Abstract
Objective
Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics, tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.
Methods
Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50−600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles. Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.
Results
Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea (85.7%), vomiting (28.6%), nausea (25.0%) and decreased appetite (17.9%). No grade 4 drug-related adverse events were reported. At 50−600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response (CR), and three achieved partial response (PR). The objective response rate (ORR) and disease control rate (DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival (PFS) was 3.98 months.
Conclusions
Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase III trial (No. NCT05122494).
Keywords: Advanced breast cancer, HER2-positive, Hemay022, first-in-human trial
Introduction
Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor (EGFR) family, which is overexpressed in 15%−20% of human breast cancers (1-3). The discovery that HER2 amplification or overexpression is associated with inferior survival in breast cancer patients eventually led to the development of HER2 monoclonal antibody (mAb) trastuzumab (4). The dependence of tumor on HER2, coupled with effective HER2-targeted drugs such as trastuzumab, pertuzumab and most recently, tucatinib, pyrotinib and trastuzumab deruxtecan, has contributed to these survival improvements in patients with HER2-positive breast cancer (5-8). The standard first-line therapy for HER2-positive metastatic breast cancer is the combination of anti-HER2 monoclonal antibodies trastuzumab and pertuzumab plus chemotherapy (docetaxel or paclitaxel); HER2 antibody-drug conjugate fam-trastuzumab deruxtecan-nxkim was the recommended standard second-line therapy (9). In the third-line or beyond treatment for HER2-positive metastatic breast cancer, small-molecule tyrosine kinase inhibitors (TKIs: tucatinib, lapatinib and neratinib) play an essential role in this setting (5,9).
The small, orally active molecule TKIs (tucatinib, lapatinib, pyrotinib and neratinib) diffuse across the cell membrane and bind to the cytoplasmic catalytic kinase domain of the HER family proteins and compete with adenosine triphosphate (ATP), thus blocking tyrosine phosphorylation and activation of downstream signaling cascades and leading to a decreased growth and proliferation of the cancer cells (10). Hemay022 is a novel, highly selective, small-molecule TKI with comparable potencies against EGFR/HER1 (IC50, 0.4 nmol/L) and HER2 (IC50, 2.9 nmol/L). Hemay022 has demonstrated anti-tumor activity in various in vitro and xenograft models. Based on the preclinical evidence, we conducted a first-in-human phase I trial to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of oral Hemay022 in patients with HER2-positive advanced breast cancer.
Materials and methods
Ethical approval
The protocol was approved by the Independent Ethics Committee of the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences and Peking Union Medical College (No. 15-040/967). This study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the ethical principles in the Declaration of Helsinki. Each patient signed a written informed consent before participating in the trial.
Study design
This open-label, phase I trial in patients with advanced breast cancer was conducted in China [https://clinicaltrials.gov (No. NCT02476539) and http://www.chinadrugtrials.org.cn (No. CTR20150326)]. The trial was designed under the traditional 3+3 design for dose escalation, and the doses were 50 mg QD (3 subjects), 100 mg QD (3 subjects), 200 mg QD (3 subjects), 300 mg QD (3 subjects), 400 mg QD (3 subjects), 500 mg QD (3 subjects), 300 mg BID (6 subjects) and 600 mg QD (4 subjects) (Figure 1).
Figure 1.
Flow chart of subject distribution. ICF, informed consent form; DLT, dose-limiting toxicity.
Patient eligibility
Patients were eligible for enrollment if they 1) had a pathologically confirmed diagnosis of HER2-positive (defined as either an immunohistochemistry score of 3+ or 2+ together with HER2 gene amplification by fluorescence in situ hybridisation) advanced breast cancer; 2) aged between 18 and 65 years; 3) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 4) preferred to have at least one measurable lesion defined by revised Response Evaluation Criteria in Solid Tumors guidelines version 1.1 (RECIST v1.1); 5) had adequate bone marrow and organ function; and 6) left ventricular ejection fraction (LVEF) ≥50% as measured by ultrasonic cardiogram (UCG).
