Safety, tolerability, and pharmacokinetics of simotinib, a novel specific EGFR tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer: results of a phase Ib trial

Figures & data

Table 1 Baseline patient characteristics

Characteristics	Number of patients
Enrolled	41
Gender (male/female)	28/13
Median age (range), years	57 (37–65)
ECOG PS
0–1	39
2	2
TNM staging
IIIA	1
IIIB	3
IV	37
Pathology
Adenocarcinoma	41
EGFR gene-mutation type
Exon 18	1
Exon 19	27
Exon 20	0
Exon 21	13
Subgroup of EGFR mutation
19–1 loss	27
21–1 L858R	13
18 loss	1

Abbreviations: ECOG PS, Eastern Cooperative Group performance status; TNM, TNM staging system.

Table 2 Overview of adverse events in safety population

	100 mg N=2	200 mg N=3	300 mg N=3	400 mg N=15	500 mg N=12	650 mg N=6	Total N=41
Skin and subcutaneous tissue disorders
Rash, n (%)	1 (50.0)	2 (66.7)	0	2 (13.3)	9 (75.0)	3 (50)	17 (41.5)
Pruritus, n (%)	2 (100)	2 (66.7)	1 (33.3)	4 (26.7)	1 (8.3)	0	10 (24.4)
Blood and lymphatic systems disorders
Neutropenia, n (%)	0	3 (100)	1 (33.3)	3 (20.0)	2 (16.7)	2 (33.3)	11 (26.8)
Erythrocyte reduction, n (%)	0	1 (33.3)	0	4 (26.7)	2 (16.7)	2 (33.3)	9 (22.0)
Hepatobiliary disorder
Aminotransferase elevation, n (%)	0	0	1 (33.3)	2 (13.3)	2 (16.7)	3 (50.0)	8 (19.5)
Bilirubin elevation, n (%)	0	2 (66.7)	2 (66.7)	1 (6.7)	2 (16.7)	0	7 (17.1)
Gastrointestinal disorder
Diarrhea, n (%)	0	3 (100)	3 (100)	7 (46.7)	7 (58.3)	3 (50.0)	23 (56.1)
General disorders
Fatigue, n (%)	2 (100)	1 (33.3)	2 (66.7)	2 (13.3)	3 (25.0)	0	10 (24.4)

Abbreviations: n/N, number of patients; %, percentage of patients.

Table 3 Pharmacokinetic results for single dose of simotinib

Parameters(mean ± SD)	100 mg N=2	200 mg N=3	300 mg N=3	400 mg N=15	500 mg N=12	650 mg N=6
T1/2, h	5.3±0.3	12.2±3.5	9.2±1.0	13.3±6.3	28.0±33.8	29.7±32.2
Tmax, h	1.8 (1.5–2.0)	2.0 (2.0–2.0)	1.5 (1.5–2.0)	2.0 (1.0–8.0)	1.8 (0.5–4.0)	2.0 (1.0–6.0)
Cmax, ng/mL	56.5±18.2	333.0±35.4	552.5±388.2	566.4±372.0	514.5±316.4	828.5±849.0
AUC0-last, ng•hr/mL	405.6±94.8	2,339.6±479.9	2,814.0±764.5	3,581.9±1,868.5	3,791.0±2,741.1	4,652.1±3,442.1
AUC0-∞, ng•hr/mL	466.2±129.9	2,955.0±564.0	3,243.8±776.1	4,962.1±3,141.7	6,483.8±5,008.4	7,648.4±3,028.7
CL, L/h	223.1±62.2	68.9±13.2	95.2±22.8	127.4±117.6	200.5±300.1	97.7±39.2
Vd, L	1,704.0±385.8	1,250.1±579.7	1,286.1±438.6	2,097.2±1,506.8	7,166.6±12,246.1	3,873.8±3,378.1

Abbreviations: AUC_0-t, area under the curve from time 0 to the last measurable plasma concentration; AUC_0-∞, area under the curve from time 0 to infinity; CL, total body clearance; C_max, maximum plasma concentration; T_max, time to maximum concentration; T_1/2, half-life; V_d, volume distribution.

Table 4 Pharmacokinetic results for multi-dosing of simotinib

Parameters(mean±SD)	100 mg N=2	200 mg N=3	300 mg N=3	400 mg N=15	500 mg N=12	650 mg N=6
T1/2, h	6.2	9.6±4.2	10.4±7.8	13.0±11.8	8.4±2.8	9.2±1.9
Tmax, h	1.0(0–2.0)	4.0 (2.0–4.0)	1.5 (1.0–2.0)	2.0 (0–8.0)	1.8 (1.0–6.0)	2.0 (1.5–8)
Cmax, ng/mL	130.3±70.3	447.0±258.8	1,519.0±1,132.8	767.9±338.1	1,396.0±534.8	650.8±234.7
Cmin, ng/mL	54.5±32.1	207.0±152.7	288.0±117.4	251.6±127.0	378.3±132.0	214.3±84.8
Cavg, ng/mL	76.7±29.1	328.4±224.1	501.2±254.8	437.1±182.9	651.6±161.9	384.6±133.3
AUC0-last, ng•hr/mL	920.4±349.2	3,940.9±2,689.0	6,013.9±3,058.1	5,245.7±2,194.4	7,819.8±1,942.3	4,615.7±1,599.7
AUC0-∞, ng•hr/mL	956.9	6,571.6±3,241.2	9,728.6±1,648.2	10,577.7±5,867.6	12,780.6±3,894.7	8,193.3±3,211.2
CL, L/h	148.5	66.1±45.1	57.3±29.1	99.5±70.4	67.7±17.2	156.3±55.6
Vd, L	1323.3	1,050.0±1,020.6	1,019.6±1,077.5	2,000.6±3,169.6	811.3±326.9	2,021.8±635.7

Abbreviations: AUC_0-t, area under the curve from time 0 to the last measurable plasma concentration; AUC_0-∞, area under the curve from time 0 to infinity; CL, total body clearance; C_max, maximum plasma concentration; C_avg, average plasma concentration; T_max, time to maximum concentration; T_1/2, half-life; V_d, volume distribution.

Figure 1 Waterfall plot of best percent change from baseline in sum of target lesion dimensions from baseline. (A) Full analysis population and (B) per protocol population (n=40).

Data availability

Individual patient data are confidential and thus they cannot be made publicly available.