BEIJING & SHANGHAI--CANbridge Pharmaceuticals Inc., a biopharmaceutical company developing innovative drug candidates to treat underserved medical conditions, announced that it has received marketing approval from the Taiwan Food and Drug Administration for NERLYNX® (neratinib) for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy. 

NERLYNX is a kinase inhibitor indicated:...As a single agent, for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.

NERLYNX is a kinase inhibitor indicated:...In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.

The ESMO Magnitude of Clinical Benefit Score (MCBS) for the new therapies pertuzumab and neratinib were added to the recommendations.. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET).

Recommendation...Clinicians may use extended adjuvant therapy with neratinib for patients with early-stage, HER2- positive breast cancer.

…HER-2 positive disease, other recommended regimen added: neratinib plus capecitabine as a category 2A option. Invasive Breast Cancer...PERATIVE/ADJUVANT THERAPY REGIMENS:...HER-2 Positive...Useful in Certain Circumstances: Neratinib

...HER2-positive breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab were eligible. Patients were randomly assigned to oral neratinib... Eight-year overall survival rates were 90.1% (95% CI 88.3-91.6) with neratinib and 90.2% (95% CI 88.4-91.7)...Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8.1 years in women with early-stage HER2-positive breast cancer.

...phase III trials incorporating TKIs such as Neratinib (NER) and Tucatinib (TUC), there was improved OS (21m Vs 18.7, 24.7m Vs 19.2m respectively) as compared to Standard of care and chemotherapy….Both monoclonal antibodies and tyrosine kinase inhibitors show clinically significant benefits in advanced HER2 positive breast carcinoma.

NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients...Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C.

NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC....mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C...the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine.

2840 patients were randomized (1420 per group). After a median follow-up of 8.1y, 8y OS rates were 90.1% (95% CI 88.3‒91.6) for neratinib and 90.2% (95% CI 88.4‒91.7) for placebo (absolute difference –0.1%; stratified HR=0.95; 95% CI 0.75‒1.21; p=0.6914). At 5y, cumulative incidence of CNS recurrences was 1.3% (95% CI 0.8–2.1) with neratinib and 1.8% (95% CI 1.2–2.7) with placebo, and CNS-DFS rates were 97.5% (95% CI 96.4–98.3) and 96.4% (95% CI 95.2–97.4), respectively (HR=0.73; 95% CI 0.45–1.17). No new safety signals were reported. Neratinib is the first HER2-directed agent to show a trend towards improved CNS outcomes in HER2+ eBC, providing further support for current NCCN guidelines that recommend neratinib-based therapy for brain metastases from HER2-positive breast cancer.

NALA was an international, randomized, open-label, active-controlled, phase 3 study in patients with HER2+ MBC who had received ≥2...Regardless of the status of CNS metastases at baseline, patients appeared to have better outcomes in the N+C arm compared with the L+C arm.

HER2+ MBC pts were randomized 1:1 to N (240mg qd) + C (750mg/m2 bid, day 1-14) or L (1250mg qd) + C (1000mg/m2 bid, day 1-14) in 21-day cycles....In Asian pts, significant improvement in PFS (median 7.0 vs 5.4 mo, HR=0.58; p<0.001) and overall cumulative incidence of intervention for CNS disease (27.9 vs 33.8%; p=0.039) was observed for N+C vs L+C, and a positive trend in OS was noted (median: 23.8 vs 18.7 mo, HR=0.79; p=0.185).

621 patients were randomized (307 to N+C; 314 to L+C)....N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease.

After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083).

...Breast cancer must be determined to be HER2-positive prior to randomization. ...

...- HER2 positive breast cancer...

...The primary end-point of this study is to assess the safety and define the maximum tolerated dose of the combination of neratinib with capecitabine in subjects with solid tumors, and to compare the objective response rate (ORR = CR + PR) for subjects with erbB-2 positive breast cancer treated at the MTD of neratinib in combination with capecitabine versus neratinib monotherapy versus lapatinib in combination with capecitabine.`...

...- HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines...

...Diagnosis : histologically or cytologically confirmed HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on immunohistochemistry (IHC) and/or positive by in situ hybridisation (ISH)) with brain metastases, estrogen receptor and progesteron receptor status Cohort 1: with CNS metastases pre-treated with local approaches for the previous CNS events and currently progressive but locally treated CNS metastasis Cohort 2: with a first diagnosis of CNS metastases, asymptomatic or paucisymptomatic...

...- ErbB-2 positive locally recurrent or metastatic breast cancer...

...- Patients with multifocal breast cancer are included as long as none of the tumors are HER2 positive by IHC or FISH and targeted lesion meets current...

...- HER2 positive breast cancer diagnosed histologically is defined as HER2 (3+) by immunohistochemistry or HER2 (2+) with positive FISH test；...

...- Stage II through IIIC HER-2/erbB-2 positive breast cancer with node positive disease....

......

...- HER2 positive tumor...

...- Histologically confirmed Stage IB through Stage IIIC primary adenocarcinoma of the breast.- Documented HER2-positive disease based on local laboratory determination according to ASCO/CAP 2018 criteria. ...

...Confirmed pathologic diagnosis of ErbB-2-positive breast cancer (current stage IV) in female subjects for which vinorelbine plus HKI-272 is a reasonable treatment option (part 2 only).4. ...

...3.Histologically confirmed diagnosis of HER-2/erbB-2 positive breast cancer, with no evidence of recurrent or metastatic disease based on clinical/radiological assessment;...

...Subjects must have histologically confirmed primary adenocarcinoma of the breast that is erbB-2 positive by one of the following assays, performed locally: Fluorescence in Situ Hybridization (FISH) or Silver in Situ Hybridization (SISH), or Chromogenic in Situ Hybridization (CISH), or Immunohistochemistry assay.2. ...

...The primary endpoint is the comparison of the investigator assessed progression-free survival (PFS) following treatment with single agent neratinib versus lapatinib plus capecitabine in subjects with erbB-2-positive locally advanced or metastatic breast cancer. ...

...Subjects must meet all of the following criteria in order to be eligible for this study:1) Age ≥ 18 years old2) ECOG performance status ≤ 2 3) Female 4) Diagnosis : histologically or cytologically confirmed HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on immunohistochemistry (IHC) and/or positive by in situ hybridisation (ISH)) with brain metastases, estrogen receptor and progesteron receptor statusCohort 1: with CNS metastases pre-treated with local approaches for the previous CNS events and currently progressive but locally treated CNS metastasis Cohort 2: with a first diagnosis of CNS metastases, asymptomatic or paucisymptomatic not needing immediate local therapy Cohort 3: with confirmed LM defined as the presence of malignant cells in the CSF or combination of typical symptoms and MRI findings5) Specific criteria for cohorts 1 and 2 only: Must have radiologically confirmed metastatic brain lesion by MRI measurable by RANO-BM criteria 6) Specific criteria for cohort 3 only: LM defined as the presence of malignant cells in the CSF or combination of typical symptoms and MRI findings for cohort 37) Subjects should have received at least 1 previous line for the metastatic disease including taxanes based chemotherapy in combination with trastuzumab and pertuzumab (if available) unless contraindicated. ...