Patients were excluded if they had 1) received other clinical trials’ treatment within 4 weeks before the study; 2) have received other target therapy within 4 weeks before study; 3) LVEF<50%; 4) active central nervous system metastases; or 5) clinically QTc prolongation, ventricular tachycardia, ventricular fibrillation, heart block, myocardial infarction within 1 year, congestive heart failure, symptoms requiring medicine treatment patients with coronary heart diseases.
Procedures
In this dose escalation phase I trial, the traditional 3+3 design was applied with three to six patients enrolled per dose level, and the escalation continued until two or more patients had dose-limiting toxicities (DLTs) in one dose cohort during the DLT assessment period [from the administration of the first study dose to the end of the first cycle (28 d)]. The starting dose of Hemay022 was 50 mg QD and was escalated to 600 mg QD (50 mg QD, 100 mg QD, 200 mg QD, 300 mg QD, 400 mg QD, 500 mg QD, 300 mg BID and 600 mg QD) in a modified Fibonacci scheme (11).
DLT was defined as an adverse event (AE) that met any of the following criteria: grade 2 nephrotoxicity, grade 3 cardiotoxicity, grade ≥3 nonhematologic toxicity (excluding treatable grade ≥3 AE of fatigue, nausea, vomiting, diarrhoea, constipation and hypertension), grade 4 hematologic toxicity [including leukopenia, thrombocytopenia, hemoglobinopenia, grade 3 neutropenia with fever (neutrophil count <0.5×109/L and fever ≥37.5 oC) and grade 3 thrombocytopenia with a tendency to bleed].
All patients were first given a single dose of oral Hemay022. After a 7-day washout, the patient was administered continuous doses of Hemay022 once daily for four weeks in 28-day cycles. Dose interruption or reduction was permitted after the initiation of the second cycle of treatment as prespecified in the protocol. Patients who achieved complete response (CR), partial response (PR) or stable disease (SD) at the first efficacy assessment after receiving two cycles of Hemay022 could continue treatment until disease progression, intolerable toxicity, withdrawal of patient informed consent or investigator decision.
Endpoints
The primary endpoint was the maximum tolerated dose (MTD) of Hemay022 and pharmacokinetic parameters in patients with advanced breast cancer. The MTD was the highest-dose level at which ≤1/6 of the patients reported a DLT within the first cycle of multiple dosing. The secondary endpoints included safety, the investigator-assessed objective response rate (ORR, defined as the proportion of patients with CR and PR as the best overall response), disease control rate (DCR, defined as the proportion of patients with CR, PR or SD≥24 weeks) per RECIST v1.1 and progression-free survival (PFS).
Assessment
Safety and tolerability were regularly monitored from the time of the informed consent until 28 d after the last administration of the study drug. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Tumor response was measured by applying computerised tomography at baseline and every two (up to 18 cycles) or four cycles (more than 18 cycles) after the start of multiple once-daily drug administration. Each subject must have an assessment of a specific tumor lesion during the trial by applying the same evaluation techniques (e.g., enhanced computed tomography). The response was classified as CR, PR, SD or progressive disease (PD) according to RECIST v1.1 by the investigator (12).
All subjects were required to have blood samples collected for pharmacokinetic evaluation. Subjects were given a single oral dose followed by multiple oral administrations. The time points for single-dose PK blood samples were before study drug administration (C0D1) and 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (C0D1), 24 h (C0D2), 48 h (C0D3) and 72 h (C0D4) after study drug administration. The time points for multiple (daily) oral administrations of PK blood samples were C1D1, C1D7, C1D14, C1D21 and C1D28 before study drug administration, and 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h and 72 h after C1D28 study drug administration. The plasma concentrations of Hemay022 were measured by liquid chromatography with tandem mass spectrometry.
Statistical analysis
The DLT analysis set included all patients who received at least one dose of the study drug and completed the first cycle of treatment or discontinued the study drug due to AE during the first treatment cycle. The ORR and DCR were calculated, with the corresponding 95% confidence intervals (95% CIs) provided. The Kaplan-Meier test plots were used to summarize PFS and OS; their censoring rates, quartiles, and 95% CIs are listed separately. PK analysis was conducted in patients who received at least one dose of the study drug and had evaluable post-treatment PK parameters. PK parameters were calculated by applying the non-compartmental model with Phoenix WinNonlin 8.3.1 (Pharsight, Mountain View, CA, USA). All statistical analyses were conducted using SAS statistical analysis software (Version 9.4; SAS Institute Inc., Cary, USA).
