Strategies to overcome resistance in NSCLC with driver mutations

1
Strategies to overcome resistance in NSCLCwith
driver mutations

• Federico Cappuzzo
• Istituto Toscano Tumori
• Ospedale Civile
• Livorno-Italy

2
First-line therapy for metastatic NSCLC in 2012
Stratification for EGFR, ALK and histology
EGFR mutated
EGFR WT non-squamous
EGFR WT squamous
ALK
EGFR-TKI
Platinum pemetrexed /- bevacizumab
Platinum-based doublet
Crizotinib
3
Mut NSCLC EGFR-TKI Acquired Resistance
Baseline
Tumor regression (RR up to 90)
Progression (median 9 months)
Disease Flare Hospitalization and/or death
attributable to disease progression after
discontinuation of gefitinib or erlotinib and
before initiation of study drug
4
Risk of disease flare in EGFR mut NSCLC with
acquired resistance Chaft J et al. (O 19.05)
Characteristic Total patients61 N ( or range)
Male sex N () 13 (21)
Age at diagnosis (years) Median (range) 58 (26-78)
EGFR mutation N () Exon 19 deletion Exon 18 G719A Exon 21 L858R 41 (67) 1 (2) 19 (31)
Time on gefitinib or erlotinib (months) Median (range) 19 (7-78)
Age in years - Median (Range) 61 (27-80)
Karnofsky Performance Status () 90 80 70 13 (21) 37 (61) 11 (18)

• 14 of 61 patients (23, 95 CI 14-35) had a
  disease flare (hospitalization or death)
• Flare no flare group same 30 day pretrial
  hospitalization rate
• Median time from last TKI to flare was 8 days
  (range 3-21 days)
• 3 patients went on to trial treatment

5
Changes in Tumor Diameter (RECIST) After
Discontinuation and Re-introduction of EGFR TKI
50
20
Change from baseline
0
-30
EGFR TKI
stop
re-start
3 weeks
3 weeks
Riely et al, CCR 2007
6
Mechanisms responsible for EGFR-TKI resistance
Sequist et al, Science Transl Med 2011
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EGFR-TKI resistance
A
B
8
T790M Mutation causes drug resistance by
increasing affinity for ATP
Yun PNAS 2008
9
T790M mutations in EGFR-TKI naive NSCLC

• Present in up to 50 of NSCLC with EGFR-TKI
  acquired resistance
• Rare event in EGFR-TKI naive NSCLC (lt3) using
  low sensitive methods
• Detected in up to 40 of EGFR-TKI naive patients
  using high sensitive methods

10
Presence of T790M mutation predicts poor outcome
to EGFR-TKI
Su et al. JCO 2012 Rosell et al. Clin Cancer Res
2011
11
T790M mutation and acquired resistance to
gefitinib therapy
Irreversible EGFR-TKI are still effective
Kobayashi et al. NEJM, 352, 786-792, 2005
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Afatinib Dual irreversible EGFR-HER2 inhibitor

• Orally bioavailable, small molecule
• tyrosine kinase inhibitor (TKI)
• Designed to irreversibly bind to the
• ATP binding pocket of EGFR and
• HER2
• Highly specific for EGFR and HER2
• EGFR IC50 0.50 nM
• HER2 IC50 14 nM

Afatinib
EGFR or HER2 ATP binding pocket

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Afatinib active against resistance mutation

• BIBW2992 but not erlotinib is active against
  cells expressing T790M EGFR mutation

NCI-H1975
Li et al. Oncogene. 20082747024711
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Afatinib cetuximab as the best option in
presence of EGFR T790M mutation
Regales et al. JCI 2009
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Afatinib cetuximab for metastatic NSCLC Study
Design
Phase Ib, open-label, multicenter trial in the US
and The Netherlands
1EGFR G719X, exon 19 deletion, L858R, L861Q
2Progression of disease (Response Evaluation
Criteria in Solid Tumors v1.1) on continuous
treatment with erlotinib or gefitinib within the
last 30 days 3Amended from original 14-day
interval 4Acquisition of tumor tissue after the
emergence of acquired resistance was
mandated. i.v.intravenous MTDmaximum tolerated
dose NSCLCnon-small cell lung cancer SDstable
disease.
16
Tumor Regression by T790M Mutation Statusat
Recommended Dose
39 patients with proven EGFR T790M mutation
confirmed RR31
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Acquired resistance to EGFR-TKIs

• Acquired drug resistance is almost inevitable
  (10 months)

• About 30 of resistant mechanisms are unknown.

Mitsudomi, et al. Cancer Sci., 2007
18
Resistant mechanisms in 33 tumors from 6 patients
with EGFR-TKI acquired resistance
19
Inhibition of both EGFR and MET is necessary for
growth inhibition of HCC827 GR cells
125
Gefitinib
PHA665752
100
Gefitinib/PHA665752
75
of control
50
25
0
0.01
0.1
1
10
0
µ
Drug Concentration (
M)

• Irreversible EGFR inhibitors have no effect on
  HCC827 GR
• MET shRNA restores sensitivity to gefitinib

Engelman et al. Science 2007
20
EML4-ALK fusion oncogene in NSCLC

• 37 of patients with NSCLC have an EML4-ALK gene
  fusion1
• detection test available
• mainly seen in adenocarcinomas(mutually
  exclusive with EGFR mutations)2
• phase I/II trial of crizotinib, oral c-MET and
  ALK inhibitor in selected patients DCR 703
• further potential for personalising therapy in
  NSCLC

1. Koivunen, et al. Clin Cancer Res 2008 2. Shaw,
et al. ASCO 2009 3. Bang, et al. ASCO 2010
21
ALK secondary mutations and crizotinib resistance
Sasaki et al. Cancer Res 2011
22
New ALK inhibitors TAE684 and AP26113 overcome
crizotinib resistance in H3122 CR cell line
Katayama et al. PNAS 2011
23
Cell lines with ALK secondary mutation and ALK
and EGFR co-dependency
Sasaki et al. Cancer Res 2011
24
ALK amplification or ALK FISH loss as mechanisms
of crizotinib resistance
Katayama et al. PNAS 2011, Katayama et al Science
Transl Med 2012, Doebele et al. Clin Cancer Res
2012
25
Several mechanisms responsible for crizotinib
resistance clinical implications
Doebele et al. Clin Cancer Res 2012
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Conclusions

• Different mechanisms are responsible for acquired
  resistance to novel targeted therapies
• So far no proven efficacy of irreversible
  EGFR-TKIs in NSCLC with acquired resistance to
  reversible agents
• No clinically available strategies for crizotinib
  resistant patients
• New drugs and new strategies are under
  investigation