Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib
long-term responders in the phase III LUX-Lung 8 trial – Glenwood Goss
Second-line afatinib for advanced
squamous cell carcinoma of the lung:
analysis of afatinib long-term responders
in the Phase III LUX-Lung 8 trial
Glenwood Goss, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Alessandro Morabito, Istvan Albert, Gabriella Herodek, Samuel Chan,
Gyula Ostoros, Veronika Sarosi, Zsolt Kiraly, Deric Savior, Rachael Barton, Francisco Medina, Sundaram Subramanian, Andrea Ardizzoni, Enriqueta Felip,
Shirish M. Gadgeel, Vassilis Georgoulias, Nicholas Dupuis, James Love, Claudia Bühnemann, Neil Gibson, Eva Ehrnrooth, Jean-Charles Soria
Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib
long-term responders in the phase III LUX-Lung 8 trial – Glenwood Goss
• Dr Goss reports advisory board participation for and honoraria from
AstraZeneca, Boehringer Ingelheim, BMS, Pfizer
Disclosure information
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Introduction
• Overexpression/aberrations of ErbB family members (EGFR, ErbB2, ErbB4) are
implicated in the pathogenesis of SCC of the lung, providing rationale for therapeutic
targeting1-5
• The LUX-Lung 8 study compared the irreversible ErbB family blocker, afatinib, with the
reversible EGFR TKI, erlotinib, in patients with SCC of the lung6
• Afatinib significantly improved PFS and OS versus erlotinib in this setting6
‒ PFS: 2.6 months vs 1.9 months; HR=0.81 (95% CI: 0.69–0.96)
‒ OS: 7.9 months vs 6.8 months; HR=0.81 (95% CI: 0.69–0.95)
• Afatinib is approved for the treatment of metastatic SCC of the lung following
progression after platinum-based chemotherapy
OS, overall survival; PFS, progression-free survival;
SCC, squamous cell carcinoma; TKI, tyrosine-kinase inhibitor
1. Lawrence MS, et al. Nature 2013;499:214‒8; 2. Hirsch FR, et al. J Clin Oncol 2003;21:3798‒807;
3. Heinmoller P, et al. Clin Cancer Res 2003;9:5238‒43; 4. Ugocsai K, et al. Anticancer Res 2005;25:3061‒6;
5. Lopez-Malpartida AV, et al. Lung Cancer 2009; 65:25‒33; 6. Soria J-C, et al. Lancet Oncol 2015;16:897–907
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria*Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted; †Dose reduction to 100 or 50 mg permitted; ‡Tumour assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter
DCR, disease control rate; ORR, objective response rate; PRO, patient-reported outcomes; qd, once daily
LUX-Lung 8: Study design
• SCC of the lung (Stage IIIB/IV)
• Progressed after ≥4 cycles of a first-line platinum-doublet chemotherapy
• ECOG PS 0–1
• Adequate organ function
Afatinib 40 mg* qd
(n=398)
Erlotinib 150 mg† qd
(n=397)
1:1
Primary endpoint: PFS by independent review‡
Key secondary endpoint: OS
Other secondary endpoints: ORR, DCR, tumour shrinkage, PRO, safety
Stratified by
east Asian vs
non-east Asian
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Post-hoc analysis of LUX-Lung 8 ‘Long-term responders’ (LTRs)
• 12 and 18-month OS rates indicated that some
patients derived prolonged benefit with afatinib
• Post-hoc analysis identified 15 patients (LTRs)
who received ≥12 months of afatinib treatment
– Median treatment duration was 16.6 months
(range: 12.3–25.8 months)
• Possible molecular/clinical biomarkers indicative
of long-term response to afatinib were evaluated
– Baseline characteristics
– Efficacy/safety of afatinib
– Molecular genomic analysis
– VeriStrat® classification*
OS: primary analysis
3 6 9 12 15 3018 21 24 27
Time (months)
0.2
0.4
0.6
0.8
1.0
0
Estim
ate
d O
S p
rob
abili
ty
0
36.4%
28.2%
22.0%
14.4%
Afatinib
(n=398)
