Abstract
Lessons Learned
MET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for response rate and progression‐free survival.
Whether MET overexpression can be considered a potential predictive biomarker and be used as an inclusion criterion is worth investigating in a future study.
Background
Metatinib tromethamine tablet (metatinib) is a small molecule receptor kinase inhibitor targeting both c‐MET and vascular endothelial growth factor receptor 2. This phase I trial aimed to determine the dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of metatinib in patients with advanced solid tumors.
Methods
Eligible patients received a single dose of metatinib in a 3 + 3 dose‐escalation design with dose levels of 25–800 mg/day, after a single dose on day 1, then 2 days off, and then a multidose schedule of once‐daily doses for 25 consecutive days (days 4–28). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), efficacy, and biomarkers.
Results
Eighteen patients (including nine patients with hepatocellular carcinoma [HCC]) received at least one dose of study drug (one patient quit the study without continuous multiple‐dose administration after receiving a single dose of metatinib). Hand‐foot skin reaction, diarrhea, and liver dysfunction were the DLTs, and 200 mg/day was the MTD. The most common treatment‐related adverse events (TRAEs) were skin toxicity (50%), diarrhea (33.3%), and liver dysfunction (27.8%). Three patients (only one of six in the 200 mg/day cohort; the other two in the 300 mg/day cohort) experienced severe TRAEs: one patient with severe liver dysfunction and two patients with severe liver dysfunction and skin toxicity, respectively. Pharmacokinetics assessment indicated that metatinib was rapidly absorbed and metabolized to the formation of reactive metabolite, SCR‐1510, after single‐dose administration. The mean time taken to achieve maximum concentration and terminal elimination half‐life of SCR‐1510 was approximately 2.0–3.0 hours and ranged from 8 to 14 hours. Two patients had partial responses. The objective response rate and disease control rate (DCR) were 11.1% and 61.1%, respectively. The median progression‐free survival (PFS) was 2.75 months.
Conclusion
Metatinib administration of 200 mg/day was well tolerated, safe, and effective. The MTD was 200 mg/day, which should be recommended in further investigations.
Keywords: Metatinib tromethamine tablet, Advanced cancer, Phase I
Discussion
The toxicity profile of metatinib has been shown to be similar to that of other analogous agents, such as apatinib, sunitinib, anlotinib, and regorafenib. Hand‐foot skin reaction, diarrhea, and liver dysfunction were the most frequent serious TRAEs and were also the DLTs observed in the present study (Table 1). Although almost all patients had mild to moderate TRAEs, none in the lower dose group (<200 mg/day) developed grade 3–5 TRAEs. Although grade 3 skin toxicity in the 200 mg/day group was observed, it could be quickly controlled with drug discontinuation and dose reduction, suggesting continuous accumulation of toxicity that might be manageable by changing the administration protocol to a 2‐weeks‐on/1‐week‐break schedule. Nine patients with advanced liver cancer presented higher tumor load and limited liver reserve capacity; this may account for why liver toxicity was also a common adverse event (AE). The lower incidence of TRAEs (hypertension, proteinuria, fatigue) supported the advantages over similar tyrosine kinase inhibitor drugs. Palmar‐plantar erythema syndrome was remarkable and manageable. The incidence of common TRAEs in metatinib was as follows: diarrhea (33.3%), grade 3 diarrhea (5.6%), palmar‐plantar erythema syndrome (50%), and grade 3 palmar‐plantar erythema syndrome (5.6%). Similarly, in the cabozantinib group in a randomized, phase III trial [19, 26], the incidence of diarrhea and palmar‐plantar erythema syndrome was 74% and 42%, respectively, and the incidence of the common grade 3 or 4 AEs were diarrhea (13%) and palmar‐plantar erythema syndrome (8%). Discontinuation of study treatment because of AEs not related to disease occurred in 22.2% of patients and in 100% of patients administered 300 mg/day, suggesting that overall tolerability of the agent was acceptable and that 200 mg/day should be the optimal dose investigated in further study. The longest PFS was 8.5 months in a patient with rectal cancer and 5.5 months in a patient with HCC, who both received ≥100 mg/day, which suggested a substantial and promising antitumor activity of metatinib. Considering that the terminal elimination half‐life of SCR‐1510 ranges from 8 to 14 hours, daily administration is reasonable. The continuous accumulation of SCR‐1510 at day 29 was more than twice than that at day 1, and significantly, toxicity was observed in the 300 mg/day cohort. To adapt to the PK feature, whether the administration protocol should be changed to the daily treatment in a 2‐weeks‐on/1‐week‐off cycle to support the feasibility needs further study.
Table 1.
