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BEST OF ASCO LUNG CANCER 2012. David R. Gandara, MD University of California Davis Comprehensive Cancer Center. Disclosures. Research Grants: Abbott, BMS/ ImClone , Genentech, GSK, Lilly , Merck, Novartis - PowerPoint PPT Presentation
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BEST OF ASCO LUNG CANCER 2012
David R. Gandara, MDUniversity of California Davis
Comprehensive Cancer Center
Disclosures• Research Grants: Abbott, BMS/ImClone,
Genentech, GSK, Lilly, Merck, Novartis• Consultant: Abbott Molecular, AstraZeneca,
Biodesix, Boehringer-Ingelheim, BMS/ImClone, Caris, Celgene, GlaxoSmithKline, Genentech, Lilly, Merck, Novartis, Pfizer, Response Genetics, Sanofi-Aventis
BEST OF ASCO LUNG CANCER 2012
Abstracts for Discussion:– Small Cell Lung Cancer (SCLC):
• Limited & Extensive Stage– Non Small Cell Lung Cancer(NSCLC):
• Genomics: The “Big Bang” effect• Advanced Stage NSCLC
– Targeted Therapies: “Coming of Age”
» ALK
» ROS1
» MEK
– Emerging Role of Immunotherapy
SCLC Abstracts for Discussion• #7004: Concurrent TRT-Chemotherapy: 1st Cycle vs 3rd Cycle.
Phase III (Park et al)
• #7003: Amrubicin-Cisplatin vs Irinotecan-Cisplatin in E-SCLC. Phase III JCOG 0509 (Kotani et al)
• #7005: Weekly Topotecan +/- AVE0005 (Aflibercept) in 2nd line therapy of E-SCLC. Randomized Phase II S0802 (Allen et al)
#7004Limited Stage:
Timing of Chemo-Radiation
#7003Extensive Stage
1st Line Chemotherapy:Amrubicin
#7005Extensive Stage
2nd Line Therapy:AVE0005
Demographic, Biologic, Clinical & Therapeutic Differences between SCLC & NSCLC
Feature SCLC NSCLC
Incidence Decreasing Increasing
Association with Smoking Universal Highly Variable
Growth Kinetics ~Rapid Variable
Biologic Diversity (Histologic & Molecular) ~Homogeneous Distinct Subtypes
Early Metastases Universal Variable
Sensitivity to DNA-damaging chemotherapy (1st line) High Variable
Sensitivity to Radiotherapy High Variable
Advances in Therapy ~15 years Few Advances Dramatic Advances
#7004: 1st versus 3rd Cycle TRT + Cisplatin-Etoposide in L-SCLC (Park et al)
R
1st Cycle arm
(n=111)
EP
TRT
EP
EP
EP
LD-SCLCTreatment-
naïve
N=219
1:1PCI for patients with PR or CR
Primary end point: Complete response rate (WHO criteria) Secondary end point: ORR, OS, PFS, and toxicity (NCI-CTC ver. 2.0)
3rd CycleDelayed
arm
(n=108)
EP
TRT
EP
EP
EP
EP: Etoposide 100mg/m2 D1-3 Cisplatin 70mg/m2 D1, q3 wTRT: 52.5 Gy/25 fxs (2.1 Gy/fx, once daily)
Enrollment between 2003 and 2010 (7 years) Median Follow Up is 59.4 months (about 5 years)
Efficacy Comparisons: 1st (initial) vs 3rd (delayed) cycle TRT
Favors Cycle 1 but not significantly different
Perspective on this Abstract: Therapy of Limited Stage SCLC
• Platinum/Etoposide (PE) + 1st cycle concurrent thoracic radiotherapy (TRT) has been standard of care in the U.S. for ~20 years
• Regimens adding new systemic agents or substituting agents have generally failed to show sufficient promise to replace PE
• Advance: Twice day hyperfractionated RT + PE was proven superior to once daily standard fraction RT (Turrisi et al: NEJM, 1999), but has not been widely adopted in practice
• In reality, 1st cycle concurrent TRT is not feasible in a substantial subset of patients with L-SCLC
• Radiation volume considerations (V20 or other parameters)• Delays in radiation planning in some settings/countries• Need for systemic therapy on an urgent basis in some cases
• A great deal of attention has already been paid to optimizing the timing of TRT in L-SCLC. Why Revisit It Now?
