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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In a Phase I/II clinical trial of neratinib in combination with paclitaxel in patients with HER2-positive metastatic breast cancer, a high rate of response was observed compared to paclitaxel alone in both first-line and second-line settings. For NSCLC, preclinical models had shown that in cell lines with both activating EGFR mutations and T790M, neratinib was 3–4-fold more effective at suppressing cell proliferation than gefitinib. Based on this, neratinib was studied in a multicenter Phase I trial in heavily pretreated patients with NSCLC and breast cancer. Significant and durable responses were seen in a small cohort of patients with G719X EGFR mutations which led to FDA approval in 2017 for the adjuvant treatment of patients with early-stage HER2-over-expressed/amplified breast cancer (after adjuvant trastuzumab-based therapy). Further studies showed that neratinib is active against HER2/neu amplified epithelial ovarian carcinoma in both in vitro and in vivo experiments.
HER-2 as a Prognostic and Predictive Biomarker in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alexandra S. Zimmer, Suparna B. Wedamb, Stanley Lipkowitza
Neratinib is an irreversible tyrosine kinase inhibitor of HER-1, HER-2 and HER-4 [126]. In a phase I study with solid tumors, a 32% (8 of 25) response rate was seen in patients with breast cancer and all of the responders had prior treatment with trastuzumab and 7 of the 8 responders had HER-2 amplification by IHC [127]. In the I-SPY2 trial, standard neoadjuvant therapy +/- neratinib was compared in both HER-2 amplified (107 patients) and non-amplified (106 patients) breast cancer patients [128]. Using a Bayesian statistical design, the trial found that neratinib increased the pCR rates in HER-2 amplified patients but not those without HER-2 amplification. A phase III trial randomized 2840 HER-2 amplified breast cancer patients to 1 year of neratinib or placebo as an extended adjuvant therapy after completion of neoadjuvant or adjuvant chemotherapy plus trastuzumab. Neratinib increased 5-year invasive DFS from 87.7% to 90.2% (HR 0.73, 95% CI 0.57–0.92) when neratinib was offered in the adjuvant setting to HER-2-positive breast cancer patients [129]. Patients that received neratinib had a 40% frequency of grade 3 to 4 diarrhea without diarrhea prophylaxis versus 2% among those receiving placebo. OS data is not yet mature for analysis. The available data, though limited, suggest that neratinib has activity in patients with HER-2 amplified breast cancer but not in those without HER-2 amplification.
Breast Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Amy Case, Gwenllian Edwards, Catherine Pembroke
Trials are emerging regarding the role of neratinib, an irreversible HER1, HER2, and HER4 tyrosine kinase inhibitor in ER-positive, HER2-positive breast cancer. The ExteNET trial randomized patients to either 1 year of neratinib or placebo, commencing on the completion chemotherapy and 1 year of adjuvant trastuzumab.87 At 5 years of follow-up, patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 versus 163 events; stratified hazard ratio 0.73), and the invasive disease-free survival was 90.2% in the neratinib group, and 87.7% in the placebo group. Further investigation regarding the possible role of neratinib in the adjuvant setting is awaited.
Targeting the EGFR signaling pathway in cancer therapy: What’s new in 2023?
Published in Expert Opinion on Therapeutic Targets, 2023
Sushanta Halder, Soumi Basu, Shobhit P. Lall, Apar K. Ganti, Surinder K. Batra, Parthasarathy Seshacharyulu
Neratinib-(HKI-272/Nerlynx): Neratinib is a quinazoline-based, orally available small-molecule receptor tyrosine kinase inhibitor that binds irreversibly to both EGFR and HER2. It shows potential antitumor activity to HER2 and EGFR overexpressing tumors by inducing cell cycle arrest, apoptosis, and decreasing cellular proliferation. The US FDA approved neratinib as an extended adjuvant therapy for advanced or metastatic breast cancer in July 2017. The NALA (NCT01808573) study was a randomized, active-controlled, phase III trial comparing the efficacy of neratinib compared to lapatinib in combination with capecitabine in HER2-positive metastatic breast cancer patients. Neratinib (240 mg daily) showed a significant improvement in progression-free survival and onset of central nervous system-related (CNS) disease for those patients [63]. Another multicenter, randomized, double-blind, phase III trial with 2840 patients (ExteNET) validated its efficacy in improving invasive disease-free survival (iDFS) of early-stage HER-2 positive and hormone receptor-positive breast cancer patients [64]. Recently, preclinical studies have shown that neratinib, combined with c-MET inhibitor cabozantinib, can inhibit primary breast cancer cell growth and breast cancer metastasis to the brain [65]. A recent study found that the hyperactivation of the mTORC1 signaling cascade can lead to resistance to neratinib therapy [66].
Combination of HER2-targeted agents with immune checkpoint inhibitors in the treatment of HER2-positive breast cancer
Published in Expert Opinion on Biological Therapy, 2022
Ashley Matusz-Fisher, Antoinette R. Tan
In later line settings, there are several different clinical factors that can influence decision-making in the selection and sequencing of therapies for patients with metastatic disease such as, presence of brain metastases, oral compliance, and performance status. As metastatic patients with HER2-positive tumors progress through subsequent lines of treatment, it is recommended to continue anti-HER2 therapy as part of the regimen in order to continue suppressing the HER2 pathway [12]. There are currently eight FDA-approved HER2-targeted agents in the metastatic setting. This includes two commonly used monoclonal antibodies, trastuzumab and pertuzumab, a newly approved Fc-engineered monoclonal antibody, margetuximab, and the antibody drug conjugates fam-trastuzumab deruxtecan-nxki (T-DXd) and T-DM1, as well as three oral TKIs, namely neratinib, lapatinib and tucatinib. These HER2-targeted agents are approved by the EMA with the exception of margetuximab at the time of this writing. Neratinib is approved by the EMA for adjuvant therapy of early stage hormone receptor-positive HER2-positive breast cancer.
Investigational drugs in early stage clinical trials for the treatment of HER2+ breast cancer
Published in Expert Opinion on Investigational Drugs, 2019
Andrea Gombos, Maria Alice Franzoi, Ahmad Awada
With such efficacious systemic treatment options, possibly prolonging the survival of advanced cancer patients, the prevention and management of brain metastases are becoming an even more challenging and urgent topic to be addressed. Despite the continuous development of really exciting and promising new drugs in the HER2-targeting field, so far few of them are crossing the blood-brain barrier and are able to address this population of really bad prognosis. Probably the most promising tyrosine kinase inhibitor in this regard is tucatinib given in combination. Neratinib is a drug potentially effective in this setting as well. The initiative of investigators developing these drugs to include even in advanced phase trials patients diagnosed with progressive brain metastases is exemplary.