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Afatinib versus methotrexate as second-line treatment for patients with R/M HNSCC progressing
on or after platinum-based therapy: LUX-Head & Neck 3 Phase III trial
Ye Guo,1* Myung-Ju Ahn,2 Anthony Chan,3 Cheng-Hsu Wang,4 Jin Hyoung Kang,5
Sung-Bae Kim,6 Maximino Bello III,7 Rajendra Singh Arora,8 Qingyuan Zhang,9
Xiaohui He,10 Ping Li,11 Arunee Dechaphunkul,12 Vijay Kumar,13 Krishna Kamble,14
Wie Li,15 Alaa Kandil,16 Ezra Cohen,17 Yuan Geng,18 Eleftherios Zografos,19
Ping Zhang Tang20
1Shanghai East Hospital, Tongji University, Shanghai, China; 2Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, South Korea; 3Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; 4Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung, Taiwan;
5Seoul St. Mary's Hospital, Seoul, South Korea; 6Asan Medical Center, University of Ulsan College of Medicine, Seoul,
South Korea; 7St. Luke's Medical Center, Quezon City, Philippines; 8Sujan Surgical Cancer Hospital and Amravati Cancer
Foundation, Amravati, India; 9Harbin Medical University Cancer Hospital, Harbin, China; 10Cancer Hospital, Chinese
Academy of Medical Science, Beijing, China; 11West China Hospital, Sichuan University, Chengdu, China; 12Prince of Songkla University, Songkhla, Thailand; 13King George’s Medical University, Lucknow, India;
14Government Medical College and Hospital, Nagpur, India; 15First Hospital Affiliated to Jilin University, Jilin, China; 16Alexandria University Hospital, Alexandria, Egypt; 17San Diego Moores Cancer Center, University of California,
San Diego, CA, USA; 18Boehringer Ingelheim (China) Investment Co., Ltd, China; 19Boehringer Ingelheim Ltd, Bracknell,
Berkshire, UK; 20Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA, 31 May–4 June 2019
Introduction
• Second-line treatment options are limited for patients with recurrent and/or
metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC),
particularly in Asian countries1,2
• In the global, randomized, Phase III LUX-Head & Neck 1 study, the ErbB family
blocker, afatinib, was superior to methotrexate (MTX) in patients with R/M HNSCC3
– Notable benefit with afatinib was seen in patients:
• with p16-negative disease (surrogate for human papillomavirus [HPV]-negative disease)4
• not pretreated with an anti-epidermal growth factor receptor (EGFR) antibody
• HNSCC is particularly prevalent in Asian countries; moreover, p16-negative
disease is more common in Asian countries5,6
• LUX-Head & Neck 3 (NCT01856478) compared the efficacy and safety of afatinib
versus MTX in Asian patients with R/M HNSCC after platinum-based therapy
Methods
• Randomized, multi-center, open-label Phase III study
– 53 centers in 8 countries (China, India, Korea, Thailand, Egypt, Taiwan,
Hong Kong, and the Philippines)
• Patients were randomized (2:1) to a starting dose of 40 mg/day afatinib
(feeding tube or oral) or 40 mg/m2/week iv MTX
• Tolerability-guided dose adjustments were permitted
Methods cont’d
*Previous treatment with EGFR-targeted antibody therapy (but not EGFR TKIs) allowed
CV, cardiovascular; ECOG PS, Eastern Cooperative Oncology Group performance status; ILD, interstitial lung disease; iv, intravenous;
LA, locally advanced; PD, progressive disease; SCC, squamous cell carcinoma
Aged ≥18 years
ECOG PS 0/1
Not amenable to salvage surgery or radiotherapy
Documented PD after
platinum-based therapy*
Key inclusion criteria
Histologically/cytologically confirmed SCC of the
oral cavity, oropharynx, hypopharynx, or larynx More than 1 previous platinum-based systemic
regimen for R/M disease, except immunotherapy
before or after platinum-based treatment
Primary site of nasopharynx, sinuses,
and/or salivary glands
Pre-existing ILD or clinically relevant
CV abnormalities
Key exclusion criteria
PD within 3 months of curatively intended