Results
Patient characteristics
Forty patients were screened between Sep 30, 2015 and Sep 30, 2018. Among them, 28 patients were enrolled and took Hemay022. All 28 patients were HER2-positive stage IV advanced breast cancer patients who failed standard therapy. The baseline demographic characteristics of enrolled patients are presented in Table 1. The median age at enrolment was 54 (range: 25−65) years. Among the patients, 71.4% had at least three lines of prior chemotherapy, 21.4% of the patients had two lines of prior chemotherapy, and 7.1% of the patients had one line of previous chemotherapy. Among the patients, 64.3% had former anti-HER2 therapy of trastuzumab, and 3.6% had former anti-HER2 therapy of pyrotinib (an irreversible EGFR/HER2 inhibitor). Median follow-up was 3.06 (range: 0.56−33.48) months. The median PFS was 3.96 (95% CI, 2.14−9.49) months. The main reason for treatment discontinuation was PD, and 67.9% of the patients dropped out because of this reason. At the data cut-off on Aug 22, 2023, there is still one patient in the 500 mg dosage group on the treatment follow-up (d 1 was on Jun 13, 2017). No treatment-related deaths were reported.
Table 1. Demographics and baseline disease characteristics.
| Variables | n (%) | ||||||||
| 50 mg QD (N=3) |
100 mg QD (N=3) |
200 mg QD (N=3) |
300 mg QD (N=3) |
400 mg QD (N=3) |
500 mg QD (N=3) |
600 mg QD (N=4) |
300 mg BID (N=6) |
All patients (N=28) |
|
| ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization. | |||||||||
| Age (year) [median (range)] |
61 (41−65) | 36 (35−40) | 59 (58−60) | 50 (50−60) | 60 (26−62) | 54 (47−58) | 57 (52−60) | 52 (25−62) | 59 (25−65) |
| Gender: female | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 4 (100) | 6 (100) | 28 (100) |
| ECOG score | |||||||||
| 0 | 0 (0) | 0 (0) | 1 (33.3) | 2 (66.7) | 3 (100) | 3 (100) | 3 (75.0) | 6 (100) | 18 (64.3) |
| 1 | 3 (100) | 3 (100) | 2 (66.7) | 1 (33.3) | 0 (0) | 0 (0) | 1 (25.0) | 0 (0) | 10 (35.7) |
| HER2 positive | |||||||||
| IHC 3+ | 3 (100) | 2 (66.7) | 3 (100) | 2 (66.7) | 2 (66.7) | 3 (100) | 3 (75.0) | 5 (83.3) | 23 (82.1) |
| FISH+ | 0 (0) | 1 (33.3) | 0 (0) | 1 (33.3) | 1 (33.3) | 0 (0) | 1 (25.0) | 1 (16.7) | 5 (17.9) |
| Tumor stage at study entry | |||||||||
| IV | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 4 (100) | 6 (100) | 28 (100) |
| Previous therapy | |||||||||
| Surgery | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 3 (100) | 4(100) | 6 (100) | 28 (100) |
| Radiotherapy | 2 (66.7) | 1 (33.3) | 3 (100) | 2 (66.7) | 3 (100) | 2 (66.7) | 3 (75.0) | 4 (66.7) | 20 (71.4) |
| Chemotherapy | |||||||||
| 1−2 regimens | 1 (33.3) | 0 (0) | 1 (33.3) | 1 (33.3) | 2 (66.7) | 2 (66.7) | 0 (0) | 1 (16.7) | 8 (28.6) |
| 3−7 regimens | 2 (66.7) | 3 (100) | 2 (66.7) | 2 (66.7) | 1 (33.3) | 1 (33.3) | 4 (100) | 5 (83.3) | 20 (71.4) |
| Anti-HER2 therapy | |||||||||
| Trastuzumab | 1 (33.3) | 3 (100) | 3 (100) | 0 (0) | 1 (33.3) | 1 (33.3) | 6 (100) | 3 (75.0) | 18 (64.3) |
| Pyrotinib | 0 (0) | 1 (33.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (3.6) |
Safety and tolerability
The dose escalation of Hemay022 was from 50 mg QD to 600 mg QD, while with 300 mg BID administration just before the dosage of 600 mg QD. No DLT was observed in all QD dose cohorts within the first treatment cycle, and the MTD of QD administration was not reached. While DLT was observed in the 300 mg BID group (1 out of 6 patients), and thus BID administration was not further investigated.