Meta-Analysis of TRT Timing: Overall Survival
Pijls-Johannasma et al:Cancer Treat Rev, 2007
Meta-AnalysisFavors Early TRT
2-3 Year OS
5 Year OS
Amended to allow Cycle 1 or Cycle 2 TRT Testing Cycle 2 TRT in both arms
Two Ongoing Phase III Trials in L-SCLC:Testing Radiation Dose Schedules
• Both are focused on TRT Dose Schedule• Neither is investigating timing of TRT
Summary: #7004 Timing of TRT
• The results add to literature concluding that early TRT is important (but not necessarily cycle 1) in optimizing efficacy of Chemo-Radiation in L-SCLC
• Cycle 1 TRT leads to an increase in some toxicities• Other ongoing Phase III trials are investigating
alternative TRT dose schedules but not timing or radiation volume issues
• New systemic agents for inclusion into chemo-radiation regimens for L-SCLC are needed
#7003: JCOG 0509 (Kotani et al)
RANDOMIZE
Irinotecan 60 mg/m2 D1,8,15Cisplatin 60 mg/m2 D1Q4 weeks x 4 cycles
Amrubicin* 40 mg/m2 D1-3Cisplatin 60 mg/m2 D1Q3 weeks x 4 cycles
PCI if CR (2.5Gy/10 Fx)
IP
AP
ED-SCLC20-70 yrsPS 0-1
Stratification● PS● institution● sex
Sample size n= 282 (n= 141 per Arm)
• Primary Endpoint= OS• IP dose schedule was identical to J9511 & SWOG 0124• Amrubicin dose amended to 35 mg/m2 due to FN• Trial was closed early by the DSMC
Efficacy Comparisons: AP versus IP (JCOG0509)
Phase III Investigation of “Newer” Chemotherapeutic Agents in E-SCLC
from Gandara et al: NCI Early Drug Development Symposium, April 2012
Agent Response Rate in Phase II: 1st line/2nd line
Results (1st line in combination with Platinum)
Paclitaxel ~35%/~25% Negative Phase III trial(Niell et al)
Gemcitabine ~25%/14% Phase II: not promising(Hesketh et al)
Topotecan ?/~18% “Positive” Phase III:but not adopted(Heigener et al)
Irinotecan ~35%/~25% Conflicting results of Phase III trials
(Noda; Lara; Hanna)
Pemetrexed ? Negative Phase III trial(Socinski et al)
Amrubicin ~40% Negative Phase III trial as 2nd line- single agent
( Jotte et al)
S0124 did not confirm results of J9511Efficacy of Irinotecan greater in Japanese patients
Toxicity was also greater in Japanese patientsPopulation-related Pharmacogenomics may have influenced results
Comparative Efficacy of JCOG 9511 versus SWOG 0124
Lara et al: JCO, 2009
Summary: #7003: AP vs IP in 1st Line Therapy of E-SCLC
• Another promising drug in SCLC has failed to pass the Phase III test
• Approaches exploiting the initial high sensitivity of SCLC to 1st line DNA-damaging chemotherapy are worth pursuing (ECOG 2511: PARPi ABT888)
• Demonstrating new agent activity in the 2nd line setting in platinum-refractory disease may be a logical prerequisite for testing in the 1st line setting
#7005: Topotecan +/- AVE0005 (Aflibercept) in 2nd Line Therapy of E-SCLC (S0802- Allen et al)
Eligibility CriteriaSmall cell lung cancerExtensive or limited stage1 prior platinum-based chemotherapy regimenECOG PS 0-1Adequate organ functionNo “anti-angiogenic” risk factors
STRATIFY
Platinum SensitiveResponse to 1st Line Chemotherapy and Progression > 90 days (ES) or 180 days (LS)
Platinum RefractoryProgression ≤ 90 days (ES) or < 180 days (LS) after 1st Line Chemotherapy
Topotecan IV4 mg/m2 Days 1, 8, and 15AVE0005 IV6 mg/kg on Day 1
RANDOMIZE
Topotecan IV4 mg/m2 Days 1, 8, and 15
Topotecan IV4 mg/m2 Days 1, 8, and 15AVE0005 IV6 mg/kg on Day 1
Topotecan IV4 mg/m2 Days 1, 8, and 15
* Topotecan is omitted on Day 15 for all patients starting on Cycle 5.
