Third, how much do we really know about de novo and acquired resistance to trastuzumab and lapatinib? There are several possible clinical relevant mechanisms of trastuzumab resistance, including crosstalk with other receptors, amplification of the PI3K/AKT pathway, alteration of the trastuzumab binding domain, and loss of HER2 expression.
Prior to 2007, the only approved targeted agent for human epidermal growth factor receptor 2 (HER2)-driven breast cancers was trastuzumab (Herceptin). In the past 5 years, however, we have seen marked growth in options for women faced with HER2-amplified metastatic breast cancer (MBC). In 2007, lapatinib (Tykerb) was approved for use in combination with capecitabine (Xeloda) to treat advanced or metastatic disease following prior therapy with an anthracycline, a taxane, and trastuzumab; in 2010, its approved indication was expanded to include use with hormone therapy in estrogen receptor–positive tumors. The year 2012 was remarkable not only because pertuzumab (Perjeta), in combination with docetaxel and trastuzumab, showed an overall survival (OS) benefit and was approved in the first-line setting, but also because the EMILIA trial demonstrated improved OS for trastuzumab emtansine (T-DM1 [Kadcyla]) when compared with capecitabine/lapatinib, and T-DM1 was just approved in late February. In their review, Drs. Jelovac and Emens skillfully summarize the history of approved and future agents for HER2-driven MBC. These recent advances not only allow more effective treatment of HER2-positive MBC, but they also generate additional questions regarding the order, timing, and effective use of HER2-directed therapies.
Trastuzumab revolutionized treatment of HER2-amplified breast cancers by yielding a dramatic improvement in OS, but it was found to be a medication with some serious side effects. Cardiac dysfunction has been reported to variably occur, at an estimated rate of 2% to 4% with single-agent trastuzumab, up to 18% when trastuzumab is administered with a taxane, and up to 27% when trastuzumab is given in combination with an anthracycline. The second targeted agent to receive approval was lapatinib, in combination with capecitabine. Lapatinib has the advantage of crossing the blood-brain barrier, and thus is our only targeted agent known to reduce the risk for central nervous system progression. Lapatinib has the ease of oral administration, but it has significant toxicity, which can affect the quality of life (such as diarrhea and, when combined with capecitabine, hand-foot syndrome).
Recently, we have also made significant strides in combining targeted agents against HER2. The continued benefit of trastuzumab even after progression was demonstrated in a phase III trial comparing single-agent lapatinib vs lapatinib in combination with trastuzumab, which demonstrated a 50% improvement in progression-free survival (PFS) with combination therapy. Additionally, this trial also showed a preservation of quality of life with the combination and emphasized that, since we now have multiple HER2-targeted agents, regimens lacking a chemotherapeutic backbone and comprising solely targeted agents can not only be well tolerated, but they can also be efficacious.
The next revolutionary agent approved was pertuzumab. Pertuzumab binds a different extracellular domain epitope and blocks HER family dimerization, thereby circumventing resistance to trastuzumab. While pertuzumab alone had only modest activity, when combined with trastuzumab, the combination had significant antitumor activity. This led to CLEOPATRA, a trial that combined trastuzumab and pertuzumab with docetaxel in first-line HER2-positive MBC. This trial showed a 50% improvement in PFS and most recently reported an OS benefit. Treatment with the three-agent combination resulted in 6% and 2% increases in febrile neutropenia and grade 3 diarrhea, respectively, compared with patients treated with docetaxel and trastuzumab.
The breast cancer community has eagerly awaited the recent approval of T-DM1, a novel antibody-chemotherapy conjugate in which DM1, a derivative of a microtubule inhibitor, is covalently linked to trastuzumab. The pivotal trial leading to its approval was EMILIA, a large phase III trial in patients who had already progressed on trastuzumab and a taxane. Results demonstrated an improvement in OS of almost 6 months for patients treated with T-DM1, compared with those who received capecitabine/lapatinib. Importantly, T-DM1 showed an improved side-effect profile compared with that of the capecitabine/lapatinib combination, with 16% less grade 3/4 toxicities. The main toxicities of T-DM1 include thrombocytopenia and transaminitis.
Even with the therapeutic advances and trial data in HER2-driven breast cancers outlined above, many questions still remain regarding the optimum treatment of HER2-positive MBC. First, what are the best order and timing of the agents we possess in our armamentarium? It seems that the standard of care now will be pertuzumab/trastuzumab/docetaxel in the first-line metastatic setting, given the demonstrated OS improvement. In the near future, T-DM1, with its demonstrated OS benefit, will likely be the go-to therapy in the second-line setting. In subsequent lines of therapy, we still have chemotherapy with trastuzumab, capecitabine/lapatinib, and novel agents in investigational trials. How to best utilize these medications to maximize OS while minimizing toxicity and improving quality of life remains to be determined.
Second, how much importance does the chemotherapy backbone play? We have evidence that trastuzumab in combination with lapatinib is an active combination associated with a PFS of 12 months. Additionally, many patients in the CLEOPATRA trial had their chemotherapy dropped out of their treatment regimen during the trial and continued to respond to pertuzumab and trastuzumab alone. As women faced with HER2-driven MBC live longer, we must ask ourselves “Is less more?” In other words, is the toxicity of conventional chemotherapy ultimately harming our patients, and would combinations of targeted agents, without a chemotherapy backbone, instead be enough? Does some chemotherapy need to be given upfront when therapy is changed, and then how much efficacy is lost by dropping the chemotherapy? One trial that will help us to address these questions is the MARIANNE study now underway, which is examining the combination of pertuzumab and T-DM1 vs trastuzumab with a taxane vs T-DM1 alone.
Third, how much do we really know about de novo and acquired resistance to trastuzumab and lapatinib? There are several possible clinical relevant mechanisms of trastuzumab resistance, including crosstalk with other receptors, amplification of the PI3K/AKT pathway, alteration of the trastuzumab binding domain, and loss of HER2 expression. Further, we are beginning to identify the pathways associated with lapatinib therapeutic resistance. However, optimal strategies to prevent or overcome these mechanisms of trastuzumab and lapatinib resistance are still unclear.
In summary, Drs. Jelovac and Emens have not only accurately and eloquently summarized how far, and from where, we have come in the management of HER2-driven MBC, but they also have highlighted exciting recent advances and provided insight into where we are going. As a breast cancer community, we must continue to further refine and understand how to best use these options in prolonging both the quantity and quality of life for our patients.
Financial Disclosure:Dr. Blackwell serves as a consultant for Genentech/Roche. She receives research funding from Genentech/Roche and Boehringer Ingelheim. Dr. Hamilton has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.