Erlotinib
(n=397)
*Serum protein test used to assign a ‘Good’ or ‘Poor’ classification, with
prognostic and predictive utility for EGFR-targeted agents in NSCLC1 1. Gregorc V, et al. Lancet Oncol 2014;15(7):713-21
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
LTRs treated with
afatinib (n=15)
All patients treated with
afatinib (n=398)
Median age, years (range) 65 (54–81) 65 (36–84)
Female/male, % 20/80 16/84
Race, %East Asian 7 22
Non-east Asian 93 78
Smoking history, %
Never smoker 7 7
Light ex-smoker* 13 3
Current and other ex-smoker 80 91
ECOG PS, % 0/1 40/60 32/68†
Clinical stage, % IIIB/IV 20/80 12/88‡
Histology, %Squamous 100 96
Mixed 0 4
Best response to
first-line
chemotherapy, %
CR/PR 53 47
SD 47 40
Unknown 0 12
Baseline characteristics
*Less than fifteen pack-years and stopped >1 year before diagnosis; †<1% were ECOG PS 2 due to protocol violations; ‡≤1% were stage IIIA
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
OS
CR‡ (1)
PR‡ (4)
Duration of response§
End of treatment
• Median OS was 23.1 months (range: 12.9–31.6 months)
• Median PFS (independent central review) was 16.2 months (range: 2.8–24.1 months)
Treatment response* and OS in LTRs
*SD unless noted otherwise (patient 2 was classified as non-evaluable); †Patients were ordered and numbered by treatment duration, with patient 1 being on treatment longest; ‡First observed response at time of tumour measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death; ‖Received ≥1 line of chemotherapy after afatinib;
CR, complete response; PR, partial response; SD, stable disease
¶
LT
Rs
†
‖
‖
‖
‖
‖
‖
‖
Time (months)
‖
SD (9)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
• NGS was undertaken in 9/15 afatinib-treated LTRs and 132/398 afatinib-treated patients of the
overall LUX-Lung 8 population
• Certain SVs were more common in LTRs than in the overall population tested
Genomic aberrations in LTRs
*EGFR, ErbB2, ErbB3, and ErbB4 genes; †FGF3, FGF4, FGF6, FGF7, FGF10, FGF12, FGF14, FGF23, FGFR1, FGFR2, FGFR3, and FGFR4 genes
CNAs, copy number alterations; NGS, next generation sequencing; SVs, short variants
Gene, %
Afatinib LTRs
(n=9)
All afatinib-treated
(n=132)
SVs
TP53 88.9 84.8
ErbB family 44.4 20.5
ErbB2/3/4 22.2/0/11.1 6.8/4.5/2.3
EGFR 11.1 6.8
LRP1B 33.3 39.4
MLL2 33.3 34.1
MLL 33.3 12.1
KEAP1 33.3 10.6
PIK3CA 33.3 15.9
CNAs
SOX2 44.4 44.7
KLHL6 44.4 43.2
PIK3CA 33.3 38.6
MAP3K13 33.3 36.4
BCL6 33.3 34.8
FGF12 33.3 33.3
44.4
26.5
55.660.6
0
10
20
30
40
50
60
70
80
90
100
*ErbB+ †FGF+
ErbB and FGF family aberrations
(SVs or CNAs)
Most common aberrations observed in LTRs (≥3 patients)
LTRs (n=9)
LUX-Lung 8 afatinib-treated population (n=132)
Pro
port
ion o
f patients
with
SV
s o
r C
NA
s (
%)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
0 5 10 15 20 25 30 35
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0 5 10 15 20 25 30 35
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
LT
Rs
†
• 12/14* (86%) LTRs were VS ‘Good’ compared to 62% in the overall afatinib-treated dataset (n=336)
• 78% of LTRs with available data had aberrations more common in LTRs than in the overall population
VeriStrat status and biomarkers more commonly observed in LTRs
¶
*VeriStrat data for Patient 8 was not available; †Patients were ordered and numbered by treatment duration, with patient 1 being on treatment longest; ‡First observed response at time of tumour
measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death; VS, VeriStrat
OS
VeriStrat Good
VeriStrat Poor
VeriStrat Missing
CR (1)‡
PR (4)‡
Duration of response§
End of treatment
G
G
G
P
G
G
G
G
G
G
G
G
G
P
