Lung Cancer 89 (2015) 262–267
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer夽 Dongyang Liu a , Li Zhang b , Yiwen Wu a , Ji Jiang a , Fenlai Tan c , Yingxiang Wang c , Yong Liu c, Pei Hu a,∗ a
Clinical Pharmacology Research Center, Peking Union Medical College Hospital & Chinese Academy of Medical Sciences, Beijing 100032, China Department of Pulmonary Medicine, Peking Union Medical College Hospital & Chinese Academy of Medical Sciences 100032 Beijing, China c Zhejiang Beta Pharma Inc., Zhejiang, China b
a r t i c l e
i n f o
Article history: Received 5 April 2015 Received in revised form 29 May 2015 Accepted 30 May 2015 Keywords: Clinical Pharmacokinetics Safety, Activity Icotinib NSCLC Patients
a b s t r a c t Objectives: To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Materials and methods: Patients (n = 40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100 mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200 mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Results: Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17–462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2 was within 5.31–8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Conclusions: Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Icotinib hydrochloride is a potent and highly selective EGFRTKI to treat NSCLC in vivo and in vitro [1,2]. In 2007, tolerability, single-dosing escalating pharmacokinetics (PK) and food-effect studies were conducted to evaluate PK, tolerability, and food effects in healthy subjects [3]. Then, optimized biologic dose (OBD) in NSCLC patients need to be determined in 2009. Recently, five major metabolites of icotinib in humans were separated and identified [4] and two of them were found to be active (M3 and M5, unpublished data). Although icotinib proved to be non-inferior effective and more safe than gefitinib in 400 NSCLC Chinese patients [5,6],
夽 Trial registration ID: ChiCTR-ONC-08000113. Trial sponsor: Zhejiang Beta Pharma Inc., Hangzhou, Zhejiang, China. ∗ Corresponding author. Tel.: +86 10 69158366. E-mail address: [email protected] (P. Hu). http://dx.doi.org/10.1016/j.lungcan.2015.05.024 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
no safety information about these five metabolites was uncovered so far. Additionally, up to now, full PK and safety profiles, containing metabolite pharmacokinetics, of icotinib in NSCLC patients after single- and multiple-dose were still unpublished. To better understand icotinib and better assist clinical physician in treating NSCLC patients with icotinib, these characters were worthy of being reported. 2. Patient and method 2.1. Patient selection Eligible patients had pathologically confirmed, advanced NSCLC (stage III or IV) with measurable tumor that were refractory to standard therapy or that had no standard therapy; age ≥18 years; life-expectancy ≥12 weeks; Eastern Cooperative Oncology Group (ECOG) performance ≤2; time to stop previous chemotherapy ≥3 weeks; hemoglobin ≥9 g/dL; absolute neutrophil count
D. Liu et al. / Lung Cancer 89 (2015) 262–267
≥1.5 × 109 /L; platelets ≥90 × 109 /L; creatinine ≤1.5 times the upper limit of normal (ULN) or calculated creatinine clearance (CLcr ) ≥60 mL/min (Cockcroft–Gault equation [7]; bilirubin ≤1.5 × ULN; AST and ALT ≤2.5 × ULN (5 × ULN for patients with liver metastases); absence of pregnancy or lactating female, brain metastases; no gastrointestinal tract disease to affect drug absorption; and no coexisting severe, unstable or uncontrollable medical conditions. Exclusions included subjects who had taken any other human epidermal receptor (HER) inhibitors or target drugs to treat cancer. Study protocol and subject informed consent forms (ICF) were approved by Ethics Committee of Peking Union Medical College Hospital (PUMCH, Beijing, China) and the written ICFs of all patients were obtained from subjects before treatment. The study was conducted according to the Declaration of Helsinki and its amendments. 2.2. Drug administration This phase I, open-label, adaptively designed study was divided into two sequential parts. In part 1 (dose-escalation phase), all patients received a single dose of oral icotinib hydrochloride tablet (Beta Pharmaceuticals, ZheJiang, China) followed by multiple doses (b.i.d.) for continuous 28 days started on Day 4. In part 2, once the OBD was determined, 10 extra patients were enrolled to receive icotinib for a continuous 28-day treatment at the OBD level (Cohort G) and 12 additional patients were treated by icotinib (t.i.d.) at approximate daily dose of OBD with a same schedule as part 1 (Cohort H). In part 1, the starting dose, 200 mg b.i.d., represented one fifth of the NOAEL in healthy subjects. Each dose level of 100, 150, 200, 250, 300, and 400 mg BID (Cohort F, A–E) were planned to be examined in one separated cohort (n = 12) during dose-escalation phase. If less than 30% of patients discontinued treatment, dose-escalation continues. Otherwise, the lower dosage would be started. Patients who experienced dose-limited toxicity (DLT) were eligible for additional cohorts at the next lower dose level after recovery from the DLT [8]. Patients would continue treatment at the same dose level as long as icotinib was tolerated well and there was no evidence of disease progression. At least 8 patients completed corresponding study in each cohort. All patients received Icotinib under fasted condition for 2 h before and 1 h post-dose except for the first 3 patients in Cohort C (200 mg, b.i.d.), who received it with food.
of icotinib were measured by high pressure liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and positive ion selected reaction monitoring, as previously described with well accuracy and precision [10]. The five major metabolites [4] in plasma and urine were measured for Cohort B using a previously validated LC-MS/MS method. The accuracy, precision, specificity, recovery, linearity and several of stabilities have been validated for them in human plasma and urine as guided by FDA [10]. 2.5. Pharmacokinetic and pharmacodynamic analysis Pharmacokinetic analyses were performed using WinNonlin 5.1 software (Pharsight Co., California, USA). Standard noncompartmental analysis was conducted to calculate PK parameters using linear/log trapezoidal rule [3]. Descriptive analysis of elimination half-life (t1/2 = 0.693/ke ), maximum observed plasma concentration (Cmax ), trough concentration at status (Ctrough ), time to reach Cmax (Tmax ), area under the plasma concentration–time curve (AUC from 0 to 12 h or 0 to 8 h for b.i.d. or t.i.d. (AUC0-tau ), from 0 to last observed point or 24 h, (AUC0-last or AUC0-24hr ), and from 0 to infinite (AUC0-∞ = AUC0-last + Clast /ke )), apparent clearance (CL/F = Dose/AUC0-∞ ), apparent distribution volume (Vz = Dose/(AUCinf ·kel )), cumulative amount excreted into the urine (Ae,0-last ), and renal clearance (CLR = Ae,0-0-24h /AUC0-0-24h or Ae,tau /AUC0-tau for single dose and multiple doses) was performed in Excel 2003 software (Microsoft Co., USA). Accumulation ratios were calculated with average Cmax,ss /Cmax,single-dose (RCmax ), AUC0-tau,ss /AUC0-tau,single-dose (RAUCtau ), and AUC0-tau,ss /AUC0-∞,single-dose (RAUCinf ). Metabolite-toparent ratios of each metabolite were calculated in mole unit and were reported in M/PCmax,ss and M/PAUCtau . 2.6. Anti-tumor activity Response rate was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) on week 4, 8, 12, and 16 and every 8 weeks thereafter [11] Primary evaluation endpoints include objective response rate (ORR) and disease control rate (DCR). Response was classified quality of life (QoL), secondary endpoint, was accessed every 2 weeks through European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-LC13 program [12].
2.3. Safety monitoring
3. Results
All patients receiving at least one dose of icotinib were considered assessable for safety, which was accessed during the entire first dosing-cycle, at weeks 8, 12, and 16, and every 8 weeks thereafter. Toxicities were graded based on the National Cancer Institute Common Toxicity Criteria (NCICTC), version 3.0 [9]. Treatmentrelated adverse events (TRAEs) were defined as adverse events that were possibly, probably, or definitely related to Icotinib administration and occurred during the first treatment.
