Patient characteristics
From July 2014 through December 2021, 386 patients were screened for enrollment, and a total of 251 patients were randomly assigned, with 84 patients in the 12-month icotinib group, 84 patients in the 6-month icotinib group, and 83 patients in the observation group (Fig. 1). This trial was terminated early owing to slow accrual and the publication of EVIDENCE and ADAURA data. The baseline characteristics were generally well balanced between the groups: more than 60% of the patients were female, more than 85% were never smokers, and more than 59% had stage IIIA disease (Table 1). Almost all the patients had adenocarcinoma. For surgery, lobectomy was performed in the majority of the patients.
Table 1. Baseline characteristics of the intention-to-treat population.
|
Icotinib of 12 months (n=84)
|
Icotinib of 6 months (n=84)
|
Observation
(n=83)
|
Age (years), median (minimum, maximum)
|
57 (34-75)
|
56 (33-75)
|
57 (24-75)
|
Sex
|
|
|
|
Male
|
30 (35.7)
|
29 (34.5)
|
30 (36.1)
|
Female
|
54 (64.3)
|
55 (65.5)
|
53 (63.9)
|
ECOG PS
|
|
|
|
0
|
41 (48.8)
|
43 (51.2)
|
38 (45.8)
|
1
|
40 (47.6)
|
39 (46.4)
|
42 (50.6)
|
Missing
|
3 (3.6)
|
2 (2.4)
|
3 (3.6)
|
Smoking status
|
|
|
|
Never
|
72 (85.7)
|
73 (86.9)
|
72 (86.7)
|
Former
|
5 (6.0)
|
6 (7.1)
|
5 (6.0)
|
Current
|
7 (8.3)
|
5 (6.0)
|
6 (7.2)
|
Histology
|
|
|
|
Adenocarcinoma
|
83 (98.8)
|
83 (98.8)
|
83 (100.0)
|
Other
|
1 (1.2)
|
1 (1.2)
|
0
|
Stagea
|
|
|
|
IIA
|
6 (7.1%)
|
5 (6.0)
|
5 (6.0)
|
IIB
|
28 (33.3)
|
29 (34.5)
|
29 (34.9)
|
IIIA
|
50 (59.5)
|
50 (59.5)
|
49 (59.0)
|
N stage
|
|
|
|
N0
|
9 (10.7%)
|
8 (9.5%)
|
8 (9.6%)
|
N1
|
30 (35.7%)
|
29 (34.5%)
|
29 (34.9%)
|
N2
|
45 (53.6%)
|
47 (56.0%)
|
46 (55.4%)
|
Surgery type
|
|
|
|
Lobectomy
|
82 (97.6)
|
84 (100.0)
|
81 (97.6)
|
Bilobectomy
|
1 (1.2)
|
0
|
1 (1.2)
|
Pneumonectomy
|
1 (1.2)
|
|
1 (1.2)
|
Side
|
|
|
|
Left
|
39 (46.4)
|
36 (42.9)
|
40 (48.2)
|
Right
|
45 (53.6)
|
48 (57.1)
|
43 (51.8)
|
EGFR mutation
|
|
|
|
Exon 19 deletion
|
46 (54.8)
|
47 (56.0)
|
44 (53.0)
|
Exon 21 L858R
|
38 (45.2)
|
37 (44.0)
|
39 (47.0)
|
Data are presented as n (%) unless stated otherwise.
aStaging was determined according to the 7th edition of the AJCC TNM staging system for lung cancer.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; AJCC, American Joint Committee on Cancer.
For adjuvant chemotherapy, all four treatment cycles were completed in 68 (81.0%) patients in the 12-month icotinib group, 66 (78.6%) patients in the 6-month icotinib group, and 67 (80.7%) patients in the observation group. Three cycles of adjuvant chemotherapy were completed in 6, 7, and 7 patients in each group, respectively. In total, 70% of the patients received pemetrexed and carboplatin as adjuvant chemotherapy. A summary of the adjuvant chemotherapy cycles and regimens is provided in Table S1.
For treatment compliance, 65 patients (77.4%) in the 12-month icotinib group completed the planned 12-month treatment, and 66 patients (78.6%) in the 6-month icotinib group completed the planned 6-month treatment (Table S2). In the 12-month icotinib group, 19 patients discontinued icotinib treatment because of patient decisions (n = 14), AEs (n = 4), or recurrence (n = 1). In the 6-month icotinib group, 18 patients discontinued icotinib treatment because of patient decisions (n = 15) and AEs (n = 3). The median duration of treatment was 12.1 months (interquartile range (IQR), 11.7–12.5) in the 12-month icotinib group and 6.5 months (IQR, 6.0–7.0) in the 6-month icotinib group. None of the patients in the icotinib groups were still receiving the study medication at the time of analysis.