M
G
P
M
¶
ErbB4; KEAP1
KEAP1; PIK3CA; ErbB2
MLL
MLL; PIK3CA
KEAP1; EGFR
ErbB2
MLL; PIK3CA
G
G
G
P
G
G
G
G
G
G
G
G
G
P
M
Time (months)
SD (9)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Subsequent therapies reported for LTRs
*Tumour response was stable disease unless noted otherwise (patient 2 was classified as non-evaluable); †Patients were ordered and numbered by treatment duration, with patient 1 being on
treatment longest; ‡First observed response at time of tumour measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death
¶
LT
Rs*†
Navelbine
Docetaxel
Gemcitabine
Paclitaxel/carboplatin,
gemcitabineDocetaxel
Gemcitabine
Gemcitabine/carboplatin,
paclitaxel/carboplatin
Carboplatin/nanoxel
Time (months)
OSCR (1)‡
PR (4)‡Duration of response§ End of treatmentSD (9)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
• The frequency of common drug-related AEs in LTRs was similar to the overall afatinib-treated population
• Afatinib 40 mg/day was maintained in 7/15 and escalated to 50 mg in 4/15 LTRs
• 4/15 dose reduced to 30 or 20 mg; dose reductions did not seem to have a negative impact on OS
• There were no treatment-discontinuations due to AEs
Common treatment-related AEs* and tolerability-guided dose adjustments
Treatment-duration (months)
*>20% in overall afatinib-treated population; †Patients were ordered and numbered by treatment duration; ‡Treatment ongoing until death
LT
Rs
† 50 mg
40 mg
30 mg
20 mg
Data unavailable
OS‡
Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib
long-term responders in the phase III LUX-Lung 8 trial – Glenwood Goss
Conclusion
• Afatinib conferred a median survival benefit of nearly 2 years in the LTR subset
• SVs of ErbB2/4, EGFR, MLL, PIK3CA and KEAP1 were more frequent in LTRs
• 86% of LTRs* were VeriStrat-Good and nearly four times as likely to survive ≥12
months as VeriStrat-Poor patients
• The approved afatinib dose (40 mg/day) was maintained or escalated in 73% of LTRs
• Small sample size limited drawing any firm conclusions concerning molecular/clinical
markers of long term response and therefore further studies are required
*12/14 patients with available VeriStrat data
Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib
long-term responders in the phase III LUX-Lung 8 trial – Glenwood Goss
• We thank all patients and their families, and investigators and staff at all clinical sites for their valuable
participation in this study
• Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by
Hannah Detering of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the
development of this oral presentation
Acknowledgements
Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib
long-term responders in the phase III LUX-Lung 8 trial – Glenwood Goss
BACK UP
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Patient disposition in LUX-Lung 8
Did not meet entry criteria
or did not enter (n=182)
6 still on treatment 3 still on treatment
Assessed for eligibility (n=977)
307 died 325 died
392 treated 395 treated
Randomised (n=795)
Afatinib (n=398) Erlotinib (n=397)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Afatinib (n=398) Erlotinib (n=397)
Median age (years) 65 64
Male (%) 84 83
Race (%)Eastern-Asian 22 22
Non-eastern Asian 78 78
Smoking history (%)
Never smoker 7 5
Light ex-smoker* 3 3
Current and other ex-smoker† 91 92
ECOG‡ (%) 0/1 32/68 34/66
Clinical stage§ (%) IIIB/IV 12/88 12/87
Histology¶ (%)Squamous 96 96
Mixed 4 4
Best response to
first-line
chemotherapy (%)
CR/PR 47 47
SD 41 42
Unknown 12 11
Demographics and baseline characteristics in LUX-Lung 8
