Afatinib
Afatinib is an orally administered small molecule drug with irreversible inhibitory effects on HER1, 2 and 4. A phase II trial in patients with trastuzumab-resistant metastatic breast cancer showed a partial remission rate of 4/35, with adverse effects including diarrhea and rash.
The LUX-Breast 1 trial was a phase III trial of the application of vincristine + trastuzumab or afatinib in patients with metastatic breast cancer whose disease had progressed after a previous chemotherapy regimen containing trastuzumab (NCT01125566). A phase II trial also evaluated the efficacy of afatinib monotherapy or afatinib + vincristine regimens in patients with inflammatory or metastatic breast cancer (NCT01325428).
Lenatinib
Lenatinib is also an oral, irreversible inhibitor of HER1, 2 and 4. A phase II trial evaluated the efficacy of lenatinib in 136 patients with HER2-positive breast cancer. Among patients previously treated but not with trastuzumab, the median progression-free survival was 22.3 and 39.6 weeks, respectively, with objective remission rates of 24% and 56%, respectively.
Diarrhea was the most common grade 3/4 adverse reaction. Another phase I-II trial evaluated the efficacy of the lenatinib + trastuzumab regimen in 45 patients with trastuzumab-resistant metastatic breast cancer and showed an objective remission rate of 27%. Finally, a phase I-II trial evaluated the efficacy of the lenatinib + vincristine regimen in patients previously treated with trastuzumab or lapatinib (n = 77).
The objective remission rate was 42% in patients previously treated with lapatinib compared to 51% in patients not previously treated with lapatinib. A non-blinded phase II trial is testing the efficacy of lenatinib monotherapy in patients with HER2-positive brain metastases (NCT01494662). A phase III trial of adjuvant therapy (ExteNET) is also underway (NCT00878709).
MM-111
MM-11 is a monoclonal antibody that reversibly targets heterodimers of HER2 and HER3. A Phase I-II trial is currently evaluating its efficacy as monotherapy in patients with HER2-positive advanced breast cancer previously treated with trastuzumab or lapatinib (NCT00911898). Another Phase I trial is investigating the efficacy of MM-111+trastuzumab in patients with HER2-positive, protein-regulated, advanced and refractory breast cancer (NCT01097460).
HER2-targeted vaccine
Cancer vaccines capable of reducing anti-HER2 immunity are in development. Different options include protein vaccines, plasmid DNA vaccines and HER2 vaccines with viral vectors.
We have tested the efficacy of HER2 peptide vaccines in patients with HER2-positive metastatic breast cancer.
Immunized patients developed delayed allergic reactions and CD8+-specific cellular immunity acting on HER2. We also tested the efficacy of the dendritic cell vaccine in a population of patients with stage IV breast cancer. One patient showed partial remission and three patients had stable disease for more than 12 months. We tested the efficacy of the GM-CSF vaccine in combination with trastuzumab by applying different protocols.
PI3K/Akt/mTOR blocking drugs
PI3K/Akt/mTOR is an intracellular signaling pathway in breast cancer that regulates the emergence of primary or secondary HER2 drug resistance.
A phase I trial tested the efficacy of everolimus + paclitaxel (weekly) and trastuzumab regimens in 33 patients with metastatic breast cancer who had been treated many times before. Efficacy was reported to be very encouraging, with an overall disease control rate of 74% at 6 months. There are two ongoing phase III trials: BOLERO-1 evaluating the efficacy of the first-line combination of everolimus, trastuzumab and paclitaxel, and BOLERO-3 evaluating the efficacy of adding vincristine to the everolimus + trastuzumab regimen in previously treated patients. 569 patients completed the BOLERO-3 trial, and the median progression-free survival in the trial group was 7.0 months. The median progression-free survival was 7.0 months in the trial group and 5.78 months in the control group (P = 0.0067).
Histone deacetylase inhibitors
Histone deacetylase status can regulate DNA transcription factors and affect gene expression. Histone deacetylase activity decreases histone deacetylation. Histone deacetylase inhibitors can induce growth arrest and apoptosis of tumor cells. Vorinostat is approved for the treatment of cutaneous T-cell lymphoma. A phase II trial evaluating the efficacy of vorinostat + tamoxifen in hormone therapy-resistant breast cancer patients showed that the combination was better tolerated and could reverse hormone resistance, thereby increasing efficacy. Clinical trials combining vorinostat with chemotherapy, EGFR inhibitors and bevacizumab are underway.
Heat shock protein 90 pathway
Heat shock protein 90 (Hsp-90) is a molecular chaperone that maintains stability and supports the function of several proteins. Many of these proteins are tumorigenic (e.g., Brc-Abl, =c-Kit and PDGF-α). Sustained inhibition of heat shock protein 90, a molecular chaperone, leads to degradation of these proteins, and both HER-1 and HER-2 require heat shock protein 90, a molecular chaperone, to maintain their stability. Data from a phase I trial of a heat shock protein 90 inhibitor in combination with trastuzumab for second-line treatment showed antitumor activity in 63% of patients. A phase II trial included 31 patients with HER2-positive metastatic breast cancer whose disease progressed after treatment with trastuzumab. Patients were treated with weekly applications of tanespimycin and trastuzumab. The objective remission rate was 22%, with a clinical benefit rate of up to 59%.
Exploration of other options for HER2 inhibition
Ongoing trials combining anti-HER2 agents with drugs that inhibit signaling pathways are expected to further improve efficacy. Combining anti-HER2 therapy with drugs that inhibit insulin-like growth factor receptor 1 (IGFR-1) appears to be a preferable approach. In animal models, IGFR-1 inhibitors can restore sensitivity to trastuzumab. Another potentially effective combination regimen is the simultaneous inhibition of HER2 and SRC (recently shown to be a central downstream node of the trastuzumab resistance mechanism). Finally, HER3 is another PI3K/Akt signaling pathway agonist that could be positively regulated by HER2 blockade. Although still early in the study, Rb disruption strategies and CDK-4/6 inhibitors may also be effective.