3.1. Patients
2.4. Plasma and urine pharmacokinetic sampling and assay For Cohort A–F, and H, blood samples were collected to determine plasma concentrations of icotinib and its five major metabolites on Day 1 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h post-dose; on Days 11, 18, and 25 at pre-dose; and on Day 31 at pre-dose and 0.5, 1, 2, 4, and 12 h post-dose. Urine samples were collected before dosing and over the following postdose intervals: 0–4, 4–8, 8–12, and 12–24 h on Day 1 and first three intervals on Day 31. For Cohort G, blood samples at pre-dose and 2 h post-dose were collected on Days 1, 8, and 28. Plasma and urine samples were stored below −70 ◦ C until analysis. Concentrations
263
Between August 2007 and Feb 2009, 40 patients with advanced NSCLC were enrolled onto the study to receive icotinib at doses ranging from 300 to 400 mg/day. A total of 247 cycles (28 days/cycle) were observed and analyzed by Mar/2010. Their pertinent characteristics are listed in Table 1. Every patient received a fixed dose in the study until discontinued treatment. All 40 patients received at least one of dose. Thirty-seven patients completed the first 28-day treatment and three patients didn’t complete due to dyspnea, interstitial lung disease, or respiratory failure. The median time on Cohort A, B, G, H was 9, 2, 3, and 10 cycles, respectively. 3.2. Dose escalation and DLT After three patients received the initial dose (200 mg, b.i.d., Cohort B) with food, one of them (Subject B03) experienced grade 3 rash and drug-related lethal interstitial lung disease (ILD). Considering that ILD emerged during treatment of erlotinib (6.7%) and gefitinib (5.4%) in Asian patients [13,14], this cohort was discontinued and lower dosage (Cohort A) was tested. After this SAE, icotinib
264
D. Liu et al. / Lung Cancer 89 (2015) 262–267
Table 1 Patient demographics and baseline disease characteristics (n (%)). Demographics/Characteristics (N = 40)
Value
Median age, years (range) Sex, n (%) Male Female ECOG performance status, n (%) 0 1 Pathological type, n (%) Adenocarcinoma Large cell carcinoma Mixed cell carcinoma Squamous cell carcinoma Bronchioloalveolar carcinoma Stage, n (%) III IV Previous treatment Number of prior chemotherapy regimens, n (%) Chemotherapy regimen 1 2 >2 Surgery Taking TKIs before, n (%) History of smoking, n (%) Yes No
57 (47–94) 22 (55) 18 (45) 18 (45) 22 (55) 34 (85) 1 (2.5) 1 (2.5) 3 (7.5) 1 (2.5) 6 (15) 34 (85)
19 (47) 16 (40) 5 (13) 8 (20) 0 (0) 18 (45) 22 (55)
was dosed under fasted condition, where drug was administrated 1 h before taking food or 2 h post-food. At the 150 mg (b.i.d. Cohort A) dose level, a total of 13 patients were enrolled and no grade 3/4 AE was observed except for acute biliary pancreatitis and cancer disease progression. Both of the two AEs were rated as not related or unlike to be related with treatment. The cancer disease progression was firstly diagnosed as ILD followed by the pathological diagnosis of cancer diffuse metastasis in lung through autopsy, which addressed that Subject B03 experienced diffuse metastasis rather than ILD. Therefore, 200 mg b.i.d. dose level (Cohort B) was continued on the basis of well tolerance of icotinib at 150 mg dose level. Finally, a total of 6 patients were additionally enrolled onto Cohort B. Cohorts G and H were sequentially conducted in 10 and 8 patients at dose level of 150 mg b.i.d. and 125 mg t.i.d., respectively. No DLTs occurred in Cohort H (125 mg t.i.d.). At dose level of 200 mg b.i.d., a patient (B03) reported a potential DLT with grade 3 rash and respiratory failure, lethal ILD and circulation failure. He had respiratory failure on Day 7 after dosing. CT result showed
interstitial lung disease and a grade 3 rash were found as the same time. The symptoms were partially reversed by corticosteroid treatment for a period then the patient developed to circulatory failure and multiple-organ failure and died on Day 37. A biopsy of the rash confirmed skin metastasis, indicating disease progression and the SAE was judged as both drug-related and disease-related. Further escalation was not pursued because of this potential ILD and good efficacy at 125 mg t.i.d. dose level. Therefore, the safe and efficacious dose was suggested to be around 400 mg/day. 3.3. Safety Sixty-eight AEs were reported by 26/40 patients (65%). Of them, 44 AE events reported by 22/40 (55%) patients were considered to be icotinib-related by the investigator, with the most frequent being rash (18/40, 45%), gastrointestinal disease (7/40, 17.5%), and interstitial lung disease (2/40, 5%) (Table 2). Most of the events were mild (grade 1/2) and transient. Four patients suffered about 16 events of grade ≥3 severity, and 9 events of grade ≥3 severity in 3 patients (A05, A13, and B03) were suggested to be possibly or probably drug-related. All treatment-related AEs with grade ≥3 severity and treatment-related AEs with grade 1/2 reported in 5% patients were listed in Table 2. Interstitial lung disease was the only adverse event of grade ≥3 severity reported by more than 1 patient. No severe (≥grade 3) unique laboratory abnormalities were found and there was no evidence of recall of radiation injury. Rash (42.5%) and Diarrhea (7.5%) were the most popular treatment-related AE with grade 1/2. 3.4. Pharmacokinetic analysis After single dose of 125–200 mg, icotinib was absorbed quickly (range of Tmax ∼ 0.5–4 h) and eliminated in an approximately mono-exponential manner after single dose; the mean t1/2 was within 5.31–8.07 h, mean Vz was within 99.4–217 L and mean CL/F was within 13.7–20.0 L/h. Less than 0.4% of doses were excreted in unchanged icotinib through kidney (Fig. 1 and Table 3). PK exposure increased with increase of dose levels. After multiple doses, steady status was achieved after 7–11 day continuous dosing. Mean accumulation ratio expressed in Cmax , AUC0-tau , and AUC0-∞ were 1.04–1.37, 1.27–1.79, and 1.07–1.29 respectively, which suggesting a weak accumulation and approximately stationary clearance for icotinib after dosing with b.i.d. or t.i.d. method in NSCLC patients. Mean trough concentrations after multiple doses of 125 mg t.i.d., 150 mg b.i.d., and 200 mg b.i.d. were with 675–994 ng/mL. Renal clearance of icotinib is less than 0.06 L/h, which is comparable to
Table 2 Treatment-related AEs (safety population, n (%)). AE
125 mg TID(n = 8)
200 mg BID(n = 9)
Total(n = 40)
Treatment-related AEs of all grades reported in ≥5% of patients Rash 8 (34.8) Diarrhea 2 (8.7) Abdominal pain 2 (8.7) Nausea 2 (8.7) Interstitial lung disease 1 (4.3)
N (%)
150 mg BID(n = 23)
5 (62.5) 1 (12.5) 0 (0) 0 (0) 1 (12.5)
5 (55.6) 0 (0) 0 (0) 0 (0) 0 (0)
18 (45) 3 (7.5) 2 (5) 2 (5) 2 (5)
Treatment-related AEs with ≥3 Grades Interstitial lung disease Respiratory failure Rash Abdominal pain Nausea Circulation failure Multiple-organ failure
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
1 (11.1) 1 (11.1) 1 (11.1) 0 (0) 0 (0) 1 (11.1) 1 (11.1)
2 (5) 1 (2.5) 1 (2.5) 1 (2.5) 1 (2.5) 1 (2.5) 1 (2.5)
5 (62.5) 1 (12.5)
4 (44.4) 0 (0)
17 (42.5) 3 (7.5)
1 (4.3) 0 (0) 0 (0) 1 (4.3) 1 (4.3) 0 (0) 0 (0)
Treatment-related AEs with Grade 1/2 reported in ≥5% of patients Rash 8 (34.8) Diarrhea 2 (8.7)
Table 3 Summary of pharmacokinetic parameters of icotinib and its five metabolites in NSCLC patients (mean ± SD). 150 mg b.i.d.
