression
Erlotinib 150 mg QD +Bevacizumab 15 mg/kg q3w
(n = 77)
Erlotinib 150 mg QD(n = 77)
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
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
EEBPts at Risk, n Mos
4 8 122 6 10 14 18 22 2616 20 24 28
0.2
0.4
0.6
0.8
Prob
abili
ty o
f PFS
9.7 16.0
EBE
Seto T, et al. Lancet Oncol. 2014;15:1236-1244. Kato T, et al. ASCO 2014. Abstract 8005.
Erlotinib ± Bevacizumab in Advanced NSCLC With EGFR Mutations: PFS
.0015
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
LUX-Lung 3+6: OS by del(19) and L858R Mutation Status
Yang JCH, et al. Lancet Oncol. 2015;16:141-151.
1.0
0.8
0.6
0.4
0.2
0
Estim
ated
OS
Prob
abili
ty
0 6 12 18 24 30 36 42 48Mos
1.0
0.8
0.6
0.4
0.2
0
Estim
ated
OS
Prob
abili
ty
Mos0 6 12 18 24 30 36 42 48
Del(19)Afatinib (n = 236)
Chemo (n = 119)
Median, mos 31.7 20.7 HR (95% CI) 0.59 (0.45-0.77)
P = .0001
L858RAfatinib (n = 183)
Chemo (n = 93)
Median, mos 22.1 26.9 HR (95% CI) 1.25 (0.92-1.71)
P = .1600
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
EGFR Inhibitor–Associated Skin Rash: ManagementPreventive Recommended Not Recommended Comments
TopicalHydrocortisone 1% cream with
moisturizer, sunscreen twice daily Pimecrolimus 1% cream Tazarotene 0.05% cream Sunscreen as single agent
Systemic Minocycline 100 mg/day Doxycycline 100 mg BID
Tetracycline 500 mg BID Doxycycline is preferred in pts
with renal impairment;
minocycline is less photosensitizing
Treatment Recommended Not Recommended Comments
Topical Alclometasone 0.05% cream Fluocinonide 0.05% cream BID Clindamycin 1%
Vitamin K1 cream
Systemic Doxycycline 100 mg BID Minocycline 100 mg/day Isotretinoin at low doses
(20-30 mg/day)
Acitretin Photosensitizing agents
Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Oligo-PD
Systemic-PD
CNS-PD(Sanctuary)
Acquired Resistance to Targeted TKIs: PD Subtype Influences Clinical Practice
Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.
RemissionBaseline Multiple PD Lesions
TherapyContinuedTherapy
RemissionBaseline “Solitary” New Lesions
TherapyContinuedTherapy
Complete RemissionBaseline
TherapyContinuedTherapy
Brain-Only PD
InadequateCNS penetration?
Drug
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Acquired Resistance in NSCLC: Studies Comparing EGFR TKIs
Pts activating EGFR TK mutResistance to first-line gefitinib,
No prior chemo(planned N = 287)[1]
Cisplatin/Pemetrexed
Cisplatin/Pemetrexed + ongoing Gefitinib Primary endpoint: PFS
PIs: Tony Mok, Jean-Charles Soria
Stage IV NSCLCActivating EGFR TK mutation,
Resistance to first-line erlotinib,PS 0/1
(planned N = 120)[2]
Cisplatin or Carboplatin + Pemetrexed, ongoing Erlotinib
Cisplatin or Carboplatin + Pemetrexed
Primary endpoint: PFS PI: Leora Horn Erlotinib retreatment
after progression
Stratified by EGFR mutation (exons 19
vs 21), TTP on EGFR TKIs (< vs > 1 yr), PS (0 vs 1)
1. ClinicalTrials.gov. NCT01544179. 2. ClinicalTrials.gov. NCT01928160.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
IMPRESS: Cis/Pem ± Gefitinib in Stage IIIb/IV NSCLC w/EGFR Mutations and PD
Primary endpoint: PFS Secondary endpoints: OS, ORR, DCR, safety/tolerability, QoL Exploratory endpoints: biomarkers Randomization did not include stratification factors; analyses adjusted for
age (< vs ≥ 65 yrs) and prior gefitinib response (SD vs PR/CR)
Pts with stage IIIb/IV NSCLC, EGFR
mutations, chemo naive, response ≥ 4 mos with first-line
gefitinib, PD < 4 wks prior to randomization
(N = 265)
Cisplatin 75 mg/m2 +Pemetrexed 500 mg/m2 (≤ 6 cycles) +
Gefitinib 250 mg(n = 133)
Cisplatin 75 mg/m2 +Pemetrexed 500 mg/m2 (≤ 6 cycles) +
Placebo 250 mg(n = 132)
Mok T, et al. ESMO 2014. Abstract LBA2_PR.