RANDOMIZE
#7005: Efficacy of Topotecan +/- AVE0005
Perspective on this Abstract: 2nd Line Therapy of Extensive SCLC
• In 2nd line therapy, a number of chemotherapeutic agents are active in “platinum-sensitive” patients, but the “platinum-refractory” subset fares poorly
• Example: Topotecan is primarily active only in “platinum-sensitive” patients
• Identifying agents active in the “platinum-refractory” subset is therefore a high priority in clinical research in SCLC
• Additional studies evaluating novel targeted agents in SCLC are needed
Investigation of “Targeted Therapies” in Extensive SCLCSelected Agents Target(s) Results
Imatinib(Johnson et al)
KIT, SCF Inactive
Bec2/BCG(Giaccone)
GD3 ganglioside Negative Phase III trial
Bortezomib (PS-341)(Lara et al)
Proteasome Insufficient activity
Sorafenib(Gitliz et al)
VEGFR Insufficient activityPR: PlatSens: 5% PlatRef: 2%
Vandetanib (ZD6474)(Arnold et al)
EGFR/VEGFR HR 1.43 vs Placebo for OS
ABT263 & Obatoclax(Rudin et al; Langer et al)
Bcl-2 Insufficient activity
PE + GDC0449 or IMC-A12:E1508 (Belani/Rudin)
Hedgehog or IGF-1R
Pending Completion
ABT888 + PE vs PE: E2511 (Owonikoko/Belani)
PARP Pending Activation
• Biologic Activity of some Targeted Agents may occur without RECIST response• Manifest as improved DCR (CR/PR + SD), PFS/OS or Biomarker/Imaging effects• “Four Dimensional Model”
Classic Tumor Response (RECIST)
Disease Control(CR + PR + SD)or Timed DCR
Biologic Effects on Tumor(Biomarkers, Functional imaging)
Survival Endpoints (OS, PFS)
Measuring Effects of “Novel Therapeutic Agents”:A Four Dimensional Model
adapted from Gandara et al,Clin Lung Cancer, 2007
Biologic Activity without RECIST Response
Phase II Study of Aflibercept in Refractory NSCLC
Number of patients
98
Treatment Aflibercept 4 mg/kg q 2 wks
Prior treatment 69.4% pts ≥ 3 lines
Primary Objective(RECIST)
ORR 2 % 95% CI [0.2 – 7.2%]
Best response vs baseline 40
20
0
-20
-40
Bes
t % T
umor
Shr
inka
ge
Patients
Leighl et al: J Thorac Oncol , 2010
SHARP Trial: Sorafenib vs Placebo in Hepatocellular Cancer
Llovet et al: NEJM 2008
Summary: #7005: Topotecan +/-VE0005• The S0802 trial met the primary endpoint of improved 3-
month PFS• RECIST response was low & there was no impact on OS• These data remain hypothesis-generating & require
confirmation (Predictive Biomarker development is essential)• How to best combine VE0005 & Chemotherapy remains
unclear
Advances in Sequencing Technologies and Human Genomics
Automated slab gelManual
slab gel
1st generation capillary sequencer
Gel-based Systems
Capillary sequencing
2nd generationcapillary
sequencer Microwell pyrosequencing
Short-read sequencers
Single molecule?
Massively parallel sequencing
(10)
(50)
(103)(105)
(107)
(109)
(102)
Sequ
enci
ng Te
chno
logy
(kilo
base
s/da
y/m
achi
ne)
1980 1985 1995 2000 Future2010200519901975I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
IRas mutations
as 1st oncogenes (1982)
EGFR mutations(2004-2009)
ALK gene rearrangement
(2007-2011)Human Genome Project
(2001-2006)
Hum
an G
enom
ics
& Lu
ng C
ance
r (ye
ar)
Somatic mutations in lung adenocarcinoma
(2008)
The Cancer Genome Atlas
(2010- )
Small cell lung cancer genome (2009)
lung adenocarcinoma genome (2008)
1000 Human Genome(2007- )
Squamous cell lung cancer genome (2012)Li, Gandara et al: JCO 2012 (in press)
Comprehensive Characterization of Squamous Cell NSCLC (SCCA) #7006
Ramaswamy Govindan, Peter Hammerman, Neil Hayes, Matthew Wilkerson, Steve Baylin and Matthew
Meyerson On Behalf of the Lung Cancer Working Group of
The Cancer Genome Atlas (TCGA) Project
Structural variants• Translocations• Fusions• Inversion
Copy number alterations
• Amplifications• Deletions• LOH
Point mutations & indels
• Missense• Nonsense• Splice site• Frameshift
Gene expression• Outlier expression• Isoform usage• Pathways & signatures
Wild type AGTGA
Mutant AGAGA
From Govindan et al: ASCO 20`2
• This presentation: Squamous Cell Cancer• Goal 500 • Accrued so far 300• Analysis completed 178 reported here
#7006: Characterization of Genomic Alterations in Cancer (TCGA)
29
#7006: NSCLC (including SCCA) has a very high rate of somatic mutations
1 / Mb
10 / Mb
100 / Mb
0.1 / Mb
81 64 38 316 100 17 82 28n=109 119 21 40 20
Hematologic &Childhood Cancers
Carcinogen- Induced Cancers
??