AUC0-tau (h mg/L) AUC0-∞ (h mg/L) AUC0-last (h mg/L) CL/F (L/h) Cmax (ng/mL) t1/2 (h) Tmax (h)* Vz (L) Ctrough (ng/mL) CLR (L/h) Ae (%) RCmax RAUCtau RAUCinf Metabolites t1/2 (h)
200 mg b.i.d.
200 mg b.i.d.
Fasted
Fasted
Fasted
Fed
Fed
Fasted
Fasted
Single dose (n = 13)
Multiple-dose (n = 11)
Single dose (n = 8)
Multiple-dose (n = 8)
Single dose (n = 3)
Multiple-dose (n = 2)
Single dose (n = 6)
Multiple-dose (n = 5)
8.22 ± 2.60 11.4 ± 3.54 11.4 ± 3.53 14.5 ± 5.23 1550 ± 577 5.96 ± 2.89 2.0 (0.5,4.0) 121 ± 60.0 NA 0.0262 ± 0.01 0.207 ± 0.080 NA NA NA
12.7 ± 3.62 NA 11.5 ± 5.13 NA 1750 ± 1020 NA 4.0 (0.5, 4.0) NA 693 ± 416 NA NA 1.19 ± 0.363 1.66 ± 0.437 1.24 ± 0.407
6.20 ± 1.82 11.0 ± 3.90 11.0 ± 3.90 13.7 ± 8.35 1400 ± 548 5.68 ± 1.86 2.0 (1.0,2.0) 127 ± 135 NA 0.0201 ± 0.007 0.187 ± 0.080 NA NA NA
10.8 ± 3.72 NA 15.5 ± 5.50 NA 1860 ± 722 NA 1.5 (0.0, 4.0) NA 994 ± 419 NA NA 1.37 ± 0.384 1.79 ± 0.485 1.07 ± 0.403
11.8 ± 2.92 16.5 ± 4.92 16.5 ± 4.92 13.0 ± 4.28 2040 ± 836 5.31 ± 0.07 2.0 (0.5,4.0) 99.4 ± 31.6 NA 0.0334 ± 0.02 0.267 ± 0.130 NA NA NA
17.2 ± 1.77 NA 17.2 ± 1.77 NA 2400 ± 106 NA 3.0 (2.0, 4.0) NA 675 ± 14.1 NA NA 1.25 ± 0.174 1.59 ± 0.292 1.29 ± 0.475
9.33 ± 3.95 12.8 ± 6.38 12.3 ± 6.40 20.0 ± 9.90 1640 ± 375 8.07 ± 8.54 2.0 (0.5,4.0) 217 ± 223 NA 0.0566 ± 0.02 0.313 ± 0.150 NA NA NA
11.6 ± 7.00 NA 11.6 ± 7.00 NA 2098 ± 655.8 NA 1.0 (0.5,2.0) NA 938 ± 458 NA NA 1.04 ± 0.631 1.27 ± 0.690 1.23 ± 0.353
Tmax (h)
Cmax (ng/mL) AUC0-last (h·mg/L)
AUC0-∞ (h·ng/mL)
CLR (L/h)
Ae , dose% Ctrough,ss (ng/mL)
2.0 (0.5, 4.0) 2.0 (1.0, 4.0) 2.0 (1.0, 4.0) 2.0 (1.0, 4.0) 2.0 (1.0, 4.0)
37.7 ± 28.1 61.5 ± 38.7 121 ± 53.4 8.70 ± 3.90 79.9 ± 32.0
0.249 ± 0.186 0.621 ± 0.252 1.26 ± 0.751 0.081 ± 0.0249 0.610 ± 0.294
8.41 ± 6.06 3.17 ± 2.30 1.26 ± 0.97 2.94 ± 1.29 4.48 ± 2.29
0.9 ± 0.7 1.4 ± 1.2 0.9 ± 0.6 0.2 ± 0.1 1.7 ± 0.8
0.184 ± 0.181 0.594 ± 0.261 1.22 ± 0.661 0.0781 ± 0.0238 0.607 ± 0.292
Cmax,ss (ng/mL) Tmax,ss (h)
14.4 ± 9.90 27.7 ± 9.7 45.1 ± 50.6 71.6 ± 56.5 94.8 ± 53.8 132 ± 55.6 5.70 ± 2.60 8.9 ± 2.9 48.5 ± 25.2 73.8 ± 20.5
2.0 (2.0, 12.0) 3.0 (0.0, 12.0) 1.5 (0.0, 4.0) 2.0 (0.0, 4.0) 2.0 (0.0,4.0)
AUC0-tau (h·mg/L)
RAUCtau
RAUCinf
Rcmax
M/PCmax,ss M/PAUCtau
0.200 ± 0.116 0.612 ± 0.511 0.959 ± 0.399 0.0708 ± 0.0226 0.556 ± 0.220
1.0 ± 0.5 1.8 ± 1.4 1.8 ± 1.5 1.6 ± 0.6 1.4 ± 0.5
1.2 ± 0.2 0.94 ± 0.6 1.0 ± 0.6 1.0 ± 0.4 1.0 ± 0.4
0.8 ± 0.2 1.4 ± 1.2 1.5 ± 1.6 1.2 ± 0.5 1.0 ± 0.4
1.9 ± 0.9 4.6 ± 2.2 8.9 ± 4.3 0.6 ± 0.2 4.9 ± 2.1
D. Liu et al. / Lung Cancer 89 (2015) 262–267
5.0 ± 2.1 15.5 ± 11.2 9.2 ± 2.8 9.5 ± 3.0 6.7 ± 1.8
M1 M2 M3 M4 M5
125 mg t.i.d.
Fasted
1.7 ± 0.9 6.3 ± 6.1 8.6 ± 3.7 0.7 ± 0.3 5.2 ± 2.5
*Shown as median (min, max).
Conc. (ng/mL)
Conc. (ng/mL) 10000
100
1000
1
10
0.1
3000
2500
2000
1500
1000
500
0
0
12
4
125 mg t.i.d. fasted 150 mg b.i.d. fasted
72
200 mg b.i.d. fasted
200 mg b.i.d. fed
48
125 mg t.i.d. fasted
150 mg b.i.d. fasted
12
M1 M2 M3 M4 M5
72
200 mg b.i.d. fasted
60
12
M1 M2 M3 M4 M5
200 mg b.i.d. fed
8
8
48
Time (hr)
36
Time (hr)
Time (hr)
24
24
Time (hr)
265
Fig. 1. Concentration–time curve of icotinib in NSCLC patients after single (upper) and multiple doses (lower).
0
4
glomerular filtration (∼7.5 L/h for 70 kg healthy subject [15]) if we considered fu,p of icotinib was 0.015 (unpublished data), which suggested low CLR was caused by high protein binding status. After single dose of icotinib, five metabolites (FM, including M1, M2-A and B, M3, M4, and M5) and icotinib accounted for around 80% of doses (Fig. 2 and Table 3) [4]. Therefore, their PK profiles were addressed in NSCLC patients after single and multiple dosing 150 mg b.i.d. Steady status of FM was reached after continuous 7-day dosing in b.i.d. manner. After correction of molecular weight, total plasma exposure expressed in Cmax and AUC0-tau of FM was 20.9% and 22.5% of icotinib at steady status, respectively. Among them, the exposure of M3 in plasma was around 8.6% of icotinib, which is the highest metabolite in the five metabolites. Their mean elimination t1/2 were 5.0, 15.5, 9.2, 9.5, and 6.7 h for M1-5,
1000
10
0.1
100
1 0
Fig. 2. Concentration–time curve of five metabolites in NSCLC patients after single (upper) and multiple doses (lower).
Conc (ng/mL)
Conc (ng/mL)
266
D. Liu et al. / Lung Cancer 89 (2015) 262–267
Table 4 Summary for anti-tumor activity (n (%)). 150 mg b.i.d. N CR (%) PR (%) SD (%) PD (%) CR + PR (ORR%) CR + PR + SD (DCR%) PFS (day)a a
125 mg t.i.d.
200 mg b.i.d.
