1. Professor Martin Schuler MD West German Cancer Center Essen, Germany
Right patient, right treatment: Insights in EGFR mutation-positive NSCLC
Professor Martin Schuler MD West German Cancer Center Essen, Germany

2. Question: What is your current standard-of-care in the first-line treatment of patients with Del19 NSCLC?
Afatinib*
Chemotherapy
Erlotinib
Gefitinib
Other
*Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada, under the brand name GIOTRIF® and in the USA under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications.

3. Question: What is your current standard-of-care in the first-line treatment of patients with L858R NSCLC?
Afatinib
Chemotherapy
Erlotinib
Gefitinib
Other

4. Afatinib: An irreversible ErbB family blocker
Molecular potency
and selectivity
IC50 (nM)
EGFR
0.5
HER2 14
ErbB4 1
HGFR
>10,000
VEGFR2
>100,000
Li D, et al. Oncogene 2008;27:4702–11; Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50; Yang J, et al. Lancet Oncol 2012;13:539–48

5. First-generation EGFR TKIs: Clinical benefits in EGFR mutation-positive NSCLC, although no OS benefits
Trial
EGFR TKI
EGFR mutation
ORR (%)
PFS (months)
OS (months)
IPASS1,2,3
Gefitinib
261*
71 vs 47 p<0.001
9.5 vs 6.3
HR 0.48 (0.36–0.64)
21.6 vs 21.9 HR 1.00
(0.76–1.33)
NEJGSG-0024,5
224
74 vs 31 p<0.001
10.8 vs 5.4 HR 0.32 (0.24–0.44)
27.7 vs 26.6 HR 0.89 (0.63–1.24)
WJTOG34056,7
172
62 vs 32 p<0.0001
9.2 vs 6.3 HR 0.49 (0.34–0.71)
34.8 vs 37.3 HR 1.25 (0.88–1.78)
OPTIMAL8,9
Erlotinib
154
83 vs 36 p<0.0001
13.1 vs 4.6 HR 0.16 (0.10–0.26)
22.8 vs 27.2
HR 1.19 (0.83–1.71)
EURTAC10
173
65 vs 16
10.4 vs 5.2 HR 0.34 (0.23–0.49)
22.9 vs 19.5 HR 0.93
(0.64–1.35)
ENSURE11
217
63 vs 34
11.0 vs 5.5 HR 0.34 (0.22–0.51)
26.3 vs 25.5 HR 0.91 (0.63–1.31)
Rosell et al. Lancet Oncol 2012;13:239
Khozin et al. Oncologists 2014;19:774
Wu et al. Ann Oncol 2015;pii:mdv270 (epub ahead of print); ENSURE
*Out of a total of 1217 patients.
1. Mok T, et al. N Engl J Med 2009;361:947–57; 2. Fukuoka M, et al. J Clin Oncol 2011;29:2866–74; 3.Yang J, et al. Eur J Cancer 2011;47:S633–4; 4. Maemondo M, et al. New Engl J Med 2010;362:2380–8; 5. Inoue A, et al. Ann Oncol 2013;24:54–59; 6. Mitsudomi T, et al. Lancet Oncol 2010;11:121–28; 7. Yoshioka, H et al. ASCO Poster 8117; 8. Zhou C, et al. Lancet Oncol 2011;12:735–42; 9. Zhou C, et al. Ann Oncol 2015;26:1877–83; 10. Khozin S, et al. Oncologist 2014;19:774–9; 11. Wu Y, et al. Ann Oncol 2015;pii:mdv270 [Epub ahead of print]

6. First-generation EGFR TKIs: Efficacy by mutational status (Del 19 vs L858R)
Trial
EGFR TKI
EGFR mutation
ORR (%)
PFS (months)
OS (HR, 95% CI)
Del 19
L858R
IPASS1,2
Gefitinib
261*
84.8
60.9
11.0
9.2
0.79 (0.54–1.15)
1.44 (0.90–2.30)
NEJGSG-0023,4
224
82.8
67.3
11.5
10.8
0.83 (0.52–1.34)
0.82 (0.49–1.38)
OPTIMAL5,6
Erlotinib
154 -
15.3
12.5
1.52 (0.91–2.52)
0.92 (0.55–1.54)
EURTAC7,8
173
8.4
0.94 (0.57–1.54)
0.99 (0.56–1.76)
ENSURE9
217
11.1
8.3
0.79 (0.48–1.30)
1.05 (0.60–1.84)
*Out of a total of 1217 patients; -, not available or reported.
1. Fukuoka M, et al. J Clin Oncol 2011;29:2866–74; 2.Yang J, et al. Eur J Cancer 2011;47:S633–4; 3. Maemondo M, et al. New Engl J Med 2010;362:2380–8; 4. Inoue A, et al. ASCO Poster 7519; 5. Wu Y, et al. Ann Oncol 2010;21:LBA14; 6. Zhou C, et al. Ann Oncol 2015;26:1877–83; 7. Rosell R, et al. Lancet Oncol 2012;13:239–46; 8. Khozin S, et al. Oncologist 2014;19:774–9; 9. Wu Y, et al. Ann Oncol 2015;pii:mdv270 [Epub ahead of print]