The median duration of Hemay022 treatment was 2.17 (range: 0.03–26.81) months. Only one patient discontinued treatment due to AE (grade 3 diarrhoea). In this study, a total of 28 (100%) subjects entered the safety analysis set (SS), and 27 (96.4%) had at least one treatment-emergent adverse event (TEAE). There were 391 events in total, of which 287 events were of grade 1 severity, 72 events were of grade 2 severity, and 31 events were of grade 3 severity. All TEAEs occurring in ≥5% of the patients are provided in Table 2. The most frequent TEAE was diarrhoea (85.7%) and followed by vomiting (28.6%), nausea (25.0%), decreased appetite (17.9%), upper respiratory tract infections (14.3%), dizziness (14.3%), white blood cell count low (10.7%), cough (10.7%), abdominal pain (10.7%), dyspepsia (10.7%), pain in extremity (7.1%), ALT increased (7.1%), fatigue (7.1%), hypertension (7.1%), skin itchiness (7.1%), rash (7.1%), headache (7.1%) and anorexia (7.1%). Grade 3 TEAEs (data not shown) were diarrhoea (39.3%), vomiting (3.6%), pleural effusion (3.6%), blood sugar increase (3.6%,) and back pain (3.6%). There were no grade 4 and grade 5 TEAEs. There were 3 reported serious adverse events (SAEs): one SAE of respiratory failure occurred before screening (after informed consent was signed) and was considered not related to the study drug; one SAE of pleural effusion was deemed to be related to the patient’s oncological condition and was unlikely to be related to the study drug and the last SAE of pericardial effusion was considered to be related to the patient’s oncological condition and was unlikely to be related to the study drug.
Table 2. TEAEs occurring in ≥5% of patients (N=28).
| AEs | n (%) | |
| All grades | Grade 3 | |
| TEAE, treatment-emergent adverse events. No grade 4 and 5 adverse events occurred. | ||
| Diarrhea | 24 (85.7) | 11 (39.3) |
| Vomiting | 8 (28.6) | 1 (3.6) |
| Nausea | 7 (25.0) | 0 (0) |
| Decreased appetite | 5 (17.9) | 0 (0) |
| Upper respiratory tract infections | 4 (14.3) | 0 (0) |
| Dizziness | 4 (14.3) | 0 (0) |
| White blood cell count low | 3 (10.7) | 0 (0) |
| Cough | 3 (10.7) | 0 (0) |
| Abdominal pain | 3 (10.7) | 0 (0) |
| Dyspepsia | 3 (10.7) | 0 (0) |
| Pain in extremity | 2 (7.1) | 0 (0) |
| ALT increased | 2 (7.1) | 0 (0) |
| Fatigue | 2 (7.1) | 0 (0) |
| Hypertension | 2 (7.1) | 0 (0) |
| Skin itchiness | 2 (7.1) | 0 (0) |
| Rash | 2 (7.1) | 0 (0) |
| Headache | 2 (7.1) | 0 (0) |
| Anorexia | 2 (7.1) | 0 (0) |
PK
PK parameters of single and multiple dosing of Hemay022 are presented in Table 3. At 50−600 mg doses, the median time to peak concentration was 1.5−4.0 h after a single dose of Hemay022. At doses of 100−600 mg, the median terminal half-life was 14.70−17.90 h after a single dose of Hemay022, while the half-life of 50 mg dosage was 4.46 h. The clearance (CL/F) was 283−522 L/h and the apparent volume of distribution (Vz/F) was 6,200−13,500 L at the dosage range of 100−600 mg. The CL/F was 2,770 L/h, and the Vz/F was 17,800 L at the dose of 50 mg. The median time to peak concentration was 1.0−4.0 h and the median terminal half-life was 12.70−27.10 h at steady state on d 28 and the mean accumulation ratio for area under the concentration-time curve (AUC) was 1.02−2.72 at the dosage range of 50−600 mg. The steady-state apparent clearance (CLss/F) was 336−2,070 L/h, and the Vz/F was 11,300−38,100 L at the dosage range of 50−600 mg at steady state on d 28. After multiple administrations of Hemay022, the plasma exposure level [steady-state maximum plasma concentration (Css, max) and steady-state area under the curve (AUCss)] of Hemay022 in each dose group increased with the increased dose. The Css, max at the doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg QD and 300 mg BID were 16.9 ng/mL, 42.6 ng/mL, 69.5 ng/mL, 122.0 ng/mL, 110.0 ng/mL, 179.0 ng/mL, 323.0 ng/mL and 77.4 ng/mL. The AUCss at the doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg QD and 300 mg BID were 24.2 h·ng/mL, 284.0 h·ng/mL, 554.0 h·ng/mL, 702.0 h·ng/mL, 807.0 h·ng/mL, 1,130.0 h·ng/mL, 1,790.0 h·ng/mL and 429.0 h·ng/mL.