*Less than fifteen pack-years and stopped >1 year before diagnosis; †Seventy-one (17.8%) and 85 (21.4%) patients were current smokers, respectively; ‡,<1% were ECOG PS 2; § ≤1% were stage IIIA; ¶≤1% were undifferentiated (considered to be of squamous histology)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
• Median PFS was significantly longer with afatinib (2.6 months) versus erlotinib
(1.9 months; HR=0.81 [95% CI: 0.69–0.96])
LUX-Lung 8: Primary endpoint (PFS)
Afatinib 398 139 50 30 14 10 5 2 2 0
Erlotinib 397 99 34 17 10 2 1 1 1 0
1.0
0.8
0.6
0.4
0.2
0
Estim
ate
d P
FS
pro
ba
bili
ty
Time (months)3 6 9 12 15 18 21 24 27
Number at risk
0
Afatinib
(n=398)
Erlotinib
(n=397)
Median, months 2.6 1.9
HR (95% CI) 0.81 (0.69–0.96)
p value 0.0103
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Treatment duration and best response in LTRs
• Median duration of treatment was 16.6 months (range: 12.3–25.8 months)
• ORR=33% (n=5)
12.3
12.9
13.1
13.2
13.7
13.8
15.9
16.6
17.5
17.6
19.0
19.6
20.3
22.825.8
0 5 10 15 20 25 30
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Treatment duration (months)
Complete response
Partial response
Stable disease†
Non-evaluable‡
*Patients were ordered and numbered by treatment duration; †Four patients had stable non-target disease in the absence of baseline-target disease; ‡Classed non-evaluable by the assessing
oncologist due to missing baseline CTs
LT
Rs*
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
• NGS was undertaken in 9/15 afatinib-treated LTRs and 245/795 patients of the
overall LUX-Lung 8 population
• Certain SVs were more common in LTRs than in the overall population
Genomic aberrations in LTRs and in the overall NGS dataset
*EGFR, ErbB2, ErbB3, and ErbB4 genes; †FGF3, FGF4, FGF6, FGF7, FGF10, FGF12, FGF14, FGF23, FGFR1, FGFR2, FGFR3, and FGFR4 genes
NGS, next generation sequencing; CNAs, copy number alterations; SVs, short variants
Gene, % Afatinib LTRs (n=9) Overall (n=245)
SVs
TP53 88.9 87.3
ErbB family 44.4 23.3
ErbB2/3/4 22.2/0/11.1 4.9/6.1/5.7
EGFR 11.1 6.5
LRP1B 33.3 39.2
MLL2 33.3 33.1
MLL 33.3 12.2
KEAP1 33.3 10.2
PIK3CA 33.3 11.8
CNAs
SOX2 44.4 42.9
KLHL6 44.4 39.6
PIK3CA 33.3 36.3
MAP3K13 33.3 32.2
BCL6 33.3 30.6
FGF12 33.3 28.2
44.4
29.4
55.6 58.0
0
10
20
30
40
50
60
70
80
90
100
*ErbB+ †FGF+
ErbB and FGF family aberrations
(SV or CNA)
Most common aberrations observed in LTRs (≥3 patients)
LTRs (n=9)
LUX-Lung 8 population (n=245)
Pro
port
ion o
f patients
with S
Vs
or
CN
As (
%)
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
Patient
number
Line of
therapy
Additional cancer therapy
Start date,
days after last
afatinib dose
Stop date,
days after last
afatinib dose
First
compound*
Second
compound*
Third
compound*
3 3 8 69 Paclitaxel Carboplatin –
3 4 204 274 Gemcitabine – –
4 3 105 – Docetaxel – –
5 3 6 – Carboplatin Nanoxel –
6 3 2 – Navelbine – –
9 3 15 159 Gemcitabine Carboplatin Gemcitabine
9 4 223 – Paclitaxel Carboplatin –
11 3 30 110 Docetaxel – –
13 3 22 57 Gemcitabine – –
15 3 13 55 Gemcitabine – –
Details of subsequent therapy
*Dictionary term
Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders
in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria
• The frequency of drug-related AEs in LTRs was similar to the overall afatinib-treated population
• AEs generally occurred soon after treatment onset
Common treatment-related AEs*: Incidence and onset
*>20% in overall afatinib-treated population; †Grouped term
Related AEs in LTRs All grades, n (%) Grade 3, n (%)Median AE onset, days
(range)
Diarrhoea 11 (73) 1 (7) 11 (5–48)
Rash/acne† 11 (73) 1 (7) 17 (9–107)
Stomatitis 2 (13) 1 (7) 98 (11–223)