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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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
Disclaimer
• This slide deck in its original and unaltered format is for educational purposes and is current as of Friday, June 3, 2016. The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter.
• These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies or strategies described in this educational activity.
Usage Rights
• This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged.
• No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply.
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
Molecular Pathology of Lung CancerOverview and Relevance for Clinical Practice
Pasi A. Jänne, MD, PhD Program DirectorLowe Center for Thoracic OncologyDana-Farber Cancer InstituteProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts
from DFCI owned intellectual property on EGFR mutations
Disclosures
EGFR
KRAS
BRAFHER2
PIK3CA
ALK
No known
genotype
ROS1NTRK1
RET
MET
EGFR
KRASKRAS
Lung AdenocarcinomaProgress in Identifying Genomic Alterations
2009
EGFR
KRAS
BRAF HER2PIK3CAALK
No known genotype
2004
2016
1984 - 2003
No known
genotype
No known
genotype
Gandara DR, et al. Clin Cancer Res. 2015; Liao RG, et al. Lung Cancer Manag. 2012.
Lung Squamous CarcinomaGenomic Alterations
FGFR1 amplification
FGFR mutation
FGFR fusion
PIK3CAmutation/amplificationDDR2 mutation
PDGFRA amplification
BRAF mutation
EGFR amplification
ERBB2 amplification
None
Metastatic NSCLC NCCN Guidelines Version 4.2016 SYSTEMIC THERAPY
FOR METASTATIC DISEASE
HISTOLOGIC SUBTYPE
TESTING TESTING RESULTS
Metastatic Disease
• Adenocarcinoma• Large Cell• NSCLC not
otherwise specified (NOS)
• EGFR mutation testing (category 1)
• ALK testing (category 1)
• EGFR and ALKtesting should be conducted as part of broad molecular profiling
• Consider EGFRmutation and ALKtesting especially in never smokers or small biopsy specimens, or mixed histology
• EGFR and ALK testing should be conducted as part of broad molecular profiling
See First-Line Therapy (NSCL-17)
See First-Line Therapy (NSCL-18)
See First-Line Therapy (NSCL-19)
See First-Line Therapy (NSCL-17)
See First-Line Therapy (NSCL-18)
See First-Line Therapy (NSCL-20)
• Establish histologic subtype with adequate tissue for molecular testing (consider rebiopsy if appropriate)
• Smoking cessation counseling
• Integrate palliative care(See NCCN Guidelines for Palliative Care)
Squamous cell carcinoma
Sensitizing EGFR mutation positive
ALK positive
Both sensitizing EGFR mutation and ALK are negative or unknown
Sensitizing EGFR mutation positive
ALK positive
Both sensitizing EGFR mutation and ALK are negative or unknown
Lindeman NI, et al. J Mol Diagn. 2013.
“The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an
epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or
other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests.”
Lung Cancer CAP/IASLC/AMP Guideline
• Availability of test?
• How quickly can you get a result?
• Do you need to test for more than one genomic alteration?
• Cost?
• Will the result help in choosing a therapy and/or enrolling a patient into a clinical trial?
Genomic Tests Factors Affecting Choice
Gene Alteration Method LabEGFR Mutation Sequencing Molecular PathologyKRAS Mutation Sequencing Molecular PathologyALK Rearrangement FISH CytogeneticsFGFR1 Amplification FISH Cytogenetics
Genotyping can be multiplexed
FISH is difficult to multiplex
Need separate assays forALK, ROS, RET, MET, ERBB2, FGFR1
6 X $800 = $4800
Most NSCLC biopsies not amenable to 6 FISH tests & sequencing
Genomic Alterations Testing Methods
Meyerson M, et al. Nat Rev Genet. 2010.
Next-Generation SequencingTypes of Alterations Detected
Oncopanel DFCI/BWH Targeted NGS
Zutter MM, et al. Arch Pathol Lab Med. 2015.Neal Lindeman – Center for Advanced Molecular Diagnostics at Brigham and Woman’s Department of Pathology.
Frequency of BRAF MutationsMelanoma vs Lung Adenocarcinoma
V600E
Non-V600E
V600ENon-
V600E
Melanoma Lung Adenocarcinoma
Davies H, et al. Nature. 2002; Platz A, et al. Mol Oncol. 2008; Karasarides M, et al. Oncogene. 2004; Long, et al. N Engl J Med. 2014; Gilmartin, et al. Clin Cancer Res. 2011.
Inhibiting MAPK/ERK PathwayDabrafenib and Trametinib
Dabrafenib mode of action• Reversible, small molecule • BRAF inhibitor • ATP competitive• BRAF V600E: IC50 0.65 nM
Trametinib mode of action• Reversible, small molecule • MEK1 and MEK2 allosteric
One patient discontinued at day 23 and did not have any post-baseline scans for efficacy.
RR: 63%PFS: Not Reached
Break
32,316,377 bp
KIF5BATG ATG
RET Break
43,611,118 bp
ATGATG
KIF5B-RETRET-KIF5B
RET-KIF5B Translation
Cadherin
Not expressedKIF5B (exons 16-25) RET (exons 1-11)
TranslationKIF5B-RET
Kinesin Coiled coil Tyrosine kinaseKIF5B (exons 1-15) RET (exons 12-20)
Expressed
Lung AdenocarcinomaALK and RET Gene Fusions
Several drugs (sunitinib, sorafenib, vandetanib, cabozantinib) inhibit RET but none are specific RET inhibitors
Lipson D, et al. Nat Med. 2012.