treatment for LA/M HNSCC
Methods cont’d
CR, complete response; DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival;
PR, partial response; PROs, patient-reported outcomes; SD, stable disease
Primary endpoint
Secondary endpoints
• PFS by independent review
• OS, ORR, PROs
Other endpoints • Tumor shrinkage, DCR (PR+CR+SD)
Methods cont’d
• Response was assessed by investigator and independent review per RECIST v1.1,
Q6W for the first 24 weeks and Q8W thereafter
• PROs were assessed with QLQ-C30 and QLQ-H&N35
• AEs were assessed according to NCI CTCAE v3
• Tumor biomarker analysis of p16 status was assessed by IHC
AE, adverse event; IHC, immunohistochemistry; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse
Events; QLQ-C, EORTC quality of life core module; QLQ-H&N, EORTC quality of life head and neck module; Q6W, every 6 weeks;
Q8W, every 8 weeks; RECIST, Response Evaluation Criteria in Solid Tumors
Results
Patients and treatment
• 340 patients randomized (afatinib n=228; MTX n=112; Table 1) and 332 were
treated (excludes 8 patients in the MTX arm)
• Median (range) duration of treatment was 3.0 (<0.1–35.9) and 1.4 (<0.1–8.8)
months, respectively
Results
*China, Hong Kong, Korea, Taiwan; †Based on central test results; ‡9 patients received nimotuzumab and the rest received cetuximab;
mAb, monoclonal antibody
Table 1. Patient demographics and baseline characteristics
Characteristic Afatinib (n=228) MTX (n=112)
Male, n (%) 193 (85) 99 (88)
Median age, years (range)
≥65 years, n (%)
55·5 (28–83)
31 (14)
58.0 (27–76)
16 (14)
Asian, n (%)
East Asian*, n (%)
215 (94)
131 (58)
107 (96)
78 (70)
ECOG PS 0/1, n (%) 47 (21)/181 (79) 24 (21)/88 (79)
p16 status†, n (%)
Positive
Negative
No result available
9 (4)
79 (35)
140 (61)
1 (<1)
30 (27)
81 (72)
Prior use of anti-EGFR mAb for R/M disease‡, n (%) 30 (13) 13 (12)
Smoking pack-years, n (%)
<10
≥10
107 (47)
120 (53)
46 (41)
66 (59)
Localization of recurrence, n (%)
Locoregional only
Distant metastases only
Both
114 (50)
17 (8)
96 (42)
59 (53)
7 (6)
46 (41)
Best response to prior platinum-based therapy, n (%)
CR/PR
SD/PD
Unknown/missing
9 (4)/29 (13)
29 (13)/135 (59)
10 (4)/16 (7)
5 (4)/11 (10)
11 (10)/67 (60)
5 (4)/13 (12)
Efficacy
Survival outcomes
• Afatinib reduced the risk of progression or death by 37%; the benefit was
consistent across most subgroups (Figure 1A and B)
• There was no significant OS difference between arms (Figure 1C)
Efficacy cont’d
CI, confidence interval; HR, hazard ratio
Figure 1. (A) PFS, (B) subgroup PFS analysis, and (C) OS
12-week PFS 58% 41%
24-week PFS 21% 9%
0 3 6 9 12 15 18 21
PFS event, n (%)
Median PFS, months (95% CI)
HR (95% CI)
Log rank test p value
Time (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Estim
ate
d P
FS
pro
ba
bili
ty
24
200 (87.7)
2.9 (2.8–3.7)
79 (70.5)
2.6 (1.5–2.8)
0.63 (0.48–0.82)
0.0005
Afatinib
n=228
Methotrexate
n=112
228
112
99
24
35
3
19
0
9
0
3
0
3
0
3
0
3
0
Afatinib
Methotrexate
No. at risk
A
Efficacy cont’d
*Includes cisplatin alone, cisplatin+carboplatin, nedaplatin alone and other
Factors Number of patients Hazard ratio (95% CI)
Favors afatinib Favors methotrexate
11/8 8
Total
Baseline ECOG PS
0
1
Prior use of EGFR-targeted antibody for R/M HNSCC
No
Yes
Gender
Male
Female
Age
<65 years
≥65 years
Region
East Asia
Other
p16
Negative
No result available
Best response to prior platinum therapy for R/M HNSCC
CR/PR/SD
PD
Missing
Prior platinum-based therapy for R/M HNSCC
Cisplatin and other*
Carboplatin
B340
71
269
297
43
292
48
293
47
209
131
109
221
94
202
44
272
65
0.63 (0.48–0.82)
0.53 (0.30–0.93)
0.63 (0.47–0.86)
0.58 (0.44–0.77)
1.19 (0.51–2.76)
0.62 (0.46–0.82)
0.55 (0.26–1.18)
0.62 (0.46–0.82)
0.65 (0.31–1.36)
0.54 (0.39–0.76)
0.78 (0.50–1.21)
0.49 (0.30–0.82)
0.73 (0.53–1.00)
1.06 (0.61–1.82)
0.46 (0.33–0.65)
0.84 (0.42–1.70)
0.64 (0.48–0.86)