Courtesy: Gaddy Getz and Mike Lawrence, Broad Institute, MIT
Ovarian, Breast & Prostate
Cancers
“Stupid Cancers”
“Smart Cancers”
30
mRNA Expression Analysis of SCCA
15% 36% 24% 25%
PI3K alterations
NF1 loss
Gene Event Type Frequency
CDKN2A Deletion/Mutation-Methylation
72%
PI3KCA Mutation 16%PTEN Mutation/Deletion 15%
FGFR1 Amplification 15%EGFR Amplification 9%
PDGFRA Amplification/Mutation
9%
CCND1 Amplification 8%DDR2 Mutation 4%BRAF Mutation 4%
ERBB2 Amplification 4%FGFR2 Mutation 3%
New Therapeutic Targets in squamous cell lung carcinoma (SCCA)
Summary: Characterization of Squamous Cell NSCLC (SCCA)
• SCCA characterized by: Complex genomes with frequent and unique rearrangements
• Proposed a molecular sub-classification (yet to be clinically validated)
• Multiple mechanisms for alteration/inactivation of the same gene (e.g. CDKN2A)
• Potentil therapeutic targets identified in 75% of patients, including FGFRs, PI3 kinase pathway, EGFR/ERBB2 and Cyclin/CDK complexes
Unknown
FGFR1 Amp
EGFRvIII
PI3KCAEGFR
DDR2
Squamous Cell Cancer
Adenocarcinoma
“Targeted Therapies Coming of Age”(from Li, Gandara et al: JCO 2012, in press)
NSCLCas one disease
Histology-based Subtyping
#7500: LUX-Lung 3: Phase III trial of afatinib versus pemetrexed and cisplatin as first-line treatment for EGFR mutation+ adenocarcinoma
(Yang et al)
Pemetrexed + cisplatin
Stage IIIB-IV Adenocarcinoma with
EGFR mutation
● Primary endpoint: PFS
● Secondary endpoints: ORR, DCR, OS
RANDOMIZATION
Afatinib
2:1
Response Afatinib Cis/Pem
Overall 56% 23%
E19del/L858R 69% 44%
#7500: LUX-Lung 3: Phase III trial of afatinib versus pemetrexed and cisplatin as first-line treatment for EGFR mutation+
adenocarcinoma (Yang et al)
2007
2008
2010
2012
The Story of “ALK”in NSCLC
2007-2012
CrizotinibFDA approval in 2011
ALK-positive NSCLC & Impact of ALK inhibitionby Crizotinib Therapy
Activity of ALK inhibitor Crizotinib in patients with advanced ALK-positive NSCLC (Response Rate=61%)
Camidge et al: ASCO 2011; Abs #2501
• Previously treated advanced NSCLC• N=116• 59% male• 72% never-smoker• 56% ≥2 prior regimens
• Potent activity in enzymatic and cell based assays
• LDK378 treatment results in tumor regression in EML4-ALK expressing xenografts
AssayLDK378IC50 (μM)
CrizotinibIC50 (μM)
Enzymatic ALK MET
0.000153.2
0.0030.008
Cell-based ALKMET
0.0271.3
0.110.028
Mehra R, et al. ASCO. 2012; #3007
First-in-human Phase I trial of ALK inhibitor LDK378 in ALK+ solid tumorsRanee Mehra,1 D. Ross Camidge,2 Sunil Sharma,3 Enriqueta Felip,4 Daniel Tan,5 Johan Vansteenkiste,6 Tommaso De Pas,7 Dong-Wan Kim,8Armando Santoro,9 Geoffrey Liu,10 Meredith Goldwasser,11 David Dai,12 Anthony L. Boral,11 Alice Shaw13
LDK378 has antitumor activity in ALK+ NSCLC
• Of the 24 responding patients, 11 responses were confirmed, and 7 are awaiting confirmatory scans
• Response rate was 81% (21/26) in patients with NSCLC treated at ≥ 400 mg who progressed following crizotinib
Initial dose (mg) Evaluable
Patients (n) Responses (PR)
NSCLC< 400 8 2 (25)
≥ 400 33 22 (67)
Other diseases 50 – 600 6 0
Mehra R, et al. ASCO. 2012; #3007
Response to LDK378
After 6 weeks on LDK378Baseline
Mehra R, et al. ASCO. 2012; #3007
#7508: Clinical Activity of Crizotinib in Advanced
Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Rearrangement
Alice T. Shaw1, D. Ross Camidge2, Jeffrey A. Engelman1, Benjamin J. Solomon3, Eunice L. Kwak1, Jeffrey W. Clark1, Ravi Salgia4, Geoffrey I. Shapiro5, Yung-Jue Bang6, Weiwei Tan7, Lesley Tye7, Keith D. Wilner7, Patricia Stephenson8,
Marileila Varella-Garcia2, Kristen Bergethon1, A. John Iafrate1, and Sai-Hong I. Ou9
Shaw et al: ASCO Annual Meeting 2012, June 1–5, Chicago, IL
