The HER2 mutation is thought to be one of the causes of resistance to trastuzumab treatment in HER2-positive breast cancer. However, according to recent nonclinical and clinical studies, it has been reported that anti-HER2 antibody therapy such as trastuzumab or T-DM1 is clinically effective in HER2 mutant malignancies without HER2 amplification. In particular, lung cancer, where HER2 exon 20 mutations are often observed, showed a higher tumor response (30-50%) to treatment with trastuzumab, T-DM1, and trastuzumab deruxtecan than to HER2-targeted TKI.
In order to effectively inhibit the activation of the HER2 signaling system in HER2-amplified breast cancer, several studies have demonstrated that combination therapy between TKI such as trastuzumab and lapatinib is more effective than single drug administration. However, the combination effect between trastuzumab and HER2-targeted TKI in metastatic solid cancer patients with HER2 mutation has not been confirmed.

The purpose of this study is to evaluate the safety and clinical effects of neratinib, an HER2 TKI, and trastuzumab biosimilar (Herzuma®), an anti-HER2 antibody drug in advanced solid cancer patients with HER2 hotspot mutation.

Treatment

-Neratinib: 240mg once (40mg tablet *6), orally administered every morning
-Herzuma: 3-week therapy, first time 8mg/kg, maintenance period 6mg/kg intravenous administration over 90 minutes

Arm Label

Target Number of Participant

Arm Type

Arm Description

-Neratinib: 240mg once (40mg tablet *6), orally administered every morning
-Herzuma: 3-week therapy, first time 8mg/kg, maintenance period 6mg/kg intravenous administration over 90 minutes

Gender

Age

Description

1) Patients who voluntarily decide to participate and give written consent after hearing the description of the characteristics of the clinical trial and investigational drugs
2) Adult men and women over 19 years old
3) Histologically or cytologically confirmed advanced solid cancer patient, when HER2 hot spot mutation is confirmed in tumor tissue or tumor DNA (cell free tumor DNA, ctDNA) in blood as a result of K-master panel test
4) Patients with at least one measurable lesion according to RECIST v 1.1
5) Eastern Cooperative Oncology Group (ECOG) performance status is 0~2
6) Patients whose life expectancy is more than 6 months
7) Patients with more than one line of standard treatment who no longer have an effective treatment, or metastatic/progressive solid cancer patients who are judged by their doctor to be helpful with HER2 mutation targeted therapy.
8) Patients who have agreed to provide plasma/blood samples for the most recent metastatic/progressive tumor sample or new tumor biopsy for gene sequencing and other biomarker analysis.

1) Patients who received radiotherapy or surgical treatment within 2 weeks
2) If there is a brain metastasis that requires treatment with symptoms, however, registration is possible if it is stable without steroid treatment after treatment for brain metastasis.
3) In case of unsuitable HER2 mutation (non-hot spot mutation, subclonal mutation, premature stop codon or frame shift mutation):
4) If you cannot swallow tablets or do not have a doctor
5) If the toxicity of the previous treatment has not recovered to the baseline level or below Grade 1
 However, not applicable in the following cases.
(1) Inspection items separately defined in the selection criteria
(2) Vitiligo or alopecia
(3) When the investigator evaluates that the toxicity observed at the baseline is irreversible and will not be aggravated by administration of the investigational drug.
(4) When the tester evaluates that toxicity of Grade 2 or higher is controlled by appropriate adjuvant drug treatment.
6) If the screening clinical laboratory test results are as follows:

(1) Hemoglobin less than 8.0g/dL (transfusion and other treatments allowed until the test value is reached)
(2) Absolute neutrophil count (ANC) less than 1.0x10³per mm³
(3) Platelet count less than 100x10⁹/L (100,000/mm³)
(4) Total bilirubin exceeds the normal upper limit (UNL) 1.5 times (*Gilbert's syndrome not applicable)
(5) Alanine aminotransferase (ALT) or aspartic acid aminotransferase (AST) 3 times higher than normal upper limit (UNL) (*>5xULN in case of liver and bone metastasis)
(6) Above the normal upper limit of creatinine in blood (UNL) 1.5 times or less than eGFR 30 mL/min/1.73 m²
7) Left ventricular contracture rate is less than 50% by multi-gate acquisition scan (MUGA) or echocardiography
8) Significant chronic gastrointestinal disorders with diarrhea as the main symptom (eg, Crohn's disease, malabsorption, or diarrhea of ​​any etiology of grade 2 or higher according to NCI CTCAE version 5.0 is present at baseline).
9) Uncontrolled concomitant diseases including:
(1) Cardiomyopathy, a history of symptomatic congestive heart failure (NYHA Class II-IV)
(2) Myocardial infarction within 12 months of enrollment or a history of unstable angina with a new drug administration or change in dose within 6 months
(3) Patients with clinically significant arrhythmia who have difficulty participating in clinical trial
(4) Other cardiovascular diseases that are judged to be difficult to participate in clinical trials
(5) Patients with previously known severe renal impairment (renal failure, patients undergoing renal dialysis, etc.)
(6) Patients with severe hepatic impairment known in the past (liver lesions, etc.)
(7) Blood coagulation disorder that is considered difficult to participate in clinical trials
(8) Patients who have difficulty breathing or need oxygen supplementation during severe stabilization due to advanced malignancies
10) Patients with the following clinically active infections
(1) Hepatitis B (only HBs Ag as a screening test; if necessary, positive for IgM anti-HBc, HBV NAT tests)
(2) Hepatitis C (Anti-HCV only as a screening test; however, anti-HCV positive may participate if HCV RNA is negative in NAT test)
(3) HIV infection (Only Anti-HIV is performed as a screening test)
(4) Other active infections or unexplained fever >38.5°C (101.3°F) that are considered difficult to participate in the clinical trial
11) Subjects contraindicated for both MRI or CT
12) History of hypersensitivity reactions to each of the components of this clinical trial test drug 1 (neratinib), test drug 2 (trastzumab and rodent-derived protein) and combination therapy (roperamide)
13) Subjects who received contraindications or treatment prior to participation in the clinical trial and have not passed the specified period
14) Patients taking contraindications
15) Pregnant or lactating women who are not willing to stop lactation
16) Women with positive pregnancy test
17) During the clinical trial period and until 7 months (Herzuma) and 3 months (neratinib) after the final administration of the test drug, the childbearing period or less than 12 months of menopause did not agree to the continued use of the following contraceptive methods One woman
①. Oral contraceptives
②. Contraceptive patch
③. Intrauterine contraceptive device (IUD)
④. Contraceptive implants
⑤. Contraceptive injection (sustained release)
⑥. Intrauterine hormonal apparatus
⑦. Fallopian tube ligation and infertility surgery
*However, there is no need to apply continuous use of effective contraceptives.
(1) Menopause (non-therapy-induced amenorrhea more than 12 months) and negative serum pregnancy test results in women less than 12 months after menopause
(2) Women who are infertile (without ovaries and/or uterus) due to surgery
(3) Women who agreed to abstinence during the clinical trial period
However, intermittent abstinence (eg, using ovulation period, symptomatic body temperature method (symptothermal) or post-ovulation) or in vitro ejaculation is not applicable when abstinence is agreed.
18) Male subjects who do not agree with the following: Use the following effective contraception method or other effective contraceptive method during the clinical trial period and up to 7 months (Herzuma) and 3 months (Neratinib) after the final administration of the test drug. , Do not lift sperm until 7 months (Herzuma) and 3 months (Neratinib) after the clinical trial period and the end of the trial
(1) Double block by combining male condoms and female contraception
(2) Consent to the continued use of the effective contraceptive measures described above by the female partner
* However, in the case of the articles of incorporation, there is no need to apply continuous use of contraceptives.
19) Patients who have not passed 30 days from the date of signing the consent form after participating in the previous clinical trial or are currently participating in other clinical trials
20) Other diseases that the clinical trial investigator considers to be inappropriate in addition to the above items

PFS, Progression Free Survival

Time from enrollment of the study to the time the first disease progression was observed or death occurred

BORR, Best Objective Response Rate

The time from the time of enrollment in the clinical trial to the time when the first disease progression was observed or the event of death for any reason.