Phase III trial
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Gefitinib (n = 133)
Placebo (n = 132)
Median PFS, mos 5.4 5.4
Events, n (%) 98 (73.7) 107 (81.1)
HR: 0.86 (95% CI: 0.65-1.13; P = .273)
Gefitinib (n = 133)Placebo (n = 132)
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12 14
Prob
abili
ty o
f PFS
Time of Randomization (Mos)Pts at Risk, n Gefitinib Placebo
133132
110100
8885
4039
2517
125
64
00
HR < 1 implies lower risk of progression with gefitinib
Med OS: 14.8 mos (G) vs 17.2 mos (P)HR: 1.62 (P = .029) but 33% of events
IMPRESS: Cis/Pem ± Gefitinib in Stage IIIb/IV NSCLC w/EGFR Mutations: PFS
Mok T, et al. ESMO 2014. Abstract LBA2_PR.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Observed Resistance Mechanisms
N = 37
T790M (total) + EGFR amp + beta-catenin + APC
21421
MET amplification 2
PIK3CA 3
SCLC transformation 5
Epithelial-mesenchymal transition
2
No changes identified 8
Sequist LV, et al. Sci Trans Med. 2011;3:75ra26.
Repeat Biopsies for Pts With NSCLC and Acquired Resistance to EGFR inhibitors
T790M(49%)
Unknownmechanism
(30%)
WithEGFRamp
METamp(5%)
PIK3CA(5%)
SCLCtransformation(14%)
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Third Generation EGFR TKIs
EGFR TKI N ORR* T790M-
ORR T790M+
PFS Toxicity
Rociletinib (CO-1686)[1]
256 37% 53% ~8.0 mos Hyperglycemia
AZD9291[2] 253 21% 61% ~8.2 mos(9.6 mos T790+,2.8 mos T790-)
Diarrhea
HM61713[3] 34/62 12%(300 mg)
55%(800 mg)
NR Dyspnea/rash
EGF816X[4] 53 - 60% NR Rash
ASP8273[5] 47 ~33% 61% NR Hyponatremia/diarrhea
1. Sequist LV, et al. ASCO 2015. Abstract 8001. 2. Jänne PA, et al. New Engl J Med. 2015;372:1689-1699. 3. Park K, et al. ASCO 2015. Abstract 8084. 4. Tan DSW, et al. ASCO 2015. Abstract 8013. 5. Goto Y, et al. ASCO 2015. Abstract 8014.
*T790M- subgroups are very small pt populationsMultiple other agents in early development
ALK Translocation
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Tumor Responses to ALK Inhibitor Crizotinib in ALK+ Lung Cancer Most pts on study had already had ≥ 2 lines of previous therapy
Objective response rate: 60.8%
Median PFS: 9.7 mos (95% CI: 7.7-12.8)
Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019.
Crizotinib in ALK-Positive NSCLC (N = 143)
100806040200
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) PDSDPRCR
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Crizotinib(n = 173)
Chemotherapy(n = 174)
Events, n (%) 100 (58) 127 (73)
Median, mos 7.7 3.0
HR (95% CI) 0.49 (0.37-0.64)
P value < .0001
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out
Prog
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Chemotherapy
Shaw AT, et al. N Engl J Med. 2013;368:2385-2394.
Crizotinib vs Standard Chemotherapy in ALK+ NSCLC (PROFILE 1007): PFS in 2nd or 3rd Line
173174
9349
3815
114
21
00
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Outcome PROFILE 1001[1]
(N = 143)PROFILE 1005[2]
(N = 259)PROFILE 1007[3]
(N = 173)Best overall response, n (%) CR 3 (2) 4 (2) 1 (1) PR 84 (59) 151 (58) 112 (65) SD 31 (22)* 69 (27) 32 (18) PD NR 19 (7) 11 (6)
Objective response rate, % (95% CI) 60.8 (52.3-68.9) 59.8 (53.6-65.9) 65 (58-72)
Median duration of response, wks (95% CI)
49.1 (39.3-75.4) 45.6 (35.3-53.6) 32.1 (2.1-72.4)†
Median duration of treatment, wks (range)
43.1 (0.1-138.6) N/A 15.9 (2.9-73.4)
Median PFS, mos (95% CI) 9.7 (7.7-12.8) 8.1 (6.8-9.7) 7.7 (6.0-8.8)
Crizotinib in ALK-Positive NSCLC: Efficacy
1. Camidge DR, et al. Lancet Oncol. 2012;10:1011-1019. 2. Kim DW, et al. ASCO 2012. Abstract 7533. 3. Shaw AT, et al. N Engl J Med. 2013;368:2385-2394
*At Wk 8.†Range.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
PROFILE 1014: Crizotinib vs Pemetrexed/ Platinum in Advanced Untreated NSCLC
Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177. Mok T, et al. ASCO 2014. Abstract 8002.