Total
23 1(4) 6 (26) 9 (39) 7 (30) 7 (30)
8 0 (0) 2 (25) 6 (75) 0 (0) 2 (25)
9 0 (0) 1 (11) 4 (44) 4 (44) 1 (11)
40 1 (3) 9 (23) 19 (48) 11 (28) 10 (25)
16 (70)
8 (100)
5 (56)
29 (73)
140 (17, 462)
287 (84, 392)
60 (28, 392)
154 (17, 462)
Shown as median (min, max).
respectively. Renal excretion reached plateau within 12 h after dosing for FM. Icotinib and FMs excreted through kidney accounted for 5.3% of doses within 24 h after dosing. 3.5. Anti-tumor activity Thirty-seven patients completed 28-day evaluation. Other 3 patients experienced SAE, which were determined to be progressive disease (PD). All of them were evaluated in anti-tumor activity. One patient taking 150 mg b.i.d. achieved complete response (CR). A total of 9 and 22 patients received partial response (PR) and stable disease (SD), respectively. Objective response rate (ORR, CR + PR) and disease control rate (DCR, CR + PR + SD) were 25% and 73%, respectively (Table 4). The median progression-free survival (PFS) was 154 days (range: 17–462) in entire study population. All patients in 125 mg t.i.d. group received disease control and median PFS was up to 287 days. Among them, 4 patients were treated for more than 1 year, 3 of them were PD at ∼1 year post-treatment, 1 of them was treated for up to 60 weeks without disease progression, survival duration of 7/8 patients were more than 1.5 years. 4. Discussion Although maximum tolerance dose (MTD) was not achieved in this study, 125 mg t.i.d. was recommended as OBD for late phase study because of better safety and efficacy characters than other dosages. Under this dosage, adverse event with ≥3 grade was not observed in this dose level and 100% of patients received disease control in the current study. Based on the current study and other preclinical and clinical studies [2,16], safety and efficacy of icotinib with 125 mg t.i.d. dose level was designed to compare with gefitinib with 250 mg q.d. in Chinese patients with refractory NSCLC [6]. Three patients reported 8 drug-related AEs with ≥3 grade. Except for subject B03 who experienced heavy rash, ILD, and respiration failure ended up with death, 3 other AEs were reported by two patients: ILD, abdominal pain, and nausea. The most frequent drug-related AE with ≥3 grade is ILD (2 patients, 5%). The prevalence of ILD after dosing gefitinib or erlotinib was comparable with placebo group ( 10% parent drug) [21] were found in NSCLC patient and all the five major metabolites found in patients were also found in rats [4], which suggested that PK exposure of these metabolites were highly impossible to produce safety issues [22]. PK exposure expressed in AUC and Cmax of icotinib increased with dose increase over the dose range of 125–200 mg after single dose. But AUC0-tau at steady status was comparable among the three dose groups after multiple doses. Ctrough concentration at steady status also was comparable between 125 mg t.i.d. and 200 mg b.i.d., both of them were 43% and 35% higher than 150 mg b.i.d. Therefore, 125 mg t.i.d. was suggested to be the best dose regimen from the perspective of dose–PK relationship because it can offer higher Ctrough concentration with lower daily dosage after multiple doses. In this study, almost all patients were adenocarcinoma, stage IV, and treated by at least one chemo- or radio-therapy. Smoking status and sex was reported to affect erlotinib efficacy [23,24]. But these effects were not observed in the current study, which may be caused by small sample size or different metabolism mechanism. Additionally, EGFR mutation status was only detected in 14 patients in this study [25]. It was found to be associated to PFS but the association was not statistically significant due to very small sample size and huge inter-subject variability. Briefly, exon 19 deletion (3/7) and exon 21 point mutation (4/7) were found in 7 patients. Among them, one, three, two, and one patients exhibited PD, SD, PR, and CR, respectively. In patients with wild-type EGFR, four, three, and zero patients exhibited PD, SD, and PR/CR, respectively. EGFR mutation was associated with better progress-free survival (PFS) (141 days vs. 61 days) but without a statistically significant difference (P = 0.8597), and median overall survival (OS) (≥449 days vs. 140 days). Although these relationships was not statistically confirmed, icotinib was found to significantly benefit more in patients with mutant EGFR and non-smokers in later ICOGEN study [6] in 2 years later after the current study. In summary, icotinib was well tolerated and it exhibited preliminary anti-tumor activity in Chinese patients with refractory NSCLC over the daily dose range from 300 to 400 mg/day. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. OBD was recommended to be 125 mg t.i.d. for the later clinical study on the basis of lower PK exposure and higher Ctrough , comparable anti-tumor activity, and the best safety characters.
Conflict of interest None declared.
D. Liu et al. / Lung Cancer 89 (2015) 262–267
Acknowledgments The study was supported by the “12th Five-year” National Key Technology R&D Program of China [Ministry of Science and Technology of the People’s Republic of China] (No. 2012ZX09303006-002) and Zhejiang Beta Pharma Inc. (Zhejiang, China). References [1] Gao Z, Chen W, Zhang X, et al. Icotinib, a potent and specific EGFR tyrosine kinase inhibitor, inhibits growth of squamous cell carcinoma cell line A431 through negatively regulating AKT signaling. Biomed Pharmacother 2013;67(5):351–6. [2] Tan F, Shen X, Wang D, et al. Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies. Lung Cancer 2012;76(2):177–82. [3] Liu D, Jiang J, Zhang L, et al. Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects. Cancer Chemother Pharmacol 2014;73(4):721–7. [4] Liu D, Jiang J, Zhang L, et al. Metabolite characterization of a novel anticancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Rapid Commun Mass Spectrom 2011;25(15):2131–40. [5] Camidge DR. Icotinib: kick-starting the Chinese anticancer drug industry. Lancet Oncol 2013;14(10):913–4. [6] Shi Y, Zhang L, Liu X, et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 2013;14(10):953–61. [7] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31–41. [8] Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19(13):3267–79. [9] Cancer Therapy Evaluation Program, NCI, NIH. Common Terminology Criteria for Adverse Events v3.0; 2003 [available at http://ctep.cancer.gov/]. [10] Liu D, Jiang J, Hu P, et al. Quantitative determination of icotinib in human plasma and urine using liquid chromatography coupled to tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877(30):3781–6. [11] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–16.
