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: pattrickguo@gmail.com