100
80
60
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(%)
Crizotinib(n = 171)
Chemotherapy(n = 169)
HR (95% CI) P Value
ORR, % 74 45 < .001
mPFS, mos 10.9 7.0 0.45 (0.35-0.60) < .001
Adv ALK-pos nonsquamous
NSCLC not previously
treated(N = 343)
Crizotinib 250 mg BID
Pemetrexed + Cisplatin orCarboplatin
q3w x 6 cycles
Primary endpoint: PFS
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Ceritinib in ALK+ NSCLC: Best % Change From Baseline in Target LesionsOther second-generation ALK inhibitors in development:
CH5424802 (alectinib)
AP26113
X-396
ASP3026
GSK 1838705
CEP-28122
Shaw AT, et al. N Engl J Med. 2014;370:1189-1197.
ORR (CR + PR): 58%Prior crizotinib: 56% Crizotinib naive: 62%
100
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clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Phase I ASCEND-1: Ceritinib in ALK-Positive NSCLC Treatment (N = 246): 750 mg/day
(MTD from dose-escalation phase)
Antitumor activity independent of prior ALK inhibitor treatment
Most common grade 3/4 AEs: increased ALT (29.8%) and AST (9.8%)
Most common AEs (all grades): diarrhea (86.7%), nausea (82.7%), vomiting (61.6%)
ALK inhibitor treated (n = 163)ALK inhibitor naive (n = 83)All (n = 246)
0 6 12 18 24 30 36
100
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Felipe E, et al. ESMO 2014. Abstract 1295P.
PFS
(%)
Mos
Median PFS: 18.40 mos
Median PFS: 9.03 mosMedian PFS: 6.93 mos
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Alectinib in Pts With ALK-Positive NSCLC: Results
ORR: 93.5% (95% CI: 82.1-98.6); CR: 19.6%; PR: 73.9%; SD: 2.2%
Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10.
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35
Mos
PFS
Median PFS: 27.7 mos(95% CI: 26.9-NR) 1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35
Mos
OS
2-yr OS rate: 79%(95% CI: 63% to 89%)
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
AP26113 Antitumor Activity in ALK+ NSCLC Pts
72% (41/57) objective response rate (95% CI: 59% to 83%)
100% (6/6) crizotinib-naïve responded (incl. 1 CR)
– Average time to response: 9.2 wks (± 3.22 wks)
69% (35/51) post-crizotinib responded (95% CI: 54% to 81%)
– Response duration: 1.6-14.7 mos (ongoing)
– Average time to response: 9.3 wks (± 3.72 wks)
– Median PFS: 10.9 mos
Gettinger S, et al. ASCO 2014. Abstract 8047.
*Received prior crizotinib and ceritinib. †TKI naïve: 5/6 pts had best target lesion response data entered at time of analysis.
40
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Tar
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)
††
†*
††
*
Best overall response: PDSD
PRCR
Immunotherapies
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
PD-1 Inhibitor Nivolumab in Pts With Progressive Squamous NSCLC
Stage IIIB/IV squamous NSCLC
≥ 2 prior systemic therapies
ECOG PS 0-1 (N = 140 screened)
Nivolumab 3 mg/kg IV q2w until PD or
unacceptable toxicity (n = 117)
Primary: Confirmed ORR
(IRC assessed)
Secondary: Confirmed ORR (investigator
assessed)
Exploratory: Safety and tolerability PFS/OS PD-L1 expression and efficacy
Endpoints
Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.
Phase II study
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Nivolumab in Pts With Squamous NSCLC: Clinical Activity
Be aware of immune-related adverse events and quickly initiate therapy with steroids in recommended cases
Outcome Measures IRC Assessed
ORR, % (n; 95% CI) 15 (17; 9-22)
Disease control rate, % (n) 40 (47)
Median DOR, mos (range) NR (2+ to 12+)
Ongoing responders, % (n) 76 (13)
Median time to response, mos (range) 3 (2-9)
PFS rate at 1 yr, % (95% CI) 20 (13-29)
Median PFS, mos (95% CI) 2 (2-3)
Median OS, mos 8.2
OS at 1 yr , % 41
Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.
