1. Mechanisms of resistance to EGFR TKIs and related treatment strategies
Rafal Dziadziuszko
Medical University of Gdańsk, Poland
16th European Congress „Perspectives in Lung Cancer”
Torino, 06 – 07 March 2014

2. Disclosure Astra-Zeneca Roche Boehringer-Ingelheim Pfizer
Clovis Oncology

3. Currently used EGFR TKIs
Gefitinib and erlotinib (reversible, 1st generation EGFR TKIs)
Afatinib and dacomitinib* (irreversible, 2nd generation EGFR TKIs)
CO-1686* and AZD9291* (Irreversible, 3rd generation mutation-specific EGFR TKIs)
* Investigational

4. When should we exepect relapse?

5. Progression-free survival
First-line trials of EGFR tyrosine kinase inhibitors vs. chemotherapy in pts with EGFR mutations
EGFR
TKI
Comparator N
(Total)
EGFR mut-positive
Response rate
(%)
Progression-free survival
(months)
IPASS1,2
Gefitinib
Carboplatin/ paclitaxel
1217
261
71 vs 47
p=0.0001
9.5 vs 6.3
HR 0.48 (0.36‒0.64)
First-SIGNAL3
Gemcitabine/ cisplatin
309 42
85 vs 38
p=0.002
8.0 vs 6.3
HR 0.54 (0.27–1.10)
NEJ0024
224
74 vs 31
p<0.001
10.8 vs 5.4
HR 0.30 (0.22–0.41)
WJTOG-34055
Cisplatin/ docetaxel
172
62 vs 32
p<0.0001
9.2 vs 6.3
HR 0.5 (0.34–0.71)
OPTIMAL6
Erlotinib
Gemcitabine/ carboplatin
154
83 vs 36
13.1 vs 4.6
HR 0.16 (0.10–0.26)
EURTAC7
Chemotherapy
173
58 vs 15
9.7 vs 5.2
HR 0.37 (0.25–0.54)
LUX-LUNG 38
Afatinib
Pemetrexed/ cisplatin
345
56 vs 23 p<0.0001
11.1 vs 6.9 HR 0.58 (0.43–0.78)
LUX-LUNG 69
364
67 vs 23 p<0.0001
11.0 vs 5.6 HR 0.28 (0.20–0.39)
1. Mok T et al., N Engl J Med 2009;361:947–957; 2. Fukuoka M et al., J Clin Oncol 2011; 29:2866‒2874; 3. Han J-Y et al., J Clin Oncol 2012; 30:1122‒128; 4. Maemondo M et al., N Engl J Med 2010;362:2380–2388; 5. Mitsudomi T et al., Lancet Oncol 2010;:121–128; 6. Zhou C et al., Lancet Oncol 2011;12:735‒742; 7. Rosell R et al., Lancet Oncol 2012;13:239–246; 8. Yang JC et al., J Clin Oncol 2012;30 (Suppl. 16):LBA 7500, Wu Y et al., Lancet 2014; 15:213. NR = not reported

6. PFS in LUX-Lung 3 and 6 trials
Afatinib
PFS in LUX-Lung 3 and 6 trials
LUX-Lung 31 (n=345)
Afatinib vs Pem/Cis
LUX-Lung 62 (n=364)
Afatinib vs Gem/Cis
Median PFS
11.1 vs 6.9
11.0 vs 5.6
HR for PFS
0.58, P<0.001
0.28, P<0.0001
12-month PFS3
47% vs 22%
47% vs 2%
1.0
47% 2%
47%
22%
0.8
0.6
Afatinib LUX-Lung 6
Gem/cis LUX-Lung 6
PFS (probability)
0.4
Afatinib LUX-Lung 3
Pem/cis LUX-Lung 3
0.2
0.0 3 6 9 12 15 18 21 24 27
Months
Number at risk: Afatinib (LL3) Pem/cis (LL3)
Afatinib (LL6)
Gem/cis (LL6)
1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213.

7. NSCLC M+: EGFR-TKI acquired resistance
Baseline
Tumor regression
Progression
(median 10 months)
Disease Flare: ~25% of patients: Hospitalization and/or death attributable to disease progression after discontinuation of gefitinib or erlotinib and before initiation of study drug
Slide courtesy Prof. F. Cappuzzo

8. What are acquired resistance mechanisms to EGFR TKIs?

9. Aqcuired resistance Pharmacological Biological Compliance
Absorption
Distribution
Metabolism
Excretion
Biological
Alterations in drug target
Bypass signaling
Phenotypic changes
Downstream signaling

10. Absorption and metabolism - examples
Administration of proton-pump inhibitor omeprazole with erlotinib decreases erlotinib exposure (AUC) and maximal concentration (Cmax) by 46% and 61%, respectively.
Ketoconazol administration with erlotinib increases erlotinib exposure by 86% through inhibition of CYP3A4
Smoking leads to two-fold lower steady-state concentrations of erlotinib through induction of CYPA1 and CYPA2

11. Drug distribution – CNS as a sanctuary site
Mean CSF CSF penetration concentration
Gefitinib 3.7ng/mL 1.13% Erlotinib 28.7ng/mL 2.77%
Up to 20% of patients develop symptomatic CNS progression while on gefitinib or erlotinib
Togashi Y et al., Cancer Chemother Pharmacol 2012 11