Table 3. Plasma pharmacokinetics of single and multiple dosing of Hemay022.
| Variables | 50 mg QD | 100 mg QD | 200 mg QD | 300 mg QD | 400 mg QD | 500 mg QD | 600 mg QD | 300 mg BID |
| *, 300 mg BID: AUC0−12 (AUC0−24 for the QD dosage groups). Data are [median (range)] for Tmax and [geometric mean (geometric coefficient of variation (%)] for others. Tmax, time to reach Cmax; Cmax, peak plasma concentration; AUC0−24, area under the curve from time 0 to 24 h; t1/2, terminal half-life; CL/F, apparent clearance; Vz/F, apparent volume of distribution; AUCss, area under the curve for dose interval (24 h for QD and 12 h for BID); CLss/F, steady-state apparent clearance; Rac (AUC), accumulation ratio for AUC. | ||||||||
| Single dosing | n=3 | n=3 | n=3 | n=3 | n=3 | n=3 | n=4 | n=4 |
| Tmax (h) | 1.5 (0.5−3.0) | 3.0 (1.0−6.0) | 3.0 (3.0−3.0) | 4.0 (2.0−4.0) | 2.0 (1.5−6.0) | 3.0 (1.5−4.0) | 2.5 (1.5−4.0) | 3.0 (3.0−6.0) |
| Cmax (ng/mL) | 6.56 (99.2) | 32.40 (70.3) | 57.40 (39.7) | 97.90 (53.1) | 95.80 (25.0) | 129.00 (13.2) | 236.00 (14.1) | 60.20 (108.2) |
| AUC0−24
(h·ng/mL)* |
17.3 (190.0) | 190.0 (36.2) | 328.0 (40.2) | 565.0 (34.1) | 635.0 (28.1) | 915.0 (27.6) | 1,770.0 (17.8) | 303.0 (104.5) |
| t1/2 (h) | 4.46 (82.3) | 14.70 (21.7) | 16.90 (3.5) | 16.20 (8.5) | 17.90 (20.2) | 15.00 (24.9) | 15.20 (20.0) | 3.10 (7.0) |
| CL/F (L/h) | 2,770 (205.4) | 445 (34.9) | 478 (41.1) | 443 (35.2) | 522 (33.4) | 456 (28.3) | 283 (21.1) | 763 (128.2) |
| Vz/F (L) | 17,800 (64.5) | 9,410 (29.8) | 11,600 (38.3) | 10,300 (32.6) | 13,500 (12.7) | 9,850 (55.7) | 6,200 (30.8) | 3,410 (140.9) |
| Multiple dosing | n=3 | n=3 | n=3 | n=3 | n=3 | n=2 | n=3 | n=5 |
| Tmax (h) | 1.0 (0.5−3.0) | 3.0 (2.0−3.0) | 4.0 (2.0−4.0) | 2.0 (1.5−2.0) | 2.0 (1.5−3.0) | 2.4 (1.0−4.0) | 1.5 (1.0−2.0) | 2.0 (0−3.0) |
| Css, max (ng/mL) | 16.9 (152.3) | 42.6 (46.1) | 69.5 (43.2) | 122.0 (23.0) | 110.0 (69.8) | 179.0 (46.2) | 323.0 (67.9) | 77.4 (73.4) |
| AUCss (h·ng/mL)* |
24.2 (55.5) | 284.0 (31.8) | 554.0 (24.8) | 702.0 (31.6) | 807.0 (53.5) | 1,130.0 (18.0) | 1,790.0 (83.3) | 429.0 (56.1) |
| t1/2 (h) | 12.70 (214.9) | 24.90 (14.9) | 21.80 (38.0) | 26.40 (19.2) | 27.10 (13.2) | 18.60 (17.5) | 24.50 (35.1) | 17.60 (11.3) |
| CLss/F (L/h) | 2,070 (55.5) | 352 (31.8) | 361 (24.8) | 427 (31.6) | 496 (53.5) | 443 (18.0) | 336 (83.3) | 700 (56.1) |
| Vz/F (L) | 38,100 (93.9) | 12,700 (24.7) | 11,300 (59.4) | 16,300 (50.8) | 19,400 (49.9) | 11,900 (36.4) | 11,900 (136.5) | 17,800 (70.2) |