Immune-Related AE, %
Any Grade Grade 3/4
Skin 15 2
Gastrointestinal 10 3
Endocrine 6 1
Pneumonitis 5 3
Renal dysfunction
3 0
Hepatic 1 0
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
CheckMate 017: Nivolumab vs Docetaxel in Previously Treated Squamous NSCLC Open-label, randomized phase III trial
Primary endpoint: OS
Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL
Spigel DR, et al. ASCO 2015. Abstract 8009.
Pts with stage IIIB/IV squamous NSCLC and ECOG
PS 0-1 with failure of 1 previous platinum doublet
chemotherapy (N = 272)
Nivolumab 3 mg/kg IV q2w(n = 135)
Docetaxel 75 mg/m2 IV q3w(n = 137)
Until disease progression or unacceptable
toxicity
Stratified by previous paclitaxel therapy (yes vs no) and region
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
CheckMate 017: Nivolumab Significantly Improved OS and PFS vs DocetaxelEfficacy Outcome Nivolumab
(n = 135)Docetaxel (n = 137) HR (95% CI) P Value
Median OS, mos 9.2 6.0 0.59 (0.44-0.79) .00025
Median PFS, mos 3.5 2.8 0.62 (0.47-0.81) .0004
ORR, % CR PR
SDPDUnevaluable
201
19294110
909343522
.0083
Median time to response, mos 2.2 2.1
Median duration of response, mos NR 8.4
Ongoing response, % 63 33
Spigel DR, et al. ASCO 2015. Abstract 8009.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
CheckMate 057: Nivolumab vs Docetaxel in Advanced Nonsquamous Cell NSCLC
Primary endpoints: OSSecondary endpoints: PFS, ORR, QoL, PD-LI protein expression
Key eligibility criteria
≥ 18 yrs of age
Stage IIIB/IV nonsquamous NSCLC
Prior platinum-containing chemotherapy (2nd-line) required: additional TKI therapy allowed (3rd-line)
Pt may have received continuous or switch maintenance with pemetrexed, erlotinib, or bevacizumab post platinum-containing chemotherapy
ECOG PS ≤1
No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 or other antibody targeting T-cell costimulation or checkpoint pathways
ClinicalTrials.gov. NCT01673867.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
CheckMate 057: Increased Efficacy of Nivo vs Docetaxel in Nonsquamous NSCLCEfficacy Outcome Nivolumab
(n = 292)Docetaxel (n = 290) HR (95% CI) P Value
Median OS, mos 12.2 9.4 0.73 (0.59-0.89) .0015
Median PFS, mos 2.3 4.2 0.92 (0.77-1.11) .3932
ORR, %CRPRSDPDUnevaluable
191
18254411
12< 112422916
1.72 (1.1-2.6)* .0246
Median time to response, mos 2.1 2.6
Median duration of response, mos 17.2 5.6
Ongoing response, % 52 14
*Odds ratio (95% CI).
Paz-Ares L, et al. ASCO 2015. Abstract LBA109.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
KEYNOTE 001: Pembrolizumab as Initial Therapy in Pts With Advanced NSCLC
Objectives Evaluate safety, tolerability, and clinical activity of pembrolizumab, a PD-1–blocking antibody Evaluate correlation between clinical activity of pembrolizumab and PD-L1 expression
Response assessment Primary measure: RECIST v1.1 per independent central review Secondary measure: immune-related response criteria per investigator assessment
*First 11 pts randomized to 2 mg/kg q3w and 10 mg/kg q3w (until protocol Amendment 07) and could have a sensitizing EGFR mutation or ALK rearrangement.
Mandatory biopsy within 60 days of first dose
Pembrolizumab 10 mg/kg q3w
Pembrolizumab 10 mg/kg q2w
PD
PD
R1:1*
Treatment-naive, stage IV NSCLC ECOG PS 0-1 EGFR negative* No ALK rearrangement* PD-L1 positive (≥ 1% staining) No systemic steroid No autoimmune disease No or stable brain mets
Balmanoukian AS, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 2.