Adverse events of patients in the extended period (n = 10)
| Adverse events | Grade 1, n (%) | Grade 2, n (%) | Grade 3, n (%) | Total, n (%) |
|---|---|---|---|---|
| Any TRAE | 1 (10) | 5 (50) | 3 (30) | 9 (90) |
| Skin toxicities | 3 (30) | 2 (20) | 1 (10) | 6 (60) |
| Palmar‐plantar erythema syndrome (peeling) | 3 (30) | 2 (20) | 1 (10) | 6 (60) |
| Skin pain | 1 (10) | 1 (10) | 1 (10) | 3 (30) |
| Rash maculo‐papular | 0 (0) | 1 (10) | 0 (0) | 10 (10) |
| Circumoral numbness | 2 (20) | 0 (0) | 0 (0) | 2 (20) |
| Edema limbs | 1 (10) | 0 (0) | 0 (0) | 1 (10) |
| Diarrhea | 1 (10) | 2 (20) | 1 (10) | 4 (40) |
| Abdominal pain | 2 (10) | 0 (0) | 0 (0) | 2 (10) |
| Anorexia | 0 (0) | 1 (10) | 0 (0) | 1 (10) |
| Dysphagia | 1 (10) | 0 (0) | 0 (0) | 1 (10) |
| Constipation | 1 (10) | 0 (0) | 0 (0) | 1 (10) |
| Blood bilirubin elevation | 0 (0) | 1 (10) | 1 (10) | 2 (20) |
| AST elevation | 1 (10) | 1 (10) | 1 (10) | 3 (30) |
| ALT elevation | 2 (20) | 1 (10) | 1 (10) | 4 (40) |
| Hypertension | 0 (0) | 1 (10) | 0 (0) | 1 (10) |
| Thrombocytopenia | 0 (0) | 2 (20) | 0 (0) | 2 (20) |
| Anemia | 0 (0) | 1 (10) | 0 (0) | 1 (10) |
| Fatigue | 0 (0) | 1 (10) | 0 (0) | 1 (10) |
| Fever | 1 (10) | 0 (0) | 0 (0) | 1 (10) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; TRAE, treatment‐related adverse event.
Trial Information
| Disease |
Advanced cancer/solid tumor only Colorectal cancer Esophageal cancer Gastric cancer Hepatocellular carcinoma |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase I, 3 + 3 |
| Primary Endpoints |
Maximum tolerated dose Toxicity Safety Recommended phase II dose |
| Secondary Endpoints |
Pharmacokinetics Efficacy Correlative endpoint |
| Additional Details of Endpoints or Study Design | |
| Patient Eligibility: This study was a single‐center, single‐arm, open‐label, prospective phase I trial, registered in May 2013 (registration no. NCT02004548), carried out in the Department of Abdominal Oncology and Institute of Clinical Pharmacology, GCP Center, West China Hospital, Sichuan University, China, which was approved by the ethics committee and registered in a clinical trial registry. | |
| Eligibility criteria: Patients with pathologically and/or cytologically proven advanced or metastatic digestive tract cancer with no standard therapy were enrolled in the study. Eligibility criteria included age 18–74 years, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, expected survival duration of more than 3 months, weight ≥ 45 kg for men and weight ≥ 40 kg for women, and body mass index (BMI) between 18 and 28 kg/m2. Routine blood test, bone marrow, liver and kidney function, and heart function must be determined to be within normal range and with no major organ dysfunction. Patients must be capable of understanding and be willing to comply with the protocol and follow‐up and had to give signed informed consent document for the study. | |
| Exclusion criteria: Patients were not eligible if they presented the following: brain metastases; an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia, active hepatitis B or hepatitis C, active tuberculosis, or HIV positivity; involvement of major blood vessels or nerves by tumor; uncontrollable hypertension or left ventricular ejection fraction <50%; disease history of bleeding or thromboembolic events occurring within the past 6 months and need for preventive anticoagulant therapy; or third lacunar effusion with difficulty to control. | |
| Treatment Plan: All patients received escalating doses of metatinib tromethamine tablet for only a single dose of metatinib on day 1 and were evaluated for toxicity for 3 days (days 1–3). After 3 days following the first dose (single dose), subjects continued to receive metatinib once daily (multidose schedule) at the intended dose level for 25 consecutive days (days 4–28) and were closely observed in the following 4 days (days 29–32). The single dose was administered orally 2 hours before breakfast, and in the multidose schedule, the dose was daily administered orally 1 hour before breakfast, which could be modified according to the following PK data. A standard 3+3 design was applied in this study, with terms of cohort expansion to six evaluable patients if a DLT was observed in the first cycle (days 1–32) in the initial three patients. If two DLTs were observed during the first cycle (days 1–32) in a cohort, dose escalation was stopped, and dosage continued at a lower level until the MTD was identified. The planned dose levels were 25, 50, 100, 200, 300, 450, 600, and 800 mg/day, respectively. | |