Efficacy
The data cutoff date was January 15, 2024. The median duration of follow-up in the ITT population was 61.4 months (IQR, 44.9–79.8). The median follow-up for DFS was 64.5 months in the 12-month group, 60.5 months in the 6-month group, and 57.9 months in the observation group. By the time of the analysis, there had been 135 disease recurrence or death events. There were 40 (47.6%) disease relapse or death events in the 12-month group, 39 (46.4%) in the 6-month group, and 56 (67.5%) in the observation group. Adjuvant icotinib of 12 months significantly improved DFS (HR: 0.40, 95% CI, 0.27–0.61; P < 0.001) compared with observation (Fig. 2). Icotinib of 6 months also significantly improved DFS (HR: 0.41, 95% CI, 0.27–0.62; P < 0·001) compared with observation. Adjuvant icotinib of 12 months did not improve DFS (HR: 0.97; P = 0.89) compared with 6 months of this drug (Fig. 2). The median DFS was 61.8 months (95% CI, 43.3 to 80.3) for the 12-month icotinib group, 63.2 months (95% CI, 44.8 to 81.6) for the 6-month icotinib group compared with 23.7 months (95% CI, 16.5 to 30.9) for the observation group. The 5-year DFS for the 12-month icotinib, 6-month icotinib and observation groups were 51.3%, 50.1% and 24.8%, respectively (Fig. 2). The DFS benefit of 12-month icotinib over observation was generally consistent across most subgroups, including in the patients with either stage II or stage IIIA disease, those with either N0/N1 or N2 disease, and those who had exon 19 deletion or exon 21 L858R mutation (Fig. 3a). In addition, the DFS benefit of 6-month icotinib over observation was also observed in most subgroups (Fig. 3b). However, no differences in efficacy pertaining to icotinib duration were found in any of the subgroups (Table S3). Among the patients with stage II disease, the 5-year DFS for the 12-month icotinib, 6-month icotinib and observation groups were 54.9% (95% CI, 38.9 to 74.9), 55.0% (95% CI, 33.9 to 77.9) and 29.3% (95% CI, 10.9 to 47.7); respectively (Figure S1a). Among the patients with stage III disease, the 5-year DFS for the 12-month icotinib, 6-month icotinib and observation groups were 47.5% (95% CI, 32.4 to 62.6), 45.1% (95% CI, 30.6 to 59.6) and 21.9% (95% CI, 9.0 to 34.8); respectively (Figure S1b).
In the overall population, the lung was the most common first site of relapse, which occurred in 11 (13.1%), 12(14.3%), and 20 (24.1%) patients in the 12-month icotinib, 6-month icotinib, and observation groups, respectively (Table S4 and Table S5). The brain was the second most common first site of relapse, which occurred in 10 (11.9%), 12(14.3%), and 15 (17.9%) in the 12-month icotinib, 6-month icotinib, and observation groups, respectively (Table S4 and Table S5). The 12-month icotinib group had a significantly improved BMFS compared with the observation group, with a 5-year BMFS of 68.5% versus 54.5% (HR: 0.53, 95% CI, 0.32–0.88; P = 0.013; Figure S2). Icotinib of 6 months was also associated with an improved BMFS compared to observation, with the 5-year BMFS of 68.4% versus 54.5% (HR: 0.54, 95% CI, 0.33–0.90; P = 0.017; Figure S2). After disease relapse, 29, 29, and 44 patients in the 12-month, 6-month, and observation groups received a first subsequent therapy, respectively (Table S6). Most patients received an EGFR-TKI-based treatment as their first subsequent therapy. Overall, 17 (42.5%) patients in the 12-month icotinib group, 12 (30.8%) patients in the 6-month icotinib group, and 9 (16.1%) patients in the observation group received a third-generation EGFR-TKI (osimertinib, aumolertinib, or furmonertinib) as the first subsequent therapy (Table S6).