267
[12] Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 1994;30A(5):635–42. [13] Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004;45(1):93–104. [14] Yamamoto N, Horiike A, Fujisaka Y, et al. Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50-8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 2008;61(3):489–96. [15] Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res 1993;10(7):1093–5. [16] Zhao Q, Shentu J, Xu N, et al. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer 2011;73(2):195–202. [17] Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290(16):2149–58. [18] Silvestri GA, Rivera MP. Targeted therapy for the treatment of advanced nonsmall cell lung cancer: a review of the epidermal growth factor receptor antagonists. Chest 2005;128(6):3975–84. [19] Liang W, Wu X, Fang W, et al. Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS One 2014;9(2):e85245. [20] Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 2003;4(4):224–32. [21] CDER/FDA. Guidance for industry safety testing of drug metabolites; 2008 [available at http://www.fda.gov/Drugs/]. [22] Gao H, Jacobs A, White RE, et al. Meeting Report: Metabolites in safety testing (MIST) symposium-safety assessment of human metabolites: what’s really necessary to ascertain exposure coverage in safety tests. AAPS J 2013;15:970–3. [23] Clark GM, Zborowski DM, Santabarbara P, et al. Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 2006;7(6):389–94. [24] Fukudo M, Ikemi Y, Togashi Y, et al. Population Pharmacokinetics/Pharmacodynamics of Erlotinib and Pharmacogenomic Analysis of Plasma and Cerebrospinal Fluid Drug Concentrations in Japanese Patients with Non-Small Cell Lung Cancer. Clin Pharmacokinet 2013;52:593–609. [25] Ren GJ, Zhao YY, Zhu YJ, et al. Tumor gene mutations and messenger RNA expression: correlation with clinical response to icotinib hydrochloride in nonsmall cell lung cancer. Chin Med J (Engl) 2011;124(1):19–25.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer夽 Dongyang Liu a , Li Zhang b , Yiwen Wu a , Ji Jiang a , Fenlai Tan c , Yingxiang Wang c , Yong Liu c, Pei Hu a,∗ a
Clinical Pharmacology Research Center, Peking Union Medical College Hospital & Chinese Academy of Medical Sciences, Beijing 100032, China Department of Pulmonary Medicine, Peking Union Medical College Hospital & Chinese Academy of Medical Sciences 100032 Beijing, China c Zhejiang Beta Pharma Inc., Zhejiang, China b
a r t i c l e
i n f o
Article history: Received 5 April 2015 Received in revised form 29 May 2015 Accepted 30 May 2015 Keywords: Clinical Pharmacokinetics Safety, Activity Icotinib NSCLC Patients
a b s t r a c t Objectives: To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Materials and methods: Patients (n = 40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100 mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200 mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Results: Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17–462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2 was within 5.31–8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Conclusions: Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Icotinib hydrochloride is a potent and highly selective EGFRTKI to treat NSCLC in vivo and in vitro [1,2]. In 2007, tolerability, single-dosing escalating pharmacokinetics (PK) and food-effect studies were conducted to evaluate PK, tolerability, and food effects in healthy subjects [3]. Then, optimized biologic dose (OBD) in NSCLC patients need to be determined in 2009. Recently, five major metabolites of icotinib in humans were separated and identified [4] and two of them were found to be active (M3 and M5, unpublished data). Although icotinib proved to be non-inferior effective and more safe than gefitinib in 400 NSCLC Chinese patients [5,6],
夽 Trial registration ID: ChiCTR-ONC-08000113. Trial sponsor: Zhejiang Beta Pharma Inc., Hangzhou, Zhejiang, China. ∗ Corresponding author. Tel.: +86 10 69158366. E-mail address: [email protected] (P. Hu). http://dx.doi.org/10.1016/j.lungcan.2015.05.024 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
no safety information about these five metabolites was uncovered so far. Additionally, up to now, full PK and safety profiles, containing metabolite pharmacokinetics, of icotinib in NSCLC patients after single- and multiple-dose were still unpublished. To better understand icotinib and better assist clinical physician in treating NSCLC patients with icotinib, these characters were worthy of being reported. 2. Patient and method 2.1. Patient selection Eligible patients had pathologically confirmed, advanced NSCLC (stage III or IV) with measurable tumor that were refractory to standard therapy or that had no standard therapy; age ≥18 years; life-expectancy ≥12 weeks; Eastern Cooperative Oncology Group (ECOG) performance ≤2; time to stop previous chemotherapy ≥3 weeks; hemoglobin ≥9 g/dL; absolute neutrophil count
D. Liu et al. / Lung Cancer 89 (2015) 262–267
≥1.5 × 109 /L; platelets ≥90 × 109 /L; creatinine ≤1.5 times the upper limit of normal (ULN) or calculated creatinine clearance (CLcr ) ≥60 mL/min (Cockcroft–Gault equation [7]; bilirubin ≤1.5 × ULN; AST and ALT ≤2.5 × ULN (5 × ULN for patients with liver metastases); absence of pregnancy or lactating female, brain metastases; no gastrointestinal tract disease to affect drug absorption; and no coexisting severe, unstable or uncontrollable medical conditions. Exclusions included subjects who had taken any other human epidermal receptor (HER) inhibitors or target drugs to treat cancer. Study protocol and subject informed consent forms (ICF) were approved by Ethics Committee of Peking Union Medical College Hospital (PUMCH, Beijing, China) and the written ICFs of all patients were obtained from subjects before treatment. The study was conducted according to the Declaration of Helsinki and its amendments. 2.2. Drug administration This phase I, open-label, adaptively designed study was divided into two sequential parts. In part 1 (dose-escalation phase), all patients received a single dose of oral icotinib hydrochloride tablet (Beta Pharmaceuticals, ZheJiang, China) followed by multiple doses (b.i.d.) for continuous 28 days started on Day 4. In part 2, once the OBD was determined, 10 extra patients were enrolled to receive icotinib for a continuous 28-day treatment at the OBD level (Cohort G) and 12 additional patients were treated by icotinib (t.i.d.) at approximate daily dose of OBD with a same schedule as part 1 (Cohort H). In part 1, the starting dose, 200 mg b.i.d., represented one fifth of the NOAEL in healthy subjects. Each dose level of 100, 150, 200, 250, 300, and 400 mg BID (Cohort F, A–E) were planned to be examined in one separated cohort (n = 12) during dose-escalation phase. If less than 30% of patients discontinued treatment, dose-escalation continues. Otherwise, the lower dosage would be started. Patients who experienced dose-limited toxicity (DLT) were eligible for additional cohorts at the next lower dose level after recovery from the DLT [8]. Patients would continue treatment at the same dose level as long as icotinib was tolerated well and there was no evidence of disease progression. At least 8 patients completed corresponding study in each cohort. All patients received Icotinib under fasted condition for 2 h before and 1 h post-dose except for the first 3 patients in Cohort C (200 mg, b.i.d.), who received it with food.
of icotinib were measured by high pressure liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and positive ion selected reaction monitoring, as previously described with well accuracy and precision [10]. The five major metabolites [4] in plasma and urine were measured for Cohort B using a previously validated LC-MS/MS method. The accuracy, precision, specificity, recovery, linearity and several of stabilities have been validated for them in human plasma and urine as guided by FDA [10]. 2.5. Pharmacokinetic and pharmacodynamic analysis Pharmacokinetic analyses were performed using WinNonlin 5.1 software (Pharsight Co., California, USA). Standard noncompartmental analysis was conducted to calculate PK parameters using linear/log trapezoidal rule [3]. Descriptive analysis of elimination half-life (t1/2 = 0.693/ke ), maximum observed plasma concentration (Cmax ), trough concentration at status (Ctrough ), time to reach Cmax (Tmax ), area under the plasma concentration–time curve (AUC from 0 to 12 h or 0 to 8 h for b.i.d. or t.i.d. (AUC0-tau ), from 0 to last observed point or 24 h, (AUC0-last or AUC0-24hr ), and from 0 to infinite (AUC0-∞ = AUC0-last + Clast /ke )), apparent clearance (CL/F = Dose/AUC0-∞ ), apparent distribution volume (Vz = Dose/(AUCinf ·kel )), cumulative amount excreted into the urine (Ae,0-last ), and renal clearance (CLR = Ae,0-0-24h /AUC0-0-24h or Ae,tau /AUC0-tau for single dose and multiple doses) was performed in Excel 2003 software (Microsoft Co., USA). Accumulation ratios were calculated with average Cmax,ss /Cmax,single-dose (RCmax ), AUC0-tau,ss /AUC0-tau,single-dose (RAUCtau ), and AUC0-tau,ss /AUC0-∞,single-dose (RAUCinf ). Metabolite-toparent ratios of each metabolite were calculated in mole unit and were reported in M/PCmax,ss and M/PAUCtau . 2.6. Anti-tumor activity Response rate was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) on week 4, 8, 12, and 16 and every 8 weeks thereafter [11] Primary evaluation endpoints include objective response rate (ORR) and disease control rate (DCR). Response was classified quality of life (QoL), secondary endpoint, was accessed every 2 weeks through European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-LC13 program [12].
2.3. Safety monitoring
3. Results
All patients receiving at least one dose of icotinib were considered assessable for safety, which was accessed during the entire first dosing-cycle, at weeks 8, 12, and 16, and every 8 weeks thereafter. Toxicities were graded based on the National Cancer Institute Common Toxicity Criteria (NCICTC), version 3.0 [9]. Treatmentrelated adverse events (TRAEs) were defined as adverse events that were possibly, probably, or definitely related to Icotinib administration and occurred during the first treatment.
