1. Acquired EGFR TKI resistance: What are the current therapeutic strategies?
Gregory J. Riely

2. Erlotinib Demonstrates Efficacy in EGFR Mutant Lung Cancers
Rosell et al, Lancet Oncol 2012

3. Erlotinib is Better Than Chemotherapy in EGFR Mutant Lung Cancers
Rosell et al, Lancet Oncol 2012

4. Afatinib is Better Than Cisplatin/Pemetrexed in Patients with EGFR Mutant Cancers
Yang JC, et al.
Sequist et al J Clin Oncol 2013

5. How does acquired resistance occur?

6. EGFR T790M is a Mechanism of Acquired Resistance to EGFR TKI
Pao et al, PLoS Medicine 2005

7. Observed Mechanisms of Acquired Resistance to EGFR TKI
Yu et al, Clinical Cancer Research 2013

8. How do we manage acquired resistance?

9. Riely et al Clin Cancer Res. 2007
Disease Flare
Last day of TKI
Off EGFR TKI
Resumed TKI
Day 0
Day 21
Day 42
Riely et al Clin Cancer Res. 2007

10. Chaft et al Clinical Cancer Research 2011
Review of 61 patients with EGFR-mutant lung cancer who discontinued erlotinib as part of initiation of clinical trials evaluating other drugs
14/61 (23%) had hospitalization or death in a median of 7 days
No clear predictors of patients likely to have flare
Conclusion: if you plan to discontinue erlotinib, do so only after or just before initiating alternative therapy
Chaft et al Clinical Cancer Research 2011

12. The counterpoint (retrospective)…
Small, Retrospective analysis of patients with acquired resistance to erlotinib
Single-agent
Platinum-doublet
Comparing: combined erlotinib and chemotherapy vs chemotherapy alone
- Improved response rate with combination
- No differerence in OS or PFS, though small numbers lead to limited power
Goldberg et al, Oncologist 2013

13. Prospectively Evaluating the Value of Continued Erlotinib
Chemotherapy (docetaxel or pemetrexed)
Patients
Stage IIIB /IV NSCLC
Erlotinib for > 12 weeks with stable disease
ECOG PS 0-2
No more than one prior cytotoxic regimen
N=39
Erlotinib + Chemotherapy (docetaxel or pemetrexed)
N=39
Halmos et al, ASCO 2013

14. Prospectively Evaluating the Value of Continued Erlotinib
Chemotherapy (docetaxel or pemetrexed)
Patients
Stage IIIB /IV NSCLC
Erlotinib for > 12 weeks with stable disease
ECOG PS 0-2
No more than one prior cytotoxic regimen X
N=39 24
Erlotinib + Chemotherapy (docetaxel or pemetrexed) X
N=39 22
Halmos et al, ASCO 2013

15. Prospectively Evaluating the Value of Continued Erlotinib
Chemotherapy
Chemotherapy + Erlotinib
P value
Response Rate
13%
23%
0.379
Median PFS
5 months
0.56
Median OS
19 months
15 months
0.295
Halmos et al, ASCO 2013

17. Can local therapy play a role?

18. “Local Therapy” in Acquired Resistance to Erlotinib
Procedures Performed
Total 18
Lung 15
Radiofrequency ablation 2
Radiation therapy
Lobectomy 7
Wedge resection 1
Pneumonectomy 3
Lymph node (SC)
Adrenal gland
Adrenalectomy
Most surgical, most within lungs
17/18 pts had oligometastatic disease (<5 sites)
15/18 had local therapy within 4mo of radiographic progression
3/18 had post op complications (hospitalization 10-1month), grade 2,3,4
15/18 restarted TKI within one month. 3/18 did not restart 2/2 NED after local therapy
Yu et al JTO 2013

19. “Local Therapy” in Acquired Resistance to Erlotinib
Time to Progression
The median time to progression after local therapy was 10 months (95% CI: 2-27).
The median time from local therapy until a change in systemic therapy was 22 months (95%CI: ).
The median overall survival from local therapy was 41 months (95% CI: 26-not reached).
% Progression-free
Time (months)
Overall Survival
-outcomes of interest included TTP, time until change in systemic therapy (clinical trial and/or chemo), overall survival from LT
-5.4mo PFS with chemo (carbo/taxol)
% Survival
Yu et al JTO 2013
Time (months)

