1. EGFR-Mutated Advanced NSCLC
The Coming Paradigm Shift
Title Slide Layout
Faculty
Suresh S. Ramalingam, MD
Professor of Hematology/Oncology
Director, Lung Cancer Program
Winship Cancer Institute
Emory University
Atlanta, Georgia

2. Program Goals
Outline the challenges with resistance to first- generation EGFR TKIs in patients with EGFR-mutated advanced NSCLC
Identify the rationale for rebiopsy in patients with known EFGR-mutated advanced NSCLC
Evaluate the clinical efficacy and safety of investigational third-generation EGFR TKIs

3. Program Outline EGFR inhibition in advanced NSCLC
Resistance mediated by the EGFR T790M mutation
Promising therapeutic agents to treat EGFR- mutated NSCLC with acquired resistance to first-line EGFR TKIs
Update on ongoing clinical trials relevant to the setting of acquired resistance to first-line EGFR TKIs

4. Incidence of Driver Mutations in Advanced NSCLC Lung Cancer Mutation Consortium
KRAS
25%
EGFR (sensitizing)
17%
ALK 8%
EGFR (other) 4%
Mutation in > 1 gene 3%
HER2
BRAF 2%
PI3KCA 1%
MET
NRAS
MEK1
<1%
No oncogenic driver detected
36%
Kris MG, et al. JAMA. 2014;311: [1]

5. Molecularly Targeted TKI Therapy in Advanced NSCLC
> 10 years since the presence of EGFR mutations in advanced NSCLC shown to correlate with clinical response to EGFR TKI therapy
Lynch TJ, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med a
Paez JG, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004b
a. Lynch TJ, et al. N Engl J Med. 2004;350: [3]; Paez JG, et al. Science. 2004;304: [2]

6. EGFR Mutations and EGFR TKI Therapy in Advanced NSCLC
Approximate distribution and frequency of EGFR mutations in advanced NSCLCa
In the first-line setting, erlotinib (first-generation EGFR TKI) and afatinib (second-generation EGFR TKI) are FDA approved for use in patients with advanced NSCLC with tumors characterized by EGFR-sensitizing mutationsb,c
EGFR exon 19 deletion
EGFR exon 21 (L858R) substitution mutations
a. Mitsudomi T, et al. Cancer Sci. 2007;98: [11]; b. Tarceva® PI 2012[15]; c. Gilotrif® PI 2014.[16]

7. N (EGFR- mutation-positive)
First-Line EGFR TKI Therapy vs Platinum-Doublet Chemotherapy in EGFR-Mutated Advanced NSCLC: PFS
Study
(EGFR TKI)
N (EGFR- mutation-positive)
ORR (EGFR TKI)
Median PFS
(EGFR TKI vs chemotherapy)
Median OS
IPASSa (gefitinib*)
261
71.7%
9.5 vs 6.3 mo; HR = 0.48 ( ); P <.001
WJTOG 3405b (gefitinib)
177
73.7%
9.2 vs 6.3 mo; HR = ( ); P <.0001
NEJ002c
(gefitinib)
230
62%
10.8 vs 5.4 mo; HR = 0.30 ( ); P <.001
30.5 vs 23.6 mo; P =NS
OPTIMALd
(erlotinib)
165
13.1 vs 4.6 mo; HR = 0.16 ( ); P <.0001
19.3 v 19.5; P = .87
EURTACe
153
58%
9.7 vs 5.2 mo; HR = 0.37 ( ); P <.0001
22.9 vs 18.8 mo; P =.42
*First-line EGFR therapy licensed for use in some countries outside the United States.
a. Mok TS, et al. N Engl J Med. 2009;361: [4]; b. Mitsudomi T, et al. Lancet Oncol. 2010;11: [6]; c. Maemondo M, et al. N Engl J Med. 2010;362: [5]; d. Zhou C, et al. Lancet Oncol. 2011;12: [7]; e. Rosell R, et al. Lancet Oncol. 2012;13: [8]

8. Treatment until disease progression
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Study Design
Afatinib (oral) 40 mg/d
n = 230
Patients with treatment-naïve, stage IIIB/IV lung adenocarcinoma
EGFR-activating mutation
ECOG PS = 0,1
RANDOM I ZE
Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d, up to 6 cycles
n = 115
Treatment until disease progression
2:1
Stratification factors include
EGFR mutation (exon 19 del, L858R, other)
Race (Asian, non-Asian)
Primary end point
PFS
Secondary end points include
ORR; DCR; DoR; OS; PROs; safety; PK
Sequist LV, et al. J Clin Oncol. 2013;31: [10]