...1) Patients who can voluntarily sign an informed consent form; 2) Females aged ≥18 years old when signing the informed consent form; 3) ECOG PS physical status score of 0 to 2 points; 4) Histologically confirmed HER2-positive metastatic breast cancer patients; Note: HER2 positivity refers to at least one occurrence of tumor cell immunohistochemical staining intensity of 3+ or confirmed as positive by fluorescence in situ hybridization [FISH] in the pathological testing/re-review of the primary or metastatic lesions conducted by the participating center's pathology department; 5) Brain metastases confirmed by MRI/enhanced CT, with at least one measurable lesion in the brain based on RECIST 1.1 criteria; 6) Expected survival period ≥3 months; 7) Patient types: Cohort A - newly diagnosed brain metastases patients; Cohort B - patients with progression after whole-brain radiotherapy or stereotactic radiosurgery; 8) Left ventricular ejection fraction (LVEF) ≥50%; 9) QT interval corrected by Fridericia formula (QTcF) of 12-lead electrocardiogram: <450ms for males, <470ms for females; 10) The following conditions should be met in the blood routine examination:① Absolute neutrophil count (ANC) ≥1.5×10^9/L, ② Platelet count ≥100×10^9/L, ③ Hemoglobin ≥90g/L, ④ White blood cell count ≥3.0×10^9/L; 11) Liver function meets the following conditions: ① Serum total bilirubin ≤1.5×upper limit of normal (ULN), or ≤3×ULN if there are liver metastases, ② Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3×ULN, or ≤5×ULN if there are liver metastases; 12) Renal function meets the following conditions: Serum creatinine ≤1.5×ULN or creatinine clearance ≥50mL/min (calculated according to the Cockroft-Gault formula); 13) Female patients who meet the following conditions can participate in this study: ① Infertility; ② Capable of fertility, with a negative blood pregnancy test result within 7 days before the first administration of the investigational drug, not breastfeeding, and adopting effective contraceptive measures during the screening period, throughout the study, and within 6 months after the last administration of the study drug....

...Documented HER2-positive disease based on local laboratory determination according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 criteria....

To describe the tolerability and efficacy of neratinib as a monotherapy and in combination with capecitabine in advanced HER2-positive breast cancer...After a median duration of follow-up of 38.5 months, the median PFS for all patients was 5.9 months (95% confidence interval (CI) 4.9-7.4 months) and median OS was 15.0 months (95% Cl 10.4-22.2 months). Amongst the 52.7% (38/72) patients with confirmed brain metastases at baseline, median PFS was 5.7 months (95% CI 2.9-7.4 months) and median OS was 12.5 months (95% CI 7.7-21.4 months)....Neratinib monotherapy or in combination with capecitabine is a useful treatment for patients with and without brain metastases.

This study has evaluated the activity of neratinib in association with capecitabine in 10 patients with LM from HER2-positive BC...The best radiological response was stable disease in 60% of patients....This small series shows that the combination of neratinib and capecitabine is a safe treatment in LM from heavily pretreated HER2-positive BC with clinical efficacy in some patients and is worth investigating in a larger study.

Neratinib (N)...Capecitabine (X)...We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease...

When combined with fulvestrant, neratinib demonstrated efficacy in patients with HER2-positive breast cancer, regardless of their hormone receptor status.

A total of 350 patients were identified who received adjuvant T for treatment of stage I-III HER2-positive breast cancer within the inclusion timeframe...Patients receiving adjuvant N were less likely to have had a pathologic complete response (pCR) following neoadjuvant chemotherapy than those who did not receive N (23.1% versus 51.0%, P = 0.008).

Median number of cycles completed was 3 (0-13): 1/25 (4%) pts had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not evaluable for response. PFS was 2.6 months (95% CI [2.56-5.26]). The median OS was 17.4 months (95% CI [10.3, NA])....Neratinib is safe in older adults with HER2 positive or HER2 mutated MBC.

A total of 793 patients with HER2-positive MBC were included in the efficacy analysis (Asia: 271 patients; other regions: 522 patients). The overall response rate in patients from Asia was 66.4% (180/271) and the median progression-free survival was 55.6 weeks....Neratinib-based therapy is safe and effective in patients with HER2-positive MBC from Asia.

The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2+ breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2+ breast tumor xenografts in vivo.

CONTRADICTING EVIDENCE:...The anti-proliferative effects of neratinib, lapatinib, and tucatinib were examined across a panel of 115 cancer cell lines...The MDA-MB-453 cell line was the only HER2+ cell line that had a poor response to each TKI.