20. Local therapy - Conclusions
In selected patients, local therapy can lead to extended progression free intervals
Outcomes are best in the setting of oligometastatic disease
Continuation of EGFR TKI may be important
Continuation of EGFR TKI is important as proven by radiologic progression after a median of 10mo, but no change in systemic therapy was required until a median of 22 mo
Plans for prospective evaluation are ongoing. A key factor will be identifying appropriate pts- extent of disease, disease velocity, molecular/clinical markers.

21. What about new therapies?

22. Observed Mechanisms of Acquired Resistance to EGFR TKI
Yu et al, Clinical Cancer Research 2013

23. Afatinib IC50 EGFR [nM] 0.5 HER2 14 c-Met >10000 VEGFR wild type
L858R
H3255
L858R+T790M
NCI1975
Target
Binding mode
Afatinib 60
0.7 99
EGFR/HER2
Irreversible
Gefitinib
157 5
>4000
EGFR
Reversible
Erlotinib
110 40
Lapatinib
534 63

24. Afatinib in Acquired Resistance Lux Lung 1
Primary endpoint
Overall survival
Secondary endpoints
progression-free survival according to RECIST
objective response rate
Miller et al Lancet Oncol 2012

25. Afatinib in Acquired Resistance Overall Survival
Miller et al Lancet Oncol 2012

26. Afatinib in Acquired Resistance Progression-free survival
Miller et al Lancet Oncol 2012

27. Afatinib in Acquired Resistance OS in patients who had no subsequent therapy
Miller et al Lancet Oncol 2012

28. Observed Mechanisms of Acquired Resistance to EGFR TKI
Yu et al, Clinical Cancer Research 2013

29. Dual EGFR blockade with Erlotinib and Cetuximab
Janjigian Y Y et al. Clin Cancer Res 2011;17:

30. Dual EGFR blockade with Erlotinib and Cetuximab
Janjigian Y Y et al. Clin Cancer Res 2011;17:

31. Effect of BIBW-2992 + Cetuximab in EGFR T790M Tumor-Bearing Mice
Cetux / BIBW
Pretreatment
H&E H
C/L+T
Regales et al ‘09

32. Cetuximab + Afatinib
Phase Ib, open-label, multicentre trial in the USA and The Netherlands
Primary endpoints: RECIST 1.1 response and PFS, with imaging at Weeks 4, 8 and 12, and every 8 weeks thereafter
Key eligibility criteria:
Inclusion
Pathologically confirmed NSCLC
Presence of EGFR drug-sensitizing mutations or RECIST response, or SD ≥6 months on prior EGFR TKI
Gefitinib/erlotinib as last systemic treatment
Disease progression on treatment with erlotinib or gefitinib within 30 days
Biopsy (available) at time of acquired resistance
ECOG performance status 0–2
Exclusion
Prior treatment with EGFR-targeting antibodies
Symptomatic brain metastases or disease progression only in CNS
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; ECOG = Eastern Cooperative Oncology Group; CNS = central nervous system.

33. Afatinib + Cetuximab at MTD: Responses by T790M mutation
EGFR wt
Uninformative for T790M 50 40 30 20 10
–10
–20
–30
–40
–50
–60
–70
–80
–90
–100
–110
Maximum percentage decrease from baseline (%)
Overall median PFS 4.7 mos
100
Patient index sorted by maximum % decrease
Janjigian et al ESMO ‘12

34. Cetuximab and Afatinib
Proven high response rate in EGFR mutant NSCLC with acquired resistance
The combination is not FDA-approved in this setting
Randomized trials to evaluate this combination have not begun

35. What’s next?

36. Soria et al, WCLC 2013
Ranson et al, WCLC 2013

37. Management of EGFR TKI Acquired Resistance
Erlotinib/Afatinib should be continued at least until initiation of next line of therapy
Local therapy should be considered
Afatinib/Cetuximab combination has significant activity and will be evaluated in randomized trials
Mutation-specific (“3rd Generation”) EGFR TKI appear promising