3.1. Patients
2.4. Plasma and urine pharmacokinetic sampling and assay For Cohort A–F, and H, blood samples were collected to determine plasma concentrations of icotinib and its five major metabolites on Day 1 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h post-dose; on Days 11, 18, and 25 at pre-dose; and on Day 31 at pre-dose and 0.5, 1, 2, 4, and 12 h post-dose. Urine samples were collected before dosing and over the following postdose intervals: 0–4, 4–8, 8–12, and 12–24 h on Day 1 and first three intervals on Day 31. For Cohort G, blood samples at pre-dose and 2 h post-dose were collected on Days 1, 8, and 28. Plasma and urine samples were stored below −70 ◦ C until analysis. Concentrations
263
Between August 2007 and Feb 2009, 40 patients with advanced NSCLC were enrolled onto the study to receive icotinib at doses ranging from 300 to 400 mg/day. A total of 247 cycles (28 days/cycle) were observed and analyzed by Mar/2010. Their pertinent characteristics are listed in Table 1. Every patient received a fixed dose in the study until discontinued treatment. All 40 patients received at least one of dose. Thirty-seven patients completed the first 28-day treatment and three patients didn’t complete due to dyspnea, interstitial lung disease, or respiratory failure. The median time on Cohort A, B, G, H was 9, 2, 3, and 10 cycles, respectively. 3.2. Dose escalation and DLT After three patients received the initial dose (200 mg, b.i.d., Cohort B) with food, one of them (Subject B03) experienced grade 3 rash and drug-related lethal interstitial lung disease (ILD). Considering that ILD emerged during treatment of erlotinib (6.7%) and gefitinib (5.4%) in Asian patients [13,14], this cohort was discontinued and lower dosage (Cohort A) was tested. After this SAE, icotinib
264
D. Liu et al. / Lung Cancer 89 (2015) 262–267
Table 1 Patient demographics and baseline disease characteristics (n (%)). Demographics/Characteristics (N = 40)
Value
Median age, years (range) Sex, n (%) Male Female ECOG performance status, n (%) 0 1 Pathological type, n (%) Adenocarcinoma Large cell carcinoma Mixed cell carcinoma Squamous cell carcinoma Bronchioloalveolar carcinoma Stage, n (%) III IV Previous treatment Number of prior chemotherapy regimens, n (%) Chemotherapy regimen 1 2 >2 Surgery Taking TKIs before, n (%) History of smoking, n (%) Yes No
57 (47–94) 22 (55) 18 (45) 18 (45) 22 (55) 34 (85) 1 (2.5) 1 (2.5) 3 (7.5) 1 (2.5) 6 (15) 34 (85)
19 (47) 16 (40) 5 (13) 8 (20) 0 (0) 18 (45) 22 (55)
was dosed under fasted condition, where drug was administrated 1 h before taking food or 2 h post-food. At the 150 mg (b.i.d. Cohort A) dose level, a total of 13 patients were enrolled and no grade 3/4 AE was observed except for acute biliary pancreatitis and cancer disease progression. Both of the two AEs were rated as not related or unlike to be related with treatment. The cancer disease progression was firstly diagnosed as ILD followed by the pathological diagnosis of cancer diffuse metastasis in lung through autopsy, which addressed that Subject B03 experienced diffuse metastasis rather than ILD. Therefore, 200 mg b.i.d. dose level (Cohort B) was continued on the basis of well tolerance of icotinib at 150 mg dose level. Finally, a total of 6 patients were additionally enrolled onto Cohort B. Cohorts G and H were sequentially conducted in 10 and 8 patients at dose level of 150 mg b.i.d. and 125 mg t.i.d., respectively. No DLTs occurred in Cohort H (125 mg t.i.d.). At dose level of 200 mg b.i.d., a patient (B03) reported a potential DLT with grade 3 rash and respiratory failure, lethal ILD and circulation failure. He had respiratory failure on Day 7 after dosing. CT result showed
interstitial lung disease and a grade 3 rash were found as the same time. The symptoms were partially reversed by corticosteroid treatment for a period then the patient developed to circulatory failure and multiple-organ failure and died on Day 37. A biopsy of the rash confirmed skin metastasis, indicating disease progression and the SAE was judged as both drug-related and disease-related. Further escalation was not pursued because of this potential ILD and good efficacy at 125 mg t.i.d. dose level. Therefore, the safe and efficacious dose was suggested to be around 400 mg/day. 3.3. Safety Sixty-eight AEs were reported by 26/40 patients (65%). Of them, 44 AE events reported by 22/40 (55%) patients were considered to be icotinib-related by the investigator, with the most frequent being rash (18/40, 45%), gastrointestinal disease (7/40, 17.5%), and interstitial lung disease (2/40, 5%) (Table 2). Most of the events were mild (grade 1/2) and transient. Four patients suffered about 16 events of grade ≥3 severity, and 9 events of grade ≥3 severity in 3 patients (A05, A13, and B03) were suggested to be possibly or probably drug-related. All treatment-related AEs with grade ≥3 severity and treatment-related AEs with grade 1/2 reported in 5% patients were listed in Table 2. Interstitial lung disease was the only adverse event of grade ≥3 severity reported by more than 1 patient. No severe (≥grade 3) unique laboratory abnormalities were found and there was no evidence of recall of radiation injury. Rash (42.5%) and Diarrhea (7.5%) were the most popular treatment-related AE with grade 1/2. 3.4. Pharmacokinetic analysis After single dose of 125–200 mg, icotinib was absorbed quickly (range of Tmax ∼ 0.5–4 h) and eliminated in an approximately mono-exponential manner after single dose; the mean t1/2 was within 5.31–8.07 h, mean Vz was within 99.4–217 L and mean CL/F was within 13.7–20.0 L/h. Less than 0.4% of doses were excreted in unchanged icotinib through kidney (Fig. 1 and Table 3). PK exposure increased with increase of dose levels. After multiple doses, steady status was achieved after 7–11 day continuous dosing. Mean accumulation ratio expressed in Cmax , AUC0-tau , and AUC0-∞ were 1.04–1.37, 1.27–1.79, and 1.07–1.29 respectively, which suggesting a weak accumulation and approximately stationary clearance for icotinib after dosing with b.i.d. or t.i.d. method in NSCLC patients. Mean trough concentrations after multiple doses of 125 mg t.i.d., 150 mg b.i.d., and 200 mg b.i.d. were with 675–994 ng/mL. Renal clearance of icotinib is less than 0.06 L/h, which is comparable to
Table 2 Treatment-related AEs (safety population, n (%)). AE
125 mg TID(n = 8)
200 mg BID(n = 9)
Total(n = 40)
Treatment-related AEs of all grades reported in ≥5% of patients Rash 8 (34.8) Diarrhea 2 (8.7) Abdominal pain 2 (8.7) Nausea 2 (8.7) Interstitial lung disease 1 (4.3)
N (%)
150 mg BID(n = 23)
5 (62.5) 1 (12.5) 0 (0) 0 (0) 1 (12.5)
5 (55.6) 0 (0) 0 (0) 0 (0) 0 (0)
18 (45) 3 (7.5) 2 (5) 2 (5) 2 (5)
Treatment-related AEs with ≥3 Grades Interstitial lung disease Respiratory failure Rash Abdominal pain Nausea Circulation failure Multiple-organ failure
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
1 (11.1) 1 (11.1) 1 (11.1) 0 (0) 0 (0) 1 (11.1) 1 (11.1)
2 (5) 1 (2.5) 1 (2.5) 1 (2.5) 1 (2.5) 1 (2.5) 1 (2.5)
5 (62.5) 1 (12.5)
4 (44.4) 0 (0)
17 (42.5) 3 (7.5)
1 (4.3) 0 (0) 0 (0) 1 (4.3) 1 (4.3) 0 (0) 0 (0)
Treatment-related AEs with Grade 1/2 reported in ≥5% of patients Rash 8 (34.8) Diarrhea 2 (8.7)
Table 3 Summary of pharmacokinetic parameters of icotinib and its five metabolites in NSCLC patients (mean ± SD). 150 mg b.i.d.