9. First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC PFS
Cis/Pem
PFS event, n (%)
for overall population; n = 230 [afatinib]; n = 115 [chemo]
152 (66)
69 (60)
Median PFS, mo for overall population
11.1
6.9
HR (95% CI) for overall population
0.58 ( ) P = .0004
for patients with EGFR exon 19 del or L858R mutation only; n = 204 [afatinib]; n = 104 [chemo]
130 (64)
61 (59)
Median PFS, mo for patients with EGFR exon 19 del or L858R mutation only
13.6
HR (95% CI) for patients with EGFR exon 19 del or L858R mutation only
0.47 ( )
P = .001
Sequist LV, et al. J Clin Oncol. 2013;31: [10]

10. First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Safety
Selected Treatment-Related AEs (%)
Afatinib
(n = 229)
Cis/Pem
(n = 111)
All Grades ≥
Grade 3
Diarrhea
95.2%
14.4%
15.3% 0%
Rash/acne
89.1%
16.2%
6.3%
Stomatitis/mucositis
72.1%
8.7%
0.9%
Nausea
17.9%
65.8%
3.6%
Sequist LV, et al. J Clin Oncol. 2013;31: [10]

11. Treatment until disease progression
First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLC Study Design
Patients with chemotherapy-naïve stage III/IV or postoperative recurrent NSCLC
Activating mutations (exon del 19, L858R)
ECOG PS = 0,1
No brain metastases
Erlotinib (oral) 150 mg/d once daily
Bevacizumab 15 mg/kg IV every 3 wk
n = 77
RANDOM I ZE
Treatment until disease progression
1:1
Erlotinib (oral) 150 mg/d once daily
n = 77
Primary end point
PFS
Secondary end points include:
OS, tumor response, QoL, safety
Stratification factors include
EGFR mutation type
Seto T, et al. Lancet Oncol. 2014;15: [23]

12. First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLC PFS and Safety
Erlotinib + Bev (n = 77)
Erlotinib (n = 75)
Median PFS, mo
16.0
9.7
HR (95% CI)
0.54 (95% CI, )
P value*
.0015
*Log-rank test, 2-sided.
Most Common Grade 3 AEs
Erlotinib + Bev (n = 77)
Erlotinib (n = 75)
Rash
25%
19%
Hypertension
60%
10%
Proteinuria 8% 0%
Serious AEs
Occurred with the same frequency (~25%) in both arms.
Seto T, et al. Lancet Oncol. 2014;15: [23]

13. Approximate Frequency, %
Some Characteristics of EGFR-Mutated Advanced NSCLC With Acquired Resistance to First-Line EGFR TKI
Molecular Alteration
Approximate Frequency, %
EGFR Target Alteration (~60%)
T790M alone ~
T790M with EGFR amplification
~10
Other EGFR point mutations
1 - 2
Bypass Tracts (~20%)
HER2 amplification
~8 - 13
SCLC alone ~6
SCLC with PI3K ~4
MET amplification ~5
PI3KCA
~1 - 2
BRAF ~1
No Acquired Resistance Mechanism Identified (~15% to 20%)
Camidge DR, et al. Nat Rev Clin Oncol. 2014;11: [26]

14. EGFR T790M Mutation-Positive Advanced NSCLC in Acquired Resistance
EGFR T790M-mutated advanced NSCLC
Occurs on exon 20 and is found in > 50% of patients with acquired resistance to an EGFR TKI
Increases relative affinity of mutated EGFR for ATP, and may also sterically hinder binding of erlotinib
More likely to show progression in lungs/pleura
Less commonly detected in CNS
Patients with disease characterized by the EGFR T790M mutation may have a better prognosis than patients with EGFR T790M mutation-negative disease
Oxnard GR, et al. Clin Cancer Res. 2011;17: [27]

15. Rationale for Rebiopsy Following Disease Progression on First-Line EGFR TKI
To determine whether transformation to SCLC has occurred
To evaluate for the presence of the EGFR T790M mutation and identify appropriate clinical trials when available
To evaluate for the presence of other actionable mutations for which a clinical trial may be available
A rebiopsy is critically important for optimal assessment and treatment selection of patients with disease progression on first-line EGFR TKI therapy