| Extended period: After the patients completed the single dose and then the multidose schedule daily for 25 consecutive days, if clinical benefits were achieved at the efficacy evaluation on the 32nd day (±3 days), then the patients continued the corresponding daily dose treatment in the extended period. The treatment period was to be extended until the disease progressed, intolerable AEs occurred, or the patient withdrew informed consent. | |
| Efficacy assessment: Efficacy assessment was evaluated according to the National Cancer Institute RECIST version 1.1. The evaluated lesions were assessed on day 32 (±3 days) compared with the baseline imaging examination done within 4 weeks before the first dose. For all patients enrolled into the extended period of treatment, the imaging evaluation was performed every 6 weeks, and the standard imaging examination (computed tomography or magnetic resonance imaging) and physical examination (for superficial lesions) was used for every evaluation. | |
| Safety assessment: All adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, and the attribution between AE and the study drug was determined. Safety was evaluated daily after the first dose administration in the following 29 days, then every 3 weeks during the first four follow‐up visits during the extended treatment period; then, every 6 weeks after that, the AE and laboratory tests were evaluated. During treatment, vital signs (body temperature, pulse, respiration, blood pressure) were monitored every day, and physical examination was carried out daily from day 1 to day 29. The safety endpoints were DLT, MTD, AEs, laboratory examination (hematology, clinical biochemistry, urinary routine, and coagulation), ECG, adrenocorticotropic hormone level, and thyroid function. The safety follow‐up continued until 30 days after the treatment. All patients were followed up by telephone every 3 months until the patient died. | |
| Pharmacokinetic assessment: In single‐dose studies, the serial blood samples were collected before and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours after the first dose. In multiple‐dose studies, blood samples were collected 0.5 hour before dosing on days 8, 15, and 29 and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the last dosing on day 29. All blood samples were centrifuged to prepare plasma fractions and stored at −70°C for subsequently analysis. The main PK parameters in single‐dose studies were as follows: the maximum concentration (Cmax) and the time taken to achieve Cmax (Tmax), the area under concentration‐time curve up to the last measured time point (AUC0–t), the area under concentration‐time curve up to positive infinity (AUC0–∞), and terminal elimination half‐life (t1/2). The PK parameters in multiple‐dose studies were Tmax, Cmax, AUC0–t, AUC0–∞, and fluctuation coefficient. The plasma concentration of the reactive metabolites of metatinib tromethamine tablet (SCR‐1510 and SCR‐1512) after single‐dose and multiple‐dose administration at each dose level, were detected by Phoenix WinNonlin 6.1 (Certara USA, Inc., Princeton, NJ). | |
| Statistical analysis: The measurement data use means ± SD or medians (min, max) for statistical description and paired t test to compare the difference within the group with baseline data. Frequency (constituent ratio) is used for statistical description to the enumeration data and the changes in each dose group before and after the treatments. The two‐sided test is used for all statistical tests, and a value of p < .05 was considered to be statistically significant. A noncompartmental analysis model was used to calculate the plasma pharmacokinetic parameters AUC0–t, AUC0–∞, and t1/2. Cmax and Tmax were adopted as the measured value. The correlation between dosage and drug plasma exposure was evaluated by the power model method, and the ratio of the main parameters between fed and fasted as well as the 90% confidence interval (CIs) were calculated. Phoenix WinNonlin version 6.3 was used to perform pharmacokinetic analyses. A value of p < .05 was considered to be statistically significant. | |
| Investigator's Analysis | Active and should be pursued further |
Drug Information: Metatinib Tromethamine Tablet
| Generic/Working Name | Metatinib tromethamine tablet |
| Company Name | Jiangsu Simcere Pharmaceutical Co., Ltd |
| Drug Type | Small molecule |
| Drug Class | MET ‐ c‐MET |
| Dose | 25–300 mg (tablets) per day milligrams (mg) per flat dose |
| Route | Oral (p.o.) |
| Schedule of Administration | All patients received escalating doses of metatinib tromethamine tablet with a single dose on day 1, then 2 days off, and then a multidose schedule, meaning once daily for 25 consecutive days (days 4–28). The single dose was administered orally 2 hours before the breakfast; in the multidose schedule, the daily dose was administered orally 1 hour before the breakfast and could be modified according to the following PK data. A standard 3 + 3 design was applied in this study, with terms of cohort expansion to six evaluable patients if a DLT was observed in the first cycle (days 1–32) in the initial three patients. If two DLTs were observed during the first cycle (days 1–32) in a cohort, dose escalation was stopped, and dosage continued at a lower level until the MTD was identified. The planned doses were 25, 50, 100, 200, 300, 450, 600, and 800 mg/day, respectively. |