Phase I trial (N = 45)
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
KEYNOTE-001 Study: Survival
Treatment naive– Median PFS: 27 wks (95% CI: 14-45)– 24-wk PFS: 51%
Previously treated– Median PFS: 10 wks (95% CI: 9.1-15.3)– 24-wk PFS: 26%
Treatment naive– Median OS: NR (95% CI: NE-NE)– 6-month OS: 86%
Previously treated– Median OS: 8.2 mos (95% CI: 7.3-NR)– 6-month OS: 59%
0 8 16 24 32 40 48
100
80
60
40
20
0
PFS
(%)
WksPts at Risk, nTreatment naive
Previously treated45
21739
1592581
1133
413
22
00
Treatment naivePreviously treated
OS
(%)
Mos45
21738
1461333
78
2477
41192
20
00
Treatment naivePreviously treated
OSPFS (RECIST v1.1, Central Review)
Garon E, et al. ESMO 2014. Abstract LBA43.
100
80
60
40
20
00 2 4 6 8 10 12 14
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
KEYNOTE-010 (NCT01905657)PD-L1+ advanced NSCLC*PD following platinum doublet chemotherapy
Pembro2 mg/kg
q3w
Pembro10 mg/kg
q3w
R1:1:1
N = 920
Docetaxel
KEYNOTE-024 (NCT02142738)Strongly PD-L1+ advanced NSCLC*No prior therapy
Pembro200 mg
q3w
Platinum-based chemo
R1:1
N = 300
KEYNOTE-042 (NCT02220894)PD-L1+ advanced NSCLC*No prior therapy
Pembro200 mg
q3w
Platinum-based chemo
R1:1
N = 1240
Primary endpoints: OS, PFS Primary endpoint: PFS Primary endpoint: OS
Ongoing Studies of Pembrolizumab in NSCLC
Garon EB, et al. ESMO 2014. Abstract LBA43.*As assessed using the clinical trial assay and the 22C3 antibody.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
POPLAR: Atezolizumab (MPDL3280A) Efficacy Increased With Higher PD-L1 Expression
PFS and ORR: similar trends in outcome for atezolizumab vs docetaxel based on PD-L1 expression‒ Median PFS in ITT population: 2.8 vs 3.4 mos (HR: 0.98)‒ Median PFS in TC3 or IC3 population: 7.8 vs 3.9 mos (HR: 0.57)‒ ORR in ITT population: 15% vs 15%‒ ORR in TC3 or IC3 population: 38% vs 13%
Interim data based on minimum of 10 mos of follow-up
Interim Median OS Outcomes, mos
Atezolizumab(n = 144)
Docetaxel (n = 143) HR (95% CI) P Value
ITT population (N = 287) 11.4 9.5 0.77 (0.55-1.06) .11
Subgroups based on PD-L1 expression*TC0 and IC0 (n = 92)TC1/2/3 or IC1/2/3 (n = 195)TC2/3 or IC2/3 (n = 105)TC3 or IC3 (n = 47)
9.7NR13.0NR
9.79.17.4
11.1
1.12 (0.64-1.93)0.63 (0.42-0.94)0.56 (0.33-0.94)0.46 (0.19-1.09)
.70.024.026.070
Spira AI, et al. ASCO 2015. Abstract 8010.
*PD-L1 expression measured by SP142 IHC assay (low expression – TC0/IC0, high expression - TC3/IC3).
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Select Anti–PD-L1 Immunotherapy Trials in Locally Advanced or Metastatic NSCLCTrial N Design Key Eligibility CriteriaBirch (phase II) 635 MPDL3280A PD-L1+ tumorFir (phase II)* 128 MPDL3280A PD-L1+ tumor
Poplar (phase II)* 287 MPDL3280A vs docetaxel
Failure of plt-based CT
Oak 1100 MPDL3280A vs docetaxel
Failure of plt-based CT or combined modality therapy
Pacific 702 MEDI4736 vs placebo Stage III, ≥ 2 cycles plt-based CT + RT
Arctic (planned)MEDI4736 ±
tremelimumabvs SOC CT
*Enrollment is complete.
ClinicalTrials.gov.
clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease
Summary Histology still guides the therapeutic choice for the vast majority
of pts
Molecular testing is standard of care for pts with stage IV non-small-cell lung cancer and adenocarcinoma component
Ramucirumab, nivolumab new options for treatment
Important to factor pt age and PS as well as optimal management of treatment-related adverse effects
Most pts relapse or are refractory to existing therapies; promising agents under investigation include immunotherapies and small-molecule inhibitors of EGFR and VEGFR pathways
Go Online for More CCO Coverage of NSCLC!
Expert reviews of all the key data
Additional slidesets on non-small-cell lung cancer with expert faculty commentary on all the key studies
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