Best Response % (N)
PR 44% (7/16)
Confirmed 38% (6/16)
Unconfirmed 6% (1/16)
SD 56% (9/16)
ORR 38% (95% Cl 15%-65%)
ORR12wks 36% (95% Cl 13%-65%)(5 PRs of 14 evaluable at 12 wks)
30%
0%
-30%
-60%
-90%
Confirmed PRSD
RET-Rearranged Lung AdenocarcinomaResponse to Cabozantinib
Drilon AE, et al. ASCO. 2015.
Awad MM, et al. J Clin Oncol. 2016.
NSCLCMET Exon 14 Skip Mutations
MET exon 14 cancers can have METamplification and/or high level of MET
expression
KRAS (34%)
No oncogenic mutation
identified (30%)
EGFR (19%)
ALK (3.9%)
BRAF (3.8%)
MET ex14 (3%)
PIK3CA (2.9%)
ERBB2 (2.5%)
NRAS (1%)
RET (1%)
ROS1 (1%)AKT (<1%)
HRAS (<1%)
MAP2K1 (<1%)
Prevalence of MET exon 14 skip mutations
Awad MM, et al. J Clin Oncol. 2016.
MET Exon 14 Skip TumorsSensitive to MET Inhibitors
Pre-Treatment On Crizotinib (at 2 months)
NSCLC With Genetic Alterations Emerging Targeted Agents
Clinical Practice Guidelines. NCCN. 2016.V4.
Genetic Alteration (eg, driver event)Available Targeted Agents with Activity Against Driver Event in
Lung CancerBRAF V600E mutation* vemurafenib
dabrafenibdabrafenib + trametinib
High level MET amplification or MET exon 14 skipping mutation
crizotinib
RET rearrangements cabozantinibROS1 rearrangements crizotinibHER2 mutations trastuzumab (category 2B)
afatinib (category 2B)*Non-V600E mutations have variable kinase activity and response to these agents
Do Genomic Changes Predict for Sensitivity to Immunotherapy?
Mutation Load Across Cancer TypesHigh Mutational Burden in Lung Cancer
Alexandrov LB. Nature. 2013.
1000/Mb
100/Mb
10/Mb
1/Mb
0.1/Mb
0.01/Mb
n= 2 20 133
26 23 53 114
227
14579180 63 11 216
384
213
51 20 231
186
178
6944 274
7349 96
Som
atic
mut
atio
n ra
te
Rhab
doid
LAM
Ewin
g
AML
Med
ullo
Carc
inoi
d
Thyr
oid
NB
CLL
LGG
Brea
st
Pros
tate
Panc
reas
MM
Kidn
eyRP
Kidn
eyRC OV
GBM
Ute
rine
Cerv
ical
CRC
Head
Nec
k
DLBC
L
Stom
ach
Esop
h
Blad
der
LUAD
LUSC
Mel
anom
a
C > TC > AC > GT > CT > AT > G
20
Anti-PD-1/PD-L1 mAbs in NSCLCImpact of Smoking Status
AgentORR, % (n/N)
Current/former smoker Never smoker
Pembrolizumab1,2 26%(NR/129)
8%(NR/60)
Atezolizumab3,4 26%(11/43)
10%(1/10)
AgentORR, % (n/N)
>5 pack-years ≤5 pack-years
Nivolumab5 37%(19/52)
0%(0/10)
1Garon E, et al. WCLC. 2013. (Abstract MO18.02); 2Garon E, et al. ASCO. 2014. (Abstract 8020); 3Horn L, et al. WCLC. 2013. (Abstract 2347); 4Soria J, et al. ECC. 2013. (Abstract 3408); 5Hellmann MD, et al. ESMO. 2014. (Abstract 1229PD)
NR=not reported
DCB NDB
All Tumors
# N
onsy
nony
mou
s m
utat
ions
/tum
or
1200
800
400
200
0
# N
onsy
nony
mou
s m
utat
ions
/tum
or
1200
800
400
200
0
Validation Cohort
DCB NDB
800
600
400
200
0
# N
onsy
nony
mou
s m
utat
ions
/tum
or
DCB NDB
Discovery Cohort100
50
0
% S
ensi
tivity
1 - % Specificity50 100
High nonsynonymous burdenLow nonsynonymous burden
High nonsynonymous burdenLow nonsynonymous burden
Perc
ent p
rogr
essi
on-fr
ee
Perc
ent p
rogr
essi
on-fr
eeMonths Months
Validation Cohort All Tumors
100
50
0
100
50
0
4 8 12 16 20 244 8 12 16 20 24 4 8 12 16 20 24
High nonsynonymous burdenLow nonsynonymous burden
Perc
ent p
rogr
essi
on-fr
ee
Months
Discovery Cohort
100
50
0
Clinical Benefit of Anti-PD-1 TherapyEffect of Nonsynonymous Mutation Burden
Rizvi NA, et al. Science. 2015.
Clinical Benefit of Anti-PD-1 TherapyEffect of Molecular Smoking Signature
Rizvi NA, et al. Science. 2015.
(n=18) (HR 0.15, 95% 0.06-0.39, log-rank P=.0001)
100
Months
Perc
ent p
rogr
essi
on-fr
ee
50
04 8 12 16 20 24
Transversion highTransversion low
Anti-PD-1/PD-L1 mAbs in NSCLCImpact of EGFR, KRAS Status