Patient Characteristics
| Number of patients, male | 15 |
| Number of patients, female | 3 |
| Stage | All patients had stage IV advanced or metastatic digestive tract cancer with no standard therapy options; pathological and/or cytological confirmation was required. |
| Age | Median (range): 49 (22–72) years |
| Number of prior systemic therapies | Median (range): 2 (1–3) |
| Performance status: ECOG |
0 — 8 1 — 8 2 — 2 3 — 0 Unknown — 0 |
| Other | The median BMI (kg/m2) was 20.79, ranging from 17.1 to 27.9. The numbers of patients with Child‐Pugh scores of A and B were 17 and 1, respectively. The numbers of patients with two lesions (primary and metastatic lesions) and with at least three lesions were 6 and 12, respectively. |
| Cancer types or histologic subtypes |
Esophageal cancer, 4 Liver cancer, 9 Gastric cancer, 2 Rectal cancer, 2 Jejunal cancer, 1 |
Primary Assessment Method
| Number of patients screened | 20 |
| Number of patients enrolled | 18 |
| Number of patients evaluable for toxicity | 18 |
| Number of patients evaluated for efficacy | 18 |
| Evaluation method | RECIST version 1.1 |
| Response assessment CR | n = 0 (0%) |
| Response assessment PR | n = 11.1 (2%) |
| Response assessment SD | n = 50 (9%) |
| Response assessment PD | n = 38.9 (7%) |
| Response assessment OTHER | n = 0 (0%) |
| Median duration assessments PFS | 84 days, CI: 59.887–120.891 |
| Median duration assessments TTP | 84 days, CI: 59.887–120.891 |
| Median duration of treatment | 75 days |
Outcome Notes
According to the RECIST version 1.1 criteria, 18 patients (including one patient who discontinued the study after receiving a single dose of metatinib) were assessed radiologically at day 32. In the first cycle, one patient (5.6%) in the 300 mg/day group had partial response (PR), 10 patients (55.6%) maintained stable disease (SD), 8 patients presented progressive disease (PD), and all 3 patients in the 25 mg/day group had PD.
In the first cycle, the DCR was 61.1% (11/18); among the patients who was achieved DCR, 10 patients continued on the treatment in the following extended period. During the extended period, three patients had PD, and seven patients had SD at the first efficacy evaluation; another patient in the 200 mg/day group achieved PR after 3 months entering into the extended period, although he experienced severe skin toxicity and reduced the dose to 100 mg/day. In total, in the current phase I study, two patients had PR, and nine patients exhibited SD, including four patients with tumor burden shrinkage; the objective response rate and DCR were 11.1% and 61.1%, respectively.
The median PFS in 18 patients was 2.75 months, ranging from 1.0 to 8.5 months, and the median PFS in 10 patients included in the extended period was 4.0 months, ranging from 2 to 8.5 months.
MET analysis: Samples from a total of 18 patients, in 162 paraffin‐embedded tumor slides, were evaluated for MET expression status by MET immunohistochemistry (IHC) and dual‐color fluorescence in situ hybridization (FISH), and for MET mutation by sequence analysis (Table 2). There were 2 cases with IHC 2+, 3 cases with IHC 1+, and 13 cases with IHC 0. MET gene amplification was not detected, and MET exon 14 skipping was exhibited in one patient with IHC 2+, showing a weak concordance between IHC and FISH. One patient in the 200 mg/day group whose tumor showed both MET IHC 2+ and exon 14 skipping achieved PR and 8.5 months’ PFS. A 5.5‐month PFS was also observed in another patient with MET IHC 2+, suggesting that MET status might be associated with the efficacy in the study.
Kaplan‐Meier Time Units (days)
| Time of scheduled assessment and/or time of event | No. progressed (or deaths) | No. censored | Percent at start of evaluation period | Kaplan‐Meier % | No. at next evaluation/No. at risk |
|---|---|---|---|---|---|
| 0 | 0 | 0 | 100.00 | 100.00 | 18 |
| 32 | 7 | 0 | 100.00 | 61.11 | 11 |
| 75 | 1 | 0 | 61.11 | 55.55 | 10 |
| 78 | 1 | 0 | 55.55 | 49.99 | 9 |
| 90 | 1 | 0 | 49.99 | 44.44 | 8 |
| 120 | 3 | 0 | 44.44 | 27.77 | 5 |
| 121 | 1 | 0 | 27.77 | 22.22 | 4 |
| 122 | 1 | 0 | 22.22 | 16.66 | 3 |
| 135 | 1 | 0 | 16.66 | 11.11 | 2 |
| 166 | 1 | 0 | 11.11 | 5.55 | 1 |
| 256 | 1 | 0 | 5.55 | 0.00 | 0 |
Waterfall plot of evaluable patients (n = 18) showing the largest decrease in the sum of the target lesions compared with baseline.