| Rac (AUC) | 2.72 (8.8) | 1.49 (27.9) | 1.69 (20.6) | 1.24 (35.3) | 1.27 (23.1) | 1.06 (30.5) | 1.02 (54.8) | 1.44 (97.3) |
Efficacy
Among the 28 patients with HER2-positive advanced breast cancer, 27 were evaluable for tumor response [one patient was without measurable lesions; thus, the tumor evaluation result was not available (NA)]. One of the 28 patients had CR, with a CR rate of 3.6%. Three patients (10.7%, 3/28) had PR, and nine patients had SD with an SD rate of 32.1%. The ORR in the 28 patients was 14.3% (95% CI, 1.3%−27.2%). The DCR in the 28 patients was 46.4% (95% CI, 28.0%−64.9%) (Table 4). PD occurred in 19 out of the 28 patients (67.9%). The median PFS was 3.98 (95% CI, 2.14−9.49) months, and the censoring rate was 32.1% (9/28). The most prolonged PFS was 17.1 months in the 500 mg dosage group. One patient in the 500 mg group was recruited based on the pathological results and was in remission without measurable tumor lesions, and this patient still not reached PD up to the date of preparing the manuscript on Aug 22, 2023 (d 1 of the study drug administration was Jun 13, 2017).
Table 4. Tumor response per RECIST v1.1.
| Best overall response | n (%) | ||||||||
| 50 mg QD (n=3) |
100 mg QD (n=3) |
200 mg QD (n=3) |
300 mg QD (n=3) |
400 mg QD (n=3) |
500 mg QD (n=3) |
600 mg QD (n=4) |
300 mg BID (n=6) |
All patients (n=28) |
|
| RECIST, response evaluation criteria in solid tumors; DCR, disease control rate. *, Patient no identifiable lesions on imaging but more than 6 years on Hemay022 without progression. | |||||||||
| Complete response | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (33.3) | 0 (0) | 0 (0) | 1 (3.6) |
| Partial response | 0 (0) | 0 (0) | 0 (0) | 1 (33.3) | 0 (0) | 0 (0) | 0 (0) | 2 (33.3) | 3 (10.7) |
| Stable disease | 0 (0) | 2 (66.7) | 2 (66.7) | 1 (33.3) | 0 (0) | 0 (0) | 2 (50.0) | 2 (33.3) | 9 (32.1) |
| Not available | / | / | / | / | / | 1 (33.3)* | / | / | 1 (3.6) |
| DCR [% (95% CI)] | 0 | 66.7 (13.3−100) | 66.7 (13.3−100) | 66.7 (13.3−100) | 0 | 33.3 (0−86.7) | 50.0 (1.0−99.0) | 66.7 (28.9−100) | 46.4 (28.0−64.9) |
Discussion
In this first-in-human phase I study, Hemay022 was generally well tolerated without needing to adjust doses up to 600 mg QD and 300 mg BID in both the 7-day evaluation phase and the treatment continuation phase in advanced breast cancer patients. No MTD was reached at the highest dose tested (600 mg QD) in the once-daily dosing regimen. Twice-daily dosing at the maximum dose tested (300 mg BID) indicated DLT to be grade 3 diarrhoea.