7. Preplanned OS analysis of LUX-Lung 3: Mutation subgroups
Del19 3 6 9 12 15 18 21 24 27
0.0
0.2
0.4
0.6
0.8
1.0
Estimated OS probability 30 33 36 39 42 45 48 51
Afatinib
Cis/Pem
No. at risk:
Afatinib
112
108
105
102 96 93 83 80 72 62 58 51 34 30 21 6 1
Cis/Gem 57 55 50 46 43 37 33 27 25 22 20 16 10
Time of overall survival (months)
Del19
L858R
Afatinib (n=112)
Cis/Pem (n=57)
Afatinib (n=91)
Cis/Pem (n=47)
Median, months
33.3
21.1
27.6
40.3
HR (95% CI) p value
0.54 (0.36–0.79) p=0.0015
1.30* (0.80–2.11) p=0.29
*HR 1.02 (0.62–1.69) when adjusted for baseline imbalances.
Yang J, et al. Lancet Oncol 2015;16:141–51

8. Preplanned OS analysis of LUX-Lung 6: Mutation subgroups
Del19
1.0
Afatinib
Cis/Gem
0.8
0.6
Estimated OS probability
0.4
0.2
0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
No. at risk:
Afatinib
124
122
118
115
106 99 90 80 73 69 59 39 16 8 1
Cis/Gem 62 58 53 49 44 35 30 28 26 21 18 11 4 3
Time of overall survival (months)
Del19
L858R
Afatinib (n=124)
Cis/Gem (n=62)
Afatinib (n=92)
Cis/Gem (n=46)
Median, months
31.4
18.4
19.6
24.3
HR (95% CI) p value
0.64 (0.44–0.94) p=0.023
1.22 (0.81–1.83) p=0.34
Yang J, et al. Lancet Oncol 2015;16:141–51

9. Key practical considerations in the management of EGFR mutation positive NSCLC

10. What would you do?
Newly diagnosed advanced or metastatic NSCLC (adeno) not suitable for surgical resection
1) Start chemotherapy immediately?
2) Perform biomarker analysis and treat based on analysis results?

11. What would you do?
Newly diagnosed advanced or metastatic NSCLC (adeno) not suitable for surgical resection
1) Start chemotherapy immediately?
2) Perform biomarker analysis and treat based on analysis results?
Therascreen EGFR PCR test turnaround time:1
4.9 business days (95% CI 4.5–5.5 days)
Actual time from the test request to the result:
17.8 days (95% CI 16.4–19.4 days)
August 2015)

12. Quality-of-life/symptom improvement Convenience Other
Question: What is the key factor determining your therapy choice in first-line EGFR mutation-positive NSCLC?
Efficacy
Safety
Quality-of-life/symptom improvement
Convenience
Other

13. Afatinib plasma levels: Patients with and without dose reduction
Dose reduction was more likely in patients with higher
plasma concentrations
140
120
100 80 60 40 20
Trough plasma concentrations (ng/mL)
C3V1 (Day 43)
40 mg (n=126)
30 mg (n=38)
C2V1 (Day 22)
40 mg (n=122)
40 mg (n=10)
Individual data with median and 25th/75th percentiles
10th/90th percentiles
Data points outside percentiles
After dose reduction to 30 mg ≥4 days previously (n=38)
Patients who remained on 40 mg (n=126)
Geometric mean plasma concentrations
24.4 ng/mL
23.7 ng/mL
Patients who remained on 40 mg until C3V1 (n=126) Patients whose dose was reduced to 30 mg before C3V1 (n=38; only 10 of these patients had valid trough concentrations on 40 mg afatinib at C2V1. The rest had either no PK sampling due to dose interruption, were already on 30 mg afatinib or were excluded due to invalid sampling).
Yang J, et al. J Clin Oncol 2015;(Suppl.). Abstract 8073

14. Tolerability-guided dose modification and PFS
Median PFS similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily
Time (months)
1.0
0.6
0.4
0.2
Estimated PFS probability 3 6 9 12 15 18 21 24 27
0.8
<40 mg in first 6 months
≥40 mg in first 6 months
No. at risk
<40 mg in first 6 months
105 87 75 58 41 26 15 6 2
≥40 mg for first 6 months
124 93 76 62 36 24 16 4 1
<40 mg in first 6 months (n=105)
≥40 mg for first 6 months (n=124)
Median PFS, months
11.3
11.0
HR (95% CI); p value
1.25 (0.91–1.72); 0.175
CI, confidence interval; HR, hazard ratio.
Yang J, et al. J Clin Oncol 2015;(Suppl.). Abstract 8073

15. Summary and conclusion
First-generation EGFR TKIs have provided significant clinical benefits to patients with EGFR mutation-positive NSCLC. However, no OS advantage has been formally demonstrated so far
First-line afatinib significantly improved OS vs chemotherapy in EGFR Del19 patients in two randomised trials
LUX-Lung 3: median 33.3 vs 21.1 months, HR 0.54, p=0.0015
LUX-Lung 6: median 31.4 vs 18.4 months, HR 0.64, p=0.023
No significant difference in OS of patients with L858R mutations treated with afatinib, individually, or in exploratory combined analysis
However, benefit in PFS, ORR and PRO have been demonstrated in LUX-Lung 3 and 6
Afatinib also showed robust activity in patients with most frequent uncommon EGFR mutations including those with point mutations or duplications in exons 18–21 (ORR 71.1%, PFS 10.7 months, OS 19.4 months)
Certain practical considerations may be important in maximising benefit in first-line treatment of patients with EGFR mutation+ NSCLC and should be kept in mind when managing these patients

16. Questions and discussion