A New World of Targeted Therapies for HER2-Positive Breast Cancer Takes Shape

Komal Jhaveri

Assistant Professor, Department of Medicine Clinical Faculty Member

In 1998, the human monoclonal antibody trastuzumab (Herceptin) became a game changer in the treatment of women with human epidermal growth factor receptor 2 (HER2)—positive breast cancers. When added to standard chemotherapy, trastuzumab not only dramatically improved disease-free survival rates for patients with metastatic disease, but also resulted in a clear survival advantage unprecedented for most treatments of metastatic breast cancer. It quickly became the standard of care, ushering in trials adding this targeted therapy in the adjuvant setting for these aggressive cancers that were notoriously resistant to hormonal therapies. Since then, trastuzumab’s benefits have remained clear for many patients, but resistance still occurs: median survival for patients with metastatic disease is 25 months and a quarter of patients have a recurrence, underscoring the urgent need for new and even more precise anti-HER2–directed therapies.

Fresh Anti-HER2 Strategies

So, how are we doing? The good news is that the sci¬entific landscape for what we can offer our patients is rapidly evolving, along with progress born of clinical trials. New targeted and combination therapies have emerged within the past five years, initially using lapatinib, a dual tyrosine kinase inhibitor of HER2 and epidermal growth factor receptor (EGFR), with chemotherapy. More recently, pertuzumab, a HER dimerization inhibitor, was approved in 2012 as a first-line therapy for HER2-positive metastatic breast cancers. This was based on the results of the phase III international CLEOPATRA trial, with 800 women in 250 centers, which at primary analysis in May 2011 had shown improved progression-free survival, with a trend toward overall survival (OS) after first-line treatment with docetaxel/trastuzumab/ pertuzumab compared with placebo/trastuzumab/docetaxel.

Updated OS results were recently reported by the CLEOPATRA researchers at the 2014 ESMO Congress in Madrid. At a median follow-up of 50 months (range 0 to 70 months), median OS was 40.8 months in the placebo arm and 56.5 months in the pertuzumab arm, a difference of 15.7 months. The OS of 56.5 months is unprecedented in the first-line setting and confirms the value of pertuzumab-containing regimens. Pertuzumab has also achieved accelerated drug approval in the neodjuvant setting and its role in the adjuvant setting along with trastuzumab for one year is being evaluated in the APHINITY trial.

Antibody—Drug Conjugates

Another flourishing avenue of research is in the nascent field of antibody—drug conjugates, and the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center is assuming an active role in its development. Antibody–drug conjugates are novel molecules that chemically link a monoclonal antibody to an anticancer drug. This drug design permits deliv¬ery of the monoclonal antibody directly to cancer cells, thus enhancing the cytotoxic potential of monoclonal antibodies while sparing normal cells. Moreover, we believe such linkage results in synergistic effects, enhancing both the selectivity and therapeutic impact of chemotherapeutic drugs. T-DM1 (trastuzumab emtansine) is one such novel antibody–drug conjugate. Part monoclonal antibody (trastuzumab) and part cytotoxic anti-microtubule agent (DM1), it is designed to be released within targeted cells. The FDA approved T-DM1 in 2013 for patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, progressed on their most recent treatment in the locally advanced or metastatic setting, or are within 6 months of adjuvant trastuzumab for early-stage disease. Research with this agent is especially promising and our team at the Perlmutter Cancer Center is already investigating T-DM1 in combination with other targeted agents in an attempt to overcome trastuzumab resistance in the metastatic setting and further improve the outcomes in this patient population. One of the best characterized mechanisms of HER2 resistance is hyperactivation of the PI3K/AKT/ mTOR pathway. We hypothesized that simultaneously targeting HER2 with T-DM1 and the PI3K/AKT/ mTOR pathway with everolimus, an mTOR inhibitor, would be safe and potentially more efficacious, and are therefore planning a phase Ib trial of T-DM1 plus everolimus.

Specifically, with this trial, for which I will be the principal investigator, our long-term goal is to identify those patients most likely to benefit. To accomplish this, we have planned tumor biopsies to provide an indepth understanding of the putative targets and the molecular basis of response and/or resistance to the combination of T-DM1 and everolimus. We estimate that accrual will commence by the end of 2014. Based on our emerging expertise, I was selected to serve as the national clinical trial principal investigator for the innovative National Cancer Institute’s MATCH (Molecular Analysis for Therapy CHoice) trial, specifically for the T-DM1/HER2 amplified arm.

Heat Shock Proteins

Treatments exploiting the role of heat shock proteins are also under active investigation at the Perlmutter Cancer Center. Under normal conditions, heat shock proteins protect the molecules in cells that maintain homeostasis. However, in patients with cancer, higher-than-normal levels of heat shock proteins allow cancer cells to grow and proliferate.

My research team is working with inhibitors of the heat shock protein HSP90, aiming to deplete cells of the excess protein, many of which are oncoproteins with important functions in the development and promotion of cancer. Notably, HER2 is among the most sensitive HSP90 client proteins and preclinical data suggest better sensitization of tumors when HSP90 inhibitors are combined with cytotoxic chemotherapy. As the principal investigators for a phase I clinical trial testing the novel HSP90 inhibitor ganetespib, our group, along with Dr Shanu Modi’s group from Memorial Sloan Kettering, are studying ganetespib in combination with paclitaxel and trastuzumab as a treatment for advanced or metastatic HER2-positive breast cancer. Establishing ganetespib as a safe and well-tolerated HSP90 inhibitor is the first step toward a phase II trial of this triplet combination that might in turn provide a path for approval of HSP90 inhibitors for HER2-positive advanced breast cancer.

Other Tyrosine Kinase Inhibitors

I am also serving as a co-principal investigator with Nancy U. Lin, MD, from Dana-Farber Cancer Institute on a phase I/II clinical trial of the investigational small molecule kinase inhibitor KD019 in combination with trastuzumab in women with metastatic disease. An oral agent, KD019 targets four different pathways involved in the growth of HER2-positive cancer. Preclinical research also suggests that KD019 penetrates the blood-brain barrier. Demonstrating safety and tolerability, as well as efficacy systemically and in the brain, could lead to better treatment of women with brain metastases. Overall, these trials will not only enhance our familiarity with the biology of HER2-positive breast cancer, but also provide our patients with access to an array of novel targeted agents currently or soon to be in the pipeline of several pharmaceutical companies.