1. Afatinib versus erlotinib for second-line treatment of Chinese patients with advanced squamous cell carcinoma of the lung: a subgroup analysis of the Phase III LUX-Lung 8 trial
Shun Lu,1 Wei Li,2 Caicun Zhou,3 Cheng-Ping Hu,4 Shukui Qin,5 Gang Cheng,6 Jifeng Feng,7 Jie Wang,8,9 Agnieszka Cseh,10 Barbara Peil,11 Neil Gibson,12 Eva Ehrnrooth,13 Li Zhang14
1Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai, China; 2Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China; 3Department of Oncology, Shanghai Pulmonary Hospital, Shanghai, China; 4Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China; 5People’s Liberation Army Cancer Center, Nanjing Bayi Hospital, Nanjing, Jiangsu, China; 6Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China; 7Department of Internal Medicine, Jiangsu Provincial Tumor Hospital, Nanjing, Jiangsu, China; 8Department of Internal Medicine, Capital Medical University, Beijing, China; 9Peking University School of Oncology, Beijing Cancer Hospital, Beijing, China; 10Department of Medical Affairs, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 11Biostatistics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 12Translational Medicine and Clinical Oncology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 13Division of Oncology, Boehringer Ingelheim, Danmark A/S, Copenhagen, Denmark; 14Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China 

2. Introduction
In the global LL8 trial in patients with advanced SCC of the lung, who had progressed after ≥4 cycles of platinum-based chemotherapy, the irreversible ErbB family blocker afatinib significantly improved PFS, OS, and PROs versus erlotinib, and was also well tolerated1,2
Based on the results of LL8, afatinib was approved globally in this setting, most recently in China3
This post-hoc subgroup analysis evaluated whether efficacy and safety outcomes and PROs in LL8 patients from China were comparable to those in the overall trial population (OTP)
LL8, LUX-Lung 8; OS, overall survival; OTP, overall trial population; PFS, progression-free survival; PROs, patient-reported outcomes; SCC, squamous cell carcinoma
Soria J-C, et al. Lancet Oncol 2015;16:897–907
Felip E, et al. Clin Lung Cancer 2017 [In press]
afatinib-approved-lung- cancer-china (accessed August 2017)

3. LUX-Lung 8 study design and trial endpoints
1:1
Advanced SCC of the lung
≥4 cycles of first-line platinum-based chemotherapy
Measurable disease (RECIST v1.1)
Availability of tumor tissue
ECOG PS 0–1
Afatinib
40 mg/day*
Erlotinib 150 mg/day†
Treatment
until PD or
unacceptable
AEs
Primary and key secondary endpoints
Other secondary endpoints
PFS (assessed by independent central review in intent-to-treat population) and OS
ORR DCR PROs
*Dose escalation to 50 mg/day and reduction to 30 or 20 mg/day permitted
†Dose reduction to 100 or 50 mg/day permitted
AEs, adverse events; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, objective response rate; PD, progressive disease; RECIST, Response Evaluation Criteria In Solid Tumors

4. Baseline demographics/characteristics were comparable between the Chinese subgroup and the OTP in LL8
Chinese subgroup (N=67)
OTP (N=795)1
Characteristic
Afatinib (n=36)
Erlotinib (n=31)
Afatinib (n=398)
Erlotinib (n=397)
Sex, n (%)
Female
Male
5 (13.9)
31 (86.1)
2 (6.5)
29 (93.5)
63 (15.8)
335 (84.2)
66 (16.6)
331 (83.4)
Median age, years (range)
62.0 (36–74)
60.0 (43–78)
65.0 (36–84)
64.0 (35–88)
ECOG PS, n (%) 1 2
9 (25.0)
27 (75.0)
8 (25.8)
23 (74.2)
126 (31.7)
269 (67.6)
3 (0.8)
134 (33.8)
262 (66.0)
1 (0.3)
Ethnic origin, n (%)
Non-eastern Asian
Eastern Asian
36 (100.0)
31 (100.0)
312 (78.4)
86 (21.6)
311 (78.3)
86 (21.7)
Smoking status, n (%)
Never smoked
Light ex-smoker
Current or ex-smoker
5 (16.1)
24 (77.4)
26 (6.5)
11 (2.8)
361 (90.7)
18 (4.5)
12 (3.0)
367 (92.4)
Median time since diagnosis (years, range)
0.7 (0.3–6.6)
0.6 (0.2–6.2)
0.8 (0.2–9.3)
0.7 (0.2–13.5)
Tumor histology, n (%)
Squamous
Mixed
33 (91.7)
3 (8.3)
381 (95.7)
17 (4.3)
382 (96.2)
15 (3.8)
Clinical stage/screening, n (%)
IIIA
IIIB IV
1 (2.8)
7 (19.4)
28 (77.8)
26 (83.9)
48 (12.1)
349 (87.7)
4 (1.0)
345 (86.9)
In LL8, 67/795 (8%) patients were from China:
36 received afatinib
31 received erlotinib

5. HRs for PFS and OS favored afatinib over erlotinib and were similar between the Chinese subgroup and the OTP
PFS
Chinese subgroup: HR= (95% CI: 0.38–1.27)
OTP: HR=0.81 (95% CI: 0.69–0.96)1 OS
Chinese subgroup: HR= (95% CI: 0.39–1.21)
OTP: HR=0.81 (95% CI: 0.69–0.95) 1
Soria J-C, et al. Lancet Oncol 2015;16:897–907
CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat

6. HRs for PFS by IRF and OS favored afatinib over erlotinib in the Chinese subgroup
IRF, independent review facility

7. Improvements in (A) PFS and (B) OS were largely unaffected by EGFR expression status* in the Chinese subgroup
High EGFR expression was neither prognostic nor predictive of survival outcomes in Chinese patients
*H-score; EGFR, endothelial growth factor receptor; IES, immunohistochemistry-evaluable set; NE, not evaluable

8. Tumor response rates favored afatinib over erlotinib, and were comparable between the Chinese subgroup and the OTP
Chinese subgroup (N=67)
OTP (N=795)1
Response category, %
Afatinib (n=36)
Erlotinib (n=31)
p value
Afatinib (n=398)
Erlotinib (n=397)
ORR
8.3
6.5
0.7723
 5.5
2.8
0.0551
DCR
55.6
41.9
0.2713
50.5
39.5
0.0020
4/36 Chinese patients who received afatinib for 12 months or more were identified as LTRs
DCR, disease control rate; LTR, long term responder; ORR, objective response rate
Soria J-C, et al. Lancet Oncol 2015;16:897–907

9. Changes in target lesion sum of diameters from baseline were comparable between Chinese patients and the OTP
A) Chinese patients
B) OTP

10. Improvements in PROs with afatinib versus erlotinib were similar between the Chinese subgroup and the OTP
More Chinese patients reported improved global health status/quality of life than the OTP:
Chinese patients: 53% afatinib vs 30% erlotinib; p=0.072
OTP: 36% afatinib vs 28% erlotinib; p=0.0411
Soria J-C, et al. Lancet Oncol 2015;16:897–907

11. Safety and tolerability findings with afatinib in the Chinese subgroup were consistent with findings in the OTP1
Patients with AEs, n (%)
Chinese subgroup (n=67)
Overall safety population (n=787)b
Afatinib (n=36)
Erlotinib (n=31)
Afatinib (n=392)
Erlotinib (n=395)
All
Grade 3
Any AE
36 (100.0)
8 (22.2)
28 (90.3)
6 (19.4)
390 (99.5)
124 (31.6)
385 (97.5)
138 (34.9)
Diarrhea
27 (75.0)
4 (12.9)
293 (74.7)
39 (9.9)
163 (41.3)
12 (3.0)
Rash/acnec
23 (63.9)
1 (2.8)
16 (51.6)
273 (69.6)
26 (6.6)
276 (69.9)
42 (10.6)
Stomatitisc
14 (38.9)
2 (5.6)
2 (6.5)
118 (30.1)
16 (4.1)
2 (0.5)
Fatiguec
7 (19.4)
1 (3.2)
132 (33.7)
19 (4.8)
119 (30.1)
23 (5.8)
Hemoptysis
3 (9.7)
49 (12.5)
49 (12.4)
Dyspnea
6 (16.7)
79 (20.2)
12 (3.1)
94 (23.8)
18 (4.6)
Hypokalemia
20 (5.1)
9 (2.3)
3 (0.8)
Cough
4 (11.1)
65 (16.6)
69 (17.5)
Paronychiac
43 (11.0)
1 (0.3)
Decreased appetite
97 (24.7)
103 (26.1)
8 (2.0)
Nausea
3 (8.3)
81 (20.7)
6 (1.5)
64 (16.2)
4 (1.0)
Vomiting
51 (13.0)
40 (10.1)
Constipation
43 (10.9)
The most common AEs among Chinese patients in the afatinib arm were diarrhea, rash/acne and stomatitis, with incidences similar to those reported for the OTP
The frequency of dose reductions due to AEs in the afatinib arm was 14% in the Chinese subgroup vs 27% in the OTP
The rate of discontinuations due to AEs in the afatinib arm was 11% in the Chinese subgroup vs 20% in the OTP
Notes: aThe data shown are for AEs that occurred (at any grade) in >10% of patients in the afatinib arm, in either the overall population or the Chinese subgroup. AEs were coded using MedDRA version Of the AEs listed, the following also occurred at Grade 4/5 in the afatinib arm (overall safety population): grade 4 diarrhea (n=3), grade 4 fatigue (n=1), grade 5 fatigue (n=1); grade 4 dyspnea (n=3), grade 5 dyspnea (n=3); grade 5 hemoptysis (n=2). bData on file; cGrouped term.
AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities

12. Key findings and conclusions
Although this post-hoc analysis was not powered to show significant differences between treatment arms in the Chinese subgroup, trends favoring afatinib in terms of PFS, OS, tumor control and improvements in PROs were comparable to those reported for the OTP, and afatinib was well tolerated in this subgroup
Afatinib is a viable treatment option in Chinese patients with advanced SCC of the lung, following progression during or after platinum-based chemotherapy

13. References Acknowledgments
Soria J-C, et al. Lancet Oncol 2015;16:897–907
Felip E, et al. Clin Lung Cancer 2017 [In press]
BI press release: (accessed August 2017)
Acknowledgments
This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Mike Simpson of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of the manuscript and accompanying slide deck
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