Heat shock protein 90 (HSP90) belongs to a class of molecular chaperones whose intracellular function involves facilitating the maturation and stability of many client proteins, including HER2 as well as the protein products of other oncogenes.21 Inhibition of HSP90 ultimately leads to the degradation of client proteins in the proteasome. A phase I study evaluated the combination of trastuzumab(Drug information on trastuzumab) with the HSP90 inhibitor tanespimycin (a derivative of the antibiotic geldanamycin).22 Escalating doses of weekly intravenous tanespimycin were combined with conventional weekly trastuzumab in 25 patients with advanced solid tumors, including 15 with HER2-positive metastatic breast cancer. One partial response and four tumor regressions of between 21% and 35% were seen among 15 patients with metastatic breast cancer.
The combination was then evaluated in a single-arm phase II study in 31 patients with metastatic breast cancer following one prior line of trastuzumab-containing therapy.23 Of 27 patients eligible for response assessment, 7 experienced partial responses (26%). An additional 5 patients experienced disease regressions of between 20% and 29%, and 5 patients had disease stabilization for more than 4 months, for a clinical benefit rate of 63%. Several studies are currently assessing HSP90 inhibitors for advanced HER2-positive breast cancer, including a multicenter phase II study evaluating the combination of trastuzumab and IPI-504, an agent that interconverts with tanespimycin in vivo.
In recent years the potential of harnessing potent cytotoxic drugs to targeted monoclonal antibodies has been evaluated in several cancer types. The attraction of this approach is that the cytotoxic effect of the chemotherapy agent may be directly delivered to tumor cells, while potentially reducing harmful side effects to normal cells. The first such antibody drug conjugate (ADC) to be explored in breast cancer is T-DM1, a drug created by linking a derivative of the antimicrotubule agent maytansine to trastuzumab. T-DM1 given intravenously every 3 weeks at 3.6 mg/kg was evaluated in a single-arm phase II study in 112 patients with previously treated HER2-positive metastatic breast cancer.24 This study demonstrated an overall response rate of 26.9%, with a similar overall response rate of 24.2% among patients previously treated with both trastuzumab and lapatinib.
A second open-label phase II study enrolled 110 patients who had all received prior anthracycline, taxane, capecitabine(Drug information on capecitabine), trastuzumab, and lapatinib to receive every-3-week TDM1.25 The overall response rate in this population was 32.7% by independent radiology assessment. The most commonly encountered toxicities in these studies were fatigue, nausea, and reversible thrombocytopenia. Ongoing studies are evaluating the use of T-DM1 vs combinations of cytotoxics and HER2-targeted agents in the firstline treatment of advanced disease.
Neratinib, like lapatinib, is an orally available pan-ErbB TKI, but it differs in that it inhibits HER4 as well as HER1/EGFR and HER2, and it does so in an irreversible manner. A phase I study in advanced solid tumors established the maximum tolerated dose of 320 mg daily.26 The most common adverse events with this agent included diarrhea, nausea, fatigue, and vomiting, and the dose-limiting toxicity was grade 3 diarrhea. A phase II study in breast cancer utilized a lower dose of 240 mg daily (owing to gastrointestinal effects seen in another study at the 320-mg daily dose), with a response rate of 26% in patients who had previously received trastuzumab, and 56% in patients who had not received prior trastuzumab.27
Neratinib was subsequently tested in combination with weekly trastuzumab in a phase I/II study.28 The primary endpoint of the phase II component of this study was to detect an increase in the 16-week progression-free survival from 15% to 35% with the combination. The study met this endpoint with a 16-week progression-free survival of 45%, and an overall response rate of 29%. The most common adverse events were diarrhea, nausea, anorexia, and vomiting, with grade 3 diarrhea in 11% of patients treated with the combination of neratinib at 240 mg daily and trastuzumab in the phase II portion of the study. Safety and efficacy data for neratinib in combination with chemotherapy agents including paclitaxel(Drug information on paclitaxel), capecitabine, and vinorelbine have been presented.29-31
Pertuzumab (Omnitarg), like trastuzumab, is a monoclonal HER2-targeted antibody, but it is directed against a different epitope on the receptor (extracellular domain II). Binding of the antibody to this site prevents receptor homo- and heterodimerization, a key step in the passage of downstream growth factor signaling in this receptor group. The combination of pertuzumab with trastuzumab led to an overall response rate of 24.2% in a phase II study in patients with metastatic breast cancer that had progressed after prior trastuzumab.32 An additional cohort, which was later added to this study, received pertuzumab monotherapy, with the option of again adding trastuzumab after disease progression on pertuzumab alone.33 The response rate for pertuzumab alone was low (3.4%). Nevertheless, the overall response rate among 14 patients receiving combination trastuzumab and pertuzumab after progressing on both drugs as single agents was promising (21.4%). These results confirm the validity of combined HER2 blockade to overcome mechanisms of resistance in patients progressing after trastuzumab monotherapy.