Adverse Events
| All Dose Levels, Cycle 1 | |||||||
|---|---|---|---|---|---|---|---|
| Name | NC/NA, % | Grade 1, % | Grade 2, % | Grade 3, % | Grade 4, % | Grade 5, % | All grades, % |
| Diarrhea | 67 | 17 | 11 | 6 | 0 | 0 | 33 |
| Palmar‐plantar erythrodysesthesia syndrome | 50 | 17 | 28 | 6 | 0 | 0 | 50 |
| Pain of skin | 83 | 0 | 11 | 6 | 0 | 0 | 17 |
| Rash maculo‐papular | 89 | 6 | 6 | 0 | 0 | 0 | 11 |
| Lower gastrointestinal hemorrhage | 94 | 0 | 6 | 0 | 0 | 0 | 6 |
| Abdominal pain | 94 | 0 | 6 | 0 | 0 | 0 | 6 |
| Back pain | 94 | 0 | 6 | 0 | 0 | 0 | 6 |
| Proteinuria | 94 | 0 | 6 | 0 | 0 | 0 | 6 |
| Hearing impaired | 94 | 6 | 0 | 0 | 0 | 0 | 6 |
| Insomnia | 94 | 0 | 6 | 0 | 0 | 0 | 6 |
| Neutrophil count decreased | 94 | 0 | 6 | 0 | 0 | 0 | 6 |
| Hematuria | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Aspartate aminotransferase increased | 78 | 17 | 0 | 6 | 0 | 0 | 22 |
| Alanine aminotransferase increased | 78 | 11 | 6 | 6 | 0 | 0 | 22 |
| Blood bilirubin increased | 83 | 6 | 0 | 11 | 0 | 0 | 17 |
| Electrocardiogram QT corrected interval prolonged | 78 | 11 | 11 | 0 | 0 | 0 | 22 |
| Anorexia | 78 | 11 | 11 | 0 | 0 | 0 | 22 |
| Hypoglossal nerve disorder | 83 | 17 | 0 | 0 | 0 | 0 | 17 |
| Fatigue | 83 | 17 | 0 | 0 | 0 | 0 | 17 |
| Hypertension | 83 | 17 | 0 | 0 | 0 | 0 | 17 |
| White blood cell decreased | 89 | 0 | 11 | 0 | 0 | 0 | 11 |
| Platelet count decreased | 89 | 0 | 11 | 0 | 0 | 0 | 11 |
| Palpitations | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Hemorrhoids | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Mucositis oral | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Vomiting | 89 | 6 | 6 | 0 | 0 | 0 | 11 |
| Nausea | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Fever | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Hypokalemia | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Pain in extremity | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Palmar‐plantar erythrodysesthesia syndrome | 40 | 30 | 20 | 10 | 0 | 0 | 60 |
| Pain of skin | 70 | 10 | 10 | 10 | 0 | 0 | 30 |
| Rash maculo‐papular | 90 | 0 | 10 | 0 | 0 | 0 | 10 |
| Circumoral numbness | 80 | 20 | 0 | 0 | 0 | 0 | 20 |
| Edema limbs | 90 | 10 | 0 | 0 | 0 | 0 | 10 |
| Diarrhea | 60 | 10 | 20 | 10 | 0 | 0 | 40 |
| Abdominal pain | 80 | 20 | 0 | 0 | 0 | 0 | 20 |
| Anorexia | 90 | 0 | 10 | 0 | 0 | 0 | 10 |
| Dysphagia | 90 | 10 | 0 | 0 | 0 | 0 | 10 |
| Constipation | 90 | 10 | 0 | 0 | 0 | 0 | 10 |
| Blood bilirubin increased | 80 | 0 | 10 | 10 | 0 | 0 | 20 |
| Aspartate aminotransferase increased | 70 | 10 | 10 | 10 | 0 | 0 | 30 |
| Alanine aminotransferase increased | 60 | 20 | 10 | 10 | 0 | 0 | 40 |
| Hypertension | 90 | 0 | 10 | 0 | 0 | 0 | 10 |
| Platelet count decreased | 80 | 0 | 20 | 0 | 0 | 0 | 20 |
| Anemia | 90 | 0 | 10 | 0 | 0 | 0 | 10 |
| Fatigue | 90 | 0 | 10 | 0 | 0 | 0 | 10 |
| Fever | 90 | 10 | 0 | 0 | 0 | 0 | 10 |
Adverse Events Legend
Treatment‐related adverse events of patients in the first cycle (n = 18). Abbreviation: NC/NA, no change from baseline/no adverse event.
