Precision Medicine in Advanced NonSmall Cell Lung Cancer
A therapy that works…so lets get
the most out of it that we can
Gary Middleton, University of Birmingham
1
Original Article
Activating Mutations in the Epidermal Growth
Factor Receptor Underlying Responsiveness of
Non–Small-Cell Lung Cancer to Gefitinib
Thomas J. Lynch, M.D., Daphne W. Bell, Ph.D., Raffaella Sordella, Ph.D., Sarada
Gurubhagavatula, M.D., Ross A. Okimoto, B.S., Brian W. Brannigan, B.A., Patricia L.
Harris, M.S., Sara M. Haserlat, B.A., Jeffrey G. Supko, Ph.D., Frank G. Haluska, M.D.,
Ph.D., David N. Louis, M.D., David C. Christiani, M.D., Jeff Settleman, Ph.D., and
Daniel A. Haber, M.D., Ph.D.
N Engl J Med
Volume 350(21):2129-2139
May 20, 2004
BRAF mutant NSCLC and CRC are both agressive diseases.
Gavin P G et al. Clin Cancer Res 2012;18:6531-6541
Antonio Marchetti et al. JCO 2011;29:3574-3579
However, dual BRAF/MEK blockade works in NSCLC but
doesn’t in CRC
Corcoran R. ASCO, 2014
Johnson B. ASCO, 2014
Tumor Responses to Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer.
Shaw AT et al. N Engl J Med
2014;371:1963-1971
Progression-free Survival.
Shaw AT et al. N Engl J Med 2014;371:1963-1971
Response to ALK Inhibition
Kwak EL et al. N Engl J Med 2010;363:1693-1703
But there is a problem….
7524 cases completed successfully for ALK testing between Nov
2011 and May 2015 (included
144 positive cases in total: 2%
Centre 1: 1/74 1.35%
Centre 2: 3/308 1%
Centre 3: 2/170 1.2%
Centre 4 4/253 1.6%
Centre 5: 3/356 0.85%
Centre 6: 7/434 1%
Centre 7: 7/401 1.75%
Centre 8: 7/200 3.5%
Centre 9: 6/361 1.7%
Centre 10: 6/275: 2.2%
Centre 11: 10/464: 2.1%
Phillipe Taniere, UHB.
National Lung Matrix Trial
A Multi-drug, genetic marker directed, non-comparative
multi-arm Phase II trial in NSCLC
9
Trial Design
•
•
•
•
•
•
A multi-arm non-randomised design, with treatment allocation
according to molecular phenotype
No ‘standard’ control arm
Each biomarker/drug arm will contain 30 + patients
Endpoints are principally objective response rate and duration of
response: progression free survival for some drugs
The study will be a national study open at all ECMCs
The study will be carried out under a single clinical trial protocol
and regulatory submission
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The biology of stratification
MATRIX Targets
11
12
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AZD5363 AZD4547 AZD2014 Palbociclib Crizotinib AZD9291
SUPPLEMENT NO.
A
SCC PIK3CA mutant
(11%)
SCC PIK3CA amplified
(40%)
SCC PTEN loss, not
mutated (40%)

SCC PTEN mutant (6%)

Ad - PI3kinase/AKT
deregulated (4.5%)

NSCLC harbouring AKT1
mutation

FGFR (A1) - NSCLC
harbouring FGFR
mutations (4.0% SCC and
<1% Adeno)
B
C
D
Selumetinib
+ docetaxel
E
MEDI
4736
NA



14
AZD5363
SUPPLEMENT NO.
TSC (B1) – NSCLC
harbouring TSC1/2
mutations (2.7% SCC and
0.5% adeno)
LKB1 (B2 and B3) –
NSCLC harbouring LKB1
mutations (Tier 1 - 4.6%
Ad and 1.6% SCC: Tier 2
2.4% and <1%)
SCC with proficient Rb
and p16 loss (C1)
AZD4547
A
AZD2014
B

Palbociclib Crizotinib
C
D
AZD9291 Selumetinib
+ Docetaxel
E
MEDI
4736
NA


(CDKN2A HD 29%)
CDK4 amplified NSCLC
(C2) (7% Ad and <1%
SCC)
CCND1 amplified NSCLC
(C3) (12% SCC, 5% Ad)
Adeno harbouring KRAS
mutations (C4) (25.8%)