Hemay022 was rapidly absorbed and reached Cmax within 1.0−4.0 h upon intake. At 50−600 mg doses, plasma exposure increased with the increase of doses. No saturation of absorption was observed at doses of 50−600 mg; with the terminal half-life of 12.70−27.10 h, the PK data of Hemay022 supported the once-daily administration schedule. Hemay022 showed a large apparent volume of distribution (11,300−38,100 L), suggesting that it was widely distributed in the body.
Normally, clinical responses are associated with drug exposure, in which the higher doses (thus the higher exposure) result in better clinical responses. However, in this study, this relationship is not very clear: in the 50 mg QD cohort, there was no CR, PR or SD; in the 100 mg QD cohort, there were 2 SDs in 3 patients; in the 200 mg QD cohort, there were 2 SDs in 3 patients; in the 300 mg QD cohort, there were 1 PR and 1 SD in 3 patients; in the 400 mg QD cohort, there was no CR, PR or SD; in the 500 mg QD cohort, there was 1 CR in 3 patients and in the 600 mg QD cohort, there were 2 SDs in 4 patients. This phenomenon might be due to the limited response data. In this phase of the phase I trial, the median PFS of Hemay022 was 3.98 (95% CI: 2.14−9.49) months. In the phase I trial of neratinib in solid tumor patients (13), the median PFS was 3.6 (95% CI: 1.7−5.6) months in patients with breast cancer. While in the phase Ib trial of pyrotinib in breast cancer patients (5), the median PFS was 8.2 (95% CI: 5.6−10.9) months. So, the efficacy of Hemay022 is comparable to the other irreversible TKIs. Especially in the 500 mg QD cohort of Hemay022, the PFS is 17.1 months and it is better than pyrotinib with the longest PFS of 13.7 months in the 400 mg QD cohort (5). Thus, 500 mg QD was the dosage chosen for the phase III (NCT05122494) study of Hemay022 but not as a single agent.
Hemay022 was well tolerated at doses ranging from 50 to 600 mg once daily with grade 1 and 2 diarrhea as the most common drug-related toxicity with the incidence of 85.7% (24/28). Next to diarrhea, the most common AEs were vomiting (28.6%), decreased appetite (21.4%) and nausea (21.4%). Similar toxicities have been reported in studies of other small-molecule irreversible TKIs (neratinib and pyrotinib) (13,14). The most common AE for neratinib and pyrotinib was also diarrhea, with the incidences of 31.9% (23/72) for neratinib and 60.7% (17/28) for pyrotinib. Fatigue (8.3%), vomiting (6.9%), and dehydration (5.6%) were the common AEs for neratinib. And nausea (13.2%), oral ulceration (13.2%), asthenia (10.5%) and leukopenia (10.5%) were the common AEs for pyrotinib.
Cutaneous toxicity (rash) is another common side effect of reversible TKI, like lapatinib (a reversible dual EGFR and HER2 TKI). The incidence rate of rash was 18.6% (8/43) in the phase I EGF10003 study for lapatinib, in which the patients with solid tumors (15). The incidence rates of rash varied from 21% to 41% when lapatinib was given in combination with either chemotherapy or hormonal therapy in randomized clinical trials (16-18). The incidence rate of rash of Hemay022 was only 7.1% (2/28) and for other irreversible TKIs like neratinib (an irreversible pan ErbB TKI: against EGFR, HER2 and HER4) and pyrotinib (an irreversible dual EGFR and HER2 TKI), the incidence rate of rash of neratinib was 16.7% (12/72) (8) and the incidence rate of rash of pyrotinib was 5.3% (2/38). Though the incidence rate of rash of Hemay022 is lower than lapatinib (a reversible TKI) and neratinib (an irreversible TKI), it is comparable to that of pyrotinib, both of which are irreversible dual EGFR and HER2 TKIs.
Conclusions
Hemay022 at the dose of 500 mg QD was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activites of Hemay022 in advanced breast cancer patients warrant further evaluation of Hemay022 for the treatment of breast cancer patients in current phase III (No. NCT05122494) trial in a combination therapy trial.
Acknowledgements
None.
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