12. Comprehensive review of EGFR TKI pharmacology

13. Biological mechanisms of resistance

14. Biological mechanisms of resistance
Alterations in drug target
Bypass signaling
Phenotypic changes
Downstream signaling
Camidge, D. R. et al. (2014) Acquired resistance to TKIs in solid tumours: learning from lung cancer
Nat. Rev. Clin. Oncol. doi: /nrclinonc

15. Biological mechanisms of resistance
- Implication for subsequent therapies
- Alterations in drug target
- Bypass signaling
- Phenotypic changes
- Downstream signaling
Yu, H. et al. Clin Cancer Res. 20: 5898, 2014

16. Biological mechanisms of resistance
T790M resistance mutations (~40-60%)
EGFR T790M+ cells are usually present as a minor clone in the initial tumor specimen
Clinical progression is related to clonal selection and outgrowth of EGFR T790M+ population of cells
Substitution of a bulky methionine residue for threonine at gatekeeper 790 position is believed to cause steric interference with binding of first-generation TKIs to ATP-binding pocket of EGFR tyrosine kinase.

17. Prognostic significance of T790M resistance mutations at progression on gefitinib or erlotinib – PFS and OS
Oxnard G et al., Clin Cancer Res 17: 1616; 2011

18. Prognostic significance of T790M resistance mutations at progression on gefitinib or erlotinib – overall survival
Hata A et al., Cancer 119: 4325; 2013

19. Biological mechanisms of resistance MET amplification (~5 - 25%)
MET encodes hepatocyte frowth factor (HGF) receptor
Amplification of MET is observed in ~ 5 – 25% of EGFR M+ tumors with acquired resistance to gefitinib or erlotinib
Activation of MET through enhanced ligand stimulation appears to have similar effect

20. Biological mechanisms of resistance
MET amplification
Engelman J et al., Science 2007; /science

21. Biological mechanisms of resistance
MET amplification
Suda et al., Clin Cancer Res. 16:5489; 2010

22. Biological mechanisms of resistance
HGF plasma levels
Tanaka H et al., Int J Cancer 129:1410; 2011

23. Biological mechanisms of resistance HER2 amplification (~8-13%)
Takezawa K et al., Cancer Discov. 2: 922; 2012

24. Biological mechanisms of resistance Transformation to SCLC (~2-14%)
Observed in absence of SCLC component in pre-treatment biopsy
SCLC at progression on EGFR TKI retained initial EGFR mutations and were responsive to platinum-etoposide
Exact molecular mechanism unknown (Myc amplification?)
Sequist LV et al., Sci Transl Med. 2011;3:75ra26

25. Biological mechanisms of resistance
Epithelial-to mesenchymal (EMT) transition (<10%?)
Typical phenotype: loss of E-cadherin and beta-catenin, gain of vimentin and N-cadherin as evaluated by immunohistochemistry
Postulated molecular mechanisms: NOTCH-1 upregulation, TGF-beta overexpression, MET or AXL activation
Sequist LV et al., Sci Transl Med. 2011;3:75ra26; Cortot and Janne, Eur Resp Rev 2013; 22:565

26. Biological mechanisms of resistance to afatinib
Preclinical and clinical data are scarce but indicate that T790M resistance mutation is also a resistance mechanism for afatinib
Other reports suggest transition to high-grade neuroendocrine histology
Kim Y et al. Mol Cancer Ther 2012;11:784

27. How accurate is clinical detection of mechanisms of resistance?

28. Accuracy of T790M status assessment
at progression
In 169 patients with acquired resistance to 1st and 2nd generation EGFR TKIs, 60 patients underwent more than 1 biopsy at progression
T790M mutation status was discordant in 15/60 (=25%) of these patients
Piotrowska Z, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology Abstract 11

29. EGFR T790M mutation detection in plasma of lung cancer patients

30. Plasma EGFR mutation data from a phase I/II trial of rociletinib (CO-1686)
EGFR mutation detection by NSCLC disease classification (n = 73)
Dziadziuszko R, Karlovich C et al., AACR 2014 abstract 5587

31. Best Overall Response: SD
Plasma EGFR mutation data from a phase I/II trial of rociletinib (CO-1686)
Patient A (600 mg QD)
Best Overall Response: SD
Dziadziuszko R, Karlovich C et al., AACR 2014 abstract 5587

32. Best Overall Response: SD
Plasma EGFR mutation data from a phase I/II trial of rociletinib (CO-1686)
Patient B (400 mg TID)
Best Overall Response: SD
Dziadziuszko R, Karlovich C et al., AACR 2014 abstract 5587

33. Take-home messages
Acquired resistance to EGFR TKIs develops through pharmacological and biological mechanisms
Understanding of clinical pharmacology (ADME) of EGFR TKIs is essential for practictioners
Most common mechanisms of biological resistance include T790M gatekeeper mutation, MET and HER2 amplification, SCLC and EMT transformation, and PIK3CA mutations.
Different mechanisms may be present in different metastatic sites
Plasma EGFR mutation detection and monitoring, including T790M, is close to clinical application

34. Take-home messages
Diehl F. Nat Med 14:985; 2008