AUC0-tau (h mg/L) AUC0-∞ (h mg/L) AUC0-last (h mg/L) CL/F (L/h) Cmax (ng/mL) t1/2 (h) Tmax (h)* Vz (L) Ctrough (ng/mL) CLR (L/h) Ae (%) RCmax RAUCtau RAUCinf Metabolites t1/2 (h)
200 mg b.i.d.
200 mg b.i.d.
Fasted
Fasted
Fasted
Fed
Fed
Fasted
Fasted
Single dose (n = 13)
Multiple-dose (n = 11)
Single dose (n = 8)
Multiple-dose (n = 8)
Single dose (n = 3)
Multiple-dose (n = 2)
Single dose (n = 6)
Multiple-dose (n = 5)
8.22 ± 2.60 11.4 ± 3.54 11.4 ± 3.53 14.5 ± 5.23 1550 ± 577 5.96 ± 2.89 2.0 (0.5,4.0) 121 ± 60.0 NA 0.0262 ± 0.01 0.207 ± 0.080 NA NA NA
12.7 ± 3.62 NA 11.5 ± 5.13 NA 1750 ± 1020 NA 4.0 (0.5, 4.0) NA 693 ± 416 NA NA 1.19 ± 0.363 1.66 ± 0.437 1.24 ± 0.407
6.20 ± 1.82 11.0 ± 3.90 11.0 ± 3.90 13.7 ± 8.35 1400 ± 548 5.68 ± 1.86 2.0 (1.0,2.0) 127 ± 135 NA 0.0201 ± 0.007 0.187 ± 0.080 NA NA NA
10.8 ± 3.72 NA 15.5 ± 5.50 NA 1860 ± 722 NA 1.5 (0.0, 4.0) NA 994 ± 419 NA NA 1.37 ± 0.384 1.79 ± 0.485 1.07 ± 0.403
11.8 ± 2.92 16.5 ± 4.92 16.5 ± 4.92 13.0 ± 4.28 2040 ± 836 5.31 ± 0.07 2.0 (0.5,4.0) 99.4 ± 31.6 NA 0.0334 ± 0.02 0.267 ± 0.130 NA NA NA
17.2 ± 1.77 NA 17.2 ± 1.77 NA 2400 ± 106 NA 3.0 (2.0, 4.0) NA 675 ± 14.1 NA NA 1.25 ± 0.174 1.59 ± 0.292 1.29 ± 0.475
9.33 ± 3.95 12.8 ± 6.38 12.3 ± 6.40 20.0 ± 9.90 1640 ± 375 8.07 ± 8.54 2.0 (0.5,4.0) 217 ± 223 NA 0.0566 ± 0.02 0.313 ± 0.150 NA NA NA
11.6 ± 7.00 NA 11.6 ± 7.00 NA 2098 ± 655.8 NA 1.0 (0.5,2.0) NA 938 ± 458 NA NA 1.04 ± 0.631 1.27 ± 0.690 1.23 ± 0.353
Tmax (h)
Cmax (ng/mL) AUC0-last (h·mg/L)
AUC0-∞ (h·ng/mL)
CLR (L/h)
Ae , dose% Ctrough,ss (ng/mL)
2.0 (0.5, 4.0) 2.0 (1.0, 4.0) 2.0 (1.0, 4.0) 2.0 (1.0, 4.0) 2.0 (1.0, 4.0)
37.7 ± 28.1 61.5 ± 38.7 121 ± 53.4 8.70 ± 3.90 79.9 ± 32.0
0.249 ± 0.186 0.621 ± 0.252 1.26 ± 0.751 0.081 ± 0.0249 0.610 ± 0.294
8.41 ± 6.06 3.17 ± 2.30 1.26 ± 0.97 2.94 ± 1.29 4.48 ± 2.29
0.9 ± 0.7 1.4 ± 1.2 0.9 ± 0.6 0.2 ± 0.1 1.7 ± 0.8
0.184 ± 0.181 0.594 ± 0.261 1.22 ± 0.661 0.0781 ± 0.0238 0.607 ± 0.292
Cmax,ss (ng/mL) Tmax,ss (h)
14.4 ± 9.90 27.7 ± 9.7 45.1 ± 50.6 71.6 ± 56.5 94.8 ± 53.8 132 ± 55.6 5.70 ± 2.60 8.9 ± 2.9 48.5 ± 25.2 73.8 ± 20.5
2.0 (2.0, 12.0) 3.0 (0.0, 12.0) 1.5 (0.0, 4.0) 2.0 (0.0, 4.0) 2.0 (0.0,4.0)
AUC0-tau (h·mg/L)
RAUCtau
RAUCinf
Rcmax
M/PCmax,ss M/PAUCtau
0.200 ± 0.116 0.612 ± 0.511 0.959 ± 0.399 0.0708 ± 0.0226 0.556 ± 0.220
1.0 ± 0.5 1.8 ± 1.4 1.8 ± 1.5 1.6 ± 0.6 1.4 ± 0.5
1.2 ± 0.2 0.94 ± 0.6 1.0 ± 0.6 1.0 ± 0.4 1.0 ± 0.4
0.8 ± 0.2 1.4 ± 1.2 1.5 ± 1.6 1.2 ± 0.5 1.0 ± 0.4
1.9 ± 0.9 4.6 ± 2.2 8.9 ± 4.3 0.6 ± 0.2 4.9 ± 2.1
D. Liu et al. / Lung Cancer 89 (2015) 262–267
5.0 ± 2.1 15.5 ± 11.2 9.2 ± 2.8 9.5 ± 3.0 6.7 ± 1.8
M1 M2 M3 M4 M5
125 mg t.i.d.
Fasted
1.7 ± 0.9 6.3 ± 6.1 8.6 ± 3.7 0.7 ± 0.3 5.2 ± 2.5
*Shown as median (min, max).
Conc. (ng/mL)
Conc. (ng/mL) 10000
100
1000
1
10
0.1
3000
2500
2000
1500
1000
500
0
0
12
4
125 mg t.i.d. fasted 150 mg b.i.d. fasted
72
200 mg b.i.d. fasted
200 mg b.i.d. fed
48
125 mg t.i.d. fasted
150 mg b.i.d. fasted
12
M1 M2 M3 M4 M5
72
200 mg b.i.d. fasted
60
12
M1 M2 M3 M4 M5
200 mg b.i.d. fed
8
8
48
Time (hr)
36
Time (hr)
Time (hr)
24
24
Time (hr)
265
Fig. 1. Concentration–time curve of icotinib in NSCLC patients after single (upper) and multiple doses (lower).
0
4
glomerular filtration (∼7.5 L/h for 70 kg healthy subject [15]) if we considered fu,p of icotinib was 0.015 (unpublished data), which suggested low CLR was caused by high protein binding status. After single dose of icotinib, five metabolites (FM, including M1, M2-A and B, M3, M4, and M5) and icotinib accounted for around 80% of doses (Fig. 2 and Table 3) [4]. Therefore, their PK profiles were addressed in NSCLC patients after single and multiple dosing 150 mg b.i.d. Steady status of FM was reached after continuous 7-day dosing in b.i.d. manner. After correction of molecular weight, total plasma exposure expressed in Cmax and AUC0-tau of FM was 20.9% and 22.5% of icotinib at steady status, respectively. Among them, the exposure of M3 in plasma was around 8.6% of icotinib, which is the highest metabolite in the five metabolites. Their mean elimination t1/2 were 5.0, 15.5, 9.2, 9.5, and 6.7 h for M1-5,
1000
10
0.1
100
1 0
Fig. 2. Concentration–time curve of five metabolites in NSCLC patients after single (upper) and multiple doses (lower).
Conc (ng/mL)
Conc (ng/mL)
266
D. Liu et al. / Lung Cancer 89 (2015) 262–267
Table 4 Summary for anti-tumor activity (n (%)). 150 mg b.i.d. N CR (%) PR (%) SD (%) PD (%) CR + PR (ORR%) CR + PR + SD (DCR%) PFS (day)a a
125 mg t.i.d.
200 mg b.i.d.