Serious Adverse Events
| Name | Grade | Attribution |
|---|---|---|
| Hand‐foot skin reaction | 3 | Definite |
| Diarrhea | 3 | Definite |
| Liver dysfunction | 3 | Definite |
Serious Adverse Events Legend
Hand‐foot skin reaction, diarrhea, and liver dysfunction were the most frequent serious TRAEs and were also the DLTs observed in the present study.
Pharmacokinetics/Pharmacodynamics
| See Table 3. |
Table 3.
Pharmacokinetic parameters of SCR‐1510 and SCR‐1512, concentration of the reactive metabolites of metatinib tromethamine tablet after a single dose and multiple‐dose schedule in all patients
| Parameter | Unit | Measurement of single‐dose dependent pharmacokinetics at day 1 | Measurement of multiple‐dose dependent pharmacokinetics at day 29 | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 25 mg/day (n = 3) | 50 mg/day (n = 4) | 100 mg/day (n = 3) | 200 mg/day (n = 6) | 300 mg/day (n = 2) | 25 mg/day (n = 3) | 50 mg/day (n = 3) | 100 mg/day (n = 3) | 200 mg/day (n = 5) | 300 mg/day (n = 2) | ||
| SCR‐1510 | |||||||||||
| Cmax | ng/mL | 180.35 ± 90.27 | 341.04 ± 175.61 | 792.44 ± 105.12 | 1,312.23 ± 682.62 | 2,810.83 ± 2,040.37 | 268.40 ± 66.99 | 471.62 ± 159.40 | 981.28 ± 100.04 | 2,066.41 ± 1,048.30 | 3,629.26 ± 157.97 |
| Tmax | hour | 2.67 ± 0.58 | 4.50 ± 5.07 | 2.67 ± 1.15 | 4.00 ± 2.00 | 2.50 ± 0.71 | 1.67 ± 0.28 | 1.33 ± 0.58 | 4.33 ± 1.53 | 3.60 ± 0.55 | 2.50 ± 0.71 |
| AUC0‐t |
hour*ng/ mL |
2,116.79 ± 1,554.88 | 4,861.34 ± 2,656.57 | 14,350.00 ± 6,581.95 | 21,037.57 ± 9,671.28 | 38,622.97 ± 24,309.57 | 118.53 ± 44.33 | 7,393.18 ± 3,127.88 | 23,924.26 ± 4,301.22 | 50,134.35 ± 24,593.97 | 122,532.94 ± 22,855.14 |
| AUC0‐∞ |
hour*ng/ mL |
2,161.32 ± 1,575.95 | 4,967.39 ± 2,747.22 | 14,552.67 ± 6,640.64 | 21,183.29 ± 9,717.07 | 39,340.88 ± 24,188.51 | 3,708.11 ± 1,657.55 | 7,485.62 ± 3,219.96 | 24,523.83 ± 4,837.07 | 50,832.92 ± 24,930.50 | 159,154.87 ± 55,721.86 |
| t1/2 | hour | 9.91 ± 1.27 | 8.35 ± 3.69 | 12.41 ± 4.48 | 8.48 ± 2.14 | 13.31 ± 2.70 | 11.26 ± 2.16 | 10.66 ± 2.51 | 11.30 ± 4.15 | 11.55 ± 1.40 | 31.05 ± 12.09 |
| Fluctuation coefficient | % | — | — | — | — | — | 201.45 ± 72.01 | 177.76 ± 70.61 | 86.52 ± 15.29 | 87.82 ± 22.00 | 67.91 ± 16.59 |
| SCR‐1512 | |||||||||||
| Cmax | ng/mL | 73.77 ± 43.33 | 127.18 ± 63.18 | 232.79 ± 252.96 | 335.06 ± 189.87 | 382.90 ± 323.83 | 139.25 ± 46.80 | 146.75 ± 101.19 | 311.88 ± 205.76 | 470.85 ± 327.17 | 1,415.69 ± 723.72 |
| Tmax | hour | 3.67 ± 2.08 | 13.50 ± 12.15 | 14.67 ± 8.33 | 12.17 ± 9.35 | 9.00 ± 4.24 | 3.33 ± 4.16 | 8.67 ± 5.77 | 7.33 ± 1.15 | 1.80 ± 1.10 | 1.50 ± 0.71 |
| AUC0‐t |
hour*ng/ mL |
1,607.10 ± 774.35 | 3,930.15 ± 3,826.66 | 6,772.35 ± 6,579.02 | 10,012.86 ± 6,421.09 | 10,977.71 ± 8,712.42 | 3,979.45 ± 1,799.53 | 3,994.10 ± 3,199.80 | 10,546.48 ± 7,981.98 | 14,830.55 ± 8,935.82 | 59,035.61 ± 53,496.82 |
| AUC0‐∞ |
hour*ng/ mL |