1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2University of Colorado Cancer Center, Aurora, CO, USA; 3Peter MacCallum Cancer Centre, East Melbourne, Australia; 4University of Chicago Cancer Center, Chicago, IL, USA; 5Dana Farber Cancer Institute, Boston, MA, USA; 6Seoul National University, Seoul, Korea; 7Pfizer Inc, La Jolla, CA, USA; 8Rho, Inc, Chapel Hill, NC; 9Chao Family Comprehensive Cancer Center, Orange, CA, USA
#7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al)
● ROS1 rearrangement in ~1% of NSCLC cases
● More common in younger never or light smokers with adenocarcinoma
● Multiple ROS1 fusion partners
● Measured by “Break-Apart” FISH Assay
● No overlap with other oncogenic drivers (EGFR MT)
Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012
TPM3-ROS1
SDC4-ROS1
CD74-ROS1
EZR-ROS1
LRIG3-ROS1
SLC34A2-ROS1
ROS-1 fusion partners
Abstract: 7508
Break-ApartFISH Assay
Background on ROS1 Signaling Pathways
#7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al)
Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012 Abstract: 7508
(N=14)
Docetaxel
Stage IIIB-IV NSCLC with KRAS mutation
● Primary endpoint: PFS
● Secondary endpoints: ORR, DCR, OS
RANDOMIZATION
Docetaxel + AZD6244
Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503)
Parameter Docetaxel Docetaxel/AZD6244
mPFS (mos) 2.1 5.3
Response 0% 37%
OS 5.3 9.4
Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503)
PFS OS
#7509: Clinical Activity and Safety of Anti-PD1 (BMS-936558, MDX-1106) in Advanced Non-Small-Cell Lung Cancer
J.R. Brahmer,1 L. Horn,2 S.J. Antonia,3
D. Spigel,4 L. Gandhi,5 L.V. Sequist,6 J.M. Wigginton,7
D. McDonald,7 G. Kollia,7 A. Gupta,7 S. Gettinger8
APC T cell
(+) Signal 2B7.1 CD28
TCR Signal 1MHC-Ag
Tumor
Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)
From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Activation(cytokines, proliferation, migration, lysis)
APC T cell
(+) Signal 2B7.1 CD28
TCR Signal 1MHC-Ag
TumorTumor
PD-L1
PD-1
(-)(-) (-)
Inhibitionof
Tumor Cell Defense
From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Activation(cytokines, proliferation, migration, lysis)
Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)
APC T cell
(+) Signal 2B7.1 CD28
TCR Signal 1MHC-Ag
TumorTumor
PD-L1
PD-1
(-)(-) (-)
InhibitionBlocked
Anti-PD-1
From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Activation(cytokines, proliferation, migration, lysis)
Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)
Pop Dose(mg/kg)
Ptsn
ORRn (%)
Duration of Response
(mo)
SD 24 wkn (%)
PFSR at 24 wk
(%)
ALL NSCLC 1-10 76 14 (18) 1.9+ to 30.8+ 5 (7) 26
NSCLC
1 18 1 (6) 9.2+ 1 (6) 16
3 19 6 (32) 1.9+ to 30.8+ 2 (11) 41
10 39 7 (18) 3.7 to 14.8+ 2 (5) 24
Clinical Activity in NSCLC Patients
•ORR was assessed using modified RECIST v1.0
•3 NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation
#7509: Clinical Activity and Safety of Anti-PD1 (BMS-936558, MDX-1106) in Advanced NSCLC
Pre/Post Anti-PD1 Treatment
- 58 y/o ex smoker with squam NSCLC- 4 prior regimens for Stage IV disease
Association of PD-1 Expression in Tumor and Response to Anti-PD1 Treatment
• Incremental progress in being made in understanding the underlying biology & genomics of lung cancer
• These findings are leading directly to discovery of new therapeutic targets and new therapeutic agents
• The age of “personalized therapy” for lung cancer is rapidly emerging
• Considerable challenges remain• In every challenge there are opportunities• We must take full advance of these opportunities
to advance the care & cure of lung cancer patients
Best of ASCO 2012: Lung Cancer: Gandara Summary
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