15
AZD5363
SUPPLEMENT NO.
MET (D1) – Met amplified
NSCLC (4% SCC and Ad Rx effect))
ROS (D2) –NSCLC
harbouring ROS fusions
(Ad 1.7% and SCC <1%)
EGFR mutation and
T790M+
AZD4547
A
AZD2014
B
Palbociclib Crizotinib
C
AZD9291 selumetinib
+ Docetaxel
D

E
4736
NA


NF1 (E1) –SCC
harbouring NF1
mutations (5.8%)

NF1 (E2) – Ad harbouring
NF1 mutations (4.6%)

N-RAS (E3) – NSCLC
harbouring N-RAS
mutations (Ad 0.7%)

Biomarker negative
cohorts (F)
MEDI

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NLMT – rationale for single arm design
Crizotinib, EML4-ALK and ROS fusion as exemplars – the bona
fide targeted therapy
Option for biomarker-specificity testing in biomarker negative
patients
Allows discrete bio-marker testing
Based on strong pre-clinical data (and/or clinical data) and the
appropriate implementation of those findings
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NLMT – discrete biomarker/drug cohorts
AZD5363 AZD4547 AZD2014 Palbociclib Crizotini
b
SUPPLEMENT NO.
SCC PIK3CA mutant

SCC PIK3CA amplified

SCC PTEN loss, not
mutated
SCC PTEN mutant

Ad - PI3kinase/AKT
deregulated

NSCLC harbouring AKT1
mutation

FGFR (A1) - NSCLC
harbouring FGFR
mutations (4.0% SCC
and <1% Adeno)
A
B
C
D
AZD9291 Selumetinib
+ docetaxel
E
MEDI
4736
NA


18
Implementing the implications of the pre-clinical data
FGFR – amplifications and mutation types
Liao R G et al. Cancer Res 2013;73:5195-5205
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Implementing the implications of the pre-clinical data
5363 and Palbo molecular exclusion rules
These will change with different drugs
PIK3CA, PTEN and AKT (5363) – no KRAS mutation
Davies BR et al. Mol Cancer Ther 2012;11:873-887
KRAS mutation (Palbo) – no activation of PI3K/Akt/MTOR
signaling – genetically simple models and the re-induction of
senescence with cdk4 knockdown
Puyol M et al. Cancer Cell, 2010; 18: 63 – 73
Kennedy AL et al Mol Cell. Apr 8, 2011; 42(1): 36–49
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Randomised precision medicine trials
in lung cancer
SAFIR 02 and LUNG-MAP
Assessing the benefits of the novel therapy rather
than potential prognostic effects of the biomarker
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SAFIR 02 - objectives
PRIMARY OBJECTIVE :
To evaluate whether treatment with targeted agents guided by high
throughput molecular analyses (CGH array, next generation sequencing)
improves progression-free survival as compared to standard maintenance
therapy in patients with metastatic NSCLC.
SECONDARY OBJECTIVES :
To explore the efficacy (response rate, progression-free survival, overall
survival) of the individual targeted agents
To correlate molecular mechanisms in patients with the efficacy endpoints
(response rate,progression-free and overall survival)
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SAFIR 02, MATRIX and LUNG-MAP – Gene blocks in
common
Akt 1-3, PIK3CA, PTEN, STK11, TSC1/2 (PIK3R1, mTOR)
FGFR 1-4
NRAS, KRAS, NF1 (HRAS, MAP2K1, MAP2K4, MAP3K1)
CDKN2A loss, CDK4 amplification, CCND1 amplification
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Concluding remarks – the importance of sustainability and a
unique opportunity to collaborate
“Therefore, there is maybe a place for, at least, a European
project, supported by the EU, setting up a global platform with
adequate resources (informatics, mathematics, statisticians,
etc) able to fully combined and interpreted the data, taking into
account differences in design and drugs, but aiming to propose
a unique interpretation of generated knowledge as soon as it
becomes available?”
Fabrice Barlesi
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