Total
23 1(4) 6 (26) 9 (39) 7 (30) 7 (30)
8 0 (0) 2 (25) 6 (75) 0 (0) 2 (25)
9 0 (0) 1 (11) 4 (44) 4 (44) 1 (11)
40 1 (3) 9 (23) 19 (48) 11 (28) 10 (25)
16 (70)
8 (100)
5 (56)
29 (73)
140 (17, 462)
287 (84, 392)
60 (28, 392)
154 (17, 462)
Shown as median (min, max).
respectively. Renal excretion reached plateau within 12 h after dosing for FM. Icotinib and FMs excreted through kidney accounted for 5.3% of doses within 24 h after dosing. 3.5. Anti-tumor activity Thirty-seven patients completed 28-day evaluation. Other 3 patients experienced SAE, which were determined to be progressive disease (PD). All of them were evaluated in anti-tumor activity. One patient taking 150 mg b.i.d. achieved complete response (CR). A total of 9 and 22 patients received partial response (PR) and stable disease (SD), respectively. Objective response rate (ORR, CR + PR) and disease control rate (DCR, CR + PR + SD) were 25% and 73%, respectively (Table 4). The median progression-free survival (PFS) was 154 days (range: 17–462) in entire study population. All patients in 125 mg t.i.d. group received disease control and median PFS was up to 287 days. Among them, 4 patients were treated for more than 1 year, 3 of them were PD at ∼1 year post-treatment, 1 of them was treated for up to 60 weeks without disease progression, survival duration of 7/8 patients were more than 1.5 years. 4. Discussion Although maximum tolerance dose (MTD) was not achieved in this study, 125 mg t.i.d. was recommended as OBD for late phase study because of better safety and efficacy characters than other dosages. Under this dosage, adverse event with ≥3 grade was not observed in this dose level and 100% of patients received disease control in the current study. Based on the current study and other preclinical and clinical studies [2,16], safety and efficacy of icotinib with 125 mg t.i.d. dose level was designed to compare with gefitinib with 250 mg q.d. in Chinese patients with refractory NSCLC [6]. Three patients reported 8 drug-related AEs with ≥3 grade. Except for subject B03 who experienced heavy rash, ILD, and respiration failure ended up with death, 3 other AEs were reported by two patients: ILD, abdominal pain, and nausea. The most frequent drug-related AE with ≥3 grade is ILD (2 patients, 5%). The prevalence of ILD after dosing gefitinib or erlotinib was comparable with placebo group ( 10% parent drug) [21] were found in NSCLC patient and all the five major metabolites found in patients were also found in rats [4], which suggested that PK exposure of these metabolites were highly impossible to produce safety issues [22]. PK exposure expressed in AUC and Cmax of icotinib increased with dose increase over the dose range of 125–200 mg after single dose. But AUC0-tau at steady status was comparable among the three dose groups after multiple doses. Ctrough concentration at steady status also was comparable between 125 mg t.i.d. and 200 mg b.i.d., both of them were 43% and 35% higher than 150 mg b.i.d. Therefore, 125 mg t.i.d. was suggested to be the best dose regimen from the perspective of dose–PK relationship because it can offer higher Ctrough concentration with lower daily dosage after multiple doses. In this study, almost all patients were adenocarcinoma, stage IV, and treated by at least one chemo- or radio-therapy. Smoking status and sex was reported to affect erlotinib efficacy [23,24]. But these effects were not observed in the current study, which may be caused by small sample size or different metabolism mechanism. Additionally, EGFR mutation status was only detected in 14 patients in this study [25]. It was found to be associated to PFS but the association was not statistically significant due to very small sample size and huge inter-subject variability. Briefly, exon 19 deletion (3/7) and exon 21 point mutation (4/7) were found in 7 patients. Among them, one, three, two, and one patients exhibited PD, SD, PR, and CR, respectively. In patients with wild-type EGFR, four, three, and zero patients exhibited PD, SD, and PR/CR, respectively. EGFR mutation was associated with better progress-free survival (PFS) (141 days vs. 61 days) but without a statistically significant difference (P = 0.8597), and median overall survival (OS) (≥449 days vs. 140 days). Although these relationships was not statistically confirmed, icotinib was found to significantly benefit more in patients with mutant EGFR and non-smokers in later ICOGEN study [6] in 2 years later after the current study. In summary, icotinib was well tolerated and it exhibited preliminary anti-tumor activity in Chinese patients with refractory NSCLC over the daily dose range from 300 to 400 mg/day. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. OBD was recommended to be 125 mg t.i.d. for the later clinical study on the basis of lower PK exposure and higher Ctrough , comparable anti-tumor activity, and the best safety characters.
Conflict of interest None declared.
D. Liu et al. / Lung Cancer 89 (2015) 262–267
Acknowledgments The study was supported by the “12th Five-year” National Key Technology R&D Program of China [Ministry of Science and Technology of the People’s Republic of China] (No. 2012ZX09303006-002) and Zhejiang Beta Pharma Inc. (Zhejiang, China). References [1] Gao Z, Chen W, Zhang X, et al. Icotinib, a potent and specific EGFR tyrosine kinase inhibitor, inhibits growth of squamous cell carcinoma cell line A431 through negatively regulating AKT signaling. Biomed Pharmacother 2013;67(5):351–6. [2] Tan F, Shen X, Wang D, et al. Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies. Lung Cancer 2012;76(2):177–82. [3] Liu D, Jiang J, Zhang L, et al. Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects. Cancer Chemother Pharmacol 2014;73(4):721–7. [4] Liu D, Jiang J, Zhang L, et al. Metabolite characterization of a novel anticancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Rapid Commun Mass Spectrom 2011;25(15):2131–40. [5] Camidge DR. Icotinib: kick-starting the Chinese anticancer drug industry. Lancet Oncol 2013;14(10):913–4. [6] Shi Y, Zhang L, Liu X, et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 2013;14(10):953–61. [7] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31–41. [8] Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19(13):3267–79. [9] Cancer Therapy Evaluation Program, NCI, NIH. Common Terminology Criteria for Adverse Events v3.0; 2003 [available at http://ctep.cancer.gov/]. [10] Liu D, Jiang J, Hu P, et al. Quantitative determination of icotinib in human plasma and urine using liquid chromatography coupled to tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877(30):3781–6. [11] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–16.
267
[12] Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 1994;30A(5):635–42. [13] Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004;45(1):93–104. [14] Yamamoto N, Horiike A, Fujisaka Y, et al. Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50-8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 2008;61(3):489–96. [15] Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res 1993;10(7):1093–5. [16] Zhao Q, Shentu J, Xu N, et al. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer 2011;73(2):195–202. [17] Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290(16):2149–58. [18] Silvestri GA, Rivera MP. Targeted therapy for the treatment of advanced nonsmall cell lung cancer: a review of the epidermal growth factor receptor antagonists. Chest 2005;128(6):3975–84. [19] Liang W, Wu X, Fang W, et al. Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS One 2014;9(2):e85245. [20] Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 2003;4(4):224–32. [21] CDER/FDA. Guidance for industry safety testing of drug metabolites; 2008 [available at http://www.fda.gov/Drugs/]. [22] Gao H, Jacobs A, White RE, et al. Meeting Report: Metabolites in safety testing (MIST) symposium-safety assessment of human metabolites: what’s really necessary to ascertain exposure coverage in safety tests. AAPS J 2013;15:970–3. [23] Clark GM, Zborowski DM, Santabarbara P, et al. Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 2006;7(6):389–94. [24] Fukudo M, Ikemi Y, Togashi Y, et al. Population Pharmacokinetics/Pharmacodynamics of Erlotinib and Pharmacogenomic Analysis of Plasma and Cerebrospinal Fluid Drug Concentrations in Japanese Patients with Non-Small Cell Lung Cancer. Clin Pharmacokinet 2013;52:593–609. [25] Ren GJ, Zhao YY, Zhu YJ, et al. Tumor gene mutations and messenger RNA expression: correlation with clinical response to icotinib hydrochloride in nonsmall cell lung cancer. Chin Med J (Engl) 2011;124(1):19–25.