By the time of the analysis, 73 death events had occurred, including 21 in the 12-month icotinib group, 20 in the 6-month icotinib group, and 32 in the observation group. OS was significantly more prolonged among the patients in the 12-month icotinib group than among those in the observation group (HR: 0.55, 95% CI, 0.32–0.96; P = 0.035; Fig. 4). OS was also significantly longer among those who had been assigned to the 6-month icotinib group than among those in the observation group (HR: 0.56, 95% CI, 0.32–0.98; P = 0.041; Fig. 4). However, adjuvant icotinib of 12 months did not improve OS compared with 6 months of this drug (HR: 1.00, 95% CI, 0.54–1.85; P = 0.99; Fig. 4). The 5-year OS for the 12-month, 6-month and observation groups were 74.5%, 74.0% and 65.1%, respectively. There were no significant differences between 12-month or 6-month icotinib and observation in the subgroups (Figure S3a and b), possibly because the study was not powered to examine OS benefit within the subgroups.
Safety
A summary of the AEs is provided in Table S7. AEs of any grade occurred in 65 (77.4%) patients in the 12-month group, 62 (73.8%) in the 6-month group, and 45 (54.2%) in the observation group. The most common AEs at any grade were rash (36.9%), diarrhea (21.4%), and raised aminotransferases (14.3%) in the 12-month group, and rash (38.1%), diarrhea (19.0%), and raised aminotransferases (13.1%) in the 6-month group, and leukopenia (8.4%), insomnia (8.4%), and raised aminotransferases (4.8%) in the observation group (Table 2).
Table 2. Most common all-cause AEs reported in ≥5% of patients.
|
12-month icotinib
|
6-month icotinib
|
Observation
|
All-cause AEs
|
Any grade
|
Grade ≥ 3
|
Any grade
|
Grade ≥ 3
|
Any grade
|
Grade ≥ 3
|
Totala
|
65 (77.4%)
|
7 (8.3%)
|
62 (73.8%)
|
5 (5.9%)
|
45 (54.2%)
|
2 (2.4%)
|
Rash
|
31 (36.9%)
|
3 (3.6%)
|
32 (38.1%)
|
2 (2.4%)
|
1 (1.2%)
|
0
|
Diarrhea
|
18 (21.4%)
|
1 (1.2%)
|
16 (19.0%)
|
1 (1.2%)
|
3 (3.6%)
|
0
|
Raised aminotransferases
|
12 (14.3%)
|
1 (1.2%)
|
11 (13.1%)
|
0
|
4 (4.8%)
|
0
|
Leukopenia
|
4 (4.8%)
|
1 (1.2%)
|
5 (6.0%)
|
0
|
7 (8.4%)
|
1 (1.2%)
|
Insomnia
|
6 (7.1%)
|
1 (1.2%)
|
4 (4.8%)
|
1 (1.2%)
|
7 (8.4%)
|
0
|
Fatigue
|
5 (6.0%)
|
0
|
4 (4.8%)
|
1 (1.2%)
|
3 (3.6%)
|
1 (1.2%)
|
Decreased appetite
|
4 (4.8%)
|
0
|
5 (6.0%)
|
0
|
2 (2.4%)
|
0
|
Oral ulcers
|
5 (6.0%)
|
0
|
3 (3.6%)
|
0
|
1 (1.2%)
|
0
|
Data are presented as n (%). All AEs were reported in at least 5% of the patients in either trial group, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
aTotal number of patients who had at least one AE; some patients had more than one AE.
Abbreviations: AEs, adverse events.
Grade 3 or worse AEs were reported for 7 (8.3%), 5 (5.9%), and 2 (2.4%) patients in the 12-month, 6-month, and observation groups, respectively. The grade 3 or worse AEs experienced in the 12-month group were rash in 3 patients (3.6%), diarrhea in 1 (1.2%), raised aminotransferases in 1 (1.2%), leukopenia in 1 (1.2%), and insomnia in 1 (1.2%). The grade 3 or worse AEs that occurred in the 6-month group were rash in 2 patients (2.4%), diarrhea in 1 (1.2%), insomnia in 1 (1.2%), and fatigue in 1 (1.2%). The grade 3 or worse AEs that occurred in the observation group were leukopenia in 1 patient (1.2%), and fatigue in 1 (1.2%). AEs leading to permanent treatment discontinuation were recorded in 4 (4.8%) and 3 (3.6%) patients in the 12-month and 6-month groups, respectively. No treatment-related deaths occurred in either group and no dose reductions were recorded. No new safety events have been observed since the previous reports for icotinib.