Inhibitors of the PI3K/Akt Pathway
In vivo assessment of biopsy samples from patients progressing after trastuzumab therapy demonstrates activation of the PI3K/Akt pathway as a common mechanism underlying trastuzumab resistance.34 Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that is a downstream component of the PI3K/ Akt pathway. Phase I combinations of the oral mTOR inhibitor everolimus (Afinitor) with weekly trastuzumab and chemotherapy in patients with HER2-positive metastatic breast cancer progressing after trastuzumab therapy yielded response rates of 41% with paclitaxel and 18% with vinorelbine.35,36 The most common doselimiting toxicities were neutropenia and stomatitis. Phase II studies are awaited. Inhibitors of PI3K are also being evaluated as potential modulators of trastuzumab sensitivity.
Preclinical data demonstrate HER2 and vascular endothelial growth factor (VEGF) pathway interactions, providing a rationale for targeting both receptor pathways in HER2-positive breast cancer.37 A phase II study evaluated the combination of weekly trastuzumab and biweekly bevacizumab (Avastin) as first-line therapy of HER2-positive advanced breast cancer.38 The combined monoclonal antibody treatment achieved an overall response rate of 48% and clinical benefit rate of 60%. The omission of conventional cytotoxic agents does not necessarily make this a "benign" regimen, however: While only 1 of the 50 patients experienced grade 4 cardiotoxicity, an additional 15 patients had asymptomatic declines in left-ventricular ejection fraction (LVEF) and 36% experienced grade 3 hypertension.
The use of combined HER2/VEGF blockade with dual monoclonal antibody therapy in addition to chemotherapy is currently being investigated in the adjuvant setting. Dual tyrosine kinase inhibition of HER2 and VEGF pathways (using lapatinib and pazopanib [Votrient]) in first-line therapy of advanced HER2-positive breast cancer improved the primary endpoint of progressive disease rate at week 12 and yielded marginal improvement in response rates, albeit with increased toxicities including diarrhea, transaminitis, hypertension, and changes in hair color.39 Of 76 patients on the combination arm, 4 experienced cardiac toxicity (asymptomatic LVEF decline ≥ 20% and below the lower limit of normal in 3 patients, and symptomatic LVEF decline < 20% in 1).
The combination of lapatinib (1,500 mg daily) and biweekly bevacizumab was assessed in a more pretreated HER2-positive patient population in a phase II study.40 Patients had received a median of four prior chemotherapy regimens. The confirmed overall response rate among 52 patients was 13.3%. Common toxicities included diarrhea, rash, fatigue, bleeding, nausea, and headache. Three patients—all of whom were asymptomatic—experienced LVEF declines below 50%. Several other agents targeting the VEGF pathway via tyrosine kinase inhibition (eg, sunitinib [Sutent], sorafenib [Nexavar]) or other mechanisms are being evaluated in HER2-positive breast cancer in early-phase clinical studies. Combined HER2/VEGF blockade remains investigational at this time.
Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for HER2-positive breast cancer. Emerging data from trials of these agents indicate that the HER2 pathway remains a valid therapeutic target following progression on trastuzumab, and suggest a promising role for combined HER2 blockade with two or more agents. In the coming years, it is anticipated that one or more of these agents will enter routine clinical practice for advanced HER2-positive breast cancer, and may supplement or even replace trastuzumab as the backbone of adjuvant therapy for this unique disease subset.