1,701.08 ± 764.09 | 6,010.75 ± 7,615.43 | 6,916.06 ± 6,705.61 | 10,582.82 ± 7,202.00 | 11,112.95 ± 8,672.48 | 4,224.96 ± 2,016.43 | 4,303.23 ± 3,572.96 | 12,059.26 ± 10,262.54 | 15,565.86 ± 9,588.14 | 219,535.16 ± 273,159.07 |
| t1/2 | hour | 14.84 ± 4.03 | 20.03 ± 20.51 | 12.04 ± 3.62 | 11.14 ± 5.36 | 10.83 ± 3.29 | 15.21 ± 3.22 | 15.14 ± 4.48 | 17.18 ± 7.95 | 15.00 ± 2.02 | 92.81 ± 91.03 |
| Fluctuation coefficient | % | — | — | — | — | — | 89.20 ± 20.81 | 24.75 ± 15.47 | 65.93 ± 37.33 | 55.60 ± 17.58 | 99.10 ± 39.89 |
Abbreviations: —, not available ; AUC0–t, area under the concentration‐time curve up to the last measured time point; AUC0‐∞, area under the concentration‐time curve up to positive infinity; Cmax, maximum concentration; t1/2, terminal elimination half‐life; Tmax, time to achieve maximum concentration.
Assessment, Analysis, and Discussion
| Completion | Study completed |
| Investigator's Assessment | Active and should be pursued further |
The receptor–tyrosine kinase c‐MET, which is encoded by the MET proto‐oncogene, was identified as the receptor for hepatocyte growth factor (HGF) [1, 2]. The HGF‐MET pathway was found to be vital for the growth, survival, and invasive potential of cancers by activating MAPK/ERK cascades, the PI3K/Akt axis, and the STAT3 pathway [3]; therefore, both HGF and MET are targets in anticancer drug discovery [4].
Changes in serum or tissue HGF levels and MET expression/phosphorylation in tumors were reported in several kinds of tumors, such as gastric cancer, lung cancer, breast cancer, renal cell carcinoma, and hepatocellular carcinoma [5, 6, 7, 8]. The prevalence of HGF/MET pathway activation in human malignancies has driven the development of drug programs.
Tumor angiogenesis is crucial to tumor growth, progression, and metastasis [9, 10], and antiangiogenic therapy has been a successfully used strategy for cancer treatment [11]. Whereas the therapeutic resistance toward antiangiogenic therapy is a limitation of vascular endothelial growth factor receptor (VEGFR) in clinical treatment, HGF mediates angiogenesis through positive vascular endothelial growth factor (VEGF) [12], and increased MET expression has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of several cancers [13, 14, 15]. Hence, the HGF/c‐MET pathway is one of the most investigated signaling pathways in anti‐VEGF therapy/VEGFR‐resistant tumors [16, 17]. Recent studies have suggested that blockade of both MET and VEGFR pathways may achieve better treatment outcome in cancer treatment [18]. Cabozantinib, an inhibitor of tyrosine kinases, including VEGF receptors 1, 2, and 3, MET, and AXL, exhibited its efficacy in several types of solid tumor and became the standard of care for patients with hepatocellular carcinoma (HCC) and renal cell carcinoma [19, 20, 21].
Metatinib tromethamine tablet, an inhibitor targeting both c‐MET and VEGFR‐2, has exhibited antitumor activity (in MET‐dependent and non–MET‐dependent tumor models), good pharmacokinetics (PK), and reversible toxicities.
