Neratinib resistance management

Here are three possible ways to overcome neratinib resistance in HER2-mutated metastatic breast cancer (MBC) Neratinib span>: DualHER2 targeting; combination withPI3K, mTOR, MEK or CDK4/6 inhibitors; and continuous TKI therapy. Everyone’s constitution is different and their resistance to drugs is also different. If drug resistance develops after using the drug, please inform your doctor in time and do not adjust the drug dosage yourself.

1. DualHER2 targeting: Dual targeting of HER2 by neratinib plus monoclonal antibody or antibody-drug conjugate (whether in early stage or disease progression) has been proven to be effective in patients with HER2 mutant MBC. Furthermore, the addition of trastuzumab after disease progression on neratinib plus fulvestrant resulted in re-response in four out of five patients, accompanied by a decrease in ctDNA. Preclinically, neratinib plus trastuzumab produced greater inhibition of HER2 signaling and growth than either agent alone in HER2-mutant cancer models.

2. WithCombination of PI3K, mTOR, MEK or CDK4/6 inhibitors:Preclinical data in HER2/HER3 double-mutant cell lines show that the combination of PI3K inhibitor (Alpelisib) and neratinib overcomes neratinib resistance. Combination of the mTOR inhibitor everolimus with neratinib inhibited the growth of neratinib-resistant, ER-positive, HER2-mutated organoids and xenografts. In two HER2-positive breast and colorectal PDX models harboring activating HER2 mutations (V777L and R678Q) derived from patients receiving HER2-targeted therapy, the combination of neratinib with the MEK inhibitor tramatinib, the mTOR inhibitor everolimus or sapanisertib, or the CDK4/6 inhibitor palbociclib synergistically reduced tumor volume to a greater extent than either agent alone. These combinations were well tolerated in HER2-positive preclinical PDX models. But clinical trials are currently underway.

3. ContinuousTKI therapy: SequentialTKI therapy has long been the standard therapy for EGFR-mutated non-small cell lung cancer. Similar methods can also be used for HER2-mutated MBC. The HER2 gatekeeper mutation T798I recurs in HER2-mutated MBC during clinical progression after neratinib treatment. Preclinically, AZ5104, a metabolite of afatinib, another second-generation TKI, and osimertinib, a third-generation TKI, blocked cell growth and signaling induced by the HER2 T798I mutation. These findings support the clinical study of sequencing TKI therapies in HER2-mutated cancers.

NeratinibThe original drug is marketed in China as neratinib maleate tablets and is covered by Class B medical insurance, but reimbursement is limited to patients who meet the indications. Specifications The price of each box of 40mg*180 tablets may be around RMB 7,000. Generic drugs of neratinib are also sold overseas. The drug ingredients are basically the same as those of the original drug. The price of 40mg*180 tablets produced by Bangladesh pharmaceutical factory may be around 4,000 yuan per box (the price may fluctuate due to the exchange rate). For more information about overseas drugs and specific prices, please consult Yaode Medical Consultant.