0.49 (0.26–0.91)
Efficacy cont’d
0 3 6 9 12 15 18 21
OS event, n (%)
Median OS, months (95% CI)
HR (95% CI)
Log rank test p value
Time (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Estim
ate
d O
S p
rob
abili
ty
51
195 (85.5)
6.9 (6.3–8.4)
90 (80.4)
6.4 (5.2–8.2)
0.88 (0.68–1.13)
0.3198
Afatinib
n=228
Methotrexate
n=112
228
112
187
80
127
50
83
33
47
19
34
9
20
6
17
4
0
0
Afatinib
Methotrexate
No. at risk
C
24
12
4
27
11
3
30
8
2
33
6
1
36
3
1
39
1
1
42
1
0
45
1
0
48
0
0
Efficacy cont’d
Tumor response
• Significantly more patients in the afatinib arm had an objective response (odds ratio
[OR] 2.76 [95% CI 1.47–5.18], p=0.0016)
• Median duration of response was 2.8 months (95% CI 2.6–3.9) with afatinib and
4.0 months (95% CI 1.4–4.7) with MTX (Figure 2)
• 22% and 7% of responding patients in the afatinib and MTX arms, respectively,
were still in response at Week 24
13%
28%
MTX
Afatinib
ORR
40%
67%
MTX
Afatinib
DCR
Efficacy cont’d
Figure 2. Duration of response
Afatinib
Methotrexate
0 100 200 400 600
Time (days)
Afatinib
Methotrexate
Censored
Week 12 Week 24
Health-related quality of life
PROs
• More patients had clinically relevant improvements in GHS/QoL (40% vs 23%,
p<0.01), swallowing (34% vs 18%, p=0.01) and pain (34% vs 25%, p=0.22) with
afatinib versus MTX (Figure 3)
• Post-baseline change in GHS was more favorable with afatinib versus MTX (22.9
vs 15.0; diff 7.9 [95% CI 3.5–12.4]; p=0.0005)
GHS, global health status
Health-related quality of life cont’d
Figure 3. Proportion of patients with improvement in PROs
45
40
35
30
25
20
15
10
Pa
tien
ts (
%)
40%
34%
18%
34%
25%23%
5
0Global health status
Afatinib Methotrexate
OR=2.30
p=0.009OR=2.37
p=0.012
OR=1.46
p=0.222
Swallowing Pain
Safety
*Grouped term
TRAE, treatment-related AE
Table 2. Most common TRAEs (≥10%) with afatinib
Any grade Grade ≥3
Any TRAE, n (%) 202 (89) 37 (16)
Diarrhea 153 (67) 8 (4)
Rash/acne* 126 (55) 10 (4)
Stomatitis* 86 (38) 7 (3)
Paronychia* 42 (18) 2 (<1)
Dermatitis acneiform 28 (12) 1 (<1)
Mouth ulceration 24 (11) 1 (<1)
• TRAEs (any grade/grade ≥3) were reported in 89/16% (Table 2) and 67/23%
patients treated with afatinib and MTX
Safety
• The most common grade ≥3 TRAEs were rash/acne (4%), diarrhea (4%), and
stomatitis (3%) with afatinib, and anemia, leukopenia, and fatigue (all 5%) with MTX
• The tolerability profile of afatinib was in line with previous studies and experience;
there were no unexpected safety signals
Key findings and conclusions
• Afatinib significantly improved PFS and ORR versus MTX, with a manageable
safety profile
• Efficacy benefits were complemented by improved QoL with afatinib versus MTX
• These results are consistent with the findings of LUX-Head & Neck 1,3 and support
the efficacy and feasibility of afatinib as a second-line treatment option for certain
patients with R/M HNSCC, e.g.:
– Patients with p16-negative disease
– EGFR antibody-naïve patients
References
1. Echarri MJ, et al. Cancers (Basel) 2016;8:27
2. D’Cruz A, et al. Oral Oncol 2013;49:872–77
3. Machiels JP, et al. Lancet Oncol 2015;16:583–94
4. Cohen EEW, et al. Ann Oncol 2017;28:2526–32
5. Guo L, et al. Front Oncol 2018;8:619
6. Shaikh MH, et al. BMC Cancer 2017;17:792
Acknowledgments
• This study is funded by Boehringer Ingelheim. The authors were fully responsible
for all content and editorial decisions, were involved at all stages of poster
development and have approved the final version
• Medical writing assistance, supported financially by Boehringer Ingelheim, was
provided by Fiona Scott, PhD, of GeoMed, an Ashfield company, part of UDG
Healthcare plc, during the development of this poster
• These materials are for personal use only and may not be reproduced without
written permission of the authors and the appropriate copyright permissions
• *Corresponding author email address: [email protected]