The toxicity profile of metatinib was similar to that of other analogous agents, such as apatinib, sunitinib, anlotinib, and regorafenib [22, 23, 24, 25]. Hand‐foot skin reaction, diarrhea, and liver dysfunction were the most frequent serious treatment‐related adverse events (TRAEs) and were also the dose‐limiting toxicities observed in the present study. Whereas almost all patients had mild to moderate TRAEs, none in the lower dose group (<200 mg/day) developed grade 3–5 TRAEs. Although severe skin toxicity in the 200 mg/day group was observed, it could be quickly controlled with drug discontinuation and dose decrease, suggesting a continuous accumulation of toxicity that might be manageable with a change in administration protocol to the 2‐weeks‐on/1‐week‐break schedule. Nine patients with advanced liver cancer presented higher tumor load and limited liver reserve capacity, which may account for why liver toxicity is also a common adverse event. The lower incidence of TRAEs (hypertension, proteinuria, fatigue) supported the advantages over similar tyrosine kinase inhibitor drugs. Palmar‐plantar erythema syndrome was remarkable and manageable. Similarly, in the cabozantinib group in a randomized, phase III trial [19, 26], the incidence of diarrhea and palmar‐plantar erythema syndrome was 74% and 42%, respectively; even the common grade 3 or 4 adverse events were diarrhea (13%) and palmar‐plantar erythema syndrome (8%). Discontinuation of study treatment because of adverse events not related to disease occurred in 22.2% of patients and in 100% of patients administered 300 mg/day, suggesting that overall tolerability of the agent was acceptable and that 200 mg/day should be the optimal dose investigated in further study. The longest progression‐free survival (PFS) was 8.5 months in a patient with rectal cancer and 5.5 months in a patient with HCC, who both received ≥100 mg/day, which suggested a substantial and promising antitumor activity of metatinib. Considering the t1/2 of SCR‐1510 ranged from 8 to 14 hours, daily administration is reasonable. The continuous accumulation of SCR‐1510 at day 29 was more than double that at day 1, and significantly, toxicity was observed in the 300 mg/day cohort (Figs. 1 and 2). To adapt to the PK feature, whether the administration protocol should be changed to the daily treatment in a 2‐weeks‐on/1‐week‐off cycle to support the feasibility needs further study.
Figure 1.
The mean (+1 SD) plasma concentration‐time curve of SCR‐1510 in different cohorts after a single dose on the first cycle, day 1 (A) and after multidose administration on day 29 (B).
Figure 2.
The chemical structure of metatinib.
MET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for response rate and PFS; whether MET overexpression can be considered a potential predictive biomarker and even be used as an inclusion criterion is worth investigating in future studies.
Disclosures
The authors indicated no financial relationships.
Figures and Tables
Table 2.
Correlation among MET overexpression, gene amplification, and tumor response in patients
| Patient number | Dose cohort (mg/day) | Primary tumor location | Tumor response | PFS (months) | MET IHC score | MET amplification | MET mutation |
|---|---|---|---|---|---|---|---|
| 1 | 25 | Esophageal cancer | PD | 1 | — | — | None |
| 2 | 25 | Esophageal cancer | PD | 1 | — | — | None |
| 3 | 25 | Esophageal cancer | PD | 1 | + | — | None |
| 4 | 50 | Liver cancer | PD | 1 | — | — | None |
| 5 | 50 | Liver cancer | PD | 1 | + | — | None |
| 6 | 50 | Gastric cancer | SD | 3 | — | — | None |
| 7 | 50 | Liver cancer | SD | 2.5 | — | — | None |
| 8 | 100 | Liver cancer | SD | 4.5 | + | — | None |
| 9 | 100 | Gastric cancer | PD | 1 | — | — | None |
| 10 | 100 | Liver cancer | SD | 4 | — | — | None |
| 11 | 200 | Liver cancer | SD | 5.5 | ++ | — | None |
| 12 | 200 | Liver cancer | PD | 1 | — | — | None |
| 13 | 200 | Liver cancer | SD | 4 | — | — | None |
| 14 | 200 | Liver cancer | SD | 4 | — | — | None |
| 15 | 200 | Rectal cancer | PR | 8.5 | ++ | — | Exon 14 skipping |
| 16 | 200 | Rectal cancer | SD | 4 | — | — | None |
| 17 | 300 | Jejunal cancer | SD | 3 | — | — | None |
| 18 | 300 | Esophageal cancer | PR | 3 | — | — | None |
Abbreviations: —, negative; IHC, immunohistochemistry; PD, progressive disease; PFS, progression‐free survival; PR, partial response; SD, stable disease.
Acknowledgments
We thank the patients who participated in this study, their families, and the investigators from the study center. This study was sponsored by Jiangsu Simcere Pharmaceutical Co., Ltd. This research was supported by Major Specific Project of Sichuan Province of China (2020YFS0034)
No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact commercialreprints@wiley.com. For permission information contact permissions@wiley.com.
Footnotes
- ClinicalTrials.gov Identifier: NCT02004548
- Sponsor: Jiangsu Simcere Pharmaceutical Co., Ltd
- Principal Investigator: Feng Bi and Li Zheng
- IRB Approved: Yes
Contributor Information
Feng Bi, Email: bifeng@scu.edu.cn.
Li Zheng, Email: lzheng2005618@163.com.
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