16. until disease progression*
IMPRESS Study Design
Treatment
until disease progression*
RANDOM I ZE
Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d (up to 6 cycles) +
Gefitinib (oral) 250 mg/d
n = 133
Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d up to 6 cycles +
Placebo (oral) 250 mg
n = 132
Patients with chemotherapy-naïve advanced NSCLC
EGFR-activating mutation
Achieved CR/PR ≥ 4 mo or SD > 6 mo with first-line gefitinib
Disease progression ≤ 4 weeks prior to study randomization
1:1
Primary end point
PFS
Secondary end points include
ORR; OS; DCR; safety; health-related QoL
*Tumor assessments performed ≤ 4 weeks before the start of treatment (baseline), and every 6 weeks (±7 days) after randomization until progressive disease.
Mok TSK, et al. ESMO Abstract LBA2_PR.[31]

17. IMPRESS ORR and DCR ORR, % DCR, % n = 133 n = 132 n = 133 n = 132
OR (95% CI) = 0.92 ( );
P = .760
OR (95% CI) = 1.39 (0.74, 2.62);
P = .308
ORR, %
DCR, %
There was no statistical difference in ORR or DCR between treatment arms.
n = 133
n = 132
n = 133
n = 132
Odds ratio >1 favours gefitinib
Odds ratio and p-value from logistic regression with covariates CI, confidence interval
Mok TSK, et al. ESMO Abstract LBA2_PR.[31]

18. IMPRESS PFS Gefitinib (n = 133) Placebo (n = 132) PFS event, n (%)
98 (73.7)
107 (81.1)
Median PFS, mo
5.4
HR (95% CI)
0.86 ( )
P value
.273
OS: 14.8 vs 17.2 mo, in favor of chemotherapy arm
(P = .029, although OS data are not yet mature)
Mok TSK, et al. ESMO Abstract LBA2_PR.[31]

19. Third-Generation EGFR TKIs
Orally administered agents that block T790M-mutated EGFR and EGFR characterized by the original sensitizing mutation (eg, exon 19 deletion; L858R)*
AZD9291
CO-1686 (rociletinib)
*HM61713 is another third-generation EGFR TKI in early-phase development.[44]

20. AURA Study Design
Phase 1, open-label, multicenter study of AZD9291 in patients with advanced NSCLC and progression on prior therapy with an EGFR TKIa,b
Rolling 6 study design allowing for enrollment of 2 to 6 patients concurrently on to a dose levelc
5 doses evaluated: 20 mg; 40 mg; 80 mg; 160 mg; 240 mg
Dose administered once daily
Dose escalation not preselected by EGFR T790M mutation status
Expansion study includes only patients with EGFR T790M mutation-positive disease according to central laboratory testing
a. Yang J C-H, et al. J Clin Oncol. 2014;32. Abstract 8004[22]; b. Yang JC, et al. ESMO Abstract 449PD[36]; c. Skolnik JM, et al. Clin Oncol. 2008;26: [45]
ESMO 2014; Poster Discussion, Developmental therapeutics; Sunday, September 28, 2014
*cobas® EGFR Mutation Test (Roche Molecular Systems)

21. AURA Safety Patients With an AE, % 20 mg N = 21 40 mg N = 58 80 mg
Total
N = 253
Any AE, drug-related
67%
66%
79%
94%
100%
80%
Any AE Grade ≥ 3, drug-related
10% 3%
11%
25%
14%
13%
Serious AE, drug-related 2% 4% 5% 6%
Selected AEs
Diarrhea
24%
41%
33%
68%
76%
47%
Rash
22%
32%
63%
71%
40%
Nausea
17%
18%
30%
Hyperglycemia 0%
QT prolongation
Pneumonitis-like event
Sweta: I’d like to keep the “%” here if possible.
Yang JC, et al. ESMO Abstract 449PD.[36]

22. AURA: Preliminary Outcomes in Patients With Centrally Tested EGFR T790M-Positive Disease
ORR
61%
ORR by dose
Disease control rate (CR+PR+SD): 95%
Duration of confirmed response
Preliminary median duration of response at 80 mg: 8.2 mo (N=138)
The longest duration of response to date is ongoing at > 11 mo
Median PFS
Preliminary median PFS: 9.6 mo (30% maturity; N=138)
AZD9291 Dose
20 mg
40 mg
80 mg
160 mg
240 mg N
(Total = 127) 10 32 43 28 14
ORR
50%
59%
70%
61%
Yang JC, et al. ESMO Abstract 449PD.[36]

23. Ongoing Studies of AZD9291 AURA3 FLAURA Phase 3 randomized trial
AZD9291 vs platinum-doublet chemotherapy as second-line therapy in chemotherapy-naïve patients with advanced NSCLC characterized by an EGFR T790M mutation and progression on a first-line EGFR TKI
FLAURA
AZD9291 vs erlotinib or gefitinib as first-line therapy in treatment-naïve patients with disease characterized by an EGFR-sensitizing mutation (includes patients with or without disease characterized by an EGFR T790M mutation)
a. ClinicalTrials.gov. NCT [37]; b. ClinicalTrials.gov. NCT [38]

24. CO-1686 (Rociletinib) Pre-Clinical Studies
Transgenic murine model with tumor characterized by EGFR L858R/T790M
Dramatic tumor regression with CO-1686 in contrast to tumor progression observed with afatinib
Cellular viability assay using A431 model, which is characterized by high levels of EGFR wild type
Less cell inhibition observed with increasing doses of CO compared with other EGFR TKIs
Suggests that CO-1686 may be associated with an increased likelihood of EGFR wild-type sparing .
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010[39]; Walter AO, et al. Cancer Discov ;3: [40]

25. Phase 1 and Extended Phase 2 Expansion Studies of CO-1686
Formulation and dosing
Initially evaluated as a free base
Hydrobromide (HBr) salt formulation subsequently shown to be more efficacious
Twice-daily doses of 500 mg, 625 mg, 750 mg, 1000 mg have been evaluated
Study designs
Phase 1: Patients with advanced or recurrent NSCLC characterized by an activating EGFR mutation and prior EGFR-directed therapy
CO-1686 dose escalation to MTD
Primary end points: Safety, PK
Phase 2: Patients with EGFR T790M mutation-positive disease that has progressed on prior EGFR-directed therapy
3 doses (500 mg, 625 mg, 750 mg twice daily) being evaluated as second- or higher-line therapy in 2 patient populations characterized by prior treatment
Primary end points: ORR, DoR
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]

26. CO-1686 Preliminary Outcomes
Evaluated in 40 patients with EGFR T790M mutation-positive disease treated with therapeutic doses of CO-1686
ORR
58%
PFS
Median not yet reached (estimated > 12 mo)*
*Reported in June 2014.
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]

27. CO-1686 Safety Selected AEs (%) (N = 72*) Grade 1 Grade 2 Grade 3
Diarrhea
19% 4% 0%
Rash
Nausea
14% 1%
Hyperglycemia and IGT
11%
22%
QT prolongation 7%
Sweta: I’d like to keep the “%” here if possible.
*Includes patients treated at efficacious doses.
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]

28. TIGER Trials TIGER 1a TIGER 2b TIGER 3c Phase 2 randomized trial
CO-1686 vs erlotinib as first-line therapy in treatment-naïve patients with disease characterized by an EGFR-sensitizing mutation
TIGER 2b
Phase 2 single arm trial
CO-1686 as second-line therapy in patients with advanced NSCLC characterized by an EGFR T790M mutation and progression on a first-line EGFR TKI
TIGER 3c
Phase 3 randomized trial
CO-1686 vs single-agent chemotherapy in patients with advanced NSCLC characterized by an EGFR-sensitizing mutation and progression on ≥ 1 prior EGFR TKI and platinum-doublet chemotherapy
a. ClinicalTrials.gov. NCT [41]; b. ClinicalTrials.gov. NCT [42]; c. ClinicalTrials.gov. NCT [43]

29. Summary
Resistance to first-line EGFR TKI therapy is a challenging clinical problem
The acquired resistance mutation, EGFR T790M, accounts for resistance to prior EGFR TKI therapy in nearly 60% of patients
Third-generation TKIs have demonstrated robust activity in patients with acquired resistance to a first-line EGFR TKI
Tumor biopsy after disease progression on a first-line EGFR TKI is necessary to determine